Development and synthetic application of the allylbis (silane) cyclization terminator by Timothy Scott Kercher A thesis submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Chemistry Montana State University © Copyright by Timothy Scott Kercher (1997) Abstract: In order to advance the existing methodology of allylsilane-terminated cyclizations, a series of amino-allyl(bis)silanes was prepared for use as intermediates in route to cationic cyclizations terminated by the novel allyl(bis)silane nucleophile. This terminator was found to readily participate in the intramolecular trapping of activated imines and C-acylnitrilium ions providing highly substituted and functionally diverse pyrrolidines, piperidines and pyrrolines. These processes occurred not only in high chemical efficiency under mild conditions but with excellent levels of regioselectivity and substrate based stereocontrol. As a result, this methodology was successfully applied to the stereoselective synthesis of biologically active isotropane alkaloids and the azapolycyclic core of the potent natural insecticide, stemofoline. These applications demonstrated the ability of the allyl(bis)silane terminator to engage in tandem silicon-directed cyclizations. Such reactivity was not possible with the silane terminators previously used by synthetic chemists. <  [DEVELOPMENT AND SYNTHETIC APPLICATION OF THE ALLYLBIS(SILANE) CYCLIZATION TERMINATOR by Timothy Scott Kercher A thesis submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Chemistry MONTANA STATE UNIVERSITY Bozeman, Montana April 1997 K 4? 3^ APPROVAL of a thesis submitted by Timothy Scott Kercher This thesis has been read by each member of the thesis committee and has been found to be satisfactory regarding content, English usage, format, citations, bibliographic style and consistency, and is ready for submission to the College of Graduate Studies. - _ ion, Graduate Committee Approved for the ^lajor Departme Approved for the College of Graduate Studies Date Graduate Dean iii STATEMENT OF PERMISSION TO USE In presenting this thesis in partial fulfillment of the requirements for a doctoral degree at Montana State University-Bozeman, I agree that the Library shall make it available to borrowers under the rules of the Library. I further agree that copying of this thesis is allowable only for scholarly purposes, consistent with "fair use" as prescribed in the U.S. Copyright Law. Requests for extensive copying or reproduction of this thesis should be referred to University Microfilms International, 300 North Zeeb Road, Ann Arbor, Michigan 48106, to whom I have,granted "the exclusive right to reproduce and distribute my dissertation in and from microform along with the non-exclusive right to : reproduce and distribute my abstract in any format whole or in part." Signature. To all of my wonderful family VACKNOWLEDGMENTS The successful completion of this dissertation was made possible only by the contributions of many individuals. First and foremost, Professor Livinghouse has always proven to be a valuable source of problem-solving ability, creativity and motivation all of which flow from his great enthusiasm for organic chemistry. His hard work and dedication is greatly appreciated and helped provide all of resources, tools and finances necessary for the execution of research in his labs. Thanks goes to Dr. Sears for performing all of the high resolution, mass analysis on the many compounds that were synthesized and also to Ray Larson for contributing his crystallography expertise. Additional gratitude is expressed to all of my fellow workers at Montana State University for their sharing of ideas, talents, resources and valuable time. Many individuals outside of the world of chemistry contributed my well being during the course of this graduate work. My parents, James and Linda Kercher, were and will always be an inexhaustible source of love, patients and encouragement. I cannot possibly thank them enough for all they have done for me. Various outdoor activities with many friends will never be forgotten and represent time that was both enjoyed and appreciated. Special thanks and admiration goes to my family at the Bozeman Church of Christ who are always supplying encouragement, care and love for the benefit of others. Praise be to Almighty God our Father, by and through whom all things are possible, who . j created the beautiful lands of Montana. ■! , • • I TABLE OF CONTENTS Page INTRODUCTION.................................................................................................... 1 BACKGROUND................. ...................:....................................... :...................... 5 Origin of Allyisilane Cyclizations......... ................................................ 5 Mechanistic Features of Allylsilane Terminators.......... ............................9 Allylsilane Terminated-Azacation Cyclizations............................ '.......... 14 Application to the Total Synthesis of Alkaloids..................... ..................21 Electrophilic Additions to Allylbis(silanes)...............................................25 RESULTS AND DISCUSSION....................... 29 Synthesis of Aminoallylbis(silanes).....;.........:........................................29 2-Propylidene-1,3-bis(silane) Imine Cyclizations.................................... 35 Stereoselective Synthesis of Trisubstituted Pyrrolidines............... 50 Cyclization of (S)-(-)-Ethyl Lactate-Derived !mines................................. 59 2-Propylidene-1,3-bis(silane) C-Acylnitrilium Ion Cyclizations............... 65 Stereoselective Synthesis of Piperidines................................................78 Stereoselective Synthesis of Functionalized Isotropane Alkaloids and Azabicyclononanes.................................................................................. 87 Synthesis of the Azatricyclic Core of Stemofoline................................. 101 SUMMARY....................................................................................................... •-124 EXPERIMENTAL.......... ........................ ..:.............. ................... ....................... 126 General Experimental Details................. 126 Synthesis of Amino-allylbis(silanes)......................................................128 2-Propylidene-1,3-bis(silane) !mine Cyclizations.................................. 146 vi Vll TABLE OF CONTENTS-Confmued Page Synthesis of Trisubstituted Pyrrolidines.................. ............ ............ :....164 Cyclization of (S)-EthyI Lactate-Derived !mines......... ............. ............ 181 2-Propylidene-1,3-bis(silane) Acylnitrilium Ion Cyclizations...... ...... ....'186 Stereocontrolled Synthesis of Piperidines.......... :..................... ...........208 Synthesis of Isotropane Alkaloids and Azabicyclononanes............. ....213 Model Synthesis of Stemofoline Core...................................................221 REFERENCES.............................. :.......................... ........................................ 225 LIST OF TABLES Table Page 1. Cyclization Results Using 11a and Group IV Lewis Acids................39 2. Gyclization Results for Aldimines Derived From Amine 1a...............41 3. Results for the Acylative Cyclization of Isonitrile 46a........................ 71 4. Data for Acylative Cyclizations of Isonitriles 46c-d........................... 73 5. Cyclization Data for Aryl !mines Derived from Amine 54...................86 viii LIST OF FIGURES Figure . Page 1. Well Known Cyclic Molecules........................................................... 1 2. Silicon-Based Terminators.................................................................... 3 3. Stemofoline and the Allylbis(silane) Terminator...................................4 4. The P Effect......................................... 10 5. Sites of Boronation in Allylsilanes....................................................... 12 6. The a Effect.......................................................................................... 14 7. Biologically Active, Polycyclic Alkaloids................... ........ ..................15 8. Nitrogenous Cationic Initiators........................................ 16 9. Elucidation of Structure for Cis and Trans 15h.................................43 10. Representative NOE Results for Pyrrolidines 15a-i..................... ....43 11. Transition States for Alkyl Imine Cyclizations................................. ...44 12. Transition States for Aryl Imine Cyclizations............................ 46 13. Chelated Diastereotopic Transition States........................................47 14. NOE Enhancements for 25a and 25c.............................................. 53 15. Transition State Models for 24a-b.................................................... 53 16. Transition States for !mines 26a-b and 30a-b............ 57 17. NOE Data for Pyrrolidines from Amines 1c and I d ........ ................. 58 18. Naturally Occurring, Three Center Pyrrolidine Nuclei....................... 59 19. Diastereotopic Transition States for 44a-c......... 64 20. Diagnostic NOE Data for Substituted Pyrrolines...................... -7 4 21. Diastereotopic Transition States for Cyclization of 46b-d........ :......75 22. Diagnostic NOE Results for Pyrrolidines 51-53...............................77 ix LIST OF FIGURES-Conf/mved Figure Page 23. NOE Results for Cis and Trans Piperidine 65b........................... .....83 24. Diastereotopic Transition States for Piperidines 65a-d...................85 25. Tropane Alkaloids............................................................. 87 26. Isotropane Alkaloids.............................................................. :........... 88 27. Representative Stemonaceae Alkaloids...................................... ‘...102 Xl ABSTRACT In order to advance the existing methodology of allylsilane-terminated cyclizations, a series of amino-allyl(bis)silanes was prepared for use as intermediates in route to cationic cyclizations terminated by the novel allyl(bis)silane nucleophile. This terminator was found to readily participate in the intramolecular trapping of activated imines and C-acylnitrilium ions providing highly substituted and functionally diverse pyrrolidines, piperidines and pyrrOlines. These processes occurred not only in high chemical efficiency under mild conditions but with excellent levels of regioselectivity and substrate based stereocontrol. As a result, this methodology was successfully applied to the stereoselective synthesis of biologically active isotropane alkaloids and the azapolycyclic core of the potent natural insecticide, stemofoline. These applications demonstrated the ability of the allyl(bis)silane terminator to engage in tandem silicon-directed cyclizations. Such reactivity was not possible with the silane terminators previously used by synthetic chemists. < IINTRODUCTION A vast proportion of the molecular targets of interest to the synthetic organic chemist such as natural products, pharmaceuticals and synthetic intermediates contain cyclic or polycyclic carbon frameworks. The degree of complexity of these cyclic arrays of atoms may range drastically. This becomes evident upon comparing menthol, a simple monocyclic terpene used as peppermint flavoring, to the formidable heptacyclic structure of the powerful poison, strychnine (Figure I). It is therefore no surprise that carbon-carbon bond formation in an intramolecular fashion has been the crux of countless past and present research endeavors in the field of organic chemistry. Figure 1. Well Known Cyclic Molecules The classical method for formation of such important bonds has involved the intramolecular trapping of a reactive carbon electrophile, termed the initiator, by a suitably disposed nucleophilic carbon or terminator. From a standpoint of the terminator, alkenes and alkynes have been extensively applied by virtue of the nucleophilicity of their pi electron clouds. It has been demonstrated over the course of research involving alkene terminators that, Menthol Strychnine 2unless the cyclization substrate is carefully chosen, alkene-terminated cyclizations generally result in mixtures of products. This problem originates from lack of sufficient regiocontrol in both the ring formation and elimination steps of the cyclization reaction resulting in products of various ring size and position of unsaturation respectively. Competitive reactions such alkyl and hydrogen shifts have also been shown to commonly occur, further complicating the product mixture. Fortunately, it eventually became realized that by using an alkene appended to a silane moiety, as in an allylsilane, these types of cationic cyclizations may be directed through a single reaction pathway giving rise to a single reaction product (Scheme 1). * o Alkene-Terminated CyclizationC Regioisomer Mixtures Me3Si "hSiMe3 C + Allylsilane-Terminated Cyclization -C Single Product Scheme I As a result of this observation that a strategically located silicon atom has a dramatic effect on the course of cationic cyclizations and electrophilic additions in general, a host of silicon terminators has evolved over the years (Figure 2). These nucleophiles are in constant use today in both the intramolecular and intermolecular formation of strategic bonds employing a broad spectrum of electrophiles. More specifically, the cationic cyclization 3reaction has become a more versatile and efficient synthetic tool finding broad application in the synthesis of many types of cyclic molecules. SiR3 -zvvv^ = — SiR3 Figure 2. SiR3 X SiR/ 3 Silicon-Based Terminators Despite the tremendous amount of development, there is still a strong motivation for continuing the evolution of silicon-directed cyclizations. The standards of modern synthetic chemistry demand not only regioselectivity but diastereo- and enantioselectivity from a reaction as well. Polyfunctionalization and sensitive groups in substrates also renders the need for terminators that engage under mild conditions. Ultimately, practical and concise syntheses of molecular targets of high topological complexity might be realized using silicon based terminators with the ability to direct not just a single cyclization but multi- cyclizations as well. Thus it became the goal of this research to develop a silane terminator that could potentially satisfy these criteria of today's synthetic methods. It was conceived that an allylbis(silane) terminator might meet this challenge and eventually be applicable to the synthesis of polycyclic alkaloids, particularly in the construction of the azatricyclic core of the alkaloid stemofoline (Figure 3). 4H SiMe Stemofoline Figure 3. Stemofoline and the Allylbis(silane) Terminator 5BACKGROUND Origin of Allylsilane Cyclizations When confronting the task of constructing carbocyclic and heterocyclic systems by means of a cationic approach, chemists must carefully select appropriate functionality by which to successfully initiate and terminate the ring­ forming process. In the past, the electrophilic addition of carbonium ions to alkene terminators has been a strategy of amazing success, but also severe limitations. No other work has illustrated the synthetic power of this method more than the pioneering polyene cyclizations of Johnson in which several carbon-carbon bonds are formed with regio- and diastereocontrol (Scheme 2).1 Scheme 2 In contrast, Johnson and others have encountered alkene-terminated cyclizations that proceeded in an uncontrolled fashion. This in demonstrated by the polyene cyclization of Scheme 3 in which a mixture of four regiodifferent olefins was isolated.2 Regiocontrol problems of this nature have also arisen in numerous related reactions such as Nazarov-type cyclizations3 (Scheme 4) and have severely attenuated this methodology from becoming broad in scope and general applicability despite some impressive examples existing. 6Scheme 3 Mixture of 4 diene isomers O FeCI3 78% 78:22 Scheme 4 OCHO 40% OCHO Scheme 5 As previously mentioned, a second limitation with alkene-terminated additions is ambiguity in the initial bond formation. For instance, in Evan’s formal synthesis of (+)-perhydrohistrionicotoxin,4 the key step involved an 7acyliminium ion-alkene cyclization that produced almost equal proportions of both the desired six membered cycle and the unwanted five membered spirocycle (Scheme 5). Furthermore, the need for O.TM formic acid as the solvent to promote this cyclization also presents limited applicability of the reaction to more sensitive substrates. Fortunately in 1976, Ian Fleming found a means by which total control over alkene-terminated cyclizations could be obtained.5 Prior to this original work, the reactivity patterns of intermolecular additions of allyl and propargylic silanes6 were known to be regioselective. Fleming realized that such selectivity might also be achieved in the intramolecular mode of reaction. He decided to test this possibility on another troublesome system encountered by Johnson. In the Johnson protocol, a particular oxonium ion-initiated cyclization yielded not only all three possible olefins but products resulting from solvent capture of the carbonium ion as well (Scheme 6).7 Fleming circumvented this by inserting a trimethylsilyl group on the appropriate carbon atom of the starting material. The resulting allylsilane-terminated cyclization proceeded with regiospecificity to furnish exclusively the desired product in 76% yield (Scheme 7). Noteworthy is the fact that the cyclization could now be triggered by SnCU rather than the. harsher Bronsted acidic medium needed to trigger Johnson's cyclization. 8MeOH, H + CH3 OMe OMe OMe 5 Products Isolated Scheme 6 Single Isolated Product, 76% Scheme 7 This work eventually led to the realization that by merely altering the position of the silicon electrofuge, the chemist may select a mode of cyclization that furnishes the desired ring size and olefin location in a completely controlled fashion (Scheme 8). What followed the ground breaking work of Fleming was an immediate extension of the concept to numerous classes of carbonium ion cyclizations. Not surprisingly, an early application was in polyene cyclizations such as that shown in Scheme 9. Note that in contrast to the related reaction of Scheme 2, Johnson was now able to exclusively form five membered rings in these cascade cyclizations by merely adding a trialkyl silane in the appropriate position.8 Today this methodology is widely applied to a expansive range of electrophilic additions encompassing many permutations of electrophile type and silicon-based terminators (Figure 2).9 9Scheme 8 Exclusive Pentacycle Formation Scheme 9 Mechanistic Features of Allylsilane Terminators It is clear from the initial studies of Fleming and the volume of allylsilane methodology in general that the silicon atom has a powerful influence on both the alkene reactant and the intermediates formed during the course of the reaction. Hence, from a standpoint of synthetic utility, the significance is twofold. First, the alkene engages regioselectively to give a single addition product which results in the formation of only one of two possible ring sizes. 10 Secondly, the resulting carbocation eliminates regioselectively to give one olefin upon termination of the reaction. The issue of regiocontrol in the initial bond forming process may be adequately summarized by the following generalization: allylsilanes will usually react in the manner that results in formation of a cation (3 to the silicon atom. This phenomenon has been labeled the (3 effect and is founded on the power of a silicon atom to stabilize an adjacent positive charge via overlap of the silicon- carbon a bond with the vacant p orbital (Figure 4).10 The origins of such strong hyperconjugation lies in the polarizabilty of the silicon-carbon bond. The high electronegativity of carbon (2.35) relative to silicon (1.64) induces a stronger hyperconjugative effect than that capable of alkyl groups or hydrogens. The degree of stabilization is quite high. For instance the silylethyl cation is calculated to be 38 Real mol"1 more stable than the comparative ethyl cation.11 Studies towards a quantitative determination of this P effect have been examined.12 It is also believed that cations a to silicon are relatively destabilized, an influence that also undoubtedly contributes to the regioselective nature of allylsilanes. Historically, the consequences of the P effect were first observed in 1973 by Ushakov and Itenburg who discovered that eliminations of halogen alkylsilanes were particularly rapid (Scheme 10).12 Allylsilanes were observed Figure 4. The P Effect to undergo facile electrophilic attack as early as 1948 (Scheme 11).14 It was early findings such as these that initiated the development of intermolecular and eventually intramolecular application of allylsilanes and related terminators (Figure 2).6'9 X SiR3 - XSiRa „ Relative Rate H2C = CH2 Fast X H - HX H2C = CH2 Slow Scheme 10 Me3S i HBr » + Me3SiBr Scheme 11 The tendency of the allylsilane terminator to regioselectively form (3 silylcations is believed to also be influenced from the reactant side of the reaction coordinate. There is evidence for ground state polarization of the reactive HOMO of the allylsilane. In the hydroboration of allylic silanes, a concerted process affected by ground state conditions more than product stability15, the boron resides predominately on the C-3 carbon of the silane (Figure 5).16 Other noncationic reactions, such as cycloadditions,17 show strong regioselectivity in the same sense. This data points to the C-3 carbon as the site of nucleophilicity of ground state allylsilanes. Nevertheless, regardless of ground state or thermodynamic considerations, the general rule of the (3 effect 12 usually predicts the regiochemical outcome of electrophilic additions to allylsilanes. The issue of specific collapse of the initially formed silicon-stabilized carbocation is more simply addressed. By virtue of the strong hyperconjugation present in the (3 cation, the carbon-silicon bond is very polarized and weakened. Thus the (3-silicon electrofuge is typically cleaved more rapidly than (3 hydrogens and also more rapidly than nucleophilic capture of the cation (Schemes 6 and 7). The relative thermodynamic stability of (3 silyl cations, unlike conventional primary and secondary carbocations, retards the termination against hydride shifts and Wagneer Meerwien rearrangements. These features combined with the control devices focused on previously are the primary reasons behind the capacity of the allylsilane terminator to funnel a cyclization along a single reaction pathway in route to a single, predictable product. This mechanistic analysis of the regioselectivity of the allylsilane is based on a pathway involving addition of a highly electron deficient atom to a neutral allylsilane receptor. There are however certain instances when a nucleophile may activate the allylsilane triggering an anionic pathway. The Figure 5. Sites of Boronation in Allylsilanes 13 most commonly applied nucleophilic catalyst is tetrabutyl ammonium fluoride (TBAF) which is a soluble source of fluoride anions. Fluoride anions rapidly attack allylic silanes, by virtue of the extremely strong silicon-fluorine bond (135 kcal/mol), to form pentavalent silicon anions which may also collapse into discrete allylanions (Scheme 12).18 It is uncertain as to which species is the reactive nucleophile but whether it be the electron rich pentavalent allylsilane or an actual allylanion, there is clearly an acceleration in the rate of addition. For example, the TBAF promoted addition of trimethylallylsilane to benzaldehyde proceeds without the usual lewis acid activation of the aldehyde (Scheme 13).19 Although the regioselectivity is generally lower for fluoride-initiated reactions, which suggests an ambiguous allylanion intermediate, this method does provide the chemist with alternative reaction conditions. R FI R3S i^ ^ ^ + R3SiF Scheme 12 r\ OH Scheme 13 14 One final characteristic of silanes in general20 should be revealed. This is the ability of a triakylsilicon group to stabilize an adjacent negative charge, a phenomenon sometimes called the a effect. It is believed that such stabilization arises from either overlap between the a orbital of the anion and the a * orbital of the C-Si bond or delocalization of the negative charge into the vacant, low energy 3d orbitals of the silicon atom (Figure 6).21 Although not a crucial point to the cationic cyclization itself, this feature has been exploited to assist in the synthesis of cyclization substrates. Silicon stabilized organometallic reagents such as Grignards, oraganozincs and cuprates22 have been applied to efficient syntheses of allylsilane substrates as have a silylvinyl anions generated by silicon directed hydroaluminations23 or cuprate additions24 to silyl acetylenes. Figure 6. Allylsilane Terminated-Azacation Cyclizations One of the fundamental goals of this research project was to exploit the useful chemistry of the allylsilane nucleophile in the synthesis of polycyclic alkaloids (Figure 3). Such nitrogenous compounds are one of the classes of natural products most frequently targeted for total synthesis. This is attributed to the strong pharmacological and physiological properties of many alkaloids which render them or derivatives of them potential candidates for 15 pharmaceutical use. As with most natural products and drugs, the majority of alkaloids are cyclic or polycyclic in structure.25 Familiar examples include codeine, quinine, lysergic acid diethylamide (Figure 7) and strychnine (Figure 1). When considering the synthesis of polycyclic alkaloids, allylsilane terminated cyclizations present an attractive means by which to construct strategic bonds26 within the cyclic framework. If a cationic approach is to be applied, cyclization initiators which contain a nitrogen atom are obviously necessary. Proven well suitable for this role are iminium ions27, their N-acyl28 and C-acyl29 variants as well as nitrilium ions30 (Figure 8). By the location of the nitrogen adjacent to the cationic center, these initiators benefit from stability imparted by resonance. Hence, such nitrogen stabilized cations are relatively easier to generate and also are less prone to rearrangements and migrations than conventional carbonium ions. These features make iminium and related Codeine Lysergic Acid Diethyamide Quinine Figure 7. Biologically Active, Polycyclic Alkaloids 16 ions practical choices for initiators when preparing nitrogen heterocycles by allylsilane-terminated cyclizations. The classical application of iminium ions in cyclization reactions has been the Mannich cyclization.31 These reactions involve the use of heteroatom or enol nucleophiles and represent an important early method for the construction of nitrogen heterocycles (Scheme 14). Although Mannich cyclizations have been employed for over 70 years, the progression towards applying tethered allylsilanes did not occur until the mid 1980s. R R -zvvv^ = N- R + R Figure 8. Nitrogenous Cationic Initiators HNu NHR NuH= OH, NH2, Enols, Etc. Scheme 14 Ten years after the first allylsilane cyclization of Fleming, Grieco successfully utilized Mannich type conditions in the intramolecular capture of iminium ions by allylsilanes. In these reactions, allylsilane ammonium salts 17 were treated with aldehydes under aqueous conditions resulting in the regiocontrolled formation of not just five membered but six, seven and even eight membered heterocycles (Scheme 15).32 Moreover, despite the acidic Mannich type conditions used to generate the iminium ions, protodesilylation of the allylsilane was not a competitive process. n=t 73% n=2 96% n=3 64% n=1 81% n=2 94% Scheme 15 More recently, Overman has extended this reaction to the stereocontrolled synthesis of cis and trans hydroquinolines33, a structure found in many alkaloid subclasses. This flexible method presents the option of selectively forming either the cis or trans diastereomer by merely altering the steric size of the amine substituent (Scheme 16). The mild conditions (cat. Znlg) used in forming the requisite iminium ions provides additional attractiveness to this protocol. 18 MeoSi Favored with small R1 48 - 88% Favored with large R1 Scheme 16 Although the most frequently employed, cationic routes such as Mannich type reactions are not the exclusive method for initiating iminium ion cyclizations. Thermally stable iminium salts such as conjugated perchlorate derivatives have been activated photochemically in order to promote the desilylative ring closure (Scheme 17). These novel photochemical cyclizations have been in large developed by Mariano34 and provide alternative reaction conditions. Unfortunately, with the exception of the example in Scheme 17, the chemical yields are commonly low for such processes. Scheme 17 19 In contrast to iminium ions derived from basic allylsilane amines and aldehydes32, the N-acyliminium ion28 has received considerably more use in allylsilane cyclizations. This is likely due to the numerous methods available for generation of such ions, the greater reactivity over iminium ions and the functionality value of the carbonyl substituent. The primary chemists behind the development of N-acyliminium ion- allylsilane additions which occurred in the mid 1980s were Speckamp and Hiemstra.35 Scheme 18 depicts one of their earliest results. The synthetic power of this cyclization reaction lies not only in the high yields but the ability to form numerous ring sizes with complete regio- and stereocontrol regardless of the geometry of the allylsilane substituent. For the case illustrated, the observed diastereochemical outcome is thought to be the result of an equatorial alignment of the allylsilane unit in a chair-like transition state. Another important feature is the formation of requisite acyliminium intermediates from a cyclic imide by a partial reduction-elimination sequence. This simple procedure has become the method of choice in numerous total syntheses. Scheme 18 20 To our knowledge, there has been only one account of an allylsilane- nitrilium ion cyclization and no examples of analogous C-acylnitrlium ion cyclizations. Schinzer has recently reported that nitrilium ions formed by way of a Beckman rearrangement are effectively trapped by tethered allylsilanes (Scheme 19).36 Diisobutylaluminum hydride was used as a lewis acid to promote the Beckman rearrangement and as a reductant of the intermediate bicyclic imine. Interestingly, the reaction mode of the allylsilane terminator was found to be quite dependent on the configuration of the starting oxime. If the E isomer was employed, cyclization occurred onto the electron deficient nitrogen faster than the Beckman rearrangement. Such allylsilane reactivity was previously unprecedented. HC 45% 42% Scheme 19 21 Application to Total Synthesis of Alkaloids s The successful total synthesis of a natural product offers the ultimate arena in which to test the applicability and practicality of reaction methodologies. In the past two decades the cyclizations of allylsilanes onto iminium ions such as those previously described have served as efficient key steps in several syntheses of polycyclic alkaloids.. A premier example is the ' total synthesis of both antipodes of the opium alkaloids morphine and dihydrocodeinone executed by the Overman group in 1993 (Scheme 20).37 In the synthetic sequence the central step involved application of the diastereoselective synthesis of cis and trans hydroisoquinolines previously developed by Overman (Scheme 16). In this instance the large DBS amine protecting group was used in the iminium ion-allylsilane cyclization to promote the trans configuration present in the natural target molecules. The process occurred with high diastereoselection (>20:1.0), high enantioselection (91% ee) and in high chemical yield (82%). An intramolecular Heck cyclization then furnished the common pentacyclic intermediate use to prepare both of these opiates. The absolute chirality of the products was introduced in the preparation of the requisite allylsilane amine by an enantioselective reduction. This was carried out in 96% ee and enabled the preparation both enantiomeric substrates whose absolute configuration was preserved with high stereofidelity throughout the key sequence. 22 CHO SiMe9Ph PhMe9Si EtOH, 60 0C DBS OMe OMe Heck CyclizationDBS" de > 2 0 : 1 ee = 91% (-)-morphine Scheme 20 The allylsilane - N-acyiiminium ion cyclization protocol has been particularly successful in the synthesis of indolizidine, quinolizidine and pyrolizidine alkaloids. Pertaining to the latter two classes, Speckamp and Hiemstra in 1985 exercised identical synthetic strategies for the stereoselective synthesis of both (±)-isoretronecanol and (±)-epilupinine (Scheme 21).35 A similar but improved route was used by Gramain and Remuion in a very concise and efficient synthesis of the indolizidine alkaloid (±)-mesembrine (Scheme 22).38 The synthetic series was carried out in five linear steps with an overall yield of 30%. Highlighting the scheme was the nonacidic medium (MsCI, EtgN1 CHgCIg) in which the key allylsilane-acyliminium ion cyclization was executed 2 3 thus providing improved, milder conditions than those previously used by Speckamp and Hiemstra (trifluoroacetic or formic acid).35 1) O3 , Me^S 2) LiAIH4 Isoretronecanol Scheme 21 MeO OMe OMe OMe SiMe3 I) NaBH4 r J 2 ) MsCI1 Et3N Mesembrine 5 steps total 30% overall Scheme 22 A final example illustrates the construction of polycyclic alkaloids possessing topological complexity. In 1993 progress was made towards the 2 4 synthesis of the unusual marine alkaloid sarain A. In this publication, Weinreb utilized a novel N-tosyliminium ion-allylsilane cyclization to complete the synthesis of the tricyclic nucleus of sarain A (Scheme 23).39 Despite the key cyclization proceeding in 61% yield, this approach suffers from the long linear sequence of over ten steps used to prepare the bicyclic precursor. Nevertheless, the synthetic scheme does reveal the potential of allylsilanes to form strategic bonds in complex molecular systems. Scheme 23 These are the most recent and efficient examples of the synthetic usefulness of allylsilane-temninated cyclizations from a standpoint of alkaloid synthesis, an area of high relevance to this dissertation. Clearly shown in all cases is the regiospecific nature of the cyclization processes and for the most part, the diastereoselective capabilities as well. Such high levels of substrate- based diastereocontrol were able to be found only in isolated instances such as 25 these examples. Despite the past and ongoing research activity in this area, there still exists a need for achieving general and consistent levels of high diastereocontrol in the addition of allylsilanes and related pi-nucleophiles to carbon centered electrophiles. Electrophilic Additions to Allylbis(silanes) A fundamental limitation that lies within the silicon-based pi-nucleophiles currently available to the synthetic chemist is the attachment of a single electrofugal silane group. As a result, only one directed cyclization is possible. If sequential electrophilic additions are desired in a synthetic plan, those occurring after the initial silicon-controlled reaction would have to be carried out with a conventional pi-nucleophile and would be prone to the regiocontrol problems previously addressed. An obvious advancement, particularly in the broad field of allylsilane chemistry, would be to efficiently prepare and utilize an allylbis(silane) nucleophile. Such an olefin could be apt to participate in tandem silicon- directed electrophilic additions. Ultimately, an allyl(bis)silane terminator could theoretically enable the efficient construction of polycyclic skeletons (Scheme. 24). If used in conjunction with nitrogenous initiators, this concept might be ideally suited for the regio- and stereocontrolled synthesis of polycyclic alkaloids. 2 6 Mono Allylsilane Cycliztion Allylbis(silane) Cyclization Scheme 24 At the onset of this research there were surprisingly no reported examples of cyclizations terminated by a 2-propylidene-1,3-bis(silane). In fact, prior to this dissertation there was only one account of this nucleophile used in electrophilic addition reactions. Recently, Guyot and Miginiac demonstrated that 2-trimethylsilyl allyltrimethylsilane could participate in tandem intermolecular-intramolecular additions to bifunctional electrophiles.40 It was observed that exposure of this allylbis(silane) to bis-acetals in the presence of TiCU resulted in the formation of methylene cycloalkanes . This process was proposed to occur by way of an initial intermolecular allylbis(silane)-oxonium ion addition followed by intramolecular capture of a second oxonium ion by the remaining mono allylsilane (Scheme 25). 2 7 RO RO TiCI4 OR OR SiMe3 RO OR "7810 -5 °c RO OR TiCI4 + + SiMe3 SiMe3 RO RO -TMSCl -TMSCI R=OMe n=1 93% R=OEt n=2 57%TiCI4 RO OR OR TiCI4 Scheme 25 In an analogous reaction, the same allylbis(silane) nucleophile underwent a Mannich type addition-cyclization upon treatment with paraformaldehyde and primary amines in acidic media (Scheme 26).40 Methylene substituted piperidines were obtained in good yield via a reaction pathway believed to involve initial intermolecular iminium ion capture followed by subsequent allylsilane cyclization onto a second iminium ion. Even though these reactions of Guyot and Miginiac occur in good yield and constitute the first electrophilic additions to an allylbis(silane), the protocol was not expanded to the synthesis of more complex and useful systems. As a result the impetuous for this doctoral research became twofold. First, the synthetic potential of allylbis(silane) nucleophile has been relatively uninvestigated. Hence it was deemed crucial to explore its role as a cyclization terminator capable of directing two intramolecular reactions. Secondly, stereoselective cyclizations onto iminium ions would provide an ideal area in which to apply this new silicon terminator. More explicitly, the aza tricyclic core 28 of the potent natural insecticide stemofoline might succumb to efficient total synthesis by utilizing tandem regio- and stereocontrolled cyclizations mediated by an allylbis(silane) (Scheme 27). Me3Si Me3Si (CH2 O)n TFA RNHc (CH2 O)n, TFA CH3 CN1 70 0C SiMe3 NHR SiMec R=Bn1 iPr, nBu R I R 66-71% Scheme 26 Scheme 27 2 9 RESULTS AND DISCUSSION Synthesis of Aminoallylbis(silanes) With the focus of this research directed towards the application of a newly developed allylbis(silane) terminator to the construction of cyclic alkaloids, amine Ia was selected as an initial target for synthesis. It was believed that from this amine, a variety of iminium ion and related initiators could be readily prepared allowing for the proficiency of the allylbis(silane) to behave as a cyclization terminator to be examined (Scheme 28). These cyclization precursors bearing a chain length of five atoms from initiator to terminator would initially form the pyrrolidine ring system upon monocyclization. Such a nucleus is found in many classes of alkaloids including stemofoline. Cyclization of these substrates would, in theory, occur by way of a 5-exo­ trig type process which is considered a favorable process when applying the classical rules for ring closure.41 Numerous accounts of 5-exo-trig cyclizations involving monoallylsilanes and iminium ions exist in the past literature.9- 32-35 Hence, the feasibility of allylbis(silane) cyclizations originating from amine 1a was established and a search for a synthetic route t o l a began. 5-Exo-Trig 1a Scheme 28 3 0 At the commencement of this work, there were no reported methods by which to synthesize the 2-propylidene-1,3-bis(silane) unit on a preparative scale.40- 42 After some experimentation, this goal was initially achieved using a reported 1,5 sigmatropic shift of silicon from oxygen to carbon.43 Accordingly, diketene was selectively cleaved using TlVISCHgMgCI in the presence of NiCIg (1 mol %) to afford butenoic acid 2 in 82% yield.44 Treatment of 2 with excess LDA and TMSCI at -78 0C followed by warming to room temperature furnished allylbis(silane) 4 in a maximum yield of 50% after purification and silyl ester cleavage on silica gel. In a fashion analogous to that reported, formation of 4 was believed to have occurred via a thermal 1,5 sigmatropic shift of an intermediate ketene silyl acetal upon warming of the reaction mixture to ambient temperature (Scheme 29). Despite the success of the sigmatropic migration to form the allylbis(silane) unit, the low isolated yield of 4 and the large number of transformations required for conversion into amine 1a prompted a search for a more efficient route. In addition, carboxylic acid 4 proved to be quite resistant towards reduction to the oxidation state appropriate for alteration into 1a. .0 TMSCH2 MgCl^ M e qSi I % NiCI2, THF Il Il PLDA, THF, -78 0C 2 )TMSCI, -78 - 25°C 2 (82%) Scheme 29 31 A more straightforward and efficient synthetic route, centered around a palladium catalyzed, cross coupling reaction, was eventually developed for the synthesis of 1a on a large scale. Known aldehyde 7a45 was economically prepared in 70% yield from commercially available bromo acetal 5 by substitution with potassium phthalimide followed by liberation of the carbonyl functionality with aqueous acid (Scheme 30). Olefination of the resulting aldehyde with the ylide derived from CBr4 and PPhg46 provided dibromo alkene 8a in 86% isolated yield. KPHT, DMF1 rt 5% Nal PHTN 6 (99%) 0.5M HCI reflux O Il PHTN 7a (71%) CBr4 , PPhg CH2 CI2, 0 0C PHTN 8a (86%) (TMSCH2 )2ZntTHF 7% PdCI2 (PPh3)2, i i NPHT SiMe-: 9a (96%) SiMe-: (H2 N)2, EtOH reflux H2N SiMe3 1a (94%) ^S iM e3 Scheme 30 Attachment of both trimethylsilylmethyl substituents to form phthalimide 9a was readily achieved in one pot employing a variation of coupling conditions developed by Tamaou and Minato 47 These chemists found that 1,1- dichloro-1-alkenes could be selectively mono alkylated by treatment with Grignard reagents in the presence of catalytic PdCl2 (dppb). Subsequent alkylation of the resulting 1-chloro-1-alkenes using PdCIg(PPhg)Z as the 32 catalyst then provided unsymmetrical trisubstituted alkenes in good yield with complete regiocontrol (Scheme 31). From these results it was believed that subjecting the more reactive 1,1 -dibromo-1 -alkene 8a to PdCIg(PPhs)Z and MegSiCHgMgCI should provide the desired dialkylation product 9a. During original experimentation with these conditions, formation of the desired product was observed but byproducts originating from degradation of the phthalimide protecting group in 8a allowed for only modest isolated yields. Fortunately, it was discovered that employing a mild organozinc reagent rather than the Grignard species permitted circumvention of this problem. Along these lines, exposure of 8a to (TMSCHg)gZn, prepared in situ from TMCHgMgCI and zinc chloride, in the presence of PdClg(PPhg)g (7 mol %) provided the protected amine 9a in 96% yield after purification on silica gel (Scheme 30). It was a surprising observation that none of the corresponding monoalkylated product was detected upon analyzing the products of this tandem cross coupling reaction. Phthalimide deprotection of 9a using standard conditions48 occurred cleanly to afforded the desired amine l a i n 94% yield after neutral work up and bulb to bulb distillation. This synthetic scheme repeatedly proved to be very efficient on a preparative scale. Large scale runs employing as much as 20 grams of olefin 8a in the coupling step produced the target amine in 78% overall from aldehyde 7a. It is quite conceivable that longer chain homologues of amine 1a could also be prepared in this fashion. 3 3 R^ T R 1MgX, PdCI2 (dppb)) R2 MgX, PdCl2 (PPh3 ) 2 ^ Cl Cl R2 (55-98%) (65-81%) Scheme 31 The above synthetic sequence was latter found to be quite flexible in that a series of substituted amino allylbis(silanes) was successfully synthesized by this method. These amines could theoretically give rise to trisubstituted pyrrolidines and related ring systems upon intramolecular cyclization onto iminium ions. More specifically, methyl and protected hydroxymethyl analogous of 1a were selected for synthesis by virtue of their ease of preparation and relevance to substituent patterns found in natural alkaloids. Accordingly, amines 1b-d were efficiently prepared from the appropriate aldehydes 7b-d using conditions analogous to those applied to the synthesis of amine Ia (Scheme 32). For the methyl derivatives, starting aldehydes 7b and 7c were prepared by base catalyzed, conjugate addition of phthalimide to methacrolien and crotonaldehyde respectively (Scheme 33). The synthesis of the oxygenated aldehyde 7d was more involved. Treatment of excess c/s-1-4 butenediol with fert-butyldimethylsilyl chloride (TBDMS-CI) provided a mixture of the mono- and bis silylethers (85 : 15) which was oxidized with pyridinium chIorochromate (PCC) to afford the trans enone 10 in 49% overall yield after chromatographic separation of the bis(silyl)ether. Evidence for the cis-trans isomerization during exposure of the intermediate, mono alcohol to acidic PCC was provided by a large vinylic proton coupling constant of 15.5 Hz in the spectrum of enone 10. 3 4 Base mediated addition of phthalimide to enone 10 furnished the required aldehyde 7d in 70% yield (Scheme 34). R2 R2 PHTN CBr4 lPPh3 U CH2CI2, 0 0C 7b R1=CH3, R2=H 7c R1=H, R2=CH3 7d R1=H1 R2=Ch2OTBDMS PHTN y ^ C B r 2 R1 8b (94%) 8c (98%) 8d (88%) (TMSCH2 )2ZnlTHFr 7% PdCI2 (PPh3)2, rt R2 PHTN 9b (85%) 9c (94%) 9d (95%) (H2 N)2, EtOH reflux R2 1b (91%) 1c (92%) Id (94%) Scheme 32 H3C PHT, EtOHi 10% NaOEt PHTN 0 CH3 PHTN CHo 0 PHT, EtOH 10% NaOEt H3C 0 7b (74%) 7c (45%) Scheme 33 HO OH 1) TBDMSCI, DMF, Imid 2) PCC, CH2 CI2, rt TBDMSO TBDMSO PHT, 5% DBUr DMF, rt 10 (49%) PHTN ^ " 0 7d (70%) Scheme 34 35 2-Propylidene-1,3-bis(si!ane) Imine Cyclizations With a reliable route to amino allylbis(silanes) having been established, prospective methods for generation of the cyclization initiator and execution of the subsequent cyclization were next examined. Along these lines, installation of an imine functionality was smoothly achieved by condensation of amine Ta with isobutyraldehyde under mild conditions using 4 A molecular sieves as a water trap. This provided imine 11a in quantitative yield as a single geometrical isomer as indicated by NMR. The observed geometry of 11a has been assigned as E configuration considering the preference for aldimines to adopt this thermodynamically stable, double bond geometry.49 It is believed that the corresponding Z isomer 12 would suffer thermodynamically from allylic, nonbonded interactions (Scheme 35). Furthermore, the enamine tautomer 13 of 11a and all imines subsequently prepared under these conditions was not observed in the NMR spectra. Since tautomerization might induce self condensation and imines in general are prone to hydrolysis and decomposition, it was quite a pleasing realization that the preparation of imines from amine 1a, and eventually 1b-d, occurred cleanly with no additional purification required. 36 iPrCHO, THF, rt 4 A mol sieves SiMe 11a (100%) SiMeSiMe SiMe 1,3-Allylic Strain Scheme 35 Conditions to promote cationic cyclization of imine 11a were screened next. Initially, Bronsted acids such as trifluoroacetic acid (TFA)1 camphorsulfonic acid and Me2 0 -HBF4 failed to provide either the desired cyclized product or isolable iminium salts upon exposure to imine I la as did trifluoroacetic anhydride and associated reagents. Alternative reagents that might promote an anionic cyclization such as tetrabutylammonium fluoride were not extensively screened as to avoid protodesilylation of the sensitive allylbis(silane) terminator. Data obtained from these fruitless cyclization attempts pointed to this unwanted desilylation reaction as the primary source of the problems associated with the use of Bronsted acids. Desilylation was believed to be occurring through intramolecular deprotonation of the alpha protons of the iminium ion of 11a rather than directly from the protic reagents. In support of this theory, when amine 1a was treated with TFA (0.95 equiv) in methanol at -78 0C, the corresponding ammonium salt was found to be stable at room temperature with no products originating from protodesilylation being detected. 3 7 Attention was next focused on the use of lewis acids since it was discovered that Keck had successfully performed lewis acid promoted allylations of aldimines using mono allylstannanes.50 With this in mind, imine 11a was treated with a broad range of Lewis acids including SnCLf, Sn(OTf)Z, and Cu(OTf)Z under a variety of conditions. In most cases examined, the result was the production of unwanted products, incomplete conversion of substrate or desilylation of the sensitive terminator. / It was ultimately discovered however that precomplexation of imine 11a with 1.0 equivalent of TiCLf at -78 0C followed by slow warming to ambient temperature promoted complete cyclization to the desired pyrrolidine 14a which was isolated as a single stereoisomer (>50:1.0 trans:cis) as indicated by high resolution NMR spectroscopy (Scheme 36). Careful quench of the reaction mixture using slow, inverse addition to cold KHCO3 (aq) proved necessary as to avoid the production of the undesired pyrrolidine 16. More over, desilylated imine 17 was not observed during analysis of the reaction products. Conversion of 14a to the corresponding AMosyI derivative 15a . allowed for optimal characterization of the cyclic product. It was also observed that substoichiometric amounts (0 .8-0 .9 equiv) of TiCLf also promoted complete cyclization to 14a. Catalytic amounts (15%) failed to induce any significant conversion however. Milder titanium-based Lewis acids like Ti(OiPr)CIg and Ti(OiPr)zClz did promote cyclization to afford pyrrolidine 14a but extended reaction times were required to induce even modest conversions. Cyclization experiments performed using toluene or mixtures of toluene and CHzCIz as a solvent were found to be not as clean compared to pure CHzClz- Another group IV metal complex was found to 38 promote efficient cyclization of 11a. Using (Me2 S)2ZrCl4 (1.1 equiv., CH2CI2 , - 78 0C to rt) resulted in pyrrolidine 14a in 83% yield. The results using group IV lewis acids are summarized in Table I. Scheme 36 3 9 Table 1. Cyclization Results Using 11a and Group IV Lewis Acids Group IV Lewis Acid Equiv. Time at rt from -78 0 C (hrs.) Yield of 14a (%) TiCI4 1.00 2.0 98 TiCI4 0.90 2.0 98 TiCI4 0.15 1 1 . -0 (Me2S)2ZrCI4 1.10 2.0 ' 83 TiCI3(OiPr) 1.00 2.0 26 (ca.) TiCI3(OiPr) 1.00 15 52 (ca.) TiCI2(OiPr)2 : 1.00 18 <2 0 (ca.) The conditions developed for the preparation and cyclization of imine 11a were found to be quite applicable to a broad range of alkyl and aryl iminesi51 The results of this study are summarized in Table 2. The !mines 11b-i derived from simple aldehydes and amine 1a were, as in the case of 11a, cleanly prepared and all of these !mines were found to be homogeneous with respect to imine configuration. Forthe reactive imine 11c, preparation from acetaldehyde was best carried out at -10 0C employing Short reaction times. As shown in Table 2, pyrrolidines 14b-i were synthesized in good to excellent yield after purification on Florisil or silica gel and in the case of 14a, no such techniques were necessary. Crude samples of all pyrrolidines were treated with TsCI to afford the AFtoluenesuIfonyI derivatives 15a-i. This was 4 0 found advantageous for numerous reasons. Unlike the corresponding pyrrolidines 14a-i, the NMR spectra of these derivatives clearly showed that the majority of the signals correlating to diastereotopic protons contained within the molecule were well defined and separated. This feature permitted thorough characterization, accurate analysis of diastereomer mixtures and also aided in NOE studies. The /V-tosylates also proved to be more stable during storage than the basic pyrrolidines. Moreover, the crystalline properties of some of the derivatives allowed for separation of isomers and eventually single crystal X-ray analysis. 41 Table 2. Cyclization Results for Aldimines Derived From Amine 1a .R TsCI, py SiMe3 2) TiCli Me3Si — 3) KCHO3 (aq) / f CC 14a-i Z=H 15a-i Z=Ts Aldehyde (-R) Imine Pyrrolidine (% Yield) Trans: Cis /V-Tosylate (% Yield) -CH(CH)2 11a 14a (99) >50:1.0 15a (85) -CH2CH(CH)2 11b 14b (88) >50:1.0 15b (80) CO XO 11c 14c (67) 34:1.0 15c (82) H3CO 11d 14d ( - ) >50:1.0 14e (84) 14:1.0 14f (84) 1.0: 7.3 14g (90) 1.0: 3.4 14h (99) 1.0: 1.7 14i ( - ) 1.0: 5.0 15d (62) I Se (80) 15f (84) 15g (90) ISh (86) ISi (88) 4 2 The quantification of the diastereomer composition was achieved by integration of the expanded 300 MHz ,proton NMR spectra of the crude pyrrolidines and or isolated A/-tosyIates. The spectra of diastereomeric N- tosylates was quite resolved and enabled accurate determination of ratios. Subjecting the AMosyI compounds to this analysis also eliminated ambiguity arising from trace or sometimes significant amounts of desilylated imine present in the crude pyrrolidines 14a-i. Determination of the relative configuration of the substituents at the C-2 and C-3 positions of the pyrrolidines was initially performed on the products obtained from the nonselective cyclization of imine 11h. Specifically, fractional crystallization of the mixture of AMosyIates (15h) provided pure samples of the major and minor isomers which were analyzed individually by NOE spectroscopy after definitive assignments were made from homonucleaf decoupling experiments. Irradiation of the C-3 methine proton (H3) in the major cis isomer gave rise to a 11.7% signal enhancement at H2. Irradiation in the reverse direction produced a 9.0% enhancement at H3. Corresponding irradiation of the minor trans isomer resulted in much smaller, 2.4% and 3.1%, NOE signals respectively. Eventually, the structure of the major cis compound was conclusively elucidated by single crystal X-ray analysis.(Figure 9). The relative stereochemical assignments for the remaining pyrrolidines 14a-g and 14i were derived from analogous NOE studies carried out on AMosyIates 15a- g and 15i arid some of the diagnostic results are included in Figure 10. 4 3 9.0% 11.7% C/s-pyrrolidine 15h 3.1% C/s-pyrrolidine 15hTrans-pyrrolidine 15h Figure 9. Elucidation of Structure for Cis and Trans 15h 13.1 % 4.0 % Trans-pyrrolidine 15aC/s-pyrrolidine I Sg OMe Trans-pyrrolidine 15d Figure 10. Representative NOE Results for Pyrrolidines 15a-i One of the most attractive features of the allylbis(silane) aldimine cyclizations lies in the general high levels of substrate-based diastereocontrol.52 Most notable is the preference of alkyl substituted imines 1a-c to undergo essentially a completely trans-selective mode of cyclization. Ratios in favor of the trans isomer were observed to be quite high (34->50:1.0) 4 4 regardless of the size of the alkyl substituent although significant fluctuations in stereoselectivity were observed during runs performed on the acetaldehyde imine 11c. The origin of such a high preference could be the result of the avoidance of nonbonded interactions in the transition state and it is conceivable that such steric interactions might out weigh any electronic effects. In order for products of cis configuration to form, a transition state possessing a potentially severe 1,2 steric interaction would develop along the course of bond formation (Figure 11). Alternatively, the diastereotopic transition state leading to the observed trans pyrrolidine products would avoid such a high energy interaction by rotation about the vinylic C-C bond of the terminator. Me3Si Cis R=alkyl Trans Figure 11. Transition States for Alkyl Imine Cyclizations An interesting contrast to the high trans selectivity is apparent upon reviewing the cyclization data, !mines 11f-i derived from aryl substituted 4 5 aldehydes were found to produce diastereomeric mixtures favoring the cis isomers but with lower overall selectivity than the trans selective cases. The reason for this reverse selectivity is currently unclear but could be attributed the ability of aryl groups to stabilize an adjacent cationic center. Such an influence exerted by these groups might readily promote E-Z isomerization of imine- titanium complexes possessing less pi bond character. As a result* the cationic transition state would contain rotational freedom around the C-N bond in addition to the allylic C-C bond of the terminator resulting in electronic influences, such as charge separation, to govern the structure of the transition state rather than steric effects. Transition state models of cis orientation would seemingly benefit in lower energy by having less separation of charge relative to the alternative trans transition state required for formation of the corresponding trans isomers (Figure 12). Minimization of charge separation would be preferred in noncoordinating solvents such as CHgCIg and the magnitude of such a stabilization would be affected by solvent polarity,53 For example, it was observed that only a slight increase in solvent polarity resulted in a significant change in the cis-trans ratio during the cyclization of conjugated imine 11f as evident by a ratio of 1.7:1.0 in CHCIg compared to 7.3:1.0 in CHgCIg. Unfortunately, solvents higher than CHCI3 on the polarity scale were tod reactive to consider for extending the study of this solvent effect although toluene/CHgClg mixtures generally gave lower selectivities It should be mentioned that the trans olefin geometry of the phenylethenyl substituent in 11f was preserved during cyclization as indicated by a large vinylic coupling constant of 15.7 Hz in 14f.54 This verifies the two isomers under investigation were not merely isomeric at the olefin rather than at the stereogenic centers. 4 6 SiMe SiMe Figure 12. Transition States for Aryl !mine Cyclizations It was found that complete trans stereocontrol could be achieved in the cyclization of certain aryl !mines. When the 2-methoxy derivative 11d was subjected to cyclization in place of the 4-methoxy analogue 11g, complete trans selectivity was reestablished affording trans-pyrrolidine 14d. This drastic reversal in the stereochemical outcome is most likely due to chelation by the titanium center to the ortho-disposed methoxy group in imine 11d. Unlike the transition state for cyclization of imine 11g, the corresponding transition state of this cyclization would be conformationally locked with respect to the imine geometry thus allowing the steric control elements promoting trans bond formation to dominate as in the alkyl substituted cases (Figure 13). Strong trans preference was also observed in the cyclization of the furanyl imine 11e which would proceed by an analogous 5-membered chelate. The belief that chelation 4 7 does indeed play a role in the cyclization of these two imines (11d and l ie ) prompted us to use slightly modified conditions. Slow, reverse addition of imine substrate to a TiCU solution at -78 0C was employed as to facilitate chelation and suppress coordination of two Lewis acid molecules to the imine. TransA 4d C/s-14d Figure 13. Chelated Diastereotopic Transition States In addition to the high diastereoselectivity, these initial results draw other strengths with respect to synthetic utility of the cyclization reaction. First, the residual mono allylsilane unit is preserved during the course of reaction, work up and isolation of product. This permits the substituted pyrrolidines to be exploited by the vast amount of established mono allylsilane chemistry.6-9 Secondly, the mono desilylative cyclization of allylbis(silane) imines occurred with complete regiochemical control. In all of the previously mentioned examples products arising from a competing 6-exo cyclization mode were not detected during product analysis. This is attributed to the (3 effect and 48 control elements previously discussed. For these cyclizations it could be postulated that a low energy pathway involving a |3 effect magnified by the presence of two silicon atoms adjacent to the developing cationic center might be in affect. At this moment however, there exists no experimental evidence to support this theory other than the fact that these cyclizations proceed under conditions more mild than those generally applied to mono allylsilane-iminium ion cyclizations.9-32-35 Furthermore, the 2-propylidene-1,3-bis(silane) nucleophile has shown a much stronger tendency to protodesilylation than the corresponding mono allylsilanes. At this time,, the scope of allylbis(silane) imine cyclization is generally limited to aldimine substrates. For example when cyclopentanpne and acetophenone derived ketimines 18 and 19 were exposed to the general cyclization conditions, monodesilylated imines were obtained as the sole reaction products (Scheme 37). In these instances, cyclization rate was most likely depressed by the relative electron richness of ketimines relative to aldimines. As a result the reactive 2-propylidene-1,3-bis(silane) nucleophile could now, quit feasibly, kinetically act as a Bronsted base in an intramolecular fashion. The net result of such a mechanistic change would be a desilylative imine to enamine tautomerizatidn. During the course of the reaction or during aqueous work up, reestablishment of the equilibrium favoring the imine tautomer would then afford the observed products 20 and 21.. 4 9 2R SiMe3 SiMe3 I) TiCl4, CH2CI2l 18 R1=R2= -(CH2)4- 19 R1=CH3, R2=Ph -78 °C-rt 2)KHC03 (aq) SiMe SiMe -Me3SiCl SiMe3 Iautomerizei KHCO3 (aq) 2R SiMe3 > 90% 20 R1=R2= -(CH2)4- 21 R1=CH3, R2=Ph Scheme 37 Substrates containing the C-acyl imine unit also proved resistant towards desired cyclization. Imine 22, prepared from 2,4-butanedione, afforded only mixtures of unwanted products under a variety of conditions screened to promote cyclization (Scheme 38). This problem was attributed to ambiguity at the two sites of electrophilicity present in the bifunctional C-acylimine. Various Conditions^ Not Isolated Scheme 38 5 0 Stereoselective Synthesis of Trisubstituted Pyrrolidines The successful cyclization of aldimines derived from unsubstituted amino-allylbis(silane) 1a firmly established the that the 2-propylidene-t,3- bis(silane) nucleophile could in fact fulfill the role as a cationic cyclization terminator.51 The high stereoselectivity of these cyclizations, especially for the alkyl substituted imines, motivated us to expand this methodology to the stereocontrolled formation of trisubstituted pyrrolidines. The efficient preparation of substituted amino allylbis(silanes) 1 b-c (Scheme 32) enabled us to pursue this endeavor. Cyclization of imines derived from these amines could theoretically occur with control over the relative configuration of three newly-formed stereocenters. As eluded to previously, there are published, isolated examples of mono allylsilane-iminium ion cyclizations that proceeded with complete substrate based control in the course of forming two stereocenters.9-35"39 To our knowledge there are no reported examples of the diastereoselective creation of three new centers by such a cyclization.' Alkyl rather than aryl substituted aldehydes were chosen for the condensation with amines 1b-d primarily for their high trans selectivity (34:1- 50:1) when used in conjunction with amine 1a. Transitions states for cyclization of imines of amines 1b-d should be quite sterically crowded rendering them quite sensitive to steric effects. It was initially predicted that the size of the alkyl substituent should have a significant impact on both the chemical yield and diastereoselection. With this in mind, isobutyraldehyde, isovaleryl aldehyde and acetaldehyde were implemented in order to provide a range of sterically diverse environments surrounding the electrophilic site of the corresponding 51 imines. The alkyl groups selected also have distinct and relatively simple signals in the NMR spectra which makes for easier analysis of products when considering that up to four diastereomers may form during cyclization. Amine 1b was initially used in the condensation-desilylative cyclization protocol. Condensation with isobutyraldehyde'(4 A mol. sieves, THF, rt.) provided imine 23a in high yield (Scheme 39) which afforded trans pyrrolidine 24a upon cyclization under the standard conditions (1 equiv. TiCl4 , CHgCIg, - 78 0C to rt.). This pyrrolidine was observed to be the sole product from this cyclization as indicated by both NMR and analysis by gas chromatography. Such a result is in good accord with the result obtained using amine Ia and isobutyraldehyde (Table 2). Pyrrolidine 24a was then converted to the 2- . naphthalensulfonyl derivative 25a for the purpose of NOE experiments. Similarly, when the less bulky isovaleryl aldehyde was used, traps pyrollidine 24b was also obtained in high yield as the only detected product. When amine 1b was condensed with acetaldehyde using the standardi conditions, analysis of the products indicated that imine 23c was not monomeric but had trimerized after isolation. As a result, condensations with acetaldehyde were executed at -10 0C using abbreviated reaction times. The imine was then isolated, immediately dissolved in CH2CI2 , cooled to -78 0C and treated with TiCU without delay in order to avoid polymerization. Cyclization of the reactive imine 23c and all acetaldehyde imines was carried out at -78 0C for one hour followed by 36 hours at -20 0C to achieve optimum yield and stereoselection. Despite these mild conditions, pyrrolidine 24c was obtained as an inseparable mixture of diastereomers (2.0-4.0 : 1.0) albeit in good chemical yield. Interestingly, NOE experiments performed on /V-tosylate 5 2 25c suggested that the structure of the major pyrrolidine is cis with regard to the C-2 and C-3 substituents. 23b R=iBu 23c R=CH3 24a (95%, >50:1.0) 25a Ar=2-Naph. (40%) 24b (97%, >50:1.0) 24c (89%, 1.0:3.0) 25c Ar=ToI. (85%) Scheme 39 Evidence for the all trans configuration in pyrrolidines 24a-b and the cis- trans configuration of 24c was provided by NOE experiments performed on the corresponding AMosyI or A/-2-naphthalensufonyl derivatives (25a and 25c). The most diagnostic NOE enhancements are shown in Figure 14. As before, definitive assignments were based on a series of homonuclear decoupling experiments prior to NOE analysis. For the most selective cases (24a-b) trans configuration between the C-2 and C-3 substituents is believed to be the result steric effects similar to those governing the stereochemical outcome of imines lla -c . The avoidance of a severe 1,3-allylic strain is proposed to be the 5 3 driving force behind the trans orientation of the C-3 substituent and the C-4 methyl group (Figure 15). SiMe ...Pr SO9Ar SiMe Trans-trans 25a (CDCI3 ) Cis-trans 25c (CDCI3 ) Figure 14. NOE Enhancements for 25a and 25c R=iPr, iBu A 1,3-strain - Me3SiCI SiMe Cis-Trans SiMe Trans-Trans Figure 15. Transition State Models for 24a-b This series of experiments was next performed using amine 1c and conditions identical for the previous series involving 1b. Of the three !mines prepared from 1c, only cyclization of the isovaleryl derived imine 26b was 54 found to be efficient in chemical yield and trans diastereoselectivity (Scheme 40). Complete trans selection was also observed for the case of isopropyl substituted imine 26a but with a severe decrease in yield. NMR analysis of the products obtained from cyclization of 26a showed a 2 .0 :1.0 mixture of pyrrolidine 27a and mono protodesilylated imine. Direct treatment of this mixture with TsCI secured the AMosyI derivative 28a in 46 % isolated yield from amine 1c. This trans-trans pyrrolidine was found to be isomerically homogeneous by NMR. The proposed structure of the transition state responsible for the trans orientation of the C-3 and C-5 substituents is shown in Figure 16. The cis transition state would suffer from an allylic interaction that, although significant, would be of less magnitude than that governing the cyclization of imines from amine Tb (Figure 15). Cyclization of acetaldehyde imine 26c was carried out using the modified conditions developed for cyclization of 23c. As with 23c this imine cyclized in high yield but with modest selectively. Diastereomer ratios were found to vary significantly from trial to trial and in the most selective run (6.1:1.0) NOE data pointed the major isomer having cis-trans structure (Figure 17). 55 SiMe3 1) TiCl4, CH2CI2 S |M e 3 2) KHCO3 (aq) ^ ArSO2CI, CH2CI2, py 27a (ca. 66%, >50:1.0) 27b (92%, >50:1.0) 27c (91%, 1.0:6.1 best case) R SO2Ar 28a Ar=tol (46%) 29a Ar=2-napth (33%) 28b Ar=tol (92%) 28c Ar=tol (90%) Scheme 40 Amine 1d was hoped to provide the highest levels of substrate-based diastereocontrol since the large size of the TBDMS protecting group should induce more steric control over the transition state than the methyl substituent in imines originating from amines 1 b-c. The results of the cyclization of imines 30a-c showed that this was not the case (Scheme 41). Isopropyl imine 30a was found to undergo selective trans cyclization but an almost equal proportion of protodesilylated imine was also formed. Tosylation of this 1.3:1.0 mixture provided the pure trans derivative 32a in 42% overall yield from amine 1d. Only modest levels of trans selectivity (4.7:1.0) were observed during the cyclization of imine 30b. Surprisingly, NOE data pointed to the major pyrrolidine from cyclization of methyl imine 30c as having an all trans structure. This result is inconsistent with the acetaldehyde imines originating from 1b and 56 1c and serves to illustrate the random stereochemical nature observed in the cyclization of acetaldehyde imines. The aryl imine 30d was subjected to cyclization but this resulted in even lower selectivities than the alkyl cases 30b- c. The NOE data used to determine the structure of the pyrrolidines prepared from 1d is also included in Figure 17. It should be mentioned that amounts of a third diastereomer could be detected in the product mixtures containing pyrrolidines 31b and 31 d. Although the quantities were quite small, this observation does impose some limitation on the synthetic usefulness of cyclizations of imines derived from amine 1d. TBDMSO 4 A mol selves RCHO1 THF 2) KHCO3 (aq) OTBDMS30a R=iPr 30b R=iBu 30c R=CH3 30d R=2-furyl \ \ OTBDMS OTBDMS 31a (ca. 52%, >50:1.0) 31b (76%, 3.9:1.0) 31c (95%, 1.0:5.1) 31 d (86%, 1.0:1.0) 32a (42%) 32b (87%) 32c (90%) 32d (72%) Scheme 41 57 FtiPr, iBu R1=CH3, Ch2OTBDMS SiMe - Me3SiCl SiMe N Trans-TransTrans-Cis Figure 16. Transition States for !mines 26a-b and 30a-b The results of this study concerning the stereoselective synthesis of trisubstituted pyrrolidines revealed several characteristics of the allylbis(silane) terminator. Foremost is the ability to form three new stereocenters in a stereocontrolled manner especially when alkyl groups of large steric size were employed on the starting aldehyde. Very high levels of all trans stereocontrol were obtained using isobutyraldehyde in conjunction with all three substituted amines (1 b-d) and also employing isovaleryl aldehyde with amines 1b and 1c. The limit of general and consisted levels of diastereoselection was reached upon employing the smaller, more reactive imines derived from acetaldehyde and amines I b-d. These imines were found to undergo less selective cyclizations with significant fluctuation in the relative stereochemistry of the 58 resulting pyrrolidines. It is possible that rapid E to Z equilibration of the reactive acetaldehyde imines might be responsible for the stereochemical randomness of these cyclizations. Regardless of stereoselectivity, the chemical yield of the trisubstituted pyrrolidines was generally quite high and in almost all cases, only one or two of the four possible diastereomers were detected. It is believed that this methodology might be quite applicable to the synthesis of stereodefined, pyrrolidine-based alkaloids. The remaining mono allylsilane substituent on the pyrrolidine ring should provide a versatile functional handle during synthesis of natural alkaloids. 10.0% C is -tra n s 28c (CDCI3) T rans-trans 29a (CDCI3) T rans-trans 32c (C6D6) OTBDMS T rans-trans 32a (CDCI3) Figure 17. NOE Data for Pyrrolidines from Amines 1c and Id 59 Cyclization of (S)-(-)-Ethyl Lactate-Derived !mines In the 2-propylidene-1,3-bis(silane) imine cyclizations examined thus far, control over the relative stereochemistry was achieved between substituents contained within the pyrrolidine ring. In order to further probe the limits of diastereoselectivity, experiments were designed to see if these cyclizations could proceed with control of the orientation both endo and exo disposed stereocenters in the same cyclization. If successful, this transformation might be readily applied to the synthesis of stereodefined alkaloids. A pyrrolidine nucleus containing three adjacent stereocenters, two endo and one oxygenated exo center, is found in many pyrrolidine alkaloids55, pyrrolizidine alkaloids like (-)-terneforicidine56 and also in the tricyclic core of Stemofoline (Figure 18). There are many examples of the stereoselective /nfemnolecular additions of mono allylsilanes to SP3 hybridized carbon electrophiles.6-9 Such reactions have been found to be governed by either coordination effects such as chelation control 57 or steric approach constraints58 including Cram trajectories.59 It was believed that these control devices might be applicable to the allylbis(silane) imine cyclizations in order to gain access to an additional, exocyclic stereocenter. HO (-)-Temeforcidine Figure 18. HC' O Stemofoline Naturally Occurring, Three Center Pyrrolidine Nuclei 60 !mines capable of chelation with Lewis acids were first synthesized and subjected to the cyclization conditions. The known, benzyl-protected aldehydes 33 and 34, prepared from (S)-EthyI lactate60 and 2-methyl-2-propen-1 -ol61 respectively, were condensed with amine 1a over 24 hours to provide imines 35 and 36 (Scheme 42). Conditions employing TiCU at low temperatures failed to produce any amounts of the desired pyrrolidines 37 and 38 via • chelation control originating from five and six membered chelates respectively. In fact, no cyclic products were ever detected but rather unwanted imines 39 and 40 arising from protodesilylation of 33 and 34 were obtained as the major products. Successful cyclization was never realized even after extensive experimentation with conditions and various Lewis acids. 61 CH3 I) TiCl4, CH2CI2, -78 to -200C4 A mol selves 35 (99%) la , THF 2) KHCO3 (aq) 36 (98%) Scheme 42 Alcohol protecting groups not prone to coordination with Lewis acids were next installed on the cyclization precursors. Alcohols protected by bulky trialkyl silanes such as triisopropyl silane (TIPS) were reported by Eliel not to undergo coordination with cationic magnesium, aluminium or lithium reagents.62 These groups seemed to be ideal candidates for anti approach cyclizations terminated by the large 2-propylidene-1,3-bis(silane) nucleophile. A series of silane protected hydroxy aldehydes were prepared with alkyl groups of varying size on the silicon atom. Silylation of the secondary alcohol 62 of (S)-ethyl lactate using standard conditions63 provided the silyl ethers 41a-c in good yield (Scheme 43). Partial reduction of the ester functional group to the aldehyde was then efficiently achieved using diisopropyl aluminum hydride (DIBAL-H) at low temperatures.64 A trimethylsilyl analog was also prepared but was found to be quite sensitive to Si-O cleavage during the reduction step. Hence it was eliminated from the series of aldehydes. Room temperature condensation of the resulting aldehydes 42a-c with amine 1a occurred cleanly over 24 hours to furnish the corresponding imines 43a-c. (S)-ethyl lactate R3SiCl, DMF_ OR DIBAL-H, tol, -78°C CH3 41a R=Si(f-bu)2Me (83%) 41b R=Si(I-Pr)3 (79%) 41c R=Si(Ph)2f-Bu (94%) 42a (91%) 42b (95%) 42c (97%) CH3 O p I) TiCl4, CH2CI2, -78 to -20°C 2) KHCO3 (aq) 43b 43c 44a (ca, 66%, 58% /V-Ts, 21:1.0) OR 44b (90%, 4.3:1.0) 44c (91%, 14:1.0) Scheme 43 Gratifyingly, treatment of the imines with TiCU at -78 0C for one hour followed by 24 hours at -20 0C provided the anti-trans pyrrolidines 44a-c in excellent yield after careful neutralization with KHCOg and purification on 63 Florisil (Scheme 43). More importantly, levels of diastereoselection were quite high with respect to a second isomer detected by NMR and GC in the crude product mixtures. The NMR spectrum of the products produced from TBDMS imine 43a revealed a large amount of desilylated imine had also formed (ca. 34%). This could have possibly originated from some coordination of TiCl4 to this relatively less bulky, TBDMS ether. The pyrrolidine 44a was secured as the /V-tosyl derivative in modest purified yield (58%) after direct treatment of the crude mixture with TsCI. Elucidation of the relative stereochemistry of pyrrolidines 44a-c was obtained from NOE analysis of the corresponding oxazolidinone derivatives.65 Exhaustive desilylation of 44a-c using tetrabutyl ammonium fluoride hydrate provided the crude amino alcohols which were immediately exposed, to carbonyldiimidazole to afford oxazolidinone 45 (Scheme 44). The major oxazolidinones obtained from 44a-c using this sequence were found to be identical with respect to spectrometric (1H and 13C NMR) and chromatographic (TLC) properties. Most informative was a large transannular NOE effect (7.5%) observed between the C-3 methine hydrogen and the hydrogen located on the exocyclic methine. Simple models suggest that such a through space interaction between these protons is only possible if oxazolidinone 45 is in the anti-trans stereochemical configuration shown. The high diastereoselectivity of these cyclizations can be rationalized by a transition state involving a Cram type trajectory of the allylbis(silane) nucleophile in a conformation that also avoids non bonded interaction with the imine substituent (Figure 19). 64 I) TBAF-H2O1 THF, it 2) GDI, THF, rt 45 (39-64%) < H 44a-c SiMe SiMe OSiR OSiR OSiR Cram Trajectory Anti-trans 44a-c Figure 19. Diastereotopic Transition States for 44a-c. 65 2-Propylidene-1,3-bis(silane) C-Acylnitrilium Ion Cyclizations All of the cyclizations described thus far have involved the intramolecular coupling of the allylbis(silane) nucleophile with electron deficient imines. Before progressing towards application to the synthesis of alkaloids it was deemed advantageous to test the compatibility of this cyclization terminator with other types of initiators. The C-acylnitrilium ion (Figure 8) was immediately chosen as an alternative electrophile for numerous reasons. The structure of nitrilium cations provides additional functionality and reactivity which are brought about by the presence of a carbonyl group and an additional degree of unsaturation. More importantly, this combination of initiator and silicon-based terminator has not been previously investigated and accounts of intramolecular addition of mono allylsilanes to C-acylnitrilium ions were unable to be found in the literature. The. studies that were performed involved terminators other than allylsilanes and provided little insight into the diastereoselective nature of C- acylnitrilium ion cyclizations. As a result, this portion of the allylbis(silane) research would hopefully spawn advancements and reveal knowledge with respect to both the initiator and terminator elements of the reaction. The majority of the research involving the generation and cyclization of C-acylnitrilium ions has come out of the Livinghouse research group. Work performed by previous group members has demonstrated that pi nucleophiles such as silyl enol ethers and arenes are suitable terminators for the cyclizations initiated by the acylnitrilium ion.30>66 Through this work an efficient and reliable method for the mild generation of C-acylnitrilium ions has been developed which involves the ionization of ketoimidoyl halides by silver (I) salts at low I 66 temperatures. This protocol has culminated in a efficient synthesis of the sesqueterpene alkaloid dendrobine carried out by Cheol Lee in 1991 (Scheme 45).67 Former coworker Dave Hughes has also shown that unactivated alkenes also efficiently add to keto imidolyl halides in the presence of silver salts to form fused, bridged and directly-connected bicyclic pyrrolines.68 Although this served to demonstrate the reactivity associated C-acylnitrilium ions, lack of regioselectivity was observed in some cases (Scheme 46). Implementation of a suitable mono allylsilane was, surprisingly, not performed in an attempt to gain regiospecificity. TBDMS O88% H3C (rac)-Dendrobine 8 Linear steps (6.2% overall) Scheme 45 67 Cl r N O tBu AgBF4 tBu Isomeric Olefiins X=F, OH Nu Trapping Products Scheme 46 This study commenced with the synthesis of requisite, isonitrile precursors from previously prepared amines 1a-d. Following standard procedures for the preparation of isonitriles 30,66-68 AZ-formylation of amines 1a-c was achieved by treatment with freshly neutralized and distilled ethyl formate at reflux to furnish the corresponding formamides. Dehydration of the crude formamides with POCI3 in the presence of a triethyl amine buffer furnished the target isonitriles 46a-c in good overall yield after purification on silica gel (Scheme 48). Fortunately, products resulting from electrophilic desilylation of the 2-propylidene-1,3-bis(silane) addend were not observed during the formylation-dehydration sequence. 1 )EtOCHO, reflux 2)POCI3, Et3N1 THF, O 0C 1b R1=CH3, R2=H 1c R1=H, R2=CH3 46a (85%) 46b (87%) 46c (80%) Scheme 48 68 incorporating n-butyl formate did promote complete amine to amide conversion but analysis of the isolated products also revealed that mono- and some di- protodesilylation of the sensitive 2-propylidene-1,3-bis(silane) terminator had occurred during the reaction. It is believed that the n-butanol liberated during formylation served as the proton source for this unwanted desilylation at elevated temperatures. In addition, the formation of the strong Si-O bond in the n-BuOSi(Me)3 byproduct would provide thermodynamic momentum for a carbon to oxygen transfer of the trimethylsilane group. This problem was overcome by switching to the very reactive, acetic formic anhydride69 to promote /V-formylation of amine Id. Cold temperature treatment of Ia with freshly prepared MeC0 2CH0 (1.05 equiv.) resulted in total amine consumption after 30 minutes at -78 0C. Careful basic quench using NaHCOg and dehydration of the resulting crude formamide with POCIg-EtgN then provided isonitrile 46d in 85% overall yield (Scheme 49). The sterically hindered amine 1d failed to show significant signs of reactivity during exposure to refluxing EtOgCHO. Higher temperatures OTBDMSOTBDMS 11MeCO2CHO, Et2O, -78 0C NH2 2)POCI3, Et3N, THF1 O 0C 46d (85%) Scheme 49 The alkylative cyclization of isonitrile 46a was examined first. Addition of 46a into a variety of simple and functionalized acid chlorides was found to occur cleanly at room temperature in CHgCIg to provide the intermediate 69 ketoimidoyl chlorides 47a-e (Scheme 50). Experiments performed in an NMR tube showed that a reaction time of approximately 12 hours was optimal for complete isonitrile consumption in all cases examined. These NMR experiments also revealed that, in the worst cases, only trace amounts of protodesilylated materials were formed when freshly neutralized and distilled acid chlorides were employed. This eliminated a need for an amine buffer which could possibly interfere with the ensuing cyclization process. Not all of the acyl chlorides screened underwent clean addition with 46a. When enones such as crotonyl chloride were used, the formation of large quantities of chlorotrimethylsilane and terminal olefin residues was observed while monitoring the reaction progress. It appears that functionalization of the isonitrile nucleophile was not chemoselective but rather the allylbis(silane) nucleophile also reacted with the unsaturated acyl chloride. Immediate exposure of the crude ketoimidoyl chlorides 47a-e to AgBF4 in CH2CI2-CICH2CH2CI (1,2-DCE) at a temperature range of -78 to -65 0C did provide the desired A1-pyrrolines 48a-e but in low isolated yields (<20-70%), (Table 3). During chromatographic purification of 48a-e, significant amounts of acyclic, desilylated materials were also isolated It is believed that formation of these byproducts had arisen from the presence of hydrofluoric acid in the stock solutions of AgBF4 that were prepared. Commercial AgOTf proved to be superior for inducing the ionization- cyclization sequence. This was carried out be treating a suspension of AgOTf in CH2CI2/1,2-DCE with a solution of the freshly prepared, crude ketoimidoyl chloride at -78 0C followed by stirring for 2-6 hours at -20 0C. Cautious neutralization of the cold reaction mixture was then performed with KHCO3 . Cyclizations performed in this manner provided pyrrolines 48a-e in far better z 70 isolated yields than with AgBF4 (Table 3) and these conditions became standard for all cyclizations involving isonitriles 26a-d.70 RCOCI, 47a-e 1) AgOTf, -78 - -20 0C CH2CI2Zt ,2-DCE 2) KHC03 (aq) - Me3SiOTf t KHCO3 (aq) 48a-e Scheme 50 The silver-mediated cyclization of ketoimidoyl chlorides derived from isonitrile 46b were found to proceed with excellent levels of substrate based diastereocontrol52 (>50:1.0 NMR) in favor of the trans isomers 49a and 49b (Scheme 51). Isolated yields of these two pyrrolines were quite low in comparison to those obtained from isonitrile 46a. The cyclization reactions were also carried out at -50 0C for 24 hours but no improvement in the yield of 49a and 49b was achieved. Functionalized acid chlorides were chosen not to be implemented in the cyclizations involving 46b as a result of these low yields. 71 Table 3. Results for the Acylative Cyclization of Isonitrile 46a Acylchloride (-R) A1-Pyrroline AgOTf 0ZoYieId from 46a AgBF4 -C(CH3)3 48a 82 70 -CH(CH3)2 48b 68 60 -CH2CH(CH3)2 48c 77 27 -CH2CH2CH2CI 48d 61 <20 MD 48e 91 <20 1 )RCOCI__________^ 2)AgOTf, -78 to -20°C 49a R=IBu 41%, >50:1.0 transxis 49b R=Et 40%, >50:1.0 trans:cis Scheme 51 Cyclization of ketoimidoyl chlorides prepared from isonitriles 46c and 46d did occur with greater chemical efficiency (Scheme 52). Pyrrolines 50a-e were prepared in good to excellent isolated yields but with lower diastereoselectivity in favor of the cis isomers (Table 4). As in the case of the 72 cyclizations involving 46b, longer reaction times at lower temperatures failed to promote significant change in both yield and stereoselection. Fortunately, the major cis pyrrolidine isomers could be readily separated from the minor isomer by conventional chromatography on silica gel. This enabled synthetically useful quantities (47-65%) of pure cis pyrrolidines to be obtained from isonitriles 46c and 46d. NEC I )RCOCl__________^ 2)AgOTf, -78 to -20°C 46d R2=CHoOTBDMS 50a-e (76-90%) Scheme 52 As in the analysis of the pyrrolidine products obtained from the imine cyclizations, the relative stereochemistry of the substituted A1-pyrrolines 49a-b and 50a-e was elucidated by NOE spectroscopy. Several representative NOE enhancements are illustrated in Figure 20. For the cis pyrrolines, the observance of a large NOE interaction from the C-3 and 0-5 methine hydrogens to the same proton on the centrally located, C-4 methylene was particularly diagnostic. In contrast to the cis isomers, the only significant NOE enhancements which were observed upon irradiation of the C-3 and C-5 methine protons of the minor trans isomers were to different protons on the central C-4 methylene. The stereochemical outcome of the cyclizations involving isonitriles 46b- d can be rationalized by transition state conformations that avoid non bonded 73 Table 4. Data for Acylative Cyclizations of Isohitriles 46c-d Isonitrile (-R2) Acylchloride (-R) Pyrroline Yield (Isolated Cis) Cis:Trans 46c -C(CH3)3 50a 90 (65) 4.6: 1.0 46c -CH2CH3 50b 78 (49) 3.8 : 1.0 46d -C(CH3)3 50c 87 (56) 2.6 : 1.0 46d -CH2CH2CO2Me 50d 77 (48) 4.5 : 1.0 H3C CO2Me 46d \ ^ / 50e 76 (47) qOCO interactions (Figure 21). The comparatively lower levels of 1,3 stereo induction observed in the cyclization of 46c and 46d could be the result of an allylic through space interaction that is less profound than in the cases involving high levels of 1,2 stereo induction (49a and 49b). These transition states are conceivably quite analogous to those governing the trans selective imine cyclizations involving amines tb-d (Figures 15 and 16). Hence the comparatively lower selectivities observed in the acylnitrilium ion cyclizations could very well reflect the very reactive nature of the acylnitrilium ion initiator. I 7 4 SiMe C is 50a (CDCI3)T rans 49a (CDCI3) 10.2% COoMe TBDMSO C is 50d (CDCI3) Figure 20. Diagnostic NOE Data for Substituted Pyrrolines 75 SiMeA 1,3-strain SiMe SiMe SiMe -TfOSiMe3 Trans-A9a-b R R2=CH3, Ch2OTBDMS r T: 0 + N OTf OTf -TfOSiMe3 C/s-50a-e Figure 21. Diastereotopic Transition States for Cyclization of 46b-d A sample of the A1-pyrrolines were transformed into saturated pyrrolidine analogs that have cis configuration at the C-2 and C-3 positions.70 This was performed in order to demonstrate that this cyclization methodology could be used to synthesizes pyrrolidines that stereochemically complement those prepared by the TiCLvmediated cyclization of 2-propylidene-1,3-bis(silane) imines51 (Scheme 53). 76 Metallo Imine Cyclization Acylnitrilium Ion Cyclization-Reduction MegSi ' R v- N H TransA ,2-Pyrrolidines ^ V r R H C/s-1,2-Pyrrolidines Scheme 53 It was discovered that this reduction could be readily accomplished by treatment of pyrrolines 48a, 49a and 50a with excess NaBHgCN and trifluoroacetic acid (1.05 equiv.) at -78 0C in methanol (Scheme 54). The resulting crude pyrrolidines were not purified but immediately subjected to N- tosylation under mild conditions (TsCI, DMAP, -78 to -20 0C) to afford the sulfonamide derivatives 51-53. In this fashion, the basic pyrrolidines were safe guarded against epimerization at the labile C-2 stereocenter. Such epimerization has been observed in similar pyrrolidine systems by Overman upon exposure to silica gel.71 Derivatization also enabled the major isomer of 52 to be secured from the minor by fractional crystallization. The reduction was observed to be quite stereoselective (22 to >50 : 1) for pyrrolines 48a and 48c which contain considerable facial bias around the region of unsaturation. As predicted, lower selectivities were realized during reduction of trans pyrroline 49a. Evidence for the anti approach of hydride during the reduction of was provided by NOE experiments performed on N- 77 tosylates 51-53 after definitive assignments were made from homonuclear decoupling experiments. The results of the diagnostic NOE experiments are summarized in Figure 22 and are consistent with and, therefor, serve to support the initial stereochemical assignments of pyrrolines 49a-b and 50a-e. NaBH3CN, TFA MeOH, -78 0C . TsCI, DMAP ■ CH2CI2, -78 - -20°C SiMe3 48a R1=R2=H, R3=tBu 49a R1=CH3, R2=H1 R3=tBu 50c R1=H, R2=Ch2OTBDMS, R3=IBu 51 (55%, 22:1.0) 52 (63%, 4.4:1.0) 53 (67%, >50:1.0) Scheme 54 Cis 51 (CDCI3) C is -trans 52 (C6D6) Cis-c is 53 (C6D6) Figure 22. Diagnostic NOE Results for Pyrrolidines 51-53 78 Stereoselective Synthesis of Piperidines In the course of this research, the newly developed 2-propylidene-1,3- allylbis(silane) nucleophile has been found to be a highly reactive and functionalized cyclization terminator capable of directing intramolecular ring formation onto iminium ions51 and transient acylnitrilium ions70 (Scheme 55). As a result, functionally diverse pyrrolidines and acyl pyrrolines were efficiently prepared in good chemical yield with not only complete regiochemical control but with high levels of substrate based diastereochemical control as well. SiMe3 Me3Si Scheme 55 With these results in mind, the testing of the ability of the allylbis(silane) terminator to direct the formation of six-membered azacycles via the intramolecular trapping of iminium ions was singled out as a worthy research endeavor. With an efficient synthesis of amino allylbis(silanes) of type 1 having already been devised, it was believed that the carbon chain homologue 54 79 could be rapidly assembled (Scheme 56). This would allow quick access to the experimental investigation of a stereocontrolled piperidine synthesis that utilizes this cyclization terminator. 1) RCHO 2) E+ 6-exo-trig Scheme 56 This study began with the synthesis of amino allylbis(silane) 54. Since phthalimido aldehydes were found to be suitable precursors to amines of type I 1 known aldehyde 57 was initially prepared (Scheme 57). It was reported that 57 could be synthesized by phase transfer, phthalimide substitution of commercially available 5-bromo-1 -pentene followed by oxidative cleavage of the carbon double bond with ozone.72 When this sequence was executed, it was found however that the crude aldehyde underwent unavoidable polymerization during purification after initial isolation from the ozonolysis reaction medium. Br KPHT, C6H6 t Bu4N+I", reflux PHTN 56 (95%) O3, MeOHZCH2Cl^ -60 0C1 Me2S PHTN' 57 (66% ) Scheme 57 80 A more efficient method for the production of 57 was developed. Treatment of bromo olefin 55 with KPHT in DMF containing a catalytic amount of Nal furnished phthalimide 56 in quantitative yield after purification. Rather than employing ozone, oxidative cleavage of the double bond in 56 was achieved with catalytic OSO4 and Nal0 4 under biphasic conditions.73 In this fashion pure aldehyde could be obtained in 92% purified yield without any polymerization being observed during isolation and purification (Scheme 58). With large amounts of the starting aldehyde in hand, the previously developed dibromo olefination and tandem cross coupling p ro c e d u re s 51 -73 were implemented to provide the protected amine 59 in high purified yield. Hydrazine-mediated deprotection then secured the target amine in 96% yield after bulb to bulb distillation. 55 56 (100%) 57 (92%) 59 (83%) (H2N)2-H2O^ b 9 EtOH1 reflux Me3S i 54(96%) H2N Scheme 58 81 Amine 54 was next subjected to the condensation-TiCl4 mediated cyclization protocol. Condensation of 54 with isobutyraldehyde occurred cleanly to afford imine 60 in high yield (Scheme 59). It should be mentioned that a pure sample of imine 60 in CDCI3 was observed to undergo complete decomposition after 48h at rt. and suggests thermal and or air instability of the compound. As a precaution, all cyclization experiments performed on imines prepared from amine 54 were executed without delay using immediately isolated imine. 60 (95-100%) Scheme 59 Treatment of imine 60 with freshly purified TiCU (1.00 equiv., CH2CI2 ) at -78 0C followed by slow warming to rt. and careful base quench did not result in isolation any of the desired piperidine 61 (Scheme 60). Rather, mixtures consisting primarily of desilylated imine 62 and small amounts of imine 63 were obtained. Verification of the major product was provided by the isolation of tosylamine 64 after treatment of the cyclization products with TsCI and pyridine. Similar results were obtained using either TMSOTf or Me2Si(OTf)2 in either stoichiometric or catalytic (0.5 equiv.) quantities. In these experiments acyclic desilylated materials were observed as the major products. Nitrophilic lewis acids such as Cu(OTf)2 also failed to induce cyclization. The undesired 82 imine 62 was also formed in high yield upon exposure of 60 to Bronsted acids such as TFA and EtgOHBF^ at low temperatures. Attempts to carry out alkylative or acylative cyclizations using either MeOTf, EtgO+BF^ TFAA or CNBr also met with failure to produce any of the desired cyclic products. As a result of these initial experiments, alternative strategies for initiating cyclization of imines derived from 54 and alkyl aldehydes are currently under investigation I) TiCl4, CH2CI2, -78 0C to rt ii) KHCO3 (aq) Et2OHBF4 CH2CI2, -78 0C Me3SiOTf or Me2Si(OTf)2^ 0.5 eq - 1.05 eq Me3Si TsCl, py, CH2CI2 N 62 R=CH2SiMe3 Major product 63 R=Me Scheme 60 Successful cyclizations were achieved upon employing imines derived from aryl aldehydes. For example, condensation of amine 54 with 4-anis aldehyde followed by exposure of the crude imine to TiClA under standard conditions furnished a diastereomeric mixture of piperidines 65b in 73% purified yield after treatment of the crude cycles with TsCI (Scheme 61). NMR analysis of the crude /V-tosylates indicated a 6.3 : 1.0 ratio of stereoisomers and the relative configuration of the C2 and CS substituents in the major component was found to be trans as indicated by NOE experiments 83 performed on the individual isomers (Figure 23). Most informative was the observance of a large (12.4%) NOE enhancement between the C2 and C3 methine protons in the minor isomer compared to a significantly smaller enhancement (3.6%) observed in the major component. These NOE results, combined with the values previously obtained from NOE analysis of the AMosyI pyrrolidines, permitted the major isomer to be confidently assigned as the trans stereoisomer. 1) 4-anisaldehyde, THF 4A mol sieves, rt 2) TiCI4l CH2CI2, -78 0C to rt 3) TsCI1 py, CH2CI2 Scheme 61 Figure 23. NOE Results for Cis and Trans Piperidine 65b. 84 This three step condensation-cyclization-tosylation sequence was found to occur efficiently with yields ranging from 42% to 83% when several aryl aldehydes of varying electronic properties were utilized (Table 5). Isolated yields of the purified tosyl derivatives 65a-d as well as diastereostereoslection were found to be Optimum when both the crude imine and cyclization products were carried through the synthetic sequence with minimal delay before the next step. In nearly all cases examined, high levels of trans substrate-controlled stereoselectivity were observed as indicated by NOE enhancements of 3.5 to 4.6 % in the major stereoisomers. The preference for a trans configuration is thought to be the result of transition state structures that minimize steric, nonbonded interactions. Such transition states would most likely conform to a chair structure in which both substituents are aligned in an equatorial fashion (Figure 24). This degree of stereoselection was found to be highest for the electron- deficient 4-nitrophenyl substrate (16:1.0) and lowest for the electron-rich 4- methoxyphenyl imine (6.3:1.0). This trend suggests an increased electronic influence on the transition state as the ability of the aryl group to stabilize a carbonium ion increases. Electronic effects such as minimization of charge separation would lead to a greater propensity to adopt a cis structure and would explain the observed increase in the formation of cis products as electronic donating properties of the aryl substituent increases. Additional evidence for this was observed in the case of piperidine 65a derived from einnamaldehyde. In this instance, a 2.3:1.0 preference for the cis diastereomer was observed and this is attributed to the high affinity for charge stabilization by the conjugated cinnamyl substituent relative to the aryl groups contained in 65b-d. 85 Despite the unsuccessful cyclizations performed with alkyl imines of amine 54, these results obtained with the aryl imines demonstrate the ability of the 2-propylidene-1,3-bis(silane) nucleophile to direct the formation of six membered azacycles. In all cases examined thus far, products arising from a competitive seven-membered cyclization were not detected. The high level of trans stereoselectivity found in these aryl imine cyclizations also complements the cis preference previously observed in the formation of pyrrolidines from aryl imines. -TiCI Trans 65b-d Cis 65b-d Figure 24. Diastereotopic Transition States for Piperidines 65b-d 86 Table 5. Cyclization Data for Aryl (mines Derived From Amine 54 54 1) ArCHO 2 ) TiCI4, -78 Me3S i ^ 0C to rt f Me3Si 3) TsCI1 py I ^ N' Ts + £ -Z 65a-d trans 65a-d c/s Aldehyde (-Ar) Piperidine NTs (% Yield, 3 steps) T rans : Cis C2H-C3H NOE (%) Major Minor r ^ f i 65a (55) 1.0 : 2.3 11.6 4.5 ^ O C H s J 65b (73) 6.3 : 1.0 3.6 12.4 J 65c (83) 9.5 : 1.0 4.6 — NO2 65d (42) 16.0 : 1.0 3.5 87 Stereoselective Synthesis of Functionalized Isotropane Alkaloids and Azabicyclononanes There exists in nature a class of alkaloids containing the azabicyclic octane ring system. Although quite structurally small and compact, these basic amines exhibit strong pharmacological and sometimes physiological properties when consumed by living beings. Most representative are the 2-azabicyclo- [3.2.1]-octanes which are commonly referred to as tropane alkaloids after the simplest member of this family tropine (Figure 25). Cocaine, a potent stimulant and anesthetic found in cocoa leaves, is also included in this family and is probably the most recognized. Tropine itself has biologically active properties as well.25 8-Azabicyclo-[3.2.1 ]-octane = Tropane H3C13 \ N OH Tropine: Poison H3CO2C CeH3O2C \ CH3 N Cocaine: Stimulant, Anesthetic found in cocoa leaves Figure 25. Tropane Alkaloids Isomers of the tropane skeleton in which the nitrogen is located on the bridgehead are not, however, naturally abundant but do posses properties of interest to the pharmaceutical industry (Figure 26). Past clinical studies have shown that substituted 1 -azabicyclo-[3.2.1 ]-octanes, sometimes called isotropanes, act as muscarinic antagonists in humans suffering from the effects of Alzheimer’s d is e a s e .74,75 Such activity has been linked to stimulation of 88 neural transmission which is at very low levels in patients experiencing the senile dementia associated with this terrible disease. These studies point to the structure of the isotropane ligand as well as the appended functional group as having a severe influence on the magnitude of the biological activity. Additional studies have indicated that substituted isotropanes also behave as antagonists of receptors found in the heart, central nervous system and gastrointestinal tract. Interestingly, the discovery of this biological activity was a result of screening synthetic azabicyclic octanes that were designed to mimic strained, high energy conformations of quinolizidine and indolizidine alkaloids.76 Past syntheses of the 1-azabicyclo-[3.2.1]-octane skeleton have been centered around more classical organic reactions such as Dieckman77 and Thorpe78 condensations (Scheme 62). Although these methods have proven reliable in obtaining modest yields of the target compound from readily available starting materials, they do not offer the flexibility required for the preparation of functionally diverse and multisubstituted isotropanes. n ,^ 1 \ - NHCOAr N N Figure 26. Isotropane Alkaloids 89 The clinical studies have also found that the relative stereochemical orientation of the substituents on the isotropane ligand strongly impacts the pharmacological activity of the entire molecule.74-76 Hence it was believed that the development of new methods by which to synthesize functionalized isotropanes in a stereocontrolled fashion would help contribute to the advancement of isotropanes as therapeutics. It was rationalized that substituted isotropanes might be efficiently prepared by successive iminium ion cyclizations directed by the 2-propylidene- 1,3-bis(silane) terminator (Scheme 63). The residual exocyclic olefin that would remain after this bicyclization could serve as a useful functional handle for the attachment of the groups required for biological activity. This could most likely be carried out using reliable alkene chemistry such a as hydroboration- oxidation. CO2Et NI H CO2Et 1) Dieckman Cond. 2) Decarboxylation CO2Et (40%) Scheme 62 90 Methods that might achieve a one pot, direct bicyclization of 1a were screened first. After some experimentation, it was realized that treatment of 1a with excess aqueous formaldehyde (4.0 equivalents) in acetonitrile followed by 1.00 equivalents of trifluoroacetic acid induced bicyclization to provide the corresponding isotropane 66 in 97% yield as indicated by gas chromatography analysis (Scheme 64). Mono cyclization products were not observed by GC or NMR after a reaction time of 4 to 8 hours at room temperature. This observation was not surprising since the nucleophilicity of the intermediate pyrrolidine would be quite high. Initially, isolated yields of the volatile isotropane were not a high as thought possible considering the cleanness of the reaction as indicated by GC. As a result, the solution containing the crude isotropane was treated with TFA (1.00 equivalents) at 0 0C to provide the corresponding trifluoroacetate derivative 67a in high yield upon purification. Trifluoroacetic acid was chosen for derivatization of the volatile isotropanes because the corresponding amine salts posses a marked increased solubility in organic solvents, a less 91 hygroscopic nature and also unique NMR properties.79 Isolation and purification of the corresponding hydrogen chloride salt of 66 proved to be more cumbersome and overall yields were diminished in comparison. NH2 1a SiMe3 SiMe3 Me3Si O2CCF3 SiMeI) CH2O (aq), CH3CN, rt 2) TFA1 rt 3) TFA, Et2O1 O 0C SiMe OoCCF 67a (88%)66 (97%, GO) Scheme 64 Certain experimental details were discovered to be crucial for the successful bicyclization of amine 1a. Initial trials using sequential addition of aqueous formaldehyde and TFA produced a mixture of isotropane 66 and the mono protodesilylated form of amine la. Clean conversion was only achieved if a 1-2 hour time of premixing of the amine and CHgO was carried out prior to addition of protic acid. This suggests that amine-amino alcohol equilibrium must first be completely established in order to avoid protonation of 1a and subsequent formation of the unwanted amine 68 (Scheme 65). The bicyclization reaction was also found to be sensitive to solvent polarity. Large amounts of desilylated amine 68 were detected upon employing solvents less polar than acetonitrile such as methylene chloride. 92 Presumably, media of high dielectric constants are more suitable for driving the highly charged reaction away from the amine substrate 1a. Addition of water, provided by the use aqueous formaldehyde, seemed beneficial to the rate and yield of the reaction when compared to runs performed using paraformaldehyde in anhydrous CHgCN. Additional experiments showed that 2,2,2-trifluoro- ethanol (TFE) could be used as an alternative solvent to acetonitrile but did not provide optimum yield and reaction cleanness. 1a CH 2 O(Bg)l premix TFA CH2O(Bg)l TFA ^ no premix 1a Scheme 65 OoCCF NH2 68 SiMe3 Using the conditions developed for the bicyclization of amine 1a, amines 1b-d were successfully converted in good yield to the substituted isotropanes 67b-d which, as before, were isolated as their TFA derivatives (Scheme 66). Such derivatization was unnecessary for the more massive OTBDMS product 67d which could be readily isolated as the neutral amine in high yield after purification on Florisil. Gratifyingly, relative stereochemistry was preserved with high diastereo fidelity (6.0->50:1.0) during the course of bicyclization as indicated by GC and NMR. For the example involving amine 1c, a 6.0:1.0 mixture of epimers was 9 3 obtained and was resistant towards separation. Condition modifications such as lower temperatures and more polar solvents (TFE) failed to improve this ratio. 2R NH2 1 )CH2 0 (aq), CH3CN1 rt 2)TFA, 0 0C to rt I v i e 2 O i 1b R1=CH3, R2=H 1c R1=H, R2=CH3 1d R1=H1 R2=Ch2OTBDMS 69c 69d O2CCF 3 70d 67b (82%, >50:1.0, TFA) 67c (75%, 6 .0 :1.0, TFA) 67d (95 , 26:1.0, neutral amine) Scheme 66 The relative stereochemical orientation of the C-6 substituent in 67b and the C-7 substituents in 67c-d was most likely established prior to the second desilylative cyclization. Trans configuration is believed to have been preferentially formed during the initial cyclization resulting in pyrrolidine intermediates 69b-d. In an attempt to characterize these intermediates, the cyclizations were run using only 1.00 equivalents of formaldehyde. This produced equal mixtures of the azabicyclooctane and staring material thus 94 revealing the facility of the second condensation-cyclization. As in the trans selective, imine cyclizations involving amines 1b-c, transition state structures governed by allylic through space interactions were thought to be the influence behind the eventual exo configuration of the substituents in isotropanes 69b-d. It was envisioned that the second desilylative cyclization of this tandem reaction proceeding by way of a cis pyrrolidine intermediate would be considerably impeded. Simple models suggest that in the cis isomers of iminium ions 70a-d approach of the mono allylsilane nucleophile to the cationic center would be hindered by the substituents on the same face of the . pyrrolidine. This serves to support trans pyrrolidines 69b-d as intermediates en route to 67b-d. The CHaO-TFA cyclization protocol was next used in conjunction with the metallo imine, monodesilylative cyclization methodology in order for the preparation of substituted isotropanes in a stepwise fashion. Trans pyrrolidines 14a and 14b were exposed to excess aqueous formaldehyde (2.00 equiv.) followed by TFA (1.05 equiv.) to provide the C-8 substituted isotropanes 71a and 71b in isomerically pure form (Scheme 67). Under these conditions, good yields were realized after purification on silica gel and without the need for TFA derivatization. As in the previous, direct bicyclization reactions, solvent choice was important for obtaining maximum yield of isotropanes 71 a-b. After much , experimentation with mixtures of polar solvents including HgO, CH3CN and I I TFE, a 3:1 water-tetrahydrofuran solvent system32 was found to be optimal with respect to yield, reaction rate, solubility and the suppression of unwanted j 'i byproducts. Although completely heterogeneous at the onset, the reaction \ mixtures in HgO-THF achieved homogeneity upon the addition of TFA. f ' I, I : 1 ■ ■ . ' I ___ __________________ ______ ; 95 14a R=IPr 14b R=IBu 1 ) CH2 0 (ag). 3:1 H2Q-THF, rt 2) TFA, O 0C to rt Scheme 67 H 71a (73%) 71b (76%) A very interesting phenomenon was observed to take place when the trans pyrrolidine 24a was exposed to these conditions. The expected isotropane 72a was isolated in 68% yield but small quantities (ca 12%) of a second diastereomer were also detected even though the starting substrate 24a was isomerically pure. This stereochemical scrambling also took place upon using the OTBDMS pyrrolidine 32d (Scheme 68). Evidence for the relative stereochemical disposition of 72a was provided by the 1H NMR spectrum after assignments were based on extensive homonuclear decoupling experiments. The spectrum revealed that the C-8 methine proton corresponded to only a doublet signal and the C-5 bridgehead methine proton appeared, surprisingly, as a singlet. Application of the Karplus correlation80 strongly points to dihedral angles approaching 90° between the C-8 , C-5 and C-6 protons. Simple molecular modeling points to the exo-exo structure illustrated for 58a as the only one capable of three perpendicular, adjacent protons. Such an absence of coupling has been previously noted in work involving unsubstituted isotropanes.75- 76 Further support came from HD experiments that identified the location of the C-8 methine doublet at 2.11 ppm. This is unusually up field for such a 96 proton considering normal deshielding effects. Thus it is believed that this proton lies over the shielding cone of the exocyclic olefin in 72a in an axial (endo) not equatorial (exo) alignment. 1 )CH20 (aq), 3:1 H2 O-THF, it 2) TFA1 O 0C to rt 24a, single isomer (>50:1.0) H 72a (68%, 8.0:1.0) OTBDMS 11CH2Opq), 3:1 H2O-THF, rt 2) TFA1 O 0C to rt 32d, mixture (1.0:1.0) OTBDMS 72b (88%, 1.4:1.0) Scheme 68 The stereochemical scrambling observed during the cyclization of 24a and 32d must have occurred in a pathway that permits the formation of two of the four possible diastereomers. It was conceived that a [3,3] sigmatropic aza cope rearrangement was in competition with direct desilylative ring closure for control over the fate of the initial iminium ion (Scheme 69). For the pyrrolidine substrates 24a and 32d, direct closure of the initial iminium ion would be expected to be a higher energy process than the alternative aza cope pathway This increased energy would be a result of the development of steric 97 compression during approach of the allylsilane nucleophile to the hindered iminium ion. Conversely, transannular cyclization of the aza cope product could feasibly occur onto either diastereotopic face of the iminium ion resulting in the formation of two diastereomeric bicycles. It is also conceivable that Eto Zconfigural interconversion about the iminium ion geometry could also give rise to additional diastereomeric products. If this was occurring, four diastereomeric products could potentially be generated. The observance of only two isomers in the cyclization of 24a and 32d suggests that this is not occurring. In support of the alternative aza cope pathway, Overman has also observed rapid sigmatropic rearrangements in numerous iminium ion reactions including.systems that contain vinylsilane nucleophiles (Scheme 70).81 98 [3,3]-Aza Cope Nonselective H3C Cyclization 2 Diastereomers (8.0:1.0) Scheme 69 99 Scheme 70 It was most gratifying to observe analogous bicyclization of amine 54 when exposed to the same conditions as those employed for the synthesis of 67a-d from amines 1a-d. For instance, premixing amine 54 and aqueous formaldehyde (4.00 equiv.) in CH3CN for 2h followed by addition of TFA (1.05 equiv.) resulted in formation of 1-aza[3.3.1]bicyclononane 74 after an overnight period at room temperature (Scheme 71). The free amine could be isolated and purified in modest yield (59%) but, as in the case for the volatile isotropanes, superb purified yields of the corresponding TFA derivative were achieved upon treatment of the crude product solution with TFA (1.05 eq). In this fashion, amine salt 75 was obtained in 94% yield from amine 54. Even though this study brought forth intriguing mechanistic and spectrometric observations, it also revealed the ability of the 2-propylidene-1,3- bis(silane) terminator to prepare functionalized isotropane alkaloids and azabicyclononanes in an efficient and stereocontrolled manner. Flexibility was demonstrated by applying both a direct, bicyclization approach or stepwise cyclizations in the preparation of these potentially useful compounds. 100 Me3 Me3Si H2N Si 54 I) CHgOtaq), CH3CN ii) TFA iii) work up, TFA, O °C OoCCF OpCCF 75 (94%) Scheme 71 101 Synthesis of the Azatricyclic Core of Stemofoline Since the late 1960s, Japanese natural product chemists have been isolating structurally intriguing alkaloids from the roots, stems and leaves of stemonaceae plants.82-83 These polycyclic alkaloids were found to contain numerous rings of various size and mode of connectivity. Interestingly, all of these alkaloids posses one or more y-lactones joined to the core in either a fused, spiro or directly joined fashion (Figure 27). In former days, extracts from the stemonaceae plants were utilized to eradicate zooparisites and agricultural pests on men and cattle. Even today the extracts are used as domestic insecticides for agricultural pests in localized regions of China. Of the stemonaceae alkaloids screened for biological activity, Stemofoline has been shown to posses the strongest insecticidal activity, especially against silkworm and related larvae, when administered orally.83 Stemofoline is very unique in structure upon comparison to the other members of the stemonaceae family. For the majority, the natural assembly of rings is always in a fused, spiro or directly joined pattern. Stemofoline, however, is the only member that contains a bridged array of cyclic nuclei resulting in a very rigid and compact, cage-like structure. Although no evidence currently exits, this unique structure might be responsible for Stemofoline’s potent insecticidal activity. Nevertheless, the combination of structural complexity and biological activity serves to make Stemofoline an attractive yet challenging target for total synthesis. It was considered crucial that an efficient route to the azatricyclic core of Stemofoline be developed in order for total synthesis to eventually be realized. With this in mind, bridged pyrolizidine 77 was selected as the key synthetic. 102 Stemonamine Stemonine Stemospironine Tuberostemonine Stemofoline Figure 27. Representative Stemonaceae Alkaloids target and the next goal for the application of the allylbis(silane) methodology (Scheme 72). The exocyclic double bond of viable precursor 78 would, upon oxidative cleavage, provide the ketone required for the eventual formation of the bridged ketal in the natural product 76. In addition, the resulting ketone would also provide activated alkylation sites that might permit facile attachment of the butenolide segment to the parent core. More importantly, the olefin in 78 is also the retron26 for the exocyclic, allylsilane-iminium ion cyclization transform. Retrosynthetic cleavage of the Mannich type bond in 78 reveals iminium ion 79 as an appropriate intermediate which should be readily generated from pyrrolidine 80 upon unmasking of the aldehyde or related functionality. Pyrrolidine 80 correlates 103 nicely to a 2-propylidene-1,3-bis(silane) imine cyclization involving components 1a and dicarbonyl compound 81. H H3CO ft Stemofoline TGT 77 Scheme 72 From a stereochemical-based, retrosynthetic analysis of target 77, the success of the above approach lies in the selective formation of a trans relationship between the butyl group and 1-(trimethylsilylmethyl)ethylidene 1 0 4 substituent in pyrrolidine 80. Prediction of the stereochemical outcome of the initial allylbis(silane) imine cyclization was somewhat vague but the results from the cyclization of ethyl lactate derived imines (Scheme 43) do suggest that stereoselective formation of the contiguous stereocenters in 80 is feasible. Moreover, the facility of this ketimine cyclization involving components Ia and 81 was also in question since previous attempts to efficiently cyclize imines derived from ketones met with unfavorable results. As a result, the key allylbis(silane) imine cyclization was believed to require strenuous experimentation in order to obtain proper stereochemistry and also avoid unwanted desilylation of the imine precursor. The relative orientation of the protected alcohol function in 78-80 was of lesser concern. If the stereochemical relationship of this group proves to be opposite of that in the target compound 77, it was believed that correct configuration could be established at numerous points along the synthetic sequence. This could most likely be accomplished by either Mitsinobou inversion84 or an oxidation-stereoselective reduction sequence after removal of the alcohol protecting group (Scheme 73). Considering the results of the ethyl lactate imine cyclizations, an alignment of the protected alcohol opposite of that present in the target molecule was predicted. Hence application of the inversion techniques was anticipated. 105 Mitsinobu Inversion Oxidation Steric Approach Reduction Scheme 73 The feasibility of utilizing the 2-propylidene-1,3-bis(silane) terminator in the synthesis of target 77 was initially probed on a model system lacking the protected alcohol functionality. Ethyl Ievulinate was selected for condensation with amine 1a since this ketoester contains both the electrophilic carbonyl and a suitably disposed, aldehyde surrogate capable of eventual conversion into an iminium ion analogous to ion 79. The commercial availability and inexpensiveness of ethyl Ievulinate allowed for rapid screening of the key allylbis(silane) imine cyclization. Using the standard conditions (4A mol. sieves, THF, rt.), condensation of ethyl Ievulinate with amine 1a over 24 hours afforded imine 83 (Scheme 74). Unlike the aldimines prepared via this method, NMR analysis of imine 83 showed the presence of a second compound in up to 10% composition which has been tentatively assigned as the Z isomer. The crude imine was then subjected to the standard cyclization protocol without delay. It was an extremely pleasing observation that upon immediate exposure to TiCU (1 -0 equiv., CHgCIg, -78 0C to rt.) imine 83 underwent cyclization and 106 intramolecular lactam closure to provide bicyclic lactam 85 which was isolated as a single diastereomer in 80% yield after purification on silica gel. Analysis of the crude reaction mixture showed no evidence for formation of the alternative stereoisomer of 85 but did reveal that some desilylation of the imine substrate had occurred during the course of the cyclization reaction. Once again the mode of reaction quench was crucial for high isolated yields. On a large scale run employing addition of base to the reaction mixture, desilylated product 86 was isolated in significant quantities. Slow inverse addition of the reaction solution to cold, aqueous KHCOg suppressed any formation of this undesired lactam. Initial evidence, for the desired stereochemical outcome of the bicyclization came from magnetic anisotropic effects observed in the proton NMR spectrum of 85. The two olefinic protons showed a marked difference in chemical shift (Appm = 0.23) indicating that one of these two protons lies in close proximity to the shielding cones of the carbonyl group. Such ah effect would most likely be of lesser magnitude in the alternative diastereomer. Removal of the influential carbonyl in 85 by exhaustive reduction (UAIH4 , THF, reflux) provide pyrolizidine 87 and NMR analysis clearly showed a less pronounced anisotropic effect occurring in the olefinic proton signals (Appm = O'.04). These signals in amine 87 were also 0?26 ppm downfield relative to those in lactam 85 indicating relief from shielding had occurred upon reductive removal of the carbonyl group. More conclusive evidence for the stereochemical structure of 85 eventually came from cyclization into a bridged pyrrolizidine. Oxygen to sulfur conversion was carried out on lactam 85 in order to gain access to the nucleophilic thiolactam. Along these lines, treatment of 85 107 1)TiCI4, CH2CI2, -78 0C tort 8 3 2) KHCO3faq) 0 0C EtOoC SiMeSiMe 85 (80%) Scheme 74 with Lawesson’s reagent85 in the presence of an amine buffer (EtgNiPr, PhCHg1 rt.) furnished thio derivative 88 in high yield after purification (Scheme 75). It was discovered that in the absence of the buffer, mixtures of products comprised of 88 , desiiylated thiolactam 89 and also a small amount (4%) of the epimer 90 were formed. These products must have arisen from protonation of the allylsilane unit in 88 by phosphoric acid present in the moisture-sensitive Lawesson’s reagent. The NMR spectrum of 90 indicated no significant 108 anisotropic effects on the olefinic protons and helped to reinforce the stereochemical arguments proposed for lactam 85. Lawesson's reagent IPrNEt2, PhCH3, rt SiMe 88 (93%) SiMe Scheme 75 Attention was next turned to executing the second allylsilane iminium ion cyclization. It was reported that amides could be partially reduced to amines and aldehydes86 and also that lactams generate iminium ions upon partial reduction with DIBALH.64 Unfortunately, attempts to partially reduce either lactam 85 or thiolactam 88 resulted in either no significant reaction or deprotonation to the corresponding enolate which tautomerized back to substrate upon work up. Coordination of some of the reducing agents (DIBALH, K-selectride, Red-Al1 and Super hydride) to the nucleophilic sulfur and oxygen might have facilitated internal deprotonation rather than reduction. Activation of lactam 85 towards reduction by O -alkylation prior to hydride addition was tried next.87 Treatment with MeOTf did not result in clean 109 formation of the expected iminium ether 92 but, surprisingly, mixtures containing cyclized, bridged pyrolizidine 94 were obtained (Scheme 76). Analogous results were realized during attempts to generate the corresponding Vilsmeyer salt 93 by treatment of 85 with oxallyl chloride.88 Both of the tricyclic compounds 94 and 95 were found to be too unstable for isolation and purification but their detection did indicate the propensity of the allylsilane nucleophile to engage in cyclization upon generation of even electron rich iminium ions in the bicyclic lactam. These results also provided additional evidence for the stereochemical configuration of lactam 85. SiMe R=OCH 93 R=CI 95 Scheme 76 This observation that the allylsilane nucleophile readily closes onto iminium ions that are relatively electron rich prompted us to take advantage of this surprising reactivity in securing the desired bridged pyrolizidine. After initial experimentation, it was found that treatment of the nucleophilic thiolactam 88 with either trimethyl- or triethyloxonium tetrafluoroborate, better known as Meerwein’s reagents89, resulted in clean alkylation at 0 0C as indicated by TLC to form the intermediate iminium salts 96a and 96b (Scheme 77). These salts could not be isolated but rather warming of the reaction mixture to ambient temperature then promoted thermal cyclization into the bridged pyrolizidines 110 97a and 97b. These thioaminals were obtained in high yield after purification on basic alumina and were found to be sufficiently stable during careful storage. Quench of this alkylation-cyclization reaction was best carried out using aqueous LiOH to ensure complete decomplexation of BFg from the basic nitrogen in 97a and 97b. 2) warm to rt 3) LiOH(aq) Ct F-BFc SiMe3 96a R=Et 97a R=Et1 (90%) 97b R=CH3 (82%) -FSiMe3 Scheme 77 One of the keys to the success of this reaction was the ability of thiolactam to undergo complete alkylation at temperatures below those that promoted thermal cyclization. If this could not be carried out, competitive alkylation of the cyclized product would undoubtedly ruin this reaction sequence. Although this reaction could be performed in methylene chloride, the use of the more polar CHgCN allowed for better yields and faster rate of cyclization. Fortunately, this nucleophilic solvent did not interfere with the initial alkylation step. Employing protic solvents such as TFE resulted in desilylation 111 of the allylsilane unit and also hydrolysis of the thio iminium ion to give only desilylated lactam upon isolation of products. As stated before, the room temperature cyclization of the electron rich iminium ions 93 and 96a-b was somewhat unexpected. It is believed that the preferred conformational position of the allylsilane nucleophile was ideal for bonding to the electrophilic carbon and resulted in a facile, kinetic ring closure. In addition, fluoride ion assistance provided by the BF4 ' counterion might have enhanced the rate of the desilylative ring closure. For sake of comparison, desilylated thiolactam 89 was exposed to Meerwiein’s reagent under identical conditions. No cyclized product was observed but rather iminium salt 98 was isolated in 78% yield (Scheme 78). More significantly, this salt was observed to be thermally stable even after months of storage under argon. This result not only exposed the reactive nature of silyl iminium salts 96a-b but also suggests that a potential aza cope-transannular allylsilane cyclization pathway does not ensue from these iminium ions leading to the formation of the tricyclic thioaminals (Scheme 79). Thermally Stable 2) warm to rt H3C 3 89 98 (78%) Scheme 78 112 Scheme 79 In order for this sequence to be applicable towards the formation of the desired target 77 (Scheme 72), desulfurization of the bridged pyrolizidine 97a was required. This compound proved extremely resistant towards reductive desulfurization with either W-2 Raney Ni, or a variety reductions involving potassium and lithium metal dissolved in various media. Extensive investigation with this reduction failed to produce the desired compound 99 to any appreciable extent (Scheme 80). As a result, the reduction was implemented at an earlier point in the synthetic sequence. Alkylation of 88 with Meerwien’s reagent followed by cold temperature reduction of iminium salt 96a afforded bicyclic thioaminal 100 (Scheme 80). Although more than one reducing agent promoted this partial reduction before cyclization could ensue, low temperatures (-78 0C) and optimum yield were realized upon using potassium triisopropoxy borohydride (KIPBH).90 All attempts to induce ionization of 100 and concomitant cyclization 113 of iminium ion 101 failed, generally resulting in only complex product mixtures. Ionization of 100 was attempted with numerous thiophilic reagents such as Lewis acids, mercury salts and silver salts. Even the extremely thiophilic reagent developed by Trost, (CH3)2S-SCH3+BF4 ‘ 91, failed to induce formation of the desired tricyclic amine 99 . 1) Et3O+BF' CH2CI2, 0 0C 2) KIPBH, -78 0C Scheme 80 114 Despite the inability to secure the desulfurized azatricycle, we were quite pleased in the ability of the allylbis(silane) terminator to rapidly construct the basic core of Stemofoline in a completely stereocontrolled manner. This stereoselectivity combined with the efficiency of the synthetic scheme, four steps from ethyl Ievulinate in 67 % overall yield, motivated us to test the feasibility of carrying out this sequence on substrates equipped with the required alcohol functionality. An appropriate oxygenated ketoester was quickly prepared. Following known procedures92, aldol addition of ethyl acetate to methacrolien furnished adduct 102 in 75% yield (Scheme 81). Silylation of the alcohol with tert- butyldiphenylsilyl chloride furnished silyl ether 103 which was converted into •• ' ketoester .104 in 91% yield upon ozonolysis followed by reductive work up with IVIegS. Condensation of 104 with amine 1a proceeded with low conversion to using the standard conditions ( 4A mol. sieves). After testing several reagents to promote the condensation, high levels of conversion into imine 105 were obtained when catalytic amounts of water-stable BugSnCI93 were employed in the reaction. Exposure of 105 to TiCl4 at low temperatures (-78 to -25 0C) resulted in the bicyclization product 106 but only in 25% isolated yield from amine la. Despite the low yield, this lactam was obtained in stereochemically pure form and has been tentatively assigned the diastereomer shown based on spectral comparison to bicyclic lactam 85. A slightly higher yield (34%) was obtained using (Me2S)2ZrCl4 and the less hindered OTBDMS imine substrate. Strenuous experimentation with reaction conditions involving several permutations of different Lewis acids and solvents did not result in an increase in the yield of the bicyclization. Low temperature monitoring of the reaction indicated that desilylation of the imine substrate was the preferred mode of 115 reaction and, in almost all cases examined, protodesilylated imines were isolated as the major products. These unfavorable results motivated us to seek a significantly different synthetic approach to the functionalized tricyclic core of Stemofoline using the allylbis(silane) terminator. O EtO 1) LDA, THF, -78 0C 2) methacrolein, -78 0C OEt TBDPS-Cl , lmid, DMF1 rt OH OTBDPS / 103 (96%) 1) O3, CH2CI2 -78 0C 2) Me2S 102 (75%) 104 (91%) OTBDPS EtO2C 1Q4 5% CI2SnBu2, CH3Phi 1a, 4A mol sieves 105 OTBDPS TBDPSO H3C HC ° - 1) TiCI4, CH2CI2 -78 0C to -25° C 2) KHCO3faq) SiMe-: 106 (25%, TiCI4) (34%, (Me2S)2ZrCI4 OTBDMS protection) Scheme 81 A C-acyliminium ion-initiated, polycyclization sequence was conceived as a potentially rapid method to obtain the functionalized target molecule. It was believed that an appropriate C-acyliminium ion could be generated from imidoyl chloride 74e via cuprate addition-elimination followed by activation by a suitable acid (Scheme 82). Unfortunately, reliable conditions could not be 116 found to produce imine 108 in good yield after extensive testing of various butyl cuprates under a host of conditions. Hence production of 110 by this tricyclization cascade was never able to be investigated. Scheme 82 In comparison to C-acyl iminium ions and conventional iminium ions, the N-acyl variants have received considerably more use in cyclizations terminated by allylsilanes. To our knowledge, there has been no account of such a cyclization employing an allyl(bis)silane as a terminator. With the synthesis of the Stemofoline core in mind, experiments were made in order to address the feasibility of this type of cyclization but ,unfortunately, the results have been undesirable. For example, previously prepared phthalimide 9a was partially reduced via the procedure of Speckamp28-35 to furnish hydroxy lactam 111 in high yield 117 (Scheme 83). Alkylation under biphasic, phase transfer conditions provided the methoxy derivative 112 in 83% yield. Exposure of either 111 or 113 to conditions that should promote ionization-cyclization28-35-38 did not result in any detected formation of tricyclic lactam 114. For this system, the high energy required to form an anti-aromatic iminium ion was believed to be the source of failure. As a result, lower energy pathways such as protodesilylative processes dominated. > -Q NaBH4, MeOH1 -10 0C X ZICC 95% C 111 R1O Various conditions O Types of Products 7-----\ \ / ) R i=H1 Me, SiMe3 \ — V R2=CH2SiMe3, CH3 112 R1=H NaOH, C6H6 (MeO)2SO2 ,cat. TBAI Me3Si Not formed Scheme 83 Nevertheless, it became realized that a more conventional N-acyliminium ion-allyl(bis)silane cyclization might be an attractive means by which to synthesis the Stemofoline target molecule . In this retrosynthetic analysis (Scheme 84), application of the alkylation-desilylative cyclization transform to the tricycle 115 reveals bicyclic lactam 116 as a plausible intermediate. Disconnection of the strategic Mannich-type bond in 116 furnishes acyliminium 118 ion 117 which should be accessible from cyclic imide 118 through a Grignard addition-elimination sequence. Imide 118 maps nicely onto the previously prepared amine 1a and the known, homochiral anhydride 119.94 Scheme 83 Preparation of the imide 118 was carried out by nucleophilic opening of 119 by amino-allyl(bis)silane 1a followed by immediate exposure of the intermediate acid-amide to acylation conditions (py, DMAP, AcgO), (Scheme 84). In this fashion a yield of 45-55% of the purified imide was realized. Decomposition of the sensitive 2-propylidene-1,3-bis(silane) addend was observed to be the major source of the low yield. Alternative methods to induce imide closure such as DCC, AcCI and TFAA under a variety of conditions also met with low yields and destruction of the 2-propylidene-1,3-bis(silane) unit. Using the Weinreb protocol95, a more direct route starting from diester 12094 119 was investigated (Scheme 85). This however furnished low yields even after extensive screening of a broad range of reaction conditions in which solvent, temperature and amount of AIMeg were varied. BnO O 119 i) la , CH2CI2, - IO 0C ii) Ac2O, O 0C- reflux Me3Si 120(45-55%) OBn MeO2C ^ — CO2Me l^AiMea^ solv., temp Me3Si 121 Me3Si 120 (20-30%) Scheme 85 With some quantities of the desired imide in hand, initial probing into the Grignard addition-cyclization sequence began. Treatment of 120 with nBuMgBr (1.1 equiv., EtgO, 0 0C, 0.5-1 h) resulted in rapid consumption of substrate to provide the unstable hydroxylactam 122 in near quantitative crude yield upon protic quench (NH4CI(aq)) (Scheme 86). A second minor product could be detected (TLC) and has tentatively been assigned as a minor diastereomer based on 1H NMR analysis. Evidence for regioselective attack by the Grignard nucleophile to the more activated carbonyl was provided by the observance of a large chemical shift of the OBn-methine H in the 1H NMR spectrum relative to the adjacent 120 methylene hydrogens upon introduction of the butyl group to the molecule. In addition, the reaction was found to proceed at very low temperatures (-20 0C) but excess Grignard reagent arid long reaction times (12h) were required. These results were encouraging since similar Grignard additions have been performed by both Speckamp96 and Evans.4 In these instances, addition to cyclic imides lacking activating groups such as an OBn ether proceeded with low conversions even when long reaction times (20h, rt.) or heating were employed. The corresponding ring-opened products also complicated their product mixtures but was not observed in the preparation of 122 . Development of conditions that might trigger the ionization-cyclization sequence was next undertaken. Activation of the hydroxy lactam using a variety of reagents (TFAA, MsCI, TEA, Me2Si(SMe)2) resulted in elimination products of type 123-125 frequently being isolated with no desired bicyclic lactam 126 detected (Scheme 87). The intermediate magnesium alkoxide upon treatment of 120 with nBuMgBr was exposed to both Mel and TMSCI in the hope to afford more stable iminium ion precursors but little reactivity was observed (TLC) in these reactions. In addition, direct treatment of the alkoxide with TFAA of MsCI also produced enamides 123 and 124. In fact, the hydroxylactam substrate was found to undergo decomposition after several hours at rt. in CDCIg to afford a mixture of products containing 124. In all these instances, elimination was observed to have occurred exclusively in an exo fashion. This is somewhat surprising since Speckamp and others observed primarily endo elimination in related hydroxylactam systems 96 ■i 121 OHOBn 122 (>90%, unstable) Scheme 87 With the strong tendency for hydroxylactam 122 and related derivatives to undergo facile exo elimination, it was hypothesized that removal of the relatively acidic protons on the butyl substituent prior to the critical cyclization might prevent this elimination. Such an alteration of the synthetic plan could theoretically be carried out by utilizing the vinyl Grignard reagent derived from frans-1-iodobutene in the formation of the requisite hydroxylactam. Hydrogenation of the double bond could most likely be induced later in the synthesis. To quickly test this possibility, imide 120 was treated with ethenyl- magnesium bromide (1.2 eq, EtgO, O 0C) to cleanly provide hydroxylactam 127 in 95% yield with the 1H NMR suggesting the presence of a small amount of a second diastereomer (Scheme 88). An initial attempt to induce ionization- cyclization using the mild and affective conditions of Gramian38 (TEA 1.1 eq., MsCI 1.1 eq., CHgCIg, rt.) resulted in complete consumption of 127. None of 122 the desired bicycle 128 was isolated from the reaction mixture however. Two products that were isolated contained no TMS residues and were unable to be completely characterized. Further experimentation with this synthetic route was not performed. Me3Si % V -N J .Z/ 1) CH2CH2MgBr, / - N sV OBn Etpo, 0 0C ( O 2) NH4CItaq)* > H O j i Me3Si ) 120 Me3Si 127 OBn MsCl, TEA CH2CI2, rt OBn SiMe- 128 0 Scheme 88 The /V-acyliminium ion approach has not resulted in any production of the crucial Stemofoline intermediates. In practice, the synthetic scheme has been plagued by the high propensity of the cyclization precursors to undergo elimination rather than ionization-cyclization. In the only two accounts of N- acyliminium ion cyclizations proceeding by way of tertiary hydroxylactams, both Evans4 and Speckamp96 exposed corresponding enamides to formic acid to induce /V-acyliminium ion formation. Their results and the observations of this study suggest that, unlike secondary hydroxylactams35-38, iminium ion formation from a tertiary hydroxylactam must proceed via protonation of the 123 hydroxylactams. - To this date the properly functionalized, tricyclic core of Stemofoline has not been synthesized in acceptable yield via three different synthetic strategies involving tandem allylbis(silane)-iminium ion cyclizations. Nevertheless, the efficient synthesis of the unfunctionalized azatricyclic core from amine Ia does illustrate the potential of the allylbis(silane) terminator, to construct complex, stereodefined polycycles and the results of this study show that a synthetic approach to Stembfoline via this methodology is still a worth while research endeavor. enamide, not by direct ionization. The strongly acidic conditions required for such a transformation could easily render the 2-propylidene-1,3-bis(silane) terminator useless for cationic cyclizations originating from tertiary 124 SUMMARY In response to the synthetic limitations of the mono allylsilane nucleophile, an allylbis(silane) cyclization terminator was developed for use in the synthesis of cyclic alkaloids. Amines tethered to a 2-propylidene-1,3- bis(silane) nucleophile were efficiently prepared via a scheme involving a tandem, palladium catalyzed cross coupling reaction as the pivotal step. Under mild conditions, these amines were transformed into activated imines which underwent regiospecific and stereoselective cyclizations directed by the allylbis(silane) terminator. As a result, substituted pyrrolidines and piperidines bearing a mono allylsilane were synthesized in high yield and with good control over the relative configuration of the substituents. Additional cyclizations performed on imines derived from ethyl lactate proceeded with, high levels of diastereocontrol between stereocenters disposed both within and outside of the cycle periphery. This terminator was also found to engage in cyclizations onto transient C- acylnitrilium ions generated from isocyano-allyl(bis)silanes and acid chlorides. Using this reaction, functionally diverse acylpyrrolines were synthesized in good chemical yield with moderate to high levels of diastereocontol as well as a set of pyrrolidines that stereochemically complemented those obtained from the imine cyclization protocol. Iminium ion cyclizations directed by the 2-propylidene-1,3-bis(silane) terminator were successfully applied to the stereodefined synthesis o f . therapeutic alkaloids shown to combat the symptoms of Alzheimer's disease. Azabicyclooctane and azabicyclononane ligands were synthesized in high 125 yield,by employing either tandem, one-pot bicyclizations or controlled, stepwise sequences thus revealing the synthetic flexibility of the terminator. . This feature culminated in a concise and efficient synthesis of the azatricyclic nucleus of the alkaloid StemOfoIine. In this instance, the key step involved an imine cyclization-lactam closure bicyclization that proceeded with complete stereoconfrol. Intermediates containing the functionality present in the natural product were also prepared by this reaction but in yields that did not permit completion of the total synthesis. The results of this research project demonstrated the capability of an allylbis(silane) terminator to direct cyclizations in a regio- and stereocontrolled manner. Unlike the silicon-based nucleophiles previously developed, this terminator enabled the control of two cyclizations from the same nucleophilic olefin. From this work, it quite conceivable that other bis(silanes) such as vinyl- and propargylbis(silanes) could be utilized and continue the advancement of silicon directed reactions. 126 EXPERIMENTAL General Experimental Details Physical Data: 1H NMR and 13C NMR spectra were measured at 300 and 75 MHz, respectively, with a Bruker AC-300 spectrometer. 1H NMR and 13C NMR chemical shifts are reported as S values in ppm relative to residual proton signals in CDCI3 (8 = 7.24, 77.0) or C6D6 (5= 7.15, 128.7). 1H NMR coupling constants are reported in Hz and refer to real or apparent multiplicities indicated as follows: s (singlet); d (doublet); t (triplet); q (quartet); p (pentet); sx (sextet); br (broad); m (multiplet); app (apparent); dd (doublet of doublets); dt (doublet of triplets); etc. Infrared spectra were recorded on a Bruker IPS 25 IR, Electron impact mass spectra (70 eV) were obtained with a Hewlett Packard 5970 series mass selective detector. High resolution mass spectra were recorded on a VG Instruments 70E-HF spectrometer. Melting points were obtained using a Mel- Temp Il apparatus equipped with a Fluke 51 digital thermometer and are uncorrected. Chromatography: Gas chromatographs were obtained using a Hewlett Packard 5890 Series II gas chromatograph equipped with a flame ionization detector and an Alltech Econocap SE-54 bonded phase column (15 m length, 0.54 mm id, and 0.25 m film thickness). TLC was performed on plates supplied by Alltech Associates (K42-G) using one or more following visualization techniques:97 UV illumination at 254 nm, KMn0 4 oxidation, anisaldehyde derivatization, exposure to phosphomolybdic acid or ammonium molybdate, exposure to iodine vapor or ninhydrin derivatization. Column chromatography 127 was performed according to the methods of Still98 employing Merck Silica Gel 60, Aldrich Activity 1 basic alumina (150 mesh) or commercial Florisil (100-200 mesh). Solvent systems used for elution are reported as %volume/volume. Chemical Materials. Reagents and Techniques: Tetrahydrofuran (THF), benzene, heptane and 1,2-dimethoxyethane (DME) were distilled from potassium and diethyl ether (EtgO) was distilled from sodium-benzophenone. Dichloromethane (CHgCIg) was distilled from P2O5 . Toluene, acetonitrile (CH3CN), dimethylformamide (DMF, dist. @ 15 torr), 1,2-dichloroethane (1,2- DCE), and commercially purchased amines were distilled from GaHg. Methanol (CH3OH) was distilled from Mg(OCHg)Z- Atmospheric pressure distillation of the above solvents and reagents and those mentioned hereafter was performed under an inert atmosphere of argon or nitrogen. The molarities for alkylmagnesium halide and alkyl lithium reagents were established by titration with 2-butanol using 1,10-phenanthroline as an indicator. Total base concentration of these reagents was established by titration with standard potassium bipthalate solutions using a phenolphthalein indicator. Unless otherwise noted, all reactions were carried out under an atmosphere of argon in flamed, oven-dried vessels of appropriate size and style equipped with magnetic stir bar and stir plate. Addition of reagents was carried out utilizing standard syringe-septum techniques. Unless stated otherwise, reagents were used as purchased from major chemical suppliers. Commercial alkyl halide reagents were purified by elution through Aldrich Activiy 1 basic alumina (150 mesh) prior to use. Reduced pressure concentrations were performed with a Buchi RE 121 rotary evaporator. Ii 128 Synthesis of Aminoallylbis(silanes) General Information: Standard THF solutions of anhydrous zinc chloride were prepared by flame fusing commercial zinc chloride under high vaccum (< 250 (itorr) in a volumetric flask followed by dilution with dry THF. Commercial carbon tetrabromide was purified by elution through basic alumina (CHgCIg for elution) pror to use. PdCIg(PPhg)Z was prepared from commercially purchased PdCIg using previously reported procedures." 2-(2-Phthalimidoethyl)-1,3-dioxolane (6). To a 250 ml_, single­ necked, round-bottomed flask containing a suspension of potassium phthalimide (25.6 g, 138 mmol) in DMF (100 ml_) was added 2-(2-bromoethyl)- 1,3-dioxolane (20.0 g, 110 mmol) followed by anhydrous Nal (1.00 g, 6.67 mmol). The white suspension was vigorously stirred for 30h at 25 0C. The mixture was concentrated in vacuo and the resulting white solids were triturated with ethyl acetate (3 x 50 ml_). The supernatant was filtered through a plug of silical gel with ethyl acetate for elution to give 6 (27.0 g, 99%) as a white solid upon evaporation of solvent: mp 117.2-118.0 0C (40% EtOAc/hexanes); 1H NMR (300 MHz, CDCI3) 8 7.79 (dd, J = 5.4, 3.1 Hz, 2H, ArH), 7.66 (dd, J = 5.4, 3.1 Hz, 2H, ArH), 4.91 (t, J = 4.4 Hz, IH, CM), 3.83 (m, 4H, CHgO x 2), 3.80 (t, J = 6.8 Hz, 2H, CH2N), 2.03 (dt, J = 6.9, 4.4 Hz, 2H, CH2); 13C NMR (75 MHz, CDCI3, 1H decoupled) 5 168.15, 133.70, 132.26, 123.06, 102.58, 64.90, 33.12, 32.20; IR (KBr) 2948, 2885, 1766, 1694, 1612, 1398, 1372, 1125, 1063, 892, 728, 715 cm"1. 129 PHTN 3-Phthalimidopropionaldehyde (7a). A 500 mL, single-necked, round-bottomed flask was charged with acetal 6 (10.0 g, 40.5 mmol) and degassed HCI (200 mL, 0.5 M). The reaction vessel was fitted with a condenser and the white suspension was heated at reflux for Ih during which vigorous stiring was maintained. The resulting homogeneous solution was cooled to room temperature during which a white precipitate formed. The mixture was placed in refrigeration (10 0C) overnight. The solid was collected on a fritted funnel, washed with cold HgO (3 x 25 mL) and dried in vacuo to yield 7a (5.84 g, 71%) as a white solid: mp 127.7-129.6 0C (90% EtOAc/hexanes); 1H NMR (300 MHz, CDCI3) 5 9.77 (s, 1H, O=CH), 7.72 (m, 4H, ArH), 3.98 (t, J = 7.1 Hz, 2H, CH2N), 2.82 (dt, J = 5.7, 1.2 Hz, 2H, CH2); 13C NMR (75 MHz, CDCI3, 1H decoupled) 5 199.22, 167.87, 134.00, 131.92, 123.25, 42.25, 31.61; IR (KBr) 2948, 2925, 2848, 2742, 1767, 1698, 1612, 1470, 1441, 1403, 1369, 1136, 1031, 721, cm"1. PHTN v CBr2 1,1-Dibromo-4-phthalimido-1-butene (8a). To a 500 mL, three­ necked, round-bottomed flask equipped with a 100 mL, addition funnel and a 50 mL, solid addition funnel was added CBr^ (18.7 g, 56.4 mmol) and CH2CI2 (85 mL). The resulting solution was cooled to 0 °C and PPh3 (29.6 g, 113 mmol) dissolved in CH2CI2 (50 mL) was added dropwise over 30 min. After stirring the resulting deep orange mixture for an additional 10 min at 0° C, aldehyde 7a (5.73 g, 28.2 mmol) was added over 30 min via the solid addition funnel. The dark burgundy mixture was stirred for 2h at 0 °C and then 130 concentrated in vacuo. Trituration of the solids (EtOAc, 3 x 100 mL) followed by Celite filtration of the supernatant liquid furnished the crude product as a white solid which was subjected to chromatography on silica gel (20% EtOAc / hexane elution) to afford 8a (8.72 g, 86%) as a white crystalline solid: mp 114.2-115.3 °C (50% EtOAc/hexanes); 1H NMR (300 MHz, CDCI3) 5 7.76 (m, 4H, Ar hi), 6.39 (t, J = 7.2 Hz, 1H, C=Chf), 3.73 (t, J = 6.8 Hz, 2H, NCH2), 2.44 (q, J = 7.0 Hz, 2H, CH2); 13C NMR (75 MHz, CDCI3, 1H decoupled) 5167.92, 134.46, 133.92, 131.91, 123.19, 91.44, 35.45, 32.19; IR (KBr) 3100, 3043, 3025, 2945, 1771, 1684, 1613,1403, 1365, 1248, 1133, 988, 872, 805, 792, 722, 713, 625 cm’1; HRMS calcd for C12HgNO2Br2 (M+) 356.9000, found 356.8985. (Trimethylsilyl)methylmagnesium chloride. A 1.0 L, three-necked, round-bottomed flask equipped with a 100 mL, addition funnel and condenser was charged with magnesium powder (14.1 g, 578 mmol, 50 mesh) and THF (250 mL) followed by 1,2-dibromoethane (0.80 mL, 9.28 mmol). The magnesium suspension was stirred for 10 min and chloromethyltrimethylsilane (73.3 mL, 525 mmol) was added dropwise over 2h during which exotherms resulted in a gentle reflux of the reaction mixture. Following addition, the dark reaction mixture was stirred for 4h at rt and stirring was then stopped. The mixture was allowed to stand overnight after which the solution of the title Grignard reagent was transfered under argon into a storage bottle via cannula. Titration of aliquots using 2-butanol and 1,10-phenanthroline as an indicator showed the concentration to be 1.70 M in THF and the stock solution of the Grignard reagent was storred in refrigeration (10 0C) between useage. 131 PHTN SiMe3 ^S iM e3 5-Pht halimido-2-tri methyls! Iy Imethy 1-1-tri methyls i Iy 1-2- pentene (9a). To a 500 ml_, three-necked, round-bottomed flask equipped with a 100 ml_, addition funnel was added a solution of anhydrous ZnCIg (0.47 M in THF, 98.0 ml, 45.9 mmol) via syringe. The solution was cooled to 0 °C and a solution of TMSCHgMgCI (1.69 M in THF, 54.3 ml_, 91.8 mmol) was added dropwise over 15 min via the addition funnel. The gray solution was stirred for 15 min at 0 °C and PdClg(PPhg)g (1.50 g, 2.14 mmol, 7 mol%) was added in one portion. After stirring for 15 min at 25 °C, olefin 8a (11.0 g, 30.6 mmol) in THF (60 mL) was added dropwise over 40 min via addition funnel to the black-brown reaction mixture. Stirring was continued at 25 °C for 7h whereupon the reaction mixture was poured into cold, saturated NH4CI (300 mL). Both phases were decanted into a separatory funnel and the organic phase was removed. The aqueous phase was extracted with EtgO (3 x 100 mL) and the combined organic extracts were washed with brine (2 x 200 mL), dried (MgSO^) and concentrated in vacuo. The residue was triturated with pentane and the supernatant liquid was filtered through a pad of Celite and concentrated. The crude product was purified by chromatography on silica gel (hexane - 5% EtOAc/hexane elution) to furnish the title compound (11.0 g, 96%) as a white solid: mp 57.9-58.8 °C (95% EtOH); 1H NMR (300 MHz, CDCI3) 5 7.71 (m, 4H, ArH), 4.76 (t, J =7.1 Hz, 1H, C=CH), 3.61 (t, J = 7.5 Hz, 2H, NCHg), 2.28 (q, J = 7.3 Hz, 2H, CHg), 1.44 (s, 2H, SiCH2), 1.36 (s, 2H, SiCH2), -0.02 (s, 9H, (CH3)3Si), -0.12 (s, 9H (CH3)3Si); 13C NMR (75 MHz, CDCI3, 1H decoupled) 5 168.28, 138.15, 133.66, 132.34, 123.02, 114.55, 38.09, 29.61, 132 27.86, 23.85, -0.71,-1.28; IR (KBr) 3165, 2953, 2920, 2898, 1771, 1717, 1614, 1394, 1360, 1248, 1216, 1070, 1046, 854, 718 cm"1; HRMS calcd for C20H31NO2Si2 (M+) 373.1893, found 373.1901. 4-Trimethylsilylmethyl-5-trimethylsilyl-3-penten-1-amine (1a). To a 250 mL, single-necked, round-bottomed flask containing a solution of phthalimide 9a (15.3 g, 41.0 mmol) in degassed, absolute ethanol (115 mL) was added hydrazine monohydrate (4.0 mL, 82.5 mmol) dropwise over 2 min via a syringe. The flask was fitted with a condenser and the mixture was heated at reflux for 8h during which time a white solid precipitated. Upon cooling to ambient temperature, the solid was collected by filtration and washed thoroughly with hexane. The solvents were evaporated in vacuo and the residue was triturated with hexane. Filtration of the supernatant liquid followed by solvent removal in vacuo gave a cloudy oil which was purified by bulb to bulb distillation to furnish the titile compound (9.58 g, 96%) as a clear, colorless oil: bp 40 °C, 50 ptorr; 1H NMR (300 MHz, CDCI3) 5 4.71 (t, J = 6.8 Hz, 1H, C=CH), 2.61 (t, J = 6.8 Hz, 2H, NCH2), 2.01 (q, J = 6.9 Hz, 2H, CH2), 1.44 (s, 2H, CH2Si), 1.37 (s, 2H, CH2Si), 1.09 (s, 2H, NH2), -0.02 (s, 9H, (CH3)3Si), - 0.05 (s, 9H, (CH3)3Si); 13C NMR (75 MHz, CDCI3, 1H decoupled) 5 136.54, 116.61,42.70, 33.20, 29.59, 23.85, -0.70, -1.16; IR (film) 3371,3292, 3018, 2953, 2921,2896, 1645, 1415, 1247, 1158, 1066, 837, 698, 624 cm"1; HRMS calcd for C^2H23NSi2 (M+) 243.1839, found 243.1850. SiMe3 133 P H T N ^ ^ Y ^O CH3 2-Methyl-3-phthalimidopropionaldehyde (7b). A 200 mL, three­ necked, round-bottomed flask equipped with a 25 mL, addition funnel was charged with absolute EtOH (60 mL) and freshly cut sodium metal (230 mg, 10.0 mmol) was added. The mixture was stirred until complete consumption of the Na was observed (10 min). Phthalmide (17.6 g, 120 mmol) was added in one portion and the white suspension was stirred for 10 min. An ethanolic solution of freshly distilled methacrolein (8.27 mL, 100 mmol in 10 mL EtOH) was added dropwise over 20 min via the addition funnel and the mixture was stirred at 25 0C for 6h. The reaction mixture was treated with glacial acetic acid (2 mL), stirred for 5 min and filtered through a pad of Celite to produce a sticky white solid upon evaporation of solvent. The solid was dissolved in toluene (50 mL) and eluted through a silica gel plug (toluene for elution) to give 7b (16.0 g, 74%) as a dry white powder upon pulverization: mp 83.8-85.3 0C (50% EtOAc/hexanes); 1H NMR (300 MHz, CDCI3) 5 9.63 (d, J = 1.3 Hz, 1H, O=CH), 7.66 (m, 4H, ArH), 3.91 (dd, J = 14.1,7.2 Hz, 1H, NCHH), 3.69 (dd, J = 14.1, 6.5 Hz, IH, NCHH), 2.78 (dsx, J = 7.0, 1.3 Hz, 1H, CH), 1.05 (d, J = 7.2 Hz, 3H, CH3); 13C NMR (75 MHz, CDCI3, 1H decoupled) 5 201.89, 167.90, 133.88, 131.59, 123.09, 45.51,37.90, 11.32; IR (KBr) 3099, 2975, 2939, 2881,2758, 1774, 1694, 1611, 1464, 1435, 1398, 1357, 1041, 897, 721 cm'1. PHTN """vY ^ C B r 2 CH3 1,1-Dibromo-3-methyl-4-phthalimido-1-butene (8b). Utilizing the procedure used for the preparation of olefin 8a, aldehyde 7b (10.0 g, 46.0 134 mmol) was converted into the the title compound (15.3 g, 89%) which was isolated as a white, crystalline solid: mp 104.1-106.5 0C (20% EtOAc/hexanes); 1H NMR (300 MHz, CDCI3) 5 7.73 (m, 4H, ArH), 6.22 (d, J = 9.7 Hz, 1H, C=CH), 3.58 (m, 2H, CH2N), 2.97 (m, 1H, CM), 1.04 (d, J = 6.8 Hz, 3H, CH3)] 13C NMR (75 MHz, CDCI3, 1H decoupled) 5 168.02, 140.53, 133.92, 131.92, 131.83, 123.20, 89.85, 41.69, 37.94, 16.61; IR (KBr) 3132, 2974, 2938, 1769, 1716, 1615, 1436, 1395, 1053, 720, 711, 626, cm’ 1; HRMS calcd Io rC 13H11Br2NO2 (M+) 370.9156, found 370.9162. 4-Methyl-5-phthalimido-2-trimethy Isi Iy I methyl-1 -tr imethy Isi Iyl- 2-pentene (9b). The title compound was prepared employing the procedure used for the preparation of 9a. From olefin 8b (6.0 g, 16.1 mmol), phthalimide 9b (5.32 g, 85%) was obtained as a white solid: mp 92.0-93.1 0C (95% EtOH); 1H NMR (300MHz, CDCI3) 5 7.73 (m, 4H, ArH), 4.61 (d, J = 9.4, Hz, IH, C=CH), 3.47 (m, 2H, NCHa), 1.63 (d, J = 13.4 Hz, 1H, CHHSi), 1.31 (app p, J = 13.4 Hz, 3H, CHHSi and CH2Si), 0.90 (d, J = 6.6 Hz, 3H, CH3), -0.01 (s, 9H, (CH3)3Si), - 0.11 (s, 9H, (CH3)3Si); 13C NMR (75 MHz, CDCI3, 1H decoupled) 5 168.55, 136.77, 133.69, 132.23, 123.07, 122.07, 43.97, 32.12, 29.42, 23.60, 18.79, - 0.69, -1.21; IR (KBr) 3099, 2981, 2949, 2890, 1766, 1707, 1613, 1396, 1381, 1251, 1073, 1046, 866 , 729, cm’ 1; HRMS calcd for C21 H33NO2Si2 (M+) 387.2050, found 387.2043. 135 H2N SiMe3 CH3 k SiMe3 2-Methyl-4-tri methyls! Iy Imethy l-5-trimethy Isi Iy l-3-penten-1- amine (1b). Using the procedure previously described for the preparation of 1a, phthalimide 9b (2.5 g, 6.45 mmol) was deprotected to yield amine Ib (1.51 g, 91%) as clear colorless oil after bulb to bulb distillation: bp 70-73 0C1 50 litorr; 1H NMR (300 MHz, CDCI3) 5 4.49 (d, J = 9.5 Hz, IH, C=Chf), 2.50 (dd, J = 12.1,5.8 Hz, 1H, NCHH), 2.36 (dd, J = 12.2, 7.9 Hz, 1H, NCHH), 2.19 (m, 1H, Chf), 1.62 (d, J = 13.5 Hz, 1H, CHHSi), 1.36 (ABq, Av = 33.0 Hz, J = 13.5 Hz, 2H, CH2Si), 1.29 (d, J = 13.5 Hz, 1H, CHHSi), 1.02 (s, 2H, NH2), 0.85 (d, J = 6.4 Hz, 3H, CH3), -0.01 (s, 9H, (CH3)3Si), -0.04 (s, 9H, (CH3)3Si); 13C NMR (75 MHz, CDCI3, 1H decoupled) 6 135.31, 124.01, 49.22, 36.55, 29.47, 23.86, 18.72, - 0.69, -1.13; IR (film) 3380, 3301, 2954, 2924, 2897, 2869, 1644, 1455, 1416, 1248, 1159, 1068, 943, 867, 698, 624, cm"1; HRMS calcd for C13H31NSi2 (M+) 257.1995, found 257.1987. 3-Phthalimidobutanal (7c). The preparation of 7c was carried out as described for 7b employing freshly distilled crotonaldehyde (16.6 mL, 200 mmol) and a reaction time of 24h at 25 0C to provide the title compound (19.7 g, 45%) as a white solid: mp 112.2-113.9 0C (50% EtOAc/hexanes); 1H NMR (300 MHz, CDCI3) 5 9.66 (s, 1H, O=CH), 7.67 (m, 4H, ArH), 4.82 (app sx, J = 7.1 Hz, 1H, CH), 3.22 (dd, J = 18.0, 8.2 Hz, 1H, O=CHCHH), 2.94 (dd, J = 18.0, 6.2 Hz, 1H, O=CHCHH), 1.41 (d, J = 6.9 Hz, 3H, CH3); 13C NMR (75 MHz, CDCI3, 1H decoupled) 5 199.08, 167.80, 133.81, 131.69, 123.00, 47,17, 41.27, 18.63; IR CH3 PHTN O 136 (KBr) 3 044 , 2 9 8 6 , 2 9 26 , 2 8 67 , 2 7 55 , 1771 , 1699 , 1611 , 1472 , 1395 , 1360 , 1333 , 1305 , 1145 , 1134 , 1 0 3 1 ,8 8 2 , 720 , CrrV1. 1 ,1 -D ib ro m o -4 -p h th a lim id o -1 -p e n te n e (8 c ). The reaction of aldehyde 7c (2.37 g, 10.9 mmol) with CBr^ and PPhg was carried out as described previously for the preparation of 8a to yield the title compound (4.00 g, 98%) as a white crystalline solid: mp 64.2-65.1 0C (20% EtOAc/hexanes); 1H NMR (300MHz, CDCI3) 5 7.71 (m, 4H, ArH), 6.30 (t, J = 7.3 Hz, 1H, C=CH), 4.41 (app sx, J = 6.8 Hz, 1H, NCH), 2.79 (app dt, J = 15.6, 8.3Hz, 1H, CHHCH=C), 2.52 (app dt, J = 15.0, 6.5 Hz, 1H, CHHCH=C), 1.47 (d, J = 6.9 Hz, 3H, CH3); 13C NMR (75 MHz, CDCI3, 1H decoupled) 5 168.00, 134.61, 133.85, 131.74, 123.07, 91.25, 45.55, 37.70, 18.19; IR (KBr) 3058, 2997, 2939, 2974, 1770, 1716, 1614, 1394, 1370, 1356, 1083, 1044, 795, 785, 717, cm'1; HRMS calcd for C13H11 Br2NO2 (M+) 370.9156, found 370.9157. 5 -P h th a l im id o -2 - t r im e th y ls i ly lm e th y l- 1 - t r im e th y ls i ly l -2 -h e x e n e (9c ). Using the procedure described previously for the preparation of 9a, dibromo olefin 8c (15.0 g, 40.2 mmol) was converted into the title compound (14.6 g, 94%) which was isolated as a white crystalline solid: mp 68.9-70.2 0C (95% EtOH); 1H NMR (300 MHz, CDCI3) 5 7.69 (m, 4H, ArH), 4.67 (app t, J = 7.0 Hz, IH, C=CH), 4.31 (m, 1H, NCH), 2.71 (dt, J = 14.7, 8.8 Hz, 1H, C=CHCHH), CH3 PHTN CBr2 CH3 SiMe3 137 2.31 (dt, J = 14.7, 6.1 Hz, 1H, C=CHCHH), 1.57 (d, J = 13.3 Hz, 1H, CHHSi), 1.42 (d, J = 6.9 Hz, 3H, CH3), 1.28 (ABq, Av = 29.3 Hz, J = 13.3 Hz, 2H, CH2Si), 1.26 (d, J = 13.3 Hz, 1H, C=CHHSi), -0.02 (s, 9H, (CH3)3Si), -0.26 (s, 9H, (CH3)3Si); 13C NMR (75 MHz, CDCI3, 1H decoupled) 5 168.42, 137.92, 133.57, 132.24, 122.89, 115.31,47.82, 33.36, 29.58, 24.02, 18.45, -0.63, -1.45; IR (KBr) 2970, 2952, 2894, 1767, 1696, 1614, 1467, 1394, 1374, 1165, 1077, 1169, 848, 722 cm"1; HRMS calcd for C21H33NO2Si2 (M+) 387.2050, found 387.2049. H9N" ^ 'S iMe3 SiMe3 5 -T r im e th y ls i ly lm e th y l-6 - t r im e th y ls i ly l -4 -h e x e n -2 -a m in e (1 c ). Employing the procedure for the preparation of 1a, phthalimide 9c (14.6 g, 37.7 mmol) was converted into the title amine (8.93 g, 92%) which was isolated as a clear colorless oil after bulb to bulb distillation: bp 65-75 0C, 50 ptorr; 1H NMR (300 MHz, CDCI3) 5 4.77 (t, J = 7.2 Hz, 1H, C=CH), 2.82 (app sx, J = 6.3 Hz, 1H, CM), 1.89 (app t, J = 7.4 Hz, 2H, CH2), 1.45 (ABq, Av = 33.3 Hz, J = 13.3 Hz, 2H, CH2Si), 1.38 (s, 2H, CH2Si), 1.16 (s, 2H, NH2), 1.01 (d, J = 6.2 Hz, 3H, CH3), - 0.02 (s, 9H, (CH3)3Si), -0.03 (s, 9H, (CH3)3Si); 13C NMR (75 MHz, CDCI3, 1H decoupled) 5 136.73, 116.43, 47.74, 39.55, 29.67, 23.93, 23.51,-0.65, -1.08; IR (film) 3365, 3289, 2955, 2923, 2896, 1645, 1453, 1412, 1248, 1156, 1056, 1066, 833, 699, 624 cm '1; HRMS calcd for C12H28NSi2 (M+-CH3) 242.1760, found 242.1760. 138 O E -4 -7 e r f -b u ty Id im e th y ls i ly lo x y -2 -b u te n e -1 -o n e (1 0 ). To a 500 mL, single-necked, round-bottomed flask containing a vigorously stirred solution of c/'s-2-butene-1,4-diol (33.0 mL, 0.40 mol) and imidazole (27.2 g, 0.40 mol) in DMF (200 mL) was added a solution of terf-butyldimethylsilyl chloride (30.1 g, 0.20 mol) in DMF (40 mL) dropwise over 1.5h via a 100 mL, addition funnel. Stirring was continued for 6h and the reaction mixture was slowly poured into cold brine (700 mL). The aqueous mixture was extracted with three portions of hexane (250 mL) and the combined extracts were washed twice with brine (300 mL), dried over NagSO^. and filtered through a pad of silica gel (EtgO for elution). Removal of the solvents in vacuo furnished a mixture (85:15 by NMR) of the mono and bis te/t-butyldimethylsilyl ethers which was used in the next step without further purification. A 500 mL, single-necked, round-bottomed flask containing a solution of the tert-butyldimethylsilyl ethers in CHgCIg (200 mL) was cooled to 0 0C and pyridinium chlorochromate (43.1g, 0.20 mmol) was added in one portion during which time vigorous stirring of the reaction mixture was maintained. The mixture was stirred at 0 0C for 0.5h then at room temperature for 2h. The black reaction mixture was diluted with pentane (200 mL), filtered through a pad of silica gel (EtgO for elution) and concentrated in vacuo. The residue was subjected to chromatography on silica gel (5% EtOAc/hexane for elution) to furnish the title enone (19.8 g, 49% from c/s-butene-1,4-diol) as a colorless oil: 1H NMR (300 MHz, CDCI3) 5 9.57 (d, J = 8.0 Hz, 1H, O=CH), 6.85 (dt, J = 15.5, 3.3 Hz, 1H, HC=CH), 6.37, (ddt, J = 15.5, 8.0, 2.3 Hz, 1H, HC=CH), 4.42 (dd, J = 3.1, 2.0 Hz, 2H, OCH2), 0.88 (s, 9H, (CH3)3CSi), 0.06 (s, 6H, (CH3)2Si); 13C 139 NMR (75 MHz, CDCI3, 1H decoupled) 5 193.12, 156.11, 130.65, 62.25, 25.79, 18.30, -5.47. 4 -7 e r f -b u ty ld im e th y ls i ly lo x y -3 -p h th a lim id o b u ta n a l (7 d ). To a 100 ml_, single-necked, round-bottomed flask containing a solution of enone 10 (5.00 g, 25.0 mmol) in DMF (50 mL) was sequentially added phthalimide (4.41 g, 30.0 mmol) in one portion and DBU (374 pL, 2.50 mmol). The resulting homogeneous reaction mixture was stirred for 2h at rt and was then poured into H3O (100 mL). The aqueous mixture was extracted with three portions of Et3O (40 mL) and the combined extracts were dried (MgSO^), filtered and concentrated. Purification of the residue by silica gel chromatography (10% EtOAc/hexane for elution) furnished the title aldehyde (6.00 g, 70%) as a colorless viscous material which solidified upon cold storage: 1H NMR (300 MHz, CDCI3) 5 9.73 (s, 1H, O=CH), 7.80-7.24 (m, 4H, ArH), 4.86 (dp, J = 7.5, 2.2 Hz, 1H, NCH), 3.86 (dd, J = 7.7, 3.2 Hz, 2H, SiOCH3), 3.22 (ddd, J = 17.8, 8.3, 1.3 Hz, IH, CHH), 2.99 (ddd, J = 17.9, 6.1, 1.0 Hz, 1H, CHH), 0.75 (s, 9H, (CH3)3CSi), -0.02 (s, 3H, CH3Si), -0.07 (s, 3H, SiCH3); 13C NMR (75 MHz, CDCI3, 1H decoupled) 5 198.92, 168.16, 133.99, 131.79, 123.19, 62.30, 47.53, 42.89, 25.61, 17.96, -5.58, -5.64; IR (film) 3062, 2942, 2857, 1774, 1701, 1613, 1470, 1366, 1228, 1115, 1036, 835, 779, 721, CrrT1. NPHT TBDMSO 140 NPHT TBDMSO CBr2 5 -7 e r f -b u ty ld im e th y ls i ly lo x y -1 ,1 -d ib r o m o -4 -p h th a l im id o -1 - pen ten e (8d ). Following the procedure outlined for the preparation of 8a, aldehyde 7d (5.20 g, 15.0 mmol) was converted into the title compound. In this instance, the crude product was isolated by pentane trituration of the residue obtained after concentration of the reaction mixture. The pentane solution was filtered through Celite (pentane for elution), concentrated and the crude product was purified by chromatography on silica gel (5% EtOAc/hexane for elution) to furnish the title compound (6.64 g, 88%) as a white wax: mp 39.2-49.8 0C; 1H NMR (300 MHz, CDCI3) 5 7.82-7.68 (m, 4H, ArH), 6.35 (t, J = 7.1 Hz, 1H, C=CH), 4.41 (m, 1H, NCH), 3.99 (dd, J = 10.0, 8.3 Hz, 1H, SiOCHH), 3.86 (dd, J = 10.0, 6.7 Hz, IH, SiOCHH), 2.79 (ddd, J = 17.0, 9.6, 7.5 Hz, 1H, CHH) 2.57 (ddd, J = 15.4, 6.9, 5.5 Hz, 1H, CHH), 0.73 (s, 9H, (CH3)3CSi), -0.02 (s, 3H, CHsSi), -0.09 (s, 3H, SiCH3); 13C NMR (75 MHz, CDCI3, 1H decoupled) 8 168.35, 134.36, 133.97, 131.83, 123.18, 91.35, 62.25, 52.00, 32.70, 25.60, 17.90, -5.52, -5.61; IR (film) 3030, 2942, 2857, 1776, 1706, 1614, 1469, 1372, 1258, 1113, 838, 780, 721 cm"1; HRMS calcd for C19H2SBr2NO3Si (M+) 500.9970, found 500.9968. 1 -7 e r f -b u ty Id im e th y Is ily lo x y -2 -p h th a l im id o -5 - t r im e th y I- s ily Im e th y l-6 - t r im e th y Is ily l-4 -h e x e n e (9 d ). Using dibromo olefin 8d (5.03 g, 10.0 mmol) in the procedure described for the preparation of 9a NPHT 141 produced the title compound (4.90 g, 95%) which was obtained as a colorless, viscous gel: 1H NMR (300 MHz, CDCI3), 5 7.79-7.64 (m, 4H, ArH), 4.69 (t, J = 7.0 Hz, 1H, C=CH), 4.34 (m, 1H, NCH), 4.01 (t, J = 9.9 Hz, 1H, SiOCHH), 3.81 (dd, J = 9.9, 5.5 Hz, 1H, SiOCHH), 2.65 (ddd, J = 17.9, 9.0, 5.9 Hz, 1H, CHH), 2.37 (dt, J = 14.8, 6.4 Hz, 1H, CHH), 1.57 (d, J = 13.3 Hz, 1H, SiCHH), 1.35 (d, J = 13.4 Hz, IH, SiCHH), 1.26 (dd, J = 13.5, 3.5 Hz, 2H, SiCH2), 0.73 (s, 9H, (CH3)3CSi), -0.01, (s, 9H, (CH3)3Si), -0.03 (s, 3H, (CH3)3CSiCH3),-0.01 (s, 3H, (CH3)3CSiCH3), -0.25 (s, 9H, Si(CH3)3); 13C NMR (75MHz, CDCI3, 1H decoupled) 8 168.69, 138.15, 133.60, 132.20, 122.88, 114.49, 62.70, 54.32, 29.62, 28.07, 25.65, 24.03, 17.97, -0.64, -1.44. -5.57; IR (film) 3060, 2953, 2857, 1776, 1716, 1645, 1614, 1470, 1372, 1248, 1111, 836, 777, 720 cm"1; HRMS calcd for C27H47NO3Si3 (M+) 517.2864, found 517.2845. TBDMSO 1 -T e r f -b u ty Id im e th y Is ily lo x y -5 - t r im e th y Is i Iy Im e th y I-6 - t r im e th y ls ily l-4 -h e x e n -2 -am in e ( Id ) . The procedure used for the preparation of amine 1a was followed employing phthalimide Gd (4.66 g, 9.00 mmol), hydrazine monohydrate (1.75 mL, 36.0 mmol) and a reaction time of 24h at reflux. In this instance, the crude isolated product was purified by elution through a plug of silica gel (Et2O for elution) to yield the title compound (3.28 g, 94%) as a colorless oil: 1H NMR (300 MHz, CDCI3) 8 4.77 (t, J = 7.3 Hz, 1H, C=CH), 3.55 (dd, J = 9.7, 4.1 Hz, 1H, SiOCHH), 3.33 (dd, J = 9.6, 7.1 Hz, 1H, SiOCHH), 2.77 (p, J = 6.8 Hz, 1H, NCH), 1.95 (m, 2H, CH2 ) 1.46 (dd, J = 20.3, 142 13.4 Hz, 2H, SiCH2), 1.39 (s, 2H, SiCH2), 1.29 (br s, 2H, NH2), 0.87 (s, 9H, (CH3)3 CSi), 0.02 (s, 6H, (CH3 )3CSi(CH3)2), -0.01 (s, 9H, (CH3)3Si), -0.02 (s, 9H, Si(CH3)3); 13C NMR (75 MHz, CDCI3, 1H decoupled) 5 137.06 115.75, 67.99, 53.73, 33.42, 29.69, 25.49, 23.95, 18.29, -0.64, -1.05, -5.34; IR (film) 3382, 2954, 2857, 1645, 1470, 1248, 1096, 837, 775, 699, cm '1; HRMS calcd for C19H46NOSi3 (HM+) 388.2887, found 388.2881. ^CHg PHTN ^ 5 -P h th a lim id o -l -p en ten e (56 ). To 200 mL, single-necked, round- bottomed flask containing a vigorously stirred suspension of potassium phthalimide (11.6 g, 62.6 mmol) in DMF (50 mL) was added 5-bromo-1-pentene (5.92 mL, 50.0 mmol) followed by anhydrous Nal (375 mg, 2.50 mmol). The white suspension was stirred for 18h at 25 0C. The mixture was poured into half-saturated, aqueous NaCI (100 mL) and the aqueous mixture was extracted with EtgO (3 x 50 mL). The combined extracts were washed with brine (100 mL), dried over anhydrous MgS04 and filtered through a plug of silica gel (EtgO for elution). The resulting solution was concentrated in vacuo to afford 5- phthalimido-1 -pentene72 (11.0 g, 100%) as a white solid. 4 -P h th a lim id o b u ta n a l (57 ). To a 250 mL, single-necked, round- bottomed flask containing a biphasic mixture of alkene 56 (4.30 g, 20.0 mmol) in 1:1 EtgO/HgO (100 mL) was added Os0 4 (254 mg, 1.00 mmol) in one portion and the resulting dark brown mixture was stirred for 10 min. Sodium periodate (9.41 g, 44.0 mmol) was added over 40 min via a solid addition funnel during 143 which time mild exotherms were observed. Following the addition, the reaction mixture was stirred vigorously for 2h and the organic layer was separated. The remaining aqueous phase was extracted with EtgO (2 x 25 mL) and the combined organic fractions were washed with brine (2 x 30 mL), dried over anhydrous MgSCM and filtered. Silica gel (5 mL) was added to the solution, the mixture was concentrated and the resulting tan colored, silica gel support was loaded on top of a column of silica gel. The column was eluted with EtgO to afford the known, title compound72 (4.00 g, 92%) as a white solid upon removal of solvent in vacuo. PHTN CBr2 1 ,1 -D ib ro m o -5 -p h th a l im id o -1 -p e n te n e (5 8 ). Utilizing the general procedure described for the preparation of olefin 8a, aldehyde 57 (3.95 g, 18.2 mmol) was converted into the title compound (6.09 g, 90%) which was obtained as a white crystalline solid after purification of the crude product by silica gel chromatography (toluene then 10% EtOAc/hexanes for elution): mp 115.3- 117.0 0C (20% EtOAc/hexanes); 1H NMR (300 MHz, CDCI3) 5 7.82 (m, 2H, ArH), 7.71 (m, 2H, ArH), 6.42 (t, J = 7.2 Hz, 1H, C=CH), 3.70 (t, J = 7.1 Hz, 2H, CH2N), 2.15 (q, J = 7.3 Hz, 2H, CHgC=C), 1.81 (t, J = 7.2 Hz, 2H, CH2); 13C NMR (75 MHz, CDCI3, 1H decoupled) 5 168.22, 137.06, 133.94, 131.99, 123.21,89.84, 37.17, 30.33, 26.56; IR (film) 3065, 3030, 2968, 2932,1771, 1714, 1614, 1465, 1438, 1398, 1335, 1227, 1070, 1039, 894, 832, 783, 723 cm' 1; HRMS calcd for C13H1 Br2NO2 (M+) 370.9156, found 370.9150. 144 PHTN SiMe3 SiMe3 6-Phthalimido-2-tri met hy Isi Iy Imethy I - I -trimethy Isi Iy l-2-hexene (59 ). The title compound was prepared employing the general coupling procedure used for the preparation of 9a. From olefin 58 (7.00 g, 18.8 mmol), phthalimide 59 (5.79 g, 83%) was obtained as a white solid after purification of the crude material by silica gel chromatography (hexanes - 1% EtOAc/hexanes for elution): mp 65.3-66.4 0C (95% EtOH); 1H NMR (300 MHz, CDCI3) 5 7.81 (m, 2H, ArH), 7.67 (m, 2H, ArH), 4.79 (t, J = 7.0, Hz, 1H, C=CH), 3.65 (t, J = 7.6 Hz, 2H, NCH2), 1.94 (q, J = 7.2 Hz, 2H, CHgC=C), 1.65 (p, J = 7.7 Hz, 2H, CH2), 1.42 (s, 2H, CH2Si), 1.36 (s, 2H, CH2Si), -0.02 (s, 18H, Si(CHg)S x 2); 13C NMR (75 MHz, CDCI3, 1H decoupled) 5 168.13, 135.26, 133.63, 132.14, 122.95, 117.97, 37.78, 29.33, 29.13, 26.09, 23.66, -0.76, -1.19; IR (film) 2949, 2888, 1771, 1717, 1615, 1398, 1373, 1245, 1039, 1046, 949, 837, 720 cm"1; HRMS calcd for C21H33NO2Si2 (M+) 387.2050, found 387.2045. 5 -T r im e th y ls i ly lm e th y l-6 - t r im e th y ls i ly l -4 -h e x e n -1 -a m in e (5 4 ). Using the procedure previously described for the deprotection of phthalimide 9a , phthalimide 59 (5.00 g, 12.9 mmol) was deprotected to yield amine 54 (3.18 g, 96%) as clear colorless oil after bulb to bulb distillation: bp 61-67 0C1 250 [itorr; 1H NMR (300 MHz, CDCI3) 5 4.76 (t, J = 7.0 Hz, 1H, C=CH), 2.66 (t, J = 7.2 Hz, 2H, NCHg), 1.91 (q, J = 7.2 Hz, 2H, CHgC=C), 1.43 (p, J = 7.3 Hz, 2H, CHg), 1.42 (s, 2H, CHgSi), 1.36 (s, 2H, CH2Si), 1.05 (s, 2H, NH2), 0.00 (s, 9H, SiMe3 1 4 5 (CH3)3Si), -0.03 (s, 9H, (CH3)3Si); 13C NMR (75 MHz, CDCI3, 1H decoupled) 6 134.35, 119.06, 41.95, 34.49, 29.29, 25.94, 23.62, -0.74, -1.21; IR (film) 3377, 3300, 3018, 2953, 2921,2849, 1645, 1412,1247, 1158, 1068, 847, 698, 624, cm"1; HRMS calcd for C13H31 NSi2 (M+) 257.1995, found 257.1990. 146 2-Propylidene-1,3-bis(silane) Imine Cyclizations General Information: Titanium tetrachloride was distilled under an atmosphere of nitrogen and was stored as a stock solution in toluene (1.0 M) under an argon atmosphere. All aldehydes were provided by commercial suppliers and were distilled under argon prior to use. Molecular sieves (4 A) were activated by flame drying under high vacuum. /V -(2 -m e th y Ip ro p y I id e n e ) -4 - t r im e th y Is ily Im e th y I-5 - t r im e th y ls ily l-3 -p e n te n -1 -am in e (1 1 a ). The following serves as a general experimental procedure used for the preparation of imines. To a 10 mL, single­ necked, round-bottomed flask containing a solution of amine 1a (300 mg, 1.23 mmol) in THF (3.5 mL) was added activated 4A molecular sieves (700 mg) followed by freshly distilled isobutyraldehyde (134 pL, 1.48 mmol) and the solution was stirred for 12h at rt. The reaction mixture was diluted with EtgO (3 mL) and filtered through a Celite pad. Evaporation of solvents and excess aldehyde in vacuo afforded imine 11a (364 mg, 99%) as a colorless oil which was used immediately in the next step: 1H NMR (300 MHz, CDCI3) 8 7.47 (d, J = 5.0 Hz, 1H, N=CH), 4.73 (t, J = 7.0 Hz, 1H, C=CH), 3.28 (t, J = 7.4 Hz, 2H, NCH2), 2.38 (m, 1H, CH(CH3)2), 2.17 (q, J = 7.3 Hz, 2H, CH2), 1.45 (s, 2H, CH2Si), 1.36 (s, 2H, CH2Si), 1.04 (d, J = 6.9 Hz, 6H, (CH3)2CH), 0.00 (s, 9H, (CH3)3Si), -0.04 (s, 9H, (CH3)3Si); 13C NMR (75 MHz, CDCI3, 1H decoupled) 5 169.30, 135.69, 116.68, 61.84, 33.92, 30.46, 29.48, 23.91, 19.38, -0.65, -1.14; 147 IR (film) 2956, 2894, 2829, 1669, 1646, 1464, 1247, 1156, 1064, 854, 698, 624 cm"1. 7 > a n s -A /- to s y l-2 - is o p ro p y l-3 - [ (3 - t r im e th y ls i ly l ) is o p ro p e n y l] p y rro lid in e (15a ). The following represents the general experimental procedure used for the preparation of pyrrolidines from the corresponding imines. A 25 mL, single-necked, round-bottomed flask containing a solution of freshly prepared imine 11a (364 mg, 1.22 mmol) in CHgCIg (8 mL) was cooled to -78 °C and treated dropwise over 2 min with TiCI^ (1.22 mL, 1.22 mmol of a 1.0 M toluene solution) via syringe. The resulting deep orange solution was allowed to gradually warm to room temperature (2-3h) after which stirring was maintained for an additional 2h. The reaction mixture was transferred dropwise via cannula into vigorously stirred, saturated aqueous KHCOg (16 mL) at 0 °C and the diphasic mixture was stirred for 30 min at rt. The organic layer was removed and the aqueous layer was extracted with CHgCIg (2x10 mL). The combined organic phases were then dried with NagSO^ The residual oil was dissolved in pentane (10 mL), filtered through a Celite pad and concentrated to furnish pyrrolidine 14a (272 mg, 98%) as a colorless oil with no additional purification required: 1H NMR (300 MHz, CDCI3) 8 4.64 (s, 1H, C=CHH), 4.56 (s, 1H, C=CHH), 3.44 (br s, IH, NH), 2.94 (t, J = 6.9Hz, 2H, CH2N), 2.80 (dd, J = 6.9, 6.0 Hz, 1H, CHN), 2.27 (q, J = 7.5 Hz, 1H, CHC=C), 1.92 (m, 1H, CH(CH3)2), 1.66 (m, 2H, CH2), 1.49 (s, 2H, CH2Si), 0.92 (d, J = 7.5 Hz, 3H, 148 CH3CHCH3), 0.90 (d, J = 7.5 Hz, CH3CHCH3), -0.02 (s, 9H, (CH3)3Si); 13C NMR (75 MHz, CDCI3, 1H decoupled) 5 149.20, 107.29, 68.75, 50.12, 45.75, 33.09, 31.17, 25.73, 20.80, 18.02, -1.06; IR (film) 3312, 3077, 2955, 2896, 1629, 1467, 1418, 1383, 1365, 1248, 1161, 852 cm-1 . For purposes of complete and accurate characterization as well as NOE analysis, the pyrrolidine was converted to the corresponding AMosyIate 15a. A 5.0 mL, single-necked, round-bottomed flask containing a solution of pyrrolidine 14a (100 mg, 0.44 mmol) and pyridine (108 p i, 1.32 mmol) in CH3CI3 (2.5 m l) was cooled to 0 °C and TsCI (105 mg, 0.55 mmol) was added in one portion. The mixture was stirred at 0,°C for 2h followed by an additional 2h at rt. Distilled H3O (2.0 m l) was added and the biphasic mixture was stirred vigorously for 1h. The organic layer was removed and the aqueous phase was extracted with CH3CI3 (3 x 1 ml). The combined organic phases were dried (Na3SO .^), concentrated in vacuo and the residue was eluted through a silica gel plug (5% EtOAc / hexane) to afford the purified AMosyIate 15a (142 mg, 85%) as a colorless, viscous oil: 1H NMR (300 MHz, C3D3) 5 7.82 (d, J = 8.1 Hz, 2H, ArH), 6.83 (d, J = 7.7 Hz, 2H, ArH), 4.32 (s, 1H, C=CHH), 4.25 (s, 1H, C=CHH), 3.74 (t, J = 4.4 Hz, 1H, CHN), 3.43 (dt, J = 10.7, 6.8 Hz, 1H, NCHH), 3.21 (dt, J = 10.7, 6.8 Hz, 1H, NCHH), 2.50 (m, 1H, CH(CH3)3), 2.34 (app q, J = 6.4 Hz, 1H, CHC=C), 1.95 (s, 3H, ArCH3), 1.46 (m, 1H, CHH), 1.25 (d, J = 14.3 Hz, 1H, CHHSi), 1.19 (m, 1H, CHH), 1.07 (d, J = 14.3 Hz, 1H, CHHSi), 1.00 (d, J= 7.0 Hz, 6H, (CH3)3CH), -0.07 (s, 9H, (CH3)3Si); 13C NMR (75 MHz, CDCI3, 1H decoupled) 6 147.20, 142.98, 135.60, 129.33, 127.61, 107.88, 68.77, 48.72, 47.45, 33.01,30.40, 24.75, 21.34, 19.40, 17.08, -1.29; IR (film) 3084, 3029, 149 2958, 2892, 2875, 1632, 1599, 1466, 1347, 1248, 1159, 1096, 1004, 853, 662 crrT1; HRMS calcd for C2QH33NO2SSi (M+) 379.2001, found 379.1986. Me3Si Rh Me3Si W -B en zy Ii d e n e -4 - t r I m e th y Is i Iy Im e th y l -5 - t r im e th y Is i Iy I-3 - p en ten -1 -am in e (11h ). The procedure previously described for the preparation of imine 11a was followed using benzaldehyde (126 pL, 1.24 mmol) and amine I a (250 mg, 1.03 mmol) resulting in the title compound (329 mg, 96%) which was obtained as a clear, colorless oil: 1H NMR (300 MHz, CDCI3) 5 8.24 (s, 1H, N=CH), 7.70 (m, 2H, ArH), 7.38 (m, 3H, ArH), 4.80 (t, J = 7.1 Hz, IH, C=CH), 3.57 (dt, J = 7.4, 1.0 Hz, 2H, CH2N), 2.31 (q, J = 7.3 Hz, 2H, CH2), 1.48 (s, 2H, CH2Si), 1.38 (s, 2H, CH2Si), 0.02 (s, 9H, (CH3)3Si), -0.05 (s, 9H, (CH3)3Si); 13C NMR (75 MHz, CDCI3, 1H decoupled) 5 160.63, 136.50, 136.04, 130.33, 128.48, 128.06, 116.57, 62.31,30.48, 29.53, 23.93, -0.65, - 1.18; IR (film) 3063, 3026, 2953, 2895, 2832, 1647, 1450, 1310, 1156, 1063, 852, 753, 694, 624 cm"1. Cis and f r a n s - /V - to s y l-2 -p h e n y l-3 - [ (3 - t r im e th y ls i ly l ) - is o p ro p e n y l]p y r ro lid in e (1 5 h c /s , 1 S h fra n s ). Using imine 11h (260 mg, 0.78 mmol) in the general cyclization procedure described for the preparation of 15a, an inseparable mixture of pyrrolidines 1 4 h c js and H h tran s (201 mg, 150 99%, 1.7 : 1.0 by NMR) was obtained as a colorless oil. Treatment of the mixture with TsCI as previously described furnished the purified, title AMosyIates (276 mg, 86%, 1.7 : 1.0 by NMR) as a viscous, colorless oil. A pure sample of the cis isomer was obtained via fractional crystallization (hexane) of the mixture and crystals suitable for X-ray analysis were recovered from recrystallization (10% EtgO / hexane): C/s-AMosyl-2-phenyl-3-[(3-trimethylsilyl)isopropenyl]- pyrrolidine (15hc/s). mp 107.2-109.3; 1H NMR (300 MHz, C6D6) 5 7.68 (d, J = 8,2 Hz, 2H, SO2ArH), 7.06 (m, 5H, ArH), 6.74 (d, J = 8.1 Hz, 2H, SO2ArH), 5.15 (d, J = 7.6 Hz, ,1H, NCH), 4.28 (s, 1H, C=CHH), 4.09 (s, 1H, C= CHH), 3.52 (appt, J = 9.0 Hz, 1H, NCHH), 3.31 (ddd, J = 10.6, 10.6, 6.7 Hz, 1H, NCHH), 2.26 (ddd, J= 13.1,6.4, 6.4 Hz, 1H, CHC=C), 1.89 (s, 3H, ArCH3), 1.74 (m, 1H CHH), 1.28 (dd, J = 12.1,6.0 Hz, 1H, CHH), 1.18 (ABq, Av = 41.6 Hz, J = 13.7 Hz, 2H, CH2 Si), -0.18 (s, 9H, (CH3)3 Si); 13C NMR (75 MHz, CDCI3 1H decoupled) 5 143.08, 142.32, 139.10, 135.54, 129.37, 127.51, 127.45, 126.99, 109.70, 65.07, 51.70, 47.54, 27.18, 26.53, 21.36, -1.56;, IR (film) 3086, 3063, 3031,2953,2889, 1636, 1599,1495, 1454, 1346, 1248, 1160, 1097, 1015, 841, 736, 703, 666 cm"1; HRMS calcd for C23H31NO2SSi (M+) 413.1845, found 413.1857. 7ra/7S-AMosyl-2-phenyl-3-[(3-trimethylsilyl)isopropenyl]- pyrrolidine (1 Shfrans). 1H NMR (300 MHz, C6D6) 5 7.68 (d, J = 8,1, 2H, SO2ArH),7.31 (d, J = 7.1 Hz, 2H, ArH), 7.11 (m, 3H, ArH), 6.76 (d, J= 8.1 Hz, 2H, SO2ArH), 4.80 (d, J = 6.1 Hz, 1H, NCH), 4.46 (s, 2H, C=CH2), 3.70 (ddd, J = 12.4, 7.3, 5.1 Hz, 1H, NCHH), 3.35 (ddd, J = 14.1,7.7, 6.8 Hz, 1H, NCHH), 2.38 (dd, J = 13.9, 6.5 Hz, TH, CHC=C), 1.90 (s, 3H, ArCH3), 1.44 (app sx, J = i 151 5.8 Hz, 1H, CHH), 1.29 (m, 1H, CHH), 1.25 (d, J = 13.0 Hz, 1H, CHHSi), 1.04 (d, J = 13.8 Hz, 1H, CHHSi), -0.18 (s, 9H, (CH3)3Si); 13C NMR (75 MHz, CDCI3, 1H decoupled) 6 145.44, 142.77, 139.11, 135.93, 128.24, 128.12, 127.41, 127.01, 126.42, 108.26, 67.70, 56.88, 48.69, 30.02, 25.46, 21.34, -1.45; IR (film) 3086, 3063, 3030, 2953, 2924, 2893, 1634, 1599, 1495, 1455, 1350, 1248, 1162, 1097, 1014, 851, 699, 663 cm"1. W-(3-Methy I butyl idene)-4-tri methyls i Iy Imethy l-5-trimethy Isily I- 3-penten-1-amine (11b). The general procedure used for the preparation of imine 11a was followed using amine Ia (300 mg, 1.23 mmol) and isovaleraldehyde (160 pL, 1.48 mmol) to afford the title imine (367 mg, 96%) as a colorless oil: 1H NMR (300 MHz, CDCI3) 8 7.58 (t, J = 4.8 Hz, 1H, N=CH), 4.72 (t, J = 7.0 Hz, IH, C=CH), 3.28 (t, J = 7.4 Hz, 2H, CH2N), 2.17 (q, J = 7.3 Hz, 2H, CH2), 2.08 (t, J = 6.0 Hz, 2H, N=CHCH2), 1.85 (m, 1H, CH(CH3)2), 1.43 (s, 2H, CH2Si), 1.34 (s, 2H, CH2Si), 0.90 (d, J = 6.8 Hz, 6H, (CH3)2CH), -0.02 (s, 9H, (CH3)3Si), -0.06 (s, 9H, (CH3)3Si); 13C NMR (75 MHz, CDCI3, 1H decoupled) 5 163.99, 135.73, 116.64, 62.01,44.72, 30.48, 29.47, 26.31,23.85, 22.47, -0.69, -1.18; IR (film) 2955, 2896, 2829, 1670, 1647, 1465, 1248, 1156, 1064, 854, 698, 624 cm'1. 1 5 2 7rans-AZ-tosyl-2-isobutyl-3-[(3-trimethylsilyl)isopropenyl]- pyrrolidine (15b). The general procedure used for the preparation of 15a was followed using imine 11b (200 mg, 0.64 mmol) to furnish pyrrolidine 14b (135 mg, 88%) as a viscous oil after chromatography on silica gel (5% MeOH / CHgCIg). From a crude sample of pyrrolidine 14b (108 mg, 0.45 mmol), the title AMosyIate was obtained as a thick, colorless oil (141 mg, 80%): 1H NMR (300 MHz, C6D6) 5 7.80 (d, J = 8.2 Hz, 2H, ArH), 6.82 (d, J = 8.2 Hz, 2H, ArH), 4.29 (s, IH, C=CHH), 4.17 (s, IH, CHH), 3.76 (app p, J = 4.4 Hz, 1H, CHN), 3.35 (dt, J = 10.6, 6.4 Hz, IH, CHHN), 3.22 (dt, J = 10.6, 6.4 Hz, 1H, CHHN), 2.13 (dd, J = 10.9, 6.3 Hz, 1H, CHC=C), 1.96 (m, IH, CHH), 1.93 (s, 3H, CH3Ar), 1.84 (m, 1H, CH(CH3)2), 1.45 (m, 2H, CH2CH(CH3)2), 1.23 (d, J = 14.0 Hz, 1H, CHHSi), 1.13 (m, IH, CHH), 1.04 (d, J = 6.5 Hz, 3H, CH3CHCH3), 1.00 (d, J = 6.6 Hz, 3H, CH3CHCH3), 0.96 (d, J = 14.6 Hz, CHHSi), -0.12 (s, 9H, (CH3)3Si); 13C NMR (75 MHz, C6D6, 1H decoupled) 5 146.89, 142.67, 137.15, 129.55, 127.66, 108.31,62.26, 53.26, 48.05, 47.16, 29.89, 25.60, 24.74, 23.72, 22.47, 21.09, - 1.25; IR (film) 3085, 3030, 2955, 2896, 2870, 1632, 1575, 1467, 1454, 1347, 1248, 1160, 1096, 1005, 847, 816, 662 cm'1; HRMS calcd for C21 H35NO2SSi (M+) 393.2158, found 393.2143. 153 Me3Si ph Me3Si A/-(E-3-Phenyl-2-propeny I idene)-4-trimethy Isily Imethy 1-5- trimethylsilyl-3-penten-1 -amine (11f). Using frans-cinnamaldehyde (86 |iL, 0.68 mmol), amine 1a (150 mg, 0.62 mmol) and a reaction time of 24h in the general procedure used for the preparation of imine 11a, imine 11f (101 mg, 100%) was obtained as a thick, golden oil. In this case, excess aldehyde was removed via exposure of the crude product to high vacuum (<250 ptorr, rt, 2-3 h): 1HNMR (300 MHz, CDCI3) 5 7.99 (t, J = 1.2 Hz, 1H, N=CH), 6.89-7.47 (m, 7H, ArH and ArCH=CH), 4.79 (t, J = 7.1 Hz, 1H, C=CH), 3.48 (t, J = 7.4Hz, 2H, NCH2), 2.29 (q, J = 7.3 Hz, 2H, CH2), 1.49 (s, 2H SiCHg), 1.40 (s, 2H, CH2Si), 0.02 (s, 9H, (CH3)3Si), -0.02 (s, 9H, (CH3)3Si); 13C NMR (75 MHz, CDCI3, 1H decoupled) 5 162.35, 141.22, 136.16, 135.93, 128.96, 128.76, 128.37, 127.17, 116.37, 62.07, 30.45, 29.52, 23.92, -0.67, -1.15; IR (film) 3083, 3061, 3027, 2953, 2895, 2831, 1637, 1621, 1449, 1412, 1247, 1151, 1063, 975, 853, 748, C/s-/V-tosyl-2-(E-2-phenylethenyl)-3-[(3-trimethylsilyl)- isopropenyIJpyrroIidine (15f). Utilizing imine 11f (221 mg, 0.62 mmol) in the procedure described for the preparation of 15a, pyrrolidines 14f cis and trans (153 mg, 86%) were obtained as a viscous oil upon purification of the crude product by filtration through a silica gel plug (CH2CI2 - 5% MeOH / 690 cm"1. 154 CHgCIg for elution). A crude sample of the inseparable pyrrolidines (100 mg, 0.35 mmol) was converted to a cis-trans mixture of the corresponding, purified AMosyI derivatives (129 mg, 84%, 8.0 : 1.0 by NMR) which was obtained as a viscous, colorless oil. A pure sample the title compound 15f was secured from the diastereomer mixture by fractional crystallization (light petroleum ether): mp 113.9 - 116.4°C; 1H NMR (300 MHz, C6D6) 5 7.83 (d, J = 8.1 Hz, 2H, SO2ArH), 7.14 (m, 5H, ArH), 6.86 (d, J = 15.7 Hz, 1H, ArCH=C), 6.79 (d, J = 8.0 Hz, 2H, SO2ArH), 5.93 (dd, J = 15.6, 6.2 Hz, 1H, ArC=CH), 4.72 (t, J = 6.6 Hz, 1H, NCH), 4.52 (s, IH, C=CHH), 4.44 (s, IH, C=CHH), 3.44 (app t, J = 8.9 Hz, IH, NCHH), 3.21 (dt, J = 10.2, 6.8 Hz, 1H, NCHH), 2.13 (ddd, J = 12.5, 6.1,6.1 Hz, 1H, CHC=C), 1.89 (s, 3H, CH3Ar), 1.65 (m, 1H, CHH), 1.42 (d, J = 13.7 Hz, 1H, SiCHH), 1.33 (app p, J = 5.9 Hz, 1H, CHH), 1.19 (d, J = 13.7 Hz, 1H, SiCHH), - 0.14 (s, 9H, (CH3)3Si); 13C NMR (75 MHz, CDCI3, 1H decoupled) 5 143.18, 143.00, 136.88, 135.88, 132.31, 129.53, 128.34, 127.49, 127.41, 126.59, 125.76, 109.32, 62.67, 49.80, 47.10, 26.93, 26.68, 21.36, -1.44; IR (KBr) 3084, 3025, 2952, 2873, 1631, 1598, 1495, 1341, 1335, 1246, 1163, 1097, 1044, 855, 696, 666 cm-"1; HRMS calcd for C25H33NO2SSi (M+) 439.2001, found 439.1993. /V-[(2-Furyl)methy I idene)-4-trimethy Isily Imethy I-5- trimethylsilyl-3-penten-1 -amine (11e). Amine Ia (100 mg, 0.41 mmol) and 2-furaldehyde (41 pL, 0.49 mmol) were used following the general procedure described for the preparation of imine 11a to yield the title imine 155 (132 mg, 100%) as a clear oil: 1HNMR (300 MHz, CDCI3) 5 8.04 (s, 1H, N=CH), 7.47 (s, IH, C=CHO), 6.68 (d, J = 3.3 Hz, 1H, HC=CO), 6.43 (dd, J = 3.5, 1.7 Hz, IH, HC=CHO), 4.76 (t, J = 7.1 Hz, 1H, C=CH), 3.52 (t, J = 7.4 Hz, 2H, CH2N), 2.31 (q, J = 7.3 Hz, 2H, CH2), 1.46 (s, 2H, CH2Si), 1.37 (s, 2H, CH2Si), 0.00 (s, 9H, (CH3)3Si), -0.06 (s, 9H, (CH3)3Si); 13C NMR (75 MHz, CDCI3, 1H decoupled) 6 151.82, 149.31, 144.36, 136.25, 116.28, 113.17, 111.40, 62.35, 30.41,29.49, 23.88, -0.70, -1.24; IR (film) 3125, 2954, 2895, 2828, 1646, 1485, 1247, 1155, 1014, 853, 744, 698, 624 cm"1. Trans-/V-tosyl-2-furyl-3-[(3-trimethylsilyl)isopropenyl]- pyrrolidine (15e). A 10 ml_, single-necked, round-bottomed flask containing a solution of TiC^ (360 pL, 0.39 mmol of a 1.1 M toluene solution) in CH2CI2 (3.0 mL) was cooled to -78 °C and imine 11e (125 mg, 0.39 mmol) in CH2CI2 (400 pL) was added dropwise over 45 min via a gas tight syringe. The resulting deep orange reaction mixture was allowed to reach ambient temperature gradually (2-3h) and stirring was continued for 24h. The reaction mixture was quenched and the product was isolated in the manner described in the general procedure. Elution of the crude product through a plug of Florisil (CH2CI2 for elution) furnished pyrrolidine 14e (82 mg, 84%) as a light orange oil. A crude sample of pyrrolidine 14e (80 mg, 0.32 mmol) was converted into the title N- tosyl derivative (103 mg, 80%) as described in the general procedure used for 15a. The title compound was obtained as a viscous, colorless oil: 1HNMR 1 5 6 (300 MHz, C6D6) 5 7,62 (d, J = 8.3 Hz, 2H, ArH), 6.93 (d, J = 1.7 Hz, 1H, OCH=C), 6.77 (d, J = 8.2 Hz, 2H, ArH), 6.26 (d, J = 3.2 Hz, 1H, CH=CO), 6.00 (dd, J = 3.1, 1.9 Hz, 1H, OCH=CH), 4.94 (d, J = 5.4 Hz, 1H, NCH), 4.51 (s, 1H, 3.63 (dt, J = 9.8, 6.9 Hz, 1H, NCHH), 2.77 (app q, J = 6.5 Hz, 1H, CHC=C), 1.91 (s, 3H, ArCH3), 1.73 (dq, J = 12.5, 6.6 Hz, H2, 1H, CHH), 1.41 (dq, J = 12.5, 7.2 Hz, IH, CHH), 1.30 (d, J = 13.7 Hz, 1H, CHHSi), 1.16 (d, J = 13.9 Hz, 1H, CHHSi), -0.12 (s, 9H, (CH3)3Si); 13C NMR (75 MHz, C6D6, 1H decoupled) 5 crrv1; HRMS calcd for C21H23NO3SSi (M+) 403.1637, found 403.1639. AZ-(2-Methoxy benzyl idene)-4-trimethy Isily Imethy 1-5- trimethylsilyl-3-penten-1-amine ( lid ). Using o-anisaldehyde (118 pL, 0.98 mmol) and amine 1a (200 mg, 0.82 mmol) in the general procedure desribed for the preparation of 11a yielded the title imine (299 mg, 100%) as a colorless oil: 1H NMR (300 MHz, CDCI3) 6 8.68 (s, 1H, N=CH), 7.92 (dd, J = 7.6, 1.6 Hz, IH, ArH), 7.33 (dt, J = 8.0, 1.7 Hz, IH, ArH), 6.95 (t, J = 7.5 Hz, IH, ArH), 6.86 (d, J = 7.3 Hz, 1H, ArH), 4.82 (t, J = 7.1 Hz, 1H, C=CH), 3.83 (s, 3H, ArOCH3), 3.57 (t, J = 7.4 Hz, 2H, CH2N), 2.30 (q, J = 7.3 Hz, 2H, CH2), 1.49 (s, 2H, CH2Si), 1.38 (s, 2H, CH2Si), 0.02 (s, 9H, (CH3)3Si), -0.04 (s, 9H, (CH3 )3Si); 13C NMR (75 MHz, CDCI3, 1H decoupled) 6 158.65, 156.57, 135.78, C=CHH), 4.44 (s, 1H, C=CHH), 3.63 (ddd, J = 12.9, 7.2, 5.9 Hz, 1H, NCHH), 154.96, 146.07, 142.47, 141.76, 137.67, 129.39, 127.68, 110.52, 108.38, 107.97, 61.35, 52.43, 47.98, 30.21, 25.71, 21.09, -1.42; IR (film) 3125, 3079, 3029, 2953, 2894, 1632, 1599, 1348, 1248, 1161, 1098, 1011, 852, 733, 663 157 131.45, 127.34, 125.01, 120.73, 116.72, 110.93, 62.55, 55.41, 30.64, 29.48, 23.87, -0.67, -1.23; IR (film) 3085, 2998, 2953, 2893, 2836, 1639, 1601, 1487, 1465, 1439, 1373, 1298, 1286, 1248, 1159, 1047, 1029, 853, 754, 698, 624 cm'1. NTs OMe Tra/7S-yV-tosyl-2-(2-methoxy pheny l)-[(3-trimethy Isi Iyl)- isopropenyl]pyrrolidine (15d). Using the procedure described for the preparation of 15e, imine 11d (216 mg, 0.60 mmol) was converted into a mixture of the corresponding pyrrolidine and the monoprotodesilylated isomer (182 mg, 100%, ca. 1.5 : 1.0 by NMR). Direct treatment of the crude mixture with TsCI in the manner previously described for 15a yielded the title AMosyI pyrrolidine (164 mg, 62% overall from amine 1a) as a viscous, colorless oil. A portion of this sample was crystallized from 10% EtgO/hexane to furnish colorless crystals: mp 85.5 - 88.4 0C; 1H NMR (300 MHz, CgDg) 5 7.75 (d, J = 8.0 Hz, 2H, SO2ArH), 7.46 (d, J = 7.3 Hz, IH, ArH), 7.07 (t, J = 7.6 Hz, 1H, ArH), 6.86 (t, J = 7.5 Hz, 1H, ArH), 6.78 (d, J = 8.1 Hz, 2H, SO2ArH), 6.49 (d, J = 8.1 Hz, IH, ArH), 5.38 (d, J = 3.3 Hz, IH, CHN), 4.35 (s, 1H, C=CHH), 4.33 (s, IH, C=CHH), 3.56 (app t, J = 5.8 Hz, 2H, NCH2), 3.30 (s, 3H, ArOCH3), 2.45 (ddd, J = 3.1, 6.2, 3.1 Hz, 1H, CHC=C), 1.92 (s, 3H, SO2ArCH3), 1.70 (dq, J = 12.6, 7.2 Hz, 1H, CHH), 1.59 (d, J = 13.6 Hz, 1H, CHHSi), 1.41 (dq, J = 12.0, 5.3 Hz, 1H, CHH), 1.18 (d, J = 13.7 Hz, 1H, CHHSi), -0.12 (s, 9H, (CH3 )3Si); 13C NMR (75 MHz, CgDg, 1H decoupled) 5 156.47, 146.56, 142.36, 137.57, 132.11, 129.27, 158 128.54, 128.32, 128.05, 120.79, 110.64, 107.48, 63.33, 54.83, 54.04, 48.18, 28.80, 25.58, 21.10, -1.43; IR (film) 3098, 3080, 3030, 2998, 2973, 2948, 2890, 2845, 1630, 1598, 1489, 1344, 1247, 1159, 1096, 1023, 853, 763, 665 cm"1; HRMS calcd for C24H33NO3SSi (M+) 443.1950, found 443.1930. Me3Si M e 3Oi OMe /V-(4-Methoxy benzyl idene)-4-trimethy Isily Imethy 1-5- trimethylsilyl-3-penten-1-amine (11g). Using the general procedure for the preparation of aldimine 11a, amine Ia (100 mg, 0.41 mmol) and 4- anisaldehyde (55 pL, 0.45 mmol) were converted into the title imine (146 mg, 98%) which was isolated as a colorless oil: 1H NMR (300 MHz, CDCI3 ) 8 8.16 (s, 1H, N=CH), 7.63 (d, J = 8.7 Hz, 2H, ArH), 6.89 (d, J = 8.8 Hz, 2H, ArH), 4.79 (t, J = 7.2 Hz, 1H, C=CH), 3.81 ( s, 3H, ArOCHg), 3.52 (t, J = 7.4 Hz, 2H, NCH2), 2.29 (q, J = 7.3 Hz, 2H, CHg), 1.47 (s, 2H, SiCHg), 1.37 (s, 2H, SiCHg), 0.01 (s, 9H, Si(CHa)S), -0.06 (s, 9H, Si(CHg)S); 13C NMR (75 MHz, CDCIg, 1H decoupled) 5 161.47, 159.93, 135.90, 131.92, 129.55, 116.69, 113.92, 62.21, 55.29, 30.59, 29.51,23.90, -0.65, -1.18; IR (film) 3004, 2953, 2896, 2836, 1647, 1607, 1579, 1512, 1307, 1248, 1165, 1036, 853, 699, 625 cm"1. C/s-/V-tosyl-2-(4-methoxyphenyl)-3-[(3-trimethy Isi Iyl)- isopropenyl]pyrrolidine (ISg). Imine 11g (134 mg, 0.37 mmol) was used 1 5 9 in the general cyclization procedure used for 15a with an extended reaction time of 8h after the reaction mixture reached room temperature. This produced a mixture of diastereomeric pyrrolidines (96 mg, 90 %, 3.4:1.0 by NMR) as a thick, colorless oil after purification by elution through a Florisil column (CH2Cl2 -10% MeOH/CH2Cl2 for elution). The mixture of pyrrolidines (75 mg, 0.26 mmol) was converted into a mixture of the corresponding AMosyI derivatives (103 mg, 90%, 3.3:1.0 by NMR) which was obtained as a viscous colorless oil upon chromatography on silica gel (5% EtOAc/hexane for elution). Fractional crystallization of the mixture (light petroleum ether) furnished a pure sample of the major isomer I Sg as small white needles: mp 109.4-110.5 0C; 1H NMR (300 MHZ, CDCI3) 5 7.59 (d, J = 8.1 Hz, 2H, ArM), 7.22 (d, J = 8.1 Hz, 2H, ArH), 6.95 (d, J = 8.6 Hz, 2H, ArH), 6.69 (d, J = 8.6 Hz, 2H, ArH), 4.91 (d, J = 7.5 Hz, 1H, NCH), 4.33 (s, 1H, C=CHH), 4.18 (s, 1H, C=CHH), 3.74 (s, 3H, ArOCH3), 3.68 (t, J = 8.9 Hz, 1H, NCHH), 3.36 (ddd, J = 17.1, 10.1,6.8 Hz, 1H, NCHH), 2.38 (s, 3H, S0 2ArCHs), 2.34 (app q, J = 6.8 Hz, 1H, C=CCH), 2.06 (m, 1H1CHH), 1.77 (dq, J = 12.1, 6.2 Hz, 1H, CHH), 1.40 (d, J = 13.6 Hz, 1H, SiCHH), 1.22 (d, J = 13.6 Hz, 1H, SiCHH), -0.12 (s, 9H, Si(CHg)S); 13C NMR (75 MHz, CDCI3 , 1H decoupled) ,5 158.64, 142.99, 142.50, 135.65, 131.41, 129.35, 128.64, 127.31, 112.94, 109.69, 64.60, 55.11, 51.64, 47.47, 27.17, 26.58, 21.36, -1.53; IR (film) 3084, 3064, 3031, 2953, 2836, 1635, 1612, 1.598, 1513, 1464, 1349, 1304, 1290, 1248, 1162, 1098, 1037, 851, 664 cm'1; HRMS calcd for C24H33NOsSSi (M+) 443.1950, found 443.1943. 160 Me3Si M e3Si M-Ethy lidene-4-trimethy Isily Imethy l-5-trimethy Isi Iy l-3-penten- 1-amine (11c). The title imine was characterized via a NMR tube experiment. A flame dried NMR tube was cooled under a stream of argon and charged with amine 1a (20 mg, .082 mmol) and CDCIg (350 pL). The tube was flushed with argon, fitted with a rubber septum and the solution was cooled to 0 °C. Acetaldehyde (8.0 pL, 0.14 mmol) was added via a cold syringe. The resulting cloudy mixture was kept at 0 °C for 1h, allowed to reach room temperature and was immediately analyzed. The 1H and 13C NMR spectra showed the presence of a single imine product (-100%): 1H NMR (300 MHz, CDCIg) 8 7.62 (q, J = 4.8 Hz, IH, HC=N), 4.69 (t, J = 7.0Hz, IH, C=CH), 3.26 (t, J = 7.4 Hz, 2H, CH2N), 2.15 (q, J = 9.5 Hz, 2H, CH2), 1.89 (d, J = 4.6 Hz, 3H, CH3), 1.42 (s, 2H, CH2Si), 1.34 (s, 2H, CH2Si), -0.03 (s, 9H, (CH3)3Si), -0.06 (s, 9H, (CH3)3Si); 13C NMR (75 MHz, CDCI3, 1H decoupled) 5 160.23, 135.87, 116.49, 61.72, 30.20, 29.44, 23.85, 21.99, -0.72, -1.22. 7>ans-/V-tosyl-2-methyl-[(3-trimethylsilyl)isopropenyl]- pyrrolidine (15c). A 10 mL, single-necked, round-bottomed flask containing a solution of amine Ia (200 mg, 0.82 mmol) in CH2CI2 (4 mL) and 4 A molecular sieves (400 mg) was cooled to -10 °C and acetaldehyde (50 pL, 0.90 mmol, freshly distilled) was added dropwise over I min via a gas-tight syringe. Me3Si 161 The mixture was stirred at -10 °C for 1h and quickly filtered through a Celite pad. The resulting solution of imine 11c was diluted with CHgCIg (2 mL), cooled to -78 °C without delay and TiCI^ (820 pL, 0.82 mmol of a 1.0 IVI toluene stock solution) was added dropwise. The resulting deep orange solution was gradually warmed to rt (2-3h) and stirred for an additional 2h. Reaction quench and product isolation was carried out as described in the preparation of 15a to afford pyrrolidine 14c (106 mg, 65%) as a colorless oil after purification of the crude product via filtration through a plug of Florisil (CHgCIg - 5% MeOH/ CHgCIg for elution). A sample of crude 14c (100 mg, 0.51 mmol) was treated with TsCI as described previously to furnish the purified title compound (147 mg, 82%) as a viscous, colorless oil: 1H NMR (300 MHz, CgDg) 5 7.75 (d, J = 8.2 Hz, 2H, ArH), 6.84 (d, J = 8.2 Hz, 2H, ArAV), 4.38 (d, J = 0.9 Hz, 1H, C=CAVH), 4.29 (s, 1H, C=CHAV), 3.51 (t, J = 6.4 Hz, 1H, NCAV), 3.42 (ddd, J = 14.9, 8.7, 6.2 Hz, 1H, NCAVH), 3.19 (ddd, J = 11.3, 7.5, 3.1 Hz, 1H, NCHAV), 1.97 (app q, J = 6.8 Hz, 1H, CAVC=C), 1.93 (s, 3H, CAVgAr), 1.46 (d, J = 6.2 Hz, 3H, CH3), 1.34 (m, 1H, CAVH), 1.12 (d, J = 13.8 Hz, 1H, SiCAVH), 0.97 (m, 1H, CHAV), 0.91 (d, J = 13.9 Hz, 1H, SiCHAV), -0.14 (s, 9H, (CH3)3Si); 13C NMR (75 MHz, CgD6, 1H decoupled) 5 146.11, 142.75, 136.79, 129.60, 127.81, 108.62, 59.90, 55.79, 48.48, 30.20, 24.32, 22.33, 21.10, -1.27; IR (film) 3080, 3029, 2955, 2928, 2895, 1632, 1598, 1452, 1346, 1248, 1163, 1093, 854, 816, 737, 658 cm'1; HRMS calcd for C18H29NO2SSi (M+) 351.1688, found 351.1670. 162 Me3Si M e 3O, NO2 /V-(4-Nitrobenzy lidene)-4 -trim ethy Isily lm ethy l-5-trim ethy Is ily I- 3-penten-1 -amine (11i). Using the general procedure outlined for the preparation of imine 11a, amine 1a (150 mg, 0.62 mmol) and 4- nitrobenzaldehyde (98 mg, 0.65 mmol) were converted into the title imine which was isolated as a viscous, colorless oil and was used immediately in the next step: 1H NMR (300 MHz, CDCI3) 5 8.31 (s, 1H, N=CH), 8.24 (d, J = 8.8 Hz, 2H, Ar/-/), 7.86 (d, J = 8.8 Hz, 2H, ArH), 4.77 (t, J = 7.1 Hz, 1H, C=CH), 3.63 (t, J = 7.0 Hz, 2H, NCH2), 2.33 (q, J = 7.1 Hz, 2H, Chty, 1.46 (s, 2H, SiCHg), 1.37 (s, 2H, SiCH2), 0.02 (s, 9H, Si(CH3)3), -0.07 (s, 9H, Si(CH3)3); 130 NMR (75 MHz, CDCI3, 1H decoupled) 5 158.31, 148.81, 141.82, 136.52, 128.64, 123.76, 115.94, 62.49, 30.09, 29.44, 23.88, -0.71,-1.25; IR (film) 3061,2954, 2895, 2844, 1646, 1603, 1525, 1413, 1345, 1247, 1156, 1107, 1065, 1014, 837, 769, 748, 691, 625 Crrv1. C/s-/V-tosyl-2-(4-nitrophenyl)-3-[(3-trimethylsilyl)isopropenyl]- pyrrolidine (15i). Imine 11i was used in the general cyclization procedure outlined for the preparation of 15a to afford a mixture of diastereomeric pyrrolidines. The crude mixture was directly exposed to TsCI as outlined in the general procedure for 15a to provide an inseparable mixture of the title compound and the minor trans isomer (5.0:1.0 by NMR, 250 mg, 88% from 1a) 163 as a white solid after purification by chromatography on silica gel (5%-10% EtOAc/hexanes for elution): mp 140.2-143.7 0C; 1H NMR (300 MHZ, CgDg) 8 7.94 (d, J = 8.8 Hz, 2H, ArH), 7.75 (d, J = 8.1 Hz, 2H, ArH), 6.97 (d, J = 8.3 Hz, 2H, ArH), 6.88 (d, J = 8.0 Hz, 2H, ArH), 5.09 (d, J = 7.9 Hz, 1H, NCH), 4.25 (s, 1H, C=CHH), 4.00 (s, 1H, C=CHH), 3.56 (t, J = 8.5 Hz, 1H, NCHH), 3.24 (ddd, J = 17.3, 10.7, 6.6 Hz, 1H, NCHH), 2.24 (ddd, J = 12.9, 7.1,7.1, Hz, 1H, C=CCH), 2.01 (s, 3H, SOaArCHs),'1.60 (m, 1H, CHH), 1.30 (m, 1H, CHH), .1.24 (d, J = 13.6 Hz, 1H, SiCHH), 1.08 (d, J = 13.5 Hz, 1H, SiCHH), -0.12 (s, 9H, Si(CHg)S); 13C NMR (75 MHz, CDCIg, 1H decoupled) 5 147,02, 143.83 141.50, 134.46, 129.70, 128.28, 127.28, 123.52, 122.71, 110.23, 64.27, 51.73, 47.78, 27.43, 26.45, 21.42, -1.65; IR (film) 3083, 3064, 2953, 2892, 1635, 1599, 1520, 1494, 1418, 1344, 1304, 1247, 1161, 1107, 1050, 1011,845, 772, 754, 667 cm"1; HRMS calcd for C23HgoNa0 4SSi (M+) 458.1696, found 458.1702. 164 Synthesis of Trisubstituted Pyrrolidines Me3Si M e 3Oi M-(2-Methy Ipropy lidene)-2-methy l-4-trimethy Isily Imethy 1-5- trimethylsilyl-3-penten-1 -amine (23a). The general procedure used to prepare imine 11a was followed using amine Ib (650 mg, 2.52 mmol) and isobutyraldehyde (275pL, 3.02 mmol) to yield the title imine (790 mg, 100%) as a colorless oil. 1H NMR (300 MHz, CDCI3) 5 7.40 (d, J = 5.2 Hz, IH, N=CH), 4.55 (d, J = 9.5 Hz, IH, C=CH), 3.31 (dd, J = 11.1,5.4 Hz, 1H, NCHH), 2.97 (dd, J= 11.0, 8.2 Hz, 1H, NCHH), 2.52 (m, 1H, CH3CH), 2.38 (m, IH, (CH3)2CH), 1.58 (d, J = 13.5 Hz, 1H, CHHSi), 1.33 (ABq, Av = 20.8 Hz, J = 13.2 Hz, 2H, CH2Si), 1.32 (d, J = 13.5 Hz, 1H, CHHSi), 1.03 (dd, J = 6 .8 , 1.4 Hz, 6H, (CH3)2CH), 0.83 (d, J = 6.6 Hz, 3H, CH3CH), -0.00 (s, 9H, (CH3)3Si), -0.04 (s, 9H, (CH3)3Si); 13C NMR (75 MHz, CDCI3, 1H decoupled) 6 169.54, 133.96, 124.14, 68.23, 33.95, 33.90, 29.24, 23.75, 19.43, 19.01,-0.65, -1.11; IR (film) 2956, 2926, 2895, 2820, 1673, 1645, 1456, 1417, 1366, 1247, 1156, 1065, 853. 698, cm"1. (2a,3(3,4a)-4-Methyl-3-[(3-trimethylsilyl)isopropenyl]-2- isopropylpyrrolidine (24a). Employing imine 23a (790 mg, 2.53 mmol) in the general procedure used for the preparation of 14a, the title pyrrolidine (595 165 mg, 98%) was obtained as the sole reaction product (NMR) in the form of a colorless oil: 1H NMR (300 MHz, CDCI3) 5 4.71 (d, J = 1.7 Hz, 1H, C=CAVH), 4.61 (d, J = 0.9 Hz, IR, C=CHH), 3.06 (dd, J = 10.4, 7.2 Hz, 1H, NCHH), 2.83 (dd, J = 8.2, 5.1 Hz, 1H, NCH), 2.44 (dd, J = 10.4, 8.1 Hz, 1H, NCHH), 2.12 (br s, 1H, NH), 1.96 (m, 1H, NCH2CH), 1.84 (t, 8.5 Hz, 1H, CHC=C), 1.65 (m, 1H, CH(CH3)2), 1.42 (s, 2H, CH2Si), 0.92 (d, J = 3.3 Hz, 3H, CH3CHCH3), 0.90 (d, J = 3.8 Hz, CH3CHCH3), 0.87 (d, J = 6.7 Hz, 3H, CH3), 0.01 (s, 9H, (CH3)3Si); 13C NMR (75 MHz, CDCI3, 1H decoupled) 5 145.92, 111.35, 67.98, 59.91, 52.58, 38.53, 30.89, 21.72, 20.28, 17.77, 16.77, -0.84; IR (film) 3312, 3077, 2955, 1628, 1463, 1417, 1379, 1288, 1248, 1163, 844, 692, cm"1; HRMScaIcd for C14H29NSi ( M+) 239.2069, found 239.2120. SOoAr (2a,3|3,4a)-A/-(2-Naphthalenesulfonyl)-4-methyl-3-[(3- trimethy Isi Iy I )isopropenyl]-2-isopropy I pyrrolidine (25a). For the purpose of NOE studies, pyrrolidine 24a was converted into the corresponding A/-(2-naphthalenesulfonyi) derivative. A 5.0 m l, single-necked, round-bottomed flask was charged with 24a (100 mg, 0.42 mmol), pyridine (100 pL, 1.25 mmol) and CH2CI2 (1.5 ml). The solution was cooled to 0 0C and 2-naphthalene- sulfonyl chloride (114 mg, 0.50 mmol) was added in one portion. After stirring for 10 min, the mixture was brought to ambient temperature and stirred for 10h. The resulting red mixture was treated with H2O (2 ml_) and the biphasic mixture was stirred for 1h. The organic layer was combined with three CH2CI2 extracts 166 of the aqueous layer and dried over NagSO^. The solvent was removed in vacuo and the residue was subjected to chromatography on silica gel (5% EtOAc/ hexane) to give the title compound (72 mg, 40%) as a gelatinous, colorless material: 1H NMR (300 MHz, CDCI3) 5 8.41 (s, 1H, Ar/-/), 7.93 (d, J = 8.8 Hz, 2H, ArH), 7.73 (m, 4H, ArH), 4.63 (s, 1H, C=CHH), 4.54 (s, 1H, C=CHhf), 3.87 (dd, J= 12.2, 7.1 Hz, 1H, NCHH), 3.65 (dd, J = 8.1, 3.7 Hz, 1H, NCH), 2.80 (app t, J = 11.8 Hz, IH, NCHH), 2.28 (m, 1H, CH(CH3)2), 2.11 (dd, J = 10.5, 8.6 Hz, 1H, CHC=C), 1.27 (m, 1H, CHCH3), 1.26 (d, J = 15.0 Hz, 1H, SiCHH), 1.24 (d, J = 5.0 Hz, 3H, CH3CHCH3), 1.02 (d, J = 12.9 Hz, 3H, CH3CHCH3), 0.71 (d, J = 6.3 Hz, 3H, CH3), 0.56 (d, J = 15.2 Hz, 1H, SiCHH), -0.91 (s, 9H, (CH3)3Si); 13C NMR (75 MHz, CDCI3, 1H decoupled) 5 145.04, 136.49, 134.67, 132.22, 129.26, 129.14, 128.56, 127.86, 127.53, 122.93, 113.15, 67.49, 59.16, 56.43, 36.76, 33.34, 19.46, 18.54, 17.48, 14.65, -1.17; IR (film) 3079, 3058, 2958, 2925, 2860, 1628, 1591, 1504, 1463, 1344, 1249, 1162, 1132, 1074, 1003, 912, 858, 734, 660 cm"1. /V-(3-Methy Ibuty I idene)-2-methy l-4-trimethy Isiiy Imethy I-5- trimethyIsiIyl-3-penten-1-amine (23b). The general procedure used for the preparation of imine 11a was carried out using amine Ib (100 mg, 0.39 mmol) and isovaleraldehyde (50 pL, 0.47 mmol) to provide the title imine (126 mg, 100%) as a colorless oil: 1H NMR (300 MHz, CDCI3) 5 7.55 (t, J = 5.3 Hz, 1H, N=CH), 4.57 (d, J = 9.5 Hz, 1H, C=CH), 3.35 (dd, J = 11.2, 5.1 Hz, 1H, NCHH), 2.99 (dd, J = 11.0, 8.6 Hz, 1H, NCHH), 2.54 (m, 1H, CHCH3), 2.10 (t, J 167 = 6 .1Hz, 2H, N=CHCH2), 1.87 (m, 1H, (CH3)2CH), 1.57 (d, J = 13.4 Hz, 1H, SiCHH), 1.34 (d, J = 13.0 Hz, 1H, SiCHH), 1.34 (dd, J = 20.6, 13.3 Hz, , 2H, SiCH2), 0.93 (d, J = 6.7 Hz, 6H, (CH3)2CH), 0.85 (d, J = 6.7 Hz, 3H, CH3CH), 0.00 (s, 9H, (CH3)SSi), -0.03 (s, 9H, (CH3)3Si); 13C NMR (75 MHz, CDCI3, 1H decoupled) 5 164.42, 134.05, 124.08, 68.52, 44.76, 33.95, 29.27, 26.44, 23.76, 22.55, 19.12, -0.65, -1.11; IR (film) 2955, 2822, 1670, 1646, 1458, 1419, 1368, 1247, 1157, 1065, 951, 837, 769, 698 cm"1. (2a,3(3,4a)-4-Methyl-3-[(3-trimethy Isily l)isopropeny l]-2- isobuty!pyrrolidine (24b). Employing imine 23b (123 mg, 0.38 mmol) in the general procedure used for the preparation of pyrrolidine 14a resulted in the title compound (93 mg, 97%) as the sole reaction product (NMR) which was obtained as a colorless oil: 1H NMR (300 MHz, CDCI3) 8 4.68 (d, J = 1.6 Hz, 1H, C=CHH), 4.62 (d, J = 1.5 Hz, 1H, C=CHH) 3.08 (dd, J = 10.5, 7.9 Hz, 1H, NCHH), 2.95 (dt, J = 9.2, 3.5 Hz, 1H, NCH), 2.52 (dd, J = 10.6, 7.6 Hz, 1H, NCHH), 1.99 (m, IH, CH3CH), 1.67 (m, IH, (CH3)2CH), 1.65 (br s, IH, NH), 1.58 (t, J = 8.9 Hz, IH, C=CCH), 1.43 (s, 2H, SiCH2), 1.24 (m, 2H, CH2CH(CH3)2), 0.94 (d, J = 6.7 Hz, 3H, CH3), 0.85 (dd, J = 11.6, 6.5 Hz, 6H, (CH3)2CH), 0.01 (s, 9H, (CH3)3Si); 13C NMR (75 MHz, CDCI3 , 1H decoupled) 5 147.05, 109.26, 64.15, 61.64, 53.72, 45.48, 39.48, 26.03, 23.93, 23.46, 21.78, 18.04, -0.78; IR (film) 3280, 3079, 2954, 2869, 1627, 1467, 1418, 1374, 1248, 168 1164, 848, 692 cm '1; HRMS calcd for C15H31 NSi (M+) 253.2226, found 253.2219. (2a,3a,4P)-/V-Tosyl-4-methyl-3-[(3-trimethylsilyl)isopropenyl]- 2-methylpyrrolidine (25c). Employing amine Ib (100 mg, 0.39 mmol) in the procedure outlined for the preparation of 28c, a mixture of pyrrolidine 24c and a minor diastereomer (80 mg, 97% from 1b, ave 3.0:1.0 by NMR) was obtained as a colorless oil. Complete characterization was achieved by conversion of the mixture (79 mg, 0.38 mmol) to the corresponding AMosyIates using the method previously described for 15a. The inseparable title compound and the minor isomer (115 mg, 83%, ave 3.0:1.0 by NMR) were secured as a viscous, colorless material: 1H NMR (300 MHz, CDCI3) 5 7.72 (d, J = 8.0 Hz, 2H, ArH), 7.30 (d, J = 8.1 Hz, 2H, ArH), 4.70 (s, 1H, C=CHH), 4.50 (s, 1H, C=CHH), 3.90 (p, J = 7.0 Hz, 1H, NCHCH3), 3.58 (dd, J = 9.3, 7.4 Hz, 1H, NCHH), 2.67 (t, J = 9.7 Hz, 1H, NCHH), 2.40 (s, 3H, ArCH3), 2.30 (m, 1H, CH3CH), 1.58 (t, J = 11.5 Hz, 1H, C=CCH), 1.56 (d, J = 13.5 Hz, 1H, SiCHH), 1.11 (d, J = 13.5 Hz, IH, SiCHH), 0.99 (d, J = 6.5 Hz, 3H, CH3), 0.86 (d, J = 6.3 Hz, 3H, CH3), -0.14 (s, 9H, (CH3)3Si); 13C NMR (75 MHz, CDCI3, 1H decoupled) 5 143.16, 141.97, 129.53, 127.45, 127.38, 109.11, 65.28, 57.90, 54.86, 32.39, 27.51,21.39, 18.33, 15.63, -1.40; IR (film) 3083, 3029, 2956, 2874, 1634, 1598, 1455, 1343, 1248, 1157, 1096, 1042, 852, cm'1; HRMS calcd for C19H31NO2SSi (M+) 365.1845, found 365.1845. 169 CH3 Me3Si Me3Si A/-(2-Methy I propyl idene)-5-tri methyls Ny Imethy I-6- trimethyIsilyl-4-hexen-2-amine (26a). The general procedure for the preparation of aldimine 11a was employed using amine 1c (130 mg, 0.50 mmol) and isobutyraldhyde (55 pL, 0.61 mmol) to afford the title imine (155 mg, 99%) as a colorless oil: 1H NMR (300 MHz, CDCI3) 5 7.42 (d, J = 5.6 Hz, 1H, N=CH), 4.68 (t, J = 7.1 Hz, IH, C=CH), 2.94 (sx, J = 6.5 Hz, IH, NCH), 2.37 (m, 1H, CH(CH3)2), 2.05 (m, 2H, CH2), 1.43 (ABq, Av = 32.0 Hz, J = 13.4 Hz, 2H, CH2Si), 1.35 (d, J = 3.6 Hz, 2H, CH2Si), 1.09 (d, J = 6.3 Hz, 3H, CH3CHN), 1.02 (d, J = 6.8 Hz, 6H, (CH3)2CH), -0.02 (s, 9H, (CH3)3Si), -0.05 (s, 9H, (CH3)3Si); 13C NMR (75 MHz, CDCI3, 1H decoupled) 5 167.23, 135.60, 116.53, 66.91, 37.27, 33.86, 29.51,24.01,22.21, 19.63, -0.62, -1.09; IR(film) 2958, 2928, 2896, 2832, 1668, 1371, 1248, 1156, 1064, 852, 699, 624 cm'1. (2a,3(3,5a)-/V-Tosy l-5-methyl-3-[(trimethy Isily l)isopropeny l]-2- isopropylpyrrolidine (28a). Employing freshly prepared imine 26a (483 mg, 1.55 mmol) in the general cyclization procedure used for 14a, a crude mixture (404 mg, 100%, 2.0:1.0 by NMR) of the corresponding pyrrolidine 27a and the monoprotodesilylated imine isomer was obtained. A 10 ml_, single­ H3C 170 necked, round-bottomed flask was charged with the crude mixture, CHgCIg (4.0 ml_) and pyridine (400 pL, 4.64 mmol). To the solution was added TsCI (370 mg, 1.94 mmol) in one portion and the mixture was stirred for 7h at 25 0C. Water (4.0 mL) was added and the diphasic mixture stirred for an additional 1h. The organic layer was removed, combined with three CH2CIg extractions of the aqueous layer and dried over Na2SO4. After removal of solvent in vacuo, the residue was chromatographed on silica gel (1% EtOAc/hexane - 5% EtOAc/hexane) to yield the title AMosyIpyrroIidine (280 mg, 46% from amine 1c) as a viscous colorless oil: 1H NMR (300 MHz, CDCI2) 5 7.66 (d, J = 8.0 Hz, 2H, ArH), 7.22 (d, J = 8.0 Hz, 2H, ArH), 4.09 (s, 1H, C=CHH), 4.05 (s, 1H, C=CHH), 3.71 (app sx, J = 6.6 Hz, IH, CH3CHN), 3.47 (app t, J = 4.7 Hz, 1H, NCH), 2.38 (s, 3H, ArCH3), 2.15 (m, 1H, CH(CH3)2), 1.55 (m, 2H, CH2), 1.32 (d, J = 6.3 Hz, 3H, CH3), 1.15 (ABq, Av = 28.2 Hz, J = 13.9 Hz, 2H, CH2Si), 0.96 (app t, J = 6.0 Hz, 6H, (CH3)2CH), -0.11 (s, 9H, (CH3)3Si); 13C NMR (75 MHz, CDCI3, 1H decoupled) 5 146.70, 142.94, 135.40, 129.19, 127.89, 107.98, 71.10, 56.47, 45.75, 38.01, 33.28, 24.82, 22.92, 21.41, 20.09, 17.68, -1.29; IR (film) 3098, 3029, 2958, 2895, 2870, 1633, 1599, 1464, 1343, 1249, 1162, 1093, 1022, 852, 733, 622 cm-1; HRMS calcd for C21 H35NO2SSi (M+) 393.2158, found 393.2153. SOoAr (2a,3p,5a)-A/-(2-Naphthalenesulfonyl)-5-methyl-3-[(3- trimethylsilyl)isopropenyl]-2-isopropylpyrrolidine (29a). The title 171 compound was prepared for the purpose of NOE studies. A 5.0 mL, single­ necked, round-bottomed flask was charged with the crude pyrrolidine 27a (141 mg, 0.59 mmol), CH2CI2 (2.0 mL) and pyridine (200 pL, 2.5 mmol). DMAP (100 mg, 0.82 mmol) and 2-naphthalenesulfonylchloride (175 mg, 0.77 mmol) were sequentially added and the reaction mixture was stirred for 18h at 25 0C. The mixture was treated with H2O (2.0 mL) and the diphasic mixture was stirred for an additional 2h. The organic phase was removed, combined with three CH2CI2 extracts of the aqueous phase and dried (Na2SO^. The solvent was removed in vacuo and silica gel chromatography (5% EtOAc/hexane) of the residue afforded the title compound (84 mg, 33%) as a gelatinous colorless material: 1H NMR (300 MHz, CDCI3) 5 8.35 (s, 1H, ArH), 7.90 (m, 4H, ArH), 7.59 (m, 2H, ArH), 3.98 (s, 1H, C=CHH), 3.81 (app sx J = 6.7 Hz, 1H, CH3CHN), 3.73 (s, 1H, C=CHH), 3.62 (app t, J = 4.7 Hz, 1H, NCH), 2.36 (ddd, J = 7.8, 4.5, 4.5 Hz, 1H, CHC=C), 2.16 (m, 1H, CH(CH3)2), 1,61 (m, 2H, CH2), 1.38 (d, J = 6.5 Hz, 3H, CH3), 1.16 (d, J = 13.8 Hz, IH, CHHSi), 1.03 (d, J = 7.2 Hz, 3H, CH3CHCH3), 1.01 (d, J = 7.0 Hz, 3H, CH3CHCH3), 0.98 (d, J = 13.0 Hz, 1H, CHHSi), -0.02, (s, 9H, (CH3)3Si); 13C NMR (75 MHz, CDCI3, 1H decoupled) 5 146.47, 135.53, 134.78, 132.22, 129.12, 128.89, 128.63, 128.41, 127.79, 127.26, 123.68, 107.79, 71.48, 56.61, 45.89, 37.92, 33.53, 24.86, 23.09, 20.21, 17.99, -1.39; IR (film) 3078, 3057, 2959, 2926, 2859, 1633, 1598, 1464, 1340, 1248, 1161,1132, 1057, 1019, 971 ,.791, 693, 660, 645, 618, cm'1. 172 AZ-(3-Methy Ibuty lidene)-5-trimethy Isily Imethy l-6-trimethy Isily I- 4-hexen-2-amine (26b). The general procedure used for the preparation of imine 11a was carried out using amine 1c (200 mg, 0.78 mmol) and isovaleraldehyde (100 pL, 0.93 mmol) to provide the title imine (249 mg, 98%) as a colorless oil: 1H NMR (300 MHz, CDCI3) 6 7.57 (t, J = 5.4 Hz, 1H, N=CH), 4.68 (t, J = 7.1 Hz, IH, C=CH), 2.97 (sx, J = 6.5 Hz, 1H, NCH), 2.07 (m, 4H, C=CCH2 and N=CCH2), 1.84 (m, IH, (CH3)2CH), 1.42 (ABq, Av = 24.3 Hz, J = 13.4 Hz, 2H, SiCH2), 1.34 (s, 2H, SiCH2), 1.10 (d, J = 6.3 Hz, 3H, CH3CH), 0.91 (dd, J = 6 .6 , 3.1 Hz, 6H, (CH3)2CH), -0.03 (s, 9H, (CH3)3Si), -0.05 (s, 9H, (CH3)3Si); 13C NMR (75 MHz, CDCI3, 1H decoupled) 6 161.83, 135.75, 116.49, 67.24, 44.57, 37.32, 29.54, 26.44, 23.98, 22.49, 22.38, 22.23, -0.63, -1.10; IR (film) 2955, 2832, 1668, 1646, 1464, 1418, 1368, 1247, 1157, 1065, 838, 699 cm'1. (2a,3(3,5a)-/V-Tosyl-5-methyl-3-[(3-trimethylsilyl)isopropenyl]- 2-isobuty!pyrrolidine (28b). Using imine 26b (100 mg, 0.31 mmol) in the general procedure outlined for the preparation of 14a furnished pyrrolidine 27b (73 mg, 95%) as a colorless oil. For complete characterization, the pyrrolidine was converted into the title AMosyIate (110 mg, 92%) which was 173 obtained as a colorless, viscous oil using the method previously described for 15a: 1H NMR (300 MHz, CDCI3 ) 5 7.69 (d, J = 8.2, 2H, ArH), 7.25 (d, J = 7.7 Hz, 2H, ArH), 4.28 (s, IH, C=CHH), 4.22 (s, 1H, C= CHH), 3.83 (sx, J = 5.9 Hz, 1H, NCHCH3), 3.57 (ddd, J = 13.6, 9.2, 4.6, Hz, 1H, NCH), 2.39 (s, 3H, ArCH3), 2.38 (m, IH, C=CCH), 1.76 (m, 2H, CHH and (CH3)2CH), 1.50 (m, 3H, CHH and CH2CH(CH3)2), 1.30 (d, J = 6.3 Hz, 3H, CH3CH), 1.23 (d, J = 14.2 Hz, 1H, SiCHH), 1.02 (d, J= 14.1 Hz, 1H, SiCHH), 0.93 (dd, J = 6.2, 3.9 Hz, 6H, (CH3)2CH), -0.10 (s, 9H, (CH3)3Si); 13C NMR (75 MHz, CDCI3, 1H decoupled) 8 146.00, 142.92, 136.03, 129.34, 127.65, 108.45, 63.36, 556.47, 51.41,48.50, 37.64, 25.15, 24.48, 23.70, 23.47, 22.09, 21.41, -1.29; IR (film) 3083, 3029, 2956, 2870, 1632, 1598, 1461, 1347, 1249, 1163, 1091, 1009, 853, 663 cm*1; HRMS calcd for C22H37NO2SSi (M+) 407.2314, found 407.2314. (2a,3a,5P)-AZ-Tosy l-5-methyl-3-[(trimethy Isily l)isopropeny l]-2- methy!pyrrolidine (28c). A 5.0 mL, single-necked, round-bottomed flask containing a solution of amine Ic (100 mg, 0.39 mmol) in THF (0.5 mL) and 4 A molecular sieves (260 mg) was cooled to -10 0C. Acetyaldehyde in THF (800 |iL, 0.80 mmol, 1.0 M) was added dropwise over 2 min. The mixture was stirred for 2h at -10 0C and was then diluted with Et2O (2 mL). The cold reaction mixture was filtered through Celite, concentrated and the resulting crude imine was used immediately in the next step. The colorless imine was obtained as a single isomer (NMR) in pure form: 1H NMR (300 MHz, CDCI3) 8 7.62 (q, J = 4.7 174 Hz, IN, N=CH), 4.67 (t, J = 7.2 Hz, 1H, C=CH), 2.99 (sx, J = 6.5 Hz, 1H, NCH), 2.06 (t, J = 7.4 Hz, 2H, CH2), 1.89 (d, J = 4.9 Hz, 3H, CH3C=N), 1.43 (s, 2H, SiCH2), 1.35 (s, 2H, SiCH2), 1.10 (d, 6.3 Hz, 1H, CH3), -0.02 (s, 9H, (CH3)3Si), -0.04 (s, 9H, ( CH3)3Si); 13C NMR (75 MHz, CDCI3, 1H decoupled) 5 157.84, 135.87, 116.47, 67.04, 37.28, 29.53, 24.03, 22.18, 22.03, -0.62, -1.12; IR (film) 2954, 2836, 1671, 1247, 1152, 1064, 852, 699, cm"1! Following the general cyclization procedure used for 14a and using x reaction times of 1 h at -78 0C followed by 36h at -20 0C1 the freshly prepared imine was converted into a mixture of pyrrolidine 27c and a minor stereoisomer (75 mg, 91% from 1c, 6.8:1.0 by NMR). It should be noted that additional trials showed deviance in the isomer ratio in favor of the other diastereomer. In order for complete characterization, the mixture of diastereomers was converted into the corresponding /V-tosyl derivatives using the procedure previously described for 15a. The title compound and the minor isomer (129 mg, 91%, 6.1:1.0 by NMR) were obtained as a colorless viscous material and were found to be inseparable on silica gel. Fractional crystallization (petroleum ether) of the mixture afforded a pure sample of the major, title diasteroeomer which was isolated as a white solid: mp 84.8-87.0 0C; 1H NMR (300 MHz, CDCI3) 8 7.67 (d, J = 8.1 Hz, 2H ArH), 7.20 (d, J = 7.9 Hz, 2H, ArH), 4.62 (s, IH, C=CHH), 4.49 (s, 1H, C=CHH), 4.11 (p, J = 6.4 Hz, IH, NCH), 3.93 (m, IH, NCH), 2.77 (ddd, J = 13.2, 6.7, 6.0 Hz, 1H, C=CCH), 2.38 (s, 3H, ArCH3), 2.23 (ddd, J = 16.5, 12.3, 3.9 Hz, IH 1 CHH), 1.58 (d, J = 13.6 Hz, 1H, SiCHH), 1.43 (dd, d = 12.0, 5.5 Hz, 1H, CHH), 1.24 (d, J = 13.9 Hz, 1H, SiCHH), 1.19 (d, J = 6.2, Hz, 3H, CH3), 0.88 (dd, J = 6.2, 0.9 Hz, 3H, CH3), -0.03 (s, 9H, (CH3)3Si); 13C NMR (75 MHz, CDCI3, 1H decoupled) 5143.89, 142.59, 129.37, 127.54, 126.99, 108.91, 175 58.07, 54.44, 46.55, 34.12, 27.03, 22.51, 21.38, 15.44, -1.39; IR (film) 3079, 2953, 1634, 1599, 1464, 1379, 1328, 1247, 1163, 1095, 1059, 848, 663 cm"1; HRMS, calcd for C19H31NO2SSi (M+) 365.1845, found 365.1848. TBDMSO /V-(2-Methylpropylidene)-1-ferf-butyldimethylsilyloxy-5- trimethyIsilyImethyl-6-trimethyIsilyl-4-hexen-2-amine (30a). Following the general procedure used for the preparation of imine 11a, amine 1d (169 mg, 0.44 mmol) and isobutyraldehyde (48 pL, 0.52 mmol) were converted into the title imine (188 mg, 98%) which was isolated as a clear oil: 1H NMR (300 MHz, CDCI3) 5 7.43 (d, J = 5.4 Hz, 1H, N=CH), 4.69 (t, J = 7.2 Hz, 1H, C=CH) 3.63 (dd, J = 10.0, 4.6 Hz, 1H, SiOCHH), 3.48 (dd, J = 9.9, 8.4 Hz, 1H, SiOCHH), 2.90 (p, J = 4.8 Hz, 1H, NCH), 2.39 (m, IH, (CH3)2CH), 2.20 (ddd, J = 14.1,8.0, 6.0 Hz, IH, CHH), 1.98 (dq, J= 7.1,6.9 Hz, 1H, CHH), 1.43 (ABq, Av = 29.2 Hz, J = 13.3 Hz, 2H, SiCH2), 1.35 (s, 2H, SiCH2), 1.04 (d, J = 6.8 Hz, 6H, (CH3)2CH), 0.84 (s, 9H, (CH3)3CSi), 0.04 (s, 3H, (CH3)3CSiCH3), 0.00 (s, 9H, Si(CH3)3), -0.01 (s, 3H, (CH3)3CSiCH3), -0.04 (s, 9H, Si(CH3)3); 13C NMR (75 MHz, CDCI3, 1H decoupled) 5 169.62, 135.87, 115.96, 73.51, 66.36, 34.05, 31.80, 29.53, 25.94, 24.06, 19.70, 18.30, -0.61,-1.05, -5.22, -5.32; IR (film) 2956, 2858, 1670, 1472, 1464, 1248, 1115, 838, 775 cm"1. 176 TBDMSO-" (2a,3p,5a)-/V-Tosyl-5-(ferf-butyldimethylsilyloxy)methyl-3- [(trimethyIsilyl)isopropenyl]-2-isopropy!pyrrolidine (32a). !mine 30a (188 mg, 0.42 mmol) was subjected to the general cyclization protocol used for 14a to produce a mixture of the corresponding pyrrolidine and the monodesilylated imine isomer (1.3:1.0 by NMR). This crude mixture was directly exposed to TsCI in the manner previously described to provide the crude AMosyIate. Purification by flash chromatography on silica gel (1%-5% EtOAc/hexane) furnished the title compound (93 mg, 42% from 1 d) as a colorless viscous material: 1H NMR (300 MHz, CDCI3) 5 7.67 (d, J = 8.1Hz, 2H, ArH), 7.25 (d, J = 8.0 Hz, 2H, ArH), 4.13 (s, 1H, C=CHH), 4.05 (s, 1H, C=CHH), 3.93 (dd, J = 9.5, 3.8 Hz, 1H, SiOCHH), 3.64 (m, 1H, NCH), 3.54 (dd, J = 9.1,9.1 Hz, IH, SiOCHH), 3.44 (t, J = 5.2 Hz, 1H, NCHCH(CH3)2), 2.40 (s, 3H, ArCH3), 2.39 (unresolved, 1H, C=CCH), 2.09 (m, 1H, CH(CH3)2), 1.90 (dq, J = 6.9, 6.3 Hz, 1H, CHH), 1.53 (dq, J = 6.7, 6.5 Hz, 1H, CHH), 1.17 (ABq, Av = 32.4 Hz, J = 14.0 Hz, 2H, SiCH2), 0.96 (dd, J = 9.5, 7.0 Hz, 6H, (CH3)2CH), 0.88 (s, 9H, (CH3)3CSi), 0.07 (s, 3H, (CH3)3CSiCH3), 0.06 (s, 3H, (CH3)3CSiCH3), -0.09 (s, 9H, (CH3 )3Si); 13C NMR (75 MHz, CDCI3, 1H decoupled) 6 146.52, 143.14, 135.31, 129.27, 128.04, 108.26, 71.10, 66.07, 61.59, 46.23, 33.21, 32.98, 25.93, 24.78, 21.45, 20.27, 18.30, 18.02, -1.23, -5.30; IR (film) 3084, 2956, 2857, 1634, 1599, 1471, 1347, 1250, 1163, 1094, 1005, 838, 778, 734 cm' 1 HRMScaIcdfor C27H50NO3SSi2 (MH+) 524.3050, found 524.3038. 177 TBDMSO. AZ-(3-Methylbutylidene)-1-ferf-butyldimethylsilyloxy-5- trimethyIsiiyImethyl-6-trimethylsilyl-4-hexen-2-amine (30b). Upon using amine 1d (112 mg, 0.29 mmol ) and isovaleraldehyde (37 |il 0.35 mmol) in the general procedure used for the preparation of 11a, the title imine (129 mg, 98%) was obtained as a colorless oil: 1H NMR (300 MHz, CDCI3) 5 7.57 (t, J = 5.3 Hz, 1H, N=CH), 4.70 (t, J = 7.1 Hz, IH, C=CH), 3.64 (dd, J = 10.0, 4.6 Hz, IH, SiOCHH), 3.50 (dd, J = 9.8, 8.0 Hz, IH, SiOCHH), 2.94 (p, J = 5.3 Hz, IH, NCH), 2.22 (ddd, J = 14.0, 5.9, 5.9 Hz, 1H, CHH), 2.10 (dd, J = 6.4, 5.7 Hz, 2H, CH2CHiCH3 )2), 2.00 (ddd, J = 14.2, 7.0, 7.0 Hz, 1H, CHH)), 1.86 (m, 1H, CH(CH3)2), 1.43 (ABq, Av = 20.9 Hz, J = 13.3 Hz, 2H, SiCH2), 1.36 (s, 2H, SiCH2), 0.93 (s, J = 6.6 Hz, 6H, (CH3)2CH), 0.84 (s, 9H, (CH3)3CSi), 0.00 (s, 3H, (CH3)3CSiCH3), -0.02 (s, 12H, (CHs)SSi and (CHs)SCSiCHs), -0.04 (s, 9H, (CH3)3Si); 13C NMR (75 MHz, CDCI3, 1H decoupled) 5 164.31, 136.01, 115.89, 73.84, 66.38, 44.81,31.79, 29.54, 26.40, 25.93, 24.00, 22.55, 18.30, - 0.63, -1.08, -5.24, -5.32; IR (film) 2955, 2858, 1669, 1463, 1248, 1114, 838, 775 cm'1. 178 TBDMSO"" (2a,3p,5a)-AZ-Tosyl-5-(ferf-butyldimethylsilyloxy)methyi-3- [(trimethyIsilyl)isopropenyl]-2-isobuty!pyrrolidine (32b). The general TiCU mediated aldimine cyclization procedure used for 14a was followed utilizing imine 30b (129 mg, 0.28 mmol) to produce a mixture of diastereomeric pyrrolidines (87 mg, 80%, 3.9:1.0 by NMR) as a light gold oil after elution of the crude material through a Florisil plug (CHgCIg for elution). For complete characterization, the mixture was treated with TsCI as previously described to furnish an inseparable mixture of the title compound and a minor /V-tosyl pyrrolidine diastereomer (106 mg, 87%, 3.6:1.0 by NMR) as a clear, viscous gel upon silica gel chromatography of the crude products (5% EtOAc/hexane for elution): 1H NMR (300 MHz, CDCI3) 5 7.69 (d, J = 8.1 Hz, 2H, ArH), 7.26 (d, J = 8.0 Hz, 2H, ArH), 4.29 (s, 1H, C=CHH), 4.21 (s, IH, C=CHH), 3.81 (dd, J = 10.0, 3.9 Hz, 1H, SiOCHH), 3.76 (m, 1H, NCHCH2OSi), 3.56 (dd, J = 9.3, 7.6 Hz, 1H, SiOCHH), 3.53 (dd, J = 8.3, 3.8 Hz, 1H, NCH), 2.40 (s, 3H, ArCH3), 2.38 (ddd, J = 13.4, 7.5, 7.5 Hz, 1H, C=CCH), 1.90 (ddd, J = 12.9, 7.2, 4.3 Hz, 1H, CHH), 1.72 (m, 2H, (CH3)2CHand CHH), 1.48 (m, 2H, (CH3)2CHCH2), 1.21 (d, J = 13.8 Hz, 1H, SiCHH), 1.00 (d, J = 14.0 Hz, IH SiCHH), 0.91 (dd, J = 5.9, 5.9 Hz, 6H, (CH3)2CH), 0.88 (s, 9H, (CH3)3CSi), 0.06 (d, J = 1.9 Hz, 6H, (CH3)3CSi(CH3)2), -0.10 (s, 9H, (CH3)3Si): 13C NMR (75 HMz, CDCI3, 1H decoupled) 5 146.15, 143.07, 135.81, 129.41, 127.73, 127.28, 108.57, 66.02, 63.42, 61.76, 51.74, 47.95, 32.71,25.94, 25.02, 23.75, 22.07, 21.43, 18.29, - 179 1.25, -5.33; IR (film) 3083, 3029, 2956, 2858, 1635, 1599, 1472, 1356, 1250, 1163, 1098, 1005, 839, 814, 777, cm"1; HRMS calcd for C28H51 NO3SSi2 (M+) 537.3128, found 537.3111. TBDMSO (2a,3p,5a)-AZ-Tosy l-5-(ferf-buty Idimethy Isi Iy Ioxy )methyl-3- [(trimethyIsiIyl)isopropenyl]-2-methy!pyrrolidine (32c). The procedure used for the preparation of AMosyIpyrroIidine 28c was employed using amine 1d (150 mg, 0.39 mmol) and acetylaldehyde (775 pL, 0.77 mmol, 1.0 M in THF). The corresponding imine (160 mg, 100%) was obtained as a colorless oil and was used immediately \n the next step: 1H NMR (300 MHz, CDCI3) 5 7.60 (q, J = 4.8 Hz, 1H, N=CH), 4.67 (t, J = 7.1 Hz, IH, C=CH), 3.63 (dd, J = 10.0, 4.7 Hz, SiOCHH), 3.48 (dd, J = 9.9, 7.8 Hz, 1H, SiOCHH), 2.95 (m, 1H, NCH), 2.18 (dq, J = 7.3, 6.9 Hz, 1H, CHH), 2.00 (dq, J = 7.3, 7.3 Hz, 1H, CHhf), 1.91 (d, J = 4.8 Hz, 3H, CH3), 1.42 (s, 2H, SiCH2), 1.35 (s, 2H, SiCHa), 0.84 (s, 9H, (CH3)3CSi), 0.00 (s, 6H, (CH3)3CSi(CH3)2 ), -0.02 (s, 9H, Si(CH3)3), -0.05 (s, 9H, Si(CH3)3); 13C NMR (75 MHz, CDCI3, 1H decoupled) 5 160.38, 136.09, 115.87, 73.60, 66.25, 31.64, 29.53, 25.90, 24.05, 22.06, 18.28, -0.62, -1.12, - 5.24; IR (film) 2854, 2857, 1673, 1472, 1361, 1248, 1113, 838, 775 cm"1. The freshly prepared imine was cyclized into an inseparable mixture of diastereomeric pyrrolidines (115 mg, 87%, 5.0:1.0 by NMR) which was obtained as a gold oil after elution of the crude products through a plug of Florisil 180 (CHgCIg for.elution). The mixture of pyrrolidines was converted into an inseparable mixture of the title compound and the minor AMosyIpyrroIidine (150 mg, 90%, 5.0:1.0 by NMR) which was obtained as a viscous, colorless gel after purification on silica gel (1%-5% EtOAc/hexane for elution): 1H NMR (300 MHz, C6D6) 8 7.75 (d, J = 8.1 Hz, 2H, ArH), 6.76 (d, J = 7.9 Hz, 2H, ArH), 4.50 (d, J = 13.4 Hz, 2H, C=CH2), 4.03 (m,1H, NCH)., 4.00 (dd, J = 10.4,4.1 Hz, 1H, SiOCHH), 3.69 (t, J = 9.8 Hz, 1H, SiOCHH), 3.48 (dq, J = 6.1,2.5 Hz, TH, NCHCH3), 2.48 (ddd, J = 15.1,6.8, 6.8 Hz, 1H, C=CCH), 2.00 (dd, J = 12.6, 6.4 Hz, 1H, CHH), 1.88 (s, SH1ArCH3), 1.61 (d, J = 6.1 Hz, 3H, CH3), 1.22 (m, 1H, CHH), 1.16 (d, 13.6 Hz, 1H, SiCHH), 1.09 (d, J = 13.6 Hz, 1H, SiCHH), 0.96 (s, 9H, (CH3)3CSi), 0.12 (s, 3H, (CH3 )3CSiCH3), p.M (s, 3H, (CH3)3CSiCH3), - 010 (s, 9H, (CH3)3Si); 13C NMR (75 MHz, CDCi3, 1H decoupled) 5 145.26, 143.28, 135.15, 129.54, 127.62, 108.86, 65.80, 61.85, 60.62, 53.34, 32.41, 25.94, 23.99, 22.06, 21.44, 18.31,-1.23, -5.34; IR (film) 3082, 2955, 2857, 1632, 1600, 1472, 1349, 1250, 1166, 1094, 1029, 838, 778, cm’1; HRMS calcd for c 25H45N03SSi2 (M+) 495:2659, found 495.2654. 181 CycHzation of (S)-EthyI Lactate-Derived !mines General Information: The following experimental procedures constitute the methods used to prepare silyl ethers 41a-c, aldehydes 42a-c, the corresponding (mines 43a-c and pyrrolidines 44a-c. The oxazolidinone derivative 45 derived from all major pyrrolidines was identical with respect to spectrometric (1H and 13C NMR) and chromatographic (TLC) properties. (S)-(-)-Ethyl lactate ([a] 14 -10°) was purchased from Aldrich Chemical Company, Inc. and was used without additional purification. (S)-Ethyl-(0-ferf-butyldiphenylsilyl)lactate (41c). To a 25 mL, single-necked, round-bottomed flask containing a solution of tert-butyl- chlorodiphenylsilane (2.60 mL, 10.0 mmol) and imidazole (1.63 g, 24.0 mmol) in DMF (5.0 ml) was added (S)-ethyl lactate (1.36 mL, 12.0 mmol) dropwise over 30 min via a 5.0 mL, addition funnel. During the course of the addition, mild exotherms and precipitation of a clear oil were observed. The reaction mixture was stirred for 5h at rt, poured into a separatory funnel and the layers were allowed to separate. The upper layer was removed and the remaining portion was extracted with hexane ( 3x3 mL). The combined product layer and hexane extracts were washed with H2O ( 2x5 mL), dried over MgS0 4 , filtered and concentrated. The residue was eluted through a plug of silica gel (Et2O for elution) to furnish the title ester (3.35 g, 94%) as a colorless oil: 1H NMR (300 MHz, CDCI3) 8 7.70 (dt, J = 7.7, 1.8 Hz, 4H, ArH), 7.38 (m, 6H, ArH), 4.28 (q, J = O OTBDPS CH3 182 6.7 Hz, 1H, CAT), 4.02 (q, J = 7.1 Hz, 2H, CH2), 1.38 (d, J = 6.8 Hz, 3H, CH3), 1.15 (t, J = 7.1 Hz, 3H, CH3CH2), 1.11 (s, 9H, (CH3)CSi); 13C NMR (75MHz, CDCI3, 1H decoupled) 5 173.61, 135.88, 135.72, 133.67, 133.30, 129.70, 127.58, 127.51, 68.99, 60.47, 26.82, 21.21, 19.23, 14.01, IR (film) 3072, 3050, 2933, 2859, 1753, 1428, 1273, 1196, 1138, 1061, 974, 823, 739, 703, cm"1. o ^ / OTBDPS CH3 (S)-2-(ferM3utyldiphenylsilyloxy)propanal (42c). A 25 mL, single-necked, round-bottomed flask containing a solution of 41c (2.00 g, 5.61 mmol) in toluene (11 mL) was cooled to -78 0C and diisobutylaluminum hydride (6.17 mL, 6.17 mmol, 1.0 M in toluene) was added dropwise over 20 minutes via a 10 mL, addition funnel. The reaction mixture was stirred for 2h at -78 0C and was carefully poured into half-saturated brine (30 mL). The biphasic mixture was stirred for 30 minutes at rt, transferred to a separatory funnel and the layers were allowed to separate overnight. The organic phase was removed and the remaining aqueous phase was extracted with Et2O (3x10 mL). The combined organic fractions were washed with brine (25 mL), dried over MgSO^, filtered and concentrated. The residue was eluted through a thin pad of silica gel (hexane for elution) to provide the title aldehyde (1.61g, 92%) as a colorless oil: 1H NMR (300 MHz, CDCI3) 6 9.63 (d, J = 1.1 Hz, 1 H1O=CH), 7.64 (m, 4H, ArH), 7.39 (m, 6H, ArH), 4.08 (dq, J = 6.9, 0.9 Hz, IH, CH), 1.21 (d, J = 6.9 Hz, 3H, CH3), 1.10 (s, 9H, (CH3)CSi); 13C NMR (75 MHz, CDCI3, 1H decoupled) 5 203.45, 135.69, 133.34, 132.99, 130.00, 129.95, 127.81, 127.75, 74.43, 26.87, 19.20, 18.33; IR (film) 3072, 3051,2932, 2859, 2720, 1739, 1472, 1428, 1375, 1112,1008, 823, 703 cm'1. 183 Me3Si N^y 0 CH3 OTBDPS Me3Si (S)-A/-[(2-(ferf-Butyldiphenylsilyloxy)propylidene]-4- trimethyIsilyImethyl-5-trimethyIsilyl-3-penten-1-amine (43c). To a 10 mL, single-necked, round-bottomed flask containing a solution of aldehyde 42c (384 mg, 1.23 mmol) in THF (4.0 mL) was added freshly activated 4 A molecular sieves (750 mg) followed by amine Ia (300 mg, 1.23 mmol). The reaction mixture was stirred for 24h at rt after which time anhydrous hexane (6.0 mL) was added. The resulting cloudy mixture was filtered through a pad of Celite and the solvents were removed in vacuo to yield the title imine (658 mg, 99%) as a colorless, viscous oil: 1H NMR (300 MHz, CDCI3) 8 7.67 (ddd, J = 6.1,3.8, 1.1 Hz, 4H, ArH), 7.59 (dd, J = 5.0, 1.0 Hz, IH, N=CH), 7.38 (m, 6H, ArH), 4.75 (t, J = 7.0 Hz, 1H, C=CH), 4.36 (p, J = 5.9 Hz, 1H, CH), 3.23 (t, J = 7.6 Hz, 2H, CH2N), 2.11 (m, 2H, CH2), 1.47 (s, 2H, CH2Si), 1.39 (s, 2H, CH2Si), 1.23 (d, J = 6.9 Hz, 3H, CH3), 1.08 (s, 9H, (CH3)SCSi), 0.03 (s, 9H, (CH3)3Si), -0.06 (s, 9H, (CH3)3Si); 13C NMR (75 MHz, CDCI3, 1H decoupled) 5 166.94, 135.83, 135.77, 134.15, 133.92, 130.01, 129.62, 127.76, 127.55, 116.39, 71.35, 61.29, 30.25, 29.49, 27.00, 23.84, 21.60, 19.23, -0.65, -1.12; IR (film) 3072, 2955, 2858, 1676, 1473, 1428, 1370, 1248, 1112, 1007, 854, 701, cm"1. [2S-[2a(S*),3P)]]-2-[(1-(ferf-Butyldiphenylsilyloxy)ethyl]-3-[(3- trimethylsiIyl)isopropenyI]pyrrolidine (44c). A 10 mL, single-necked, 184 round-bottomed flask containing a solution of imine 43c (500 mg, 0.93 mmol) in CHgCIg (6.0 mL) was cooled to -78 0C and TiCI^ (930 fiL, 0.93 mmol, 1.0 M in toluene) was added dropwise over 2 min via syringe. The resulting deep red- orange solution was stirred for Ih at -78 0C, followed by 24h at -20 0C. The cold reaction mixture was neutralized and the crude product was isolated in the manner previously described for the preparation of 14a. The crude material was dissolved in hexane and eluted through a plug of Florisil (EtgO for elution) to provide the title pyrrolidine (394 mg, 91%) as a viscous oil: 1H NMR (300 MHz, CDCI3) 5 7.67 (dt, J = 8.0, 1.7 Hz, 4H, ArH), 7.37 (m, 6H, ArH), 4.51 (d, J = 6.9 Hz, 2H, C=CH2), 3.85 (dq, J = 6.4, 3.0 Hz, 1H, CHOSi), 2.94 (m, 2H, NCH2), 2.80 (dd, J = 7.5, 3.1 Hz, IH, NCH), 2.40 (q, J = 8.0 Hz, 1H, C=CCH), 2.25 (br s, 1H, NH), 1.90 (dddd, J = 15.1, 12.4, 6.5, 2.4, Hz, 1H, CHH), 1.69 (dq, J = 12.6, 7.4 Hz, 1H, CHH), 1.39 (ABql Av = 25.1 Hz, J = 14.1 Hz, 2H, CH2Si), 1.10 (d, J = 6.3 Hz, 3H, CH3), 1.05 (s, 9H, (CH3)3CSi), -0.03 (s, 9H, (CH3)3Si); 13C NMR (75 MHz, CDCI3, 1H decoupled) 5 148.44, 135.99, 135.92, 134.42, 133.51, 129.72, 129.52, 127.65, 127.38, 108.23, 69.93, 69.75, 49.50, 46.30, 32.91, 27.12, 24.38, 22.08, 19.36, -1.09, IR (film) 3072, 3049, 2957, 2858, 1629, 1472, 1428, 1248, 1112, 1073, 851, 702 CrrT1; HRMS calcd for C28H44NOSi2 (MH+) 466.2961, found 466.2960. O 4S-(4a,5a, 6a)-4-Methy l-6-(1-met hy Ietheny I )-3-oxo-1- azabicyclo[3.3.0]octa-2-one (45). To a 10 mL, single-necked, round- 1 8 5 bottomed flask containing a solution of pyrrolidine 44c (100 mg, 0.12 mmol) in THF (2.0 mL) was added tetrabutylammonium fluoride hydrate (169 mg, 0.53 mmol) in one portion and the reaction mixture was stirred for 3h at rt! The mixture was concentrated and the residue was triturated with EtgO (2 x 2 mL). The EtgO extracts were dried thoroughly over NagSOj. and filtered through a pad of Celite (EtgO for elution) into a 5.0 mL, single-necked, round-bottomed flask. The solvent was evaporated and the resulting colorless residue was dissolved in THF (1.5 mL). The solution was treated with carbonyl-diimidazole (52 mg, 0.32 mmol) in one portion and the reaction mixture was stirred for 12h at rt. The reaction mixture was concentrated in vacuo and the residue was directly subjected to column chromatography on silica gel (40% EtOAc/hexane for elution) to provide the title oxazolidinone (21 mg, 53% from 44c) as a colorless oil: 1H NMR (300 MHz, CDCI3) 5 4.81 (s, 1H, C=CHH), 4.71 (s, 1H, C=CHH), 4.38 (dq, J = 6.5, 3.2 Hz, 1H, OCH), 3.56 (dt, J = 11.2, 8.6 Hz, 1H, NCHH), 3.34 (dd, J = 9.6, 3.1 Hz, 1H, NCH), 3.26 (ddd, J = 13.7, 11.5, 2.5 Hz, 1H, NCHH), 2.30 (dt, J = 10.6, 2.8 Hz, 1H, C=CCH), 2.21 (ddd, J = 10.4, 7.8, 2.7 Hz, 1H, ChiH), 1.84 (dq, J = 11.0, 9.1 Hz, 1H, CHH), 1.69 (s, SH1CH3C=C), 1.41 (d, J = 6.4 Hz, 3H, CH3CH); 13C NMR (75 MHz, CDCI3, 1H decoupled) 5 160.99, 141.92, 112.26, 75.46, 68.64, 50.86, 45.09, 31:41, 21.32, 20.57; IR (film) 3081,2975, 1751, 1645, 1383, 1247, 1051, 900, 772, cm"1; HRMS calcd for C10H15NO2 (M+) 181.1103, found 181.1102. 186 2-Propylidene-1,3-bis(silane) Acylnitrilium ion Cyclizations General Information: Silver (I) trifluoromethanesulfonate was purchased from Aldrich Chemical Company, Inc. and was used without additional purification. Acetic formic anhydride was prepared following known literature procedure.69 Commercially purchased acid chlorides and ethyl formate were distilled from CaHg under argon prior to use, (£)-3-carbomethoxy-2- methylpropenoyl chloride and 3-carbomethoxypropionyl chloride were prepared using reported procedures.66 Employing published procedures100- methyl-2-(1,3-dioxanyl)acetate was prepared from methacrolien and 1,3- propanediol. 1-Isocy ano-2-methy l-5-trimethy Isily l-4-(trimethy Isily Imethy I) pent-3-ene (46b). A 25 m l, single-necked, round-bottomed flask was charged with amine Ib (2.00 g, 7.76 mmol) and freshly distilled ethyl formate (6.0 mL). The flask was fitted with a condenser and the solution was heated at reflux for 14h. Upon cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the residue was filtered through a silica gel plug (EtgO for elution) to furnish the corresponding formamide as a viscous, colorless oil. A 50 m l, three-necked, round-bottomed flask equipped with a thermometer and a 5.0 m l, addition funnel was charged with the formamide, THF (20 mL) and triethylamine (5.15 mL, 38.8 mmol). The solution was cooled to 0 °C and phosphorus oxychloride (800 pL, 8.54 mmol) in THF (2.0 mL) was added dropwise over 15 min via the addition funnel. During the + 187 time of addition, the internal reaction temperature was not permitted to exceed 5 °C. The reaction mixture was stirred for 2h at 0 °C and was poured into chilled water (40 ml_). The organic layer was separated and the remaining aqueous phase was extracted with EtgO (3x15 mL). The combined organic fractions were washed with brine (40 mL) and dried over anhydrous MgSO^ The solvents were evaporated in vacuo and the residue was subjected to silica gel chromatography (5% EtOAc/hexane for elution) to yield isonitrile 46b (1.80 g, 87% from 1b) as a colorless oil: 1H NMR (300 MHz, CDCI3) 8 4.56 (d, J = 9.7 Hz, 1H, C=CH), 3.16 (m, 2H, C=NCH2), 2.57 (m, 1H, CM), 1.57 (d, J = 13.5 Hz, IH, SiCHH), 1.38 (q, J = 13.0 Hz, 3H, SiCHHand SiCH2), 1.03 (d, J = 6.6 Hz, 3H, CH3), 0.02 (s, 9H, (CH3)3Si), -0.01 (s, 9H, (CH3)3Si); 13C NMR (75 MHz, CDCI3, 1H decoupled) 5 156.17, 137.58, 120.13, 47.93 (t), 32.89, 29.58, 24.67, 18.49, -0.74, -1.18; IR (film) 2956, 2897, 2145, 1645, 1417, 1249, 1156, 1068, 961, 853, 700, 625 cm '1; HRMS calcd for C14H29NSi2 (M+) 267.1839, found 267.1845. 2-lsocy ano-6-trimethy Isi Iy l-5-(trimethy Isily Imethy l)hex-4-ene (46c). Sequential formylation/ dehydration of amine 1c (2.00 g, 7.76 mmol) using the procedure described for the preparation of 46b provided isonitrile 46c (1.65 g, 80%) as a colorless oil: 1H NMR (300 MHz, CDCI3) 5 4.80 (t, J = 7.3 Hz, IH, C=CH), 3.53 (app tsx, J = 6.4, 1.4 Hz, 1H, CHN=C), 2.21 (m, 2H, CH2), 1.47 (d, J = 3.7 Hz, 2H, SiCH2), 1.42 (s, 2H, SiCH2), 1.32 (ddd, J = 8.9, CH3 Me3Si 188 4.4, 2.3 Hz, 3H, CH3), 0.01 (s, 9H, (CH3)3Si), 0.00 (s, 9H, (CH3)3Si); 13C NMR (75 MHz, CDCI3, 1H decoupled) 5 139.31, 112.79, 50.62, 36.05, 29.85, 24.21, 1065, 851, 699, 625 cm'1; HRMS calcd for C14H29NSi2 (M+) 267.1839, found 267.1831. Iv ie3Sii 1-lsocyano-5-trimethy Isi Iy l-4-(trimethy Isily Imethy l)pent-3-ene (46a). Sequential formylation/ dehydration of amine 1a (2.00 g, 8.21 mmol) using the procedure described for the preparation of 46b provided isonitrile 46a (1.77 g, 85%) as a colorless oil: 1H NMR (300 MHz, CDCI3) 5 4.75 (t, J = 7.0 Hz, IH, C=CH), 3.28 (app tt, J = 6.9, 1.8 Hz, 2H, CH2C=N), 2.28 (app tq, J = 6.9, 1.8 Hz, 2H, CH2), 1.47 (s, 2H, SiCH2), 1.41 (s, 2H, SiCH2), 0.01 (s, 9H, (CH3)3Si), -0.01 (s, 9H, (CH3)3Si); 13C NMR (CDCI3, 75 MHz, 1H decoupled) 6 155.96, 139.22, 113.13, 41.81,29.69, 28.81,24.04, -0.81, -1.28; IR (film) 2985, 2954, 2896, 2146, 1647, 1415, 1247, 1153, 1063, 852, 699, 625 cm'1; HRMS calcd for C13H27NSi2 (M+) 253.1682, found 253.1675. I -ferf-Buty Idimethy Isily loxy-2-isocyano-6-trimethy Isily 1-5- (trimethyl-silylmethyl)hex-4-ene (46d). A 50 mL, single-necked, round- bottomed flask containing a solution of amine 1d (1.50 g, 3.87 mmol) in Et2O 21.14, -0.69, -1.13; IR (film) 2983, 2955, 2897, 2137, 1646, 1415, 1248, 1153, OTBS Me3Si 189 (25 mL) was cooled to -78 °C and freshly prepared formic acetic anhydride (360 mg, 4.06 mmol) was added dropwise over 5 min via a syringe. The reaction mixture was stirred for 45 min at -78 °C and was then transferred slowly by cannula into vigorously stirred, saturated aqueous KHCOg (40 mL). The resulting diphasic mixture was stirred for 30 min and the layers were separated. The aqueous phase was extracted with Et2O (2x15 mL) and the combined organic fractions were washed once with brine (35 mL), dried over IVIgSOj. and filtered through a silica gel pad (Et2O for elution) to afford the corresponding formamide as a colorless viscous oil. Dehydration of the formamide with POCIg in the manner previously described for the preparation of 46b gave the title isonitrile (1.26 g, 85% from 1d) as a colorless oil after purification of the crude product by filtration through a silica gel plug (5% EtOAc/hexane for elution): 1H NMR (300 MHz, CDCIg) 5 4.81 (t, J = 7.3 Hz, 1H, C=CH), 3.65 (d, J = 4.6 Hz, 2H, OCH2), 3.47 (p, J = 6.1 Hz, 1H, CH), 2.27 (m, 2H, CH2), 1.49 (s, 2H, SiCH2), 1.42 (s, 2H, SiCH2), 0.89 (s, 9H, (CH3)3CSi), 0.07 (s, 6H, OSi(CHg)2), 0.01 (s, 18H, Si(CH3)3 x 2); 13C NMR (75 MHz, CDCIg, 1H decoupled) 5 156.00, 139.55, 112.41,64.31, 57.11,30.58, 29.86, 25.79, 24.18, 18.21,-0.71,-1.12, - 5-40; IR (film) 2955, 2897, 2858, 2139, 1646, 1472, 1464, 1412, 1362, 1249, 1129, 836, 778, 700, 626 cm"1; HRMS calcd for C20H43NOSi3 (M+) 397.2652, found 397.2641. 5-Trimethy Iacety l-4-[1-(trimethy Isily Imethy l)ethenyl]-3,4- dihydro-2H-pyrrole (48a). The following procedure, employed for the 190 preparation of pyrroline 48a, constitutes the general procedure used for the silver ion mediated cyclization of ketoimidoyl chlorides. To a 5.0 ml_, tear- dropped flask containing a solution of isonitrile 46a (200 mg, 0.79 mmol) in CHgCIg (500 pL) was added thmethylacetyl chloride (117 pL, 0.95 mmol) and the mixture was stirred for 12h at room temperature. The volatile components were removed under reduced pressure during which time exposure of the reaction mixture to air was kept at a minimum. The residue was dissolved in a 1:1 mixture of CHgCI2 and CICHgCHgCI (800 pL) and the resulting solution of the crude keto imidoyl chloride was used immediately in the next step. A 10 mL, single-necked, round-bottomed flask was charged with AgOTf (304 mg, 1.18 mmol) and 1:1 CHgCIg/CICHgCHgCI (4.0 mL). The suspension was cooled to -78 °C and the freshly prepared solution of the crude ketoimidoyl chloride was added dropwise via a gas-tight syringe. The mixture was stirred at a temperature range of -78 °C to -65 °C for 2h during which time a white solid precipitated. Stirring was continued at -20 °C for an additional 6h after which time the cold reaction mixture was transferred dropwise via cannula into vigorously stirred, aqueous saturated KHCOg (8 mL) at 0° C. The diphasic mixture was stirred for 15 min at room temperature, decanted into a separatory funnel, and the organic layer was separated. The remaining aqueous phase was extracted with Et2O ( 2x4 mL) and the combined organic fractions were dried (MgSO^, filtered and concentrated in vacuo. The residue was subjected to chromatography on silica gel (5% EtOAc/hexane. for elution) to furnish pyrroline 48a (171 mg, 82% from 46a) as a colorless oil: 1H NMR (300 MHz, CDCI3) 5 4.51 (s, 1H, C=CHH), 4.31 (s, 1H, C=CHH), 4.06 (m, 2H, CH2N=C), 3.60 (ddd, J = 10.0, 4.3, 2.2 Hz, 1H, C=CCH), 2.12 (m, 1H, CHH), 1.71 (dddd, J 191 = 17.0, 12.2, 6.9, 4.7 Hz, 1H, CHH), 1.65 (d, J = 14.0 Hz, 1H, SiCHH), 1.50 (d, J = 13.8 Hz, 1H, SiCHH), 1.29 (s, 9H, (CH3)3C), 0.05 (s, 9H, (CH3)3Si); 13C NMR (75 MHz, CDCI3, 1H decoupled) 5 205.02, 173.89, 147.82, 107.27, 61.40, 55.29, 44.03, 30.54, 28.19, 27.02, -1.31; IR (film) 3077, 2955, 2870, 1684, 1630, 1482, 1459, 1249, 1162, 1055, 982, 848, 694 cm"1; HRMS calcd for C15H27NOSi (M+) 265.1862, found 265.1856. 5-(2-Methy Ipropanoy l)-4-[1-(tr imethy Isily Imethy l)ethenyl]-3,4- dihydro-2H-pyrrole (48b). Using isonitrile 46a (100 mg, 0.39 mmol) and isobutyryl chloride (62 ( il, 0.59 mmol) in the general procedure described for the preparation of 48a provided the title pyrroline (67 mg, 68%) as a light yellow oil after silica gel chromatography (5% EtOAc/hexane for elution): 1H NMR (300 MHz, CDCI3) 5 4.50 (s, 1H, C=CHH), 4.24 (s, 1H, C=CHH), 4.06 (m, 2H, CH2N=C), 3.60 (m, IH, CH(CH3)2), 3.57 (dd, J = 8.9, 1.9 Hz, IH, C=CCH), 2.18 (dq, J = 8 .8 , 3.6 Hz, 1H, CHH), 1.81 (ddd, J = 16.4, 7.6, 3.7 Hz, 1H, CHH), 1.69 (d, J = 13.4 Hz, IH, SiCHH), 1.52 (d, J = 13.7 Hz, 1H, SiCHH), 1.10 (dd, J = 7.0, 3.4 Hz, 6H, (CH3)2C), 0.06 (s, 9H, (CH3)3Si); 13C NMR (75 MHz, CDCI3, 1H decoupled) 5 202.96, 174.67, 147.52, 106.92, 60.90, 53.37, 35.77, 31.31, 28.15, 18.65, 17.87, -1.36; IR (film) 3076, 2955, 2875, 1698, 1630, 1468, 1383, 1299, 1159, 1052, 983, 694 cm"1; HRMS calcd for C14H25NOSi (M+) 251.1705, found 251.1705. 192 Me3Si 5-(3-Methy Ibutanoy l)-4-[1-(trimethy Isily Imethy l)ethenyl]-3,4- dihydro-2H-pyrrole (48c). The general procedure employed for the preparaton of 48a was followed using isonitrile 46a (100 mg, 0.39 mmol) and isovaleryl chloride (72 pL, 0.59 mmol) to provide the title pyrroline (81 mg, 77%) as a light yellow oil after purification of the product by chromatography on silica gel (5% EtOAc/hexane for elution): 1H NMR (300 MHz, CDCI3) 8 4.49 (s, 1H, C=CHH), 4.20 (s, 1H, C=CHH), 4.03 (m, 2H, CH2N=C), 3.57 (dt, J = 10.0, 2.6 Hz, IH, C=CCH), 2.76 (app t, J = 7.6 Hz, 2H, O=CCH2), 2.17 (m, 2H, CH(CH3)2 and CHH), 1.81 (ddd, J = 12.6, 7.5, 3.7 Hz, 1H, CHH), 1.69 (d, J = 13.4 Hz, 1H, SiCHH), 1.51 (d, J = 13.5 Hz, 1H, SiCHH), 0.90 (app t, J = 6.2 Hz, 6H, (CH3)2CH), 0.06 (s, 9H, (CH3)3Si); 13C NMR (75 MHz, CDCI3, 1H decoupled) 6 199.15, 175.70, 147.48, 106.96, 60.83, 53.32, 47.65, 31.31,28.09, 24.43, 22.69, 22.43, -1.34; IR (film) 3075, 2956, 1696, 1630, 1466, 1369, 1249, 1023, 989, 845, 693 cm'1; HRMS calcd for C15H27NOSi (M+) 265.1862, found 265.1852. 5-(4-Chlorobutanoyl)-4-[1-(trimethy Isily Imethy l)ethenyl]-3,4- dihydro-2H-pyrrole (48d). Utilization of isonitrile 46a (100 mg, 0.39 mmol) and 4-chlorobutyryl chloride (66 pL, 0.59 mmol) in the general procedure Cl 193 outlined for the preparation of 48a furnished the title pyrroline (69 mg, 61%) as a light yellow oil after purification by silica gel chromatography (5% EtOAc/ hexane for elution): 1H NMR (300 MHz, CDCI3) 5 4.49 (s, IN, C=CHH), 4.18 (s, 1H, C=CHH), 4.03 (m, 2H, CH2N=C), 3.54 (t, J = 6.4 Hz, 3H, CH2CI and C=CCH(OverIap)), 3.20 (dt, J = 18.4, 7.2 Hz, 1H, O=CCHH), 2.95 (dt, J = 18.2, 7.2 Hz, 1H, O=CCHH), 2.17 (dq, J = 12.5, 9.9 Hz, 1H, CHH), 2.07 (dp, J = 7.0, 2.0 Hz, 2H, CH2CH2CI), 1.81 (ddd, J = 16.6, 7.6, 3.8 Hz, 1H, CHH), 1.68 (d, J = 13.7 Hz, 1H, SiCHH), 1.51 (d, J = 13.6 Hz, 1H, SiCHH), 0.05 (s, 9H, (CH3)3Si); 13C NMR (75 MHz, CDCI3, 1H decoupled) 5 198.10, 175.13, 147.35, 106.99, 60.85, 53.38, 44.19, 35.92, 31.25, 27.99, 26.42, -1.35; IR (film) 3075, 2954, 1739, 1699, 1629, 1405, 1248, 1158, 1051, 983, 845, 695 cm"1; HRMS calcd for C14H24CINOSi (M+) 285.1316, found 285.1306. 2-(1,3-Dioxanyl)acetyl chloride. A 250 mL, single-necked, round- bottomed flask was charged with potassium trimethylsilanolate (2.01 g, 15.7 mmol) and THF (65 mL). To the white supension was added methyl-2-(1,3- dioxanyl) acetate (2.51 g, 15.7 mmol) in THF (7.5 mL) dropwise over 20 min via a 25 mL, addition funnel. The resulting cloudy suspension was stirred for 5.5h and then diluted with anhydrous EtaO (60 mL) producing a white precipitate. The solid was collected on a fritted funnel, washed thoroughly with anhydrous EtaO and dried in vacuo to provide the corresponding potassium salt as a white powder. A 100 mL, single-necked, round-bottomed flask was charged with the freshly prepared salt, benzene (30 mL) and two drops of DMF. To the white 194 suspension was added oxalylchloride (1.64 mL, 18.8 mmol) in benzene (5 m l) dropwise over 15 min via a 5.0 mL, addition funnel during which the evolution of gas was observed. The reaction mixture was stirred for 2h and was filtered through a Celite pad (anhydrous EtgO for elution). The resulting solution was concentrated and the residue was bulb to bulb distilled to furnish the title acid chloride (1.97 g, 76%) as a colorless liquid: bp 50-55 0C, 250 (itorr; 1H NMR (300 MHz, CDCI3) 6 4.98 (t, J = 5.2 Hz, 1H, CH), 4.08 (dd, J = 10.9, 5.0 Hz, 2H, OCHH x 2) 3.77 (dt, J = 12.4, 2.3 Hz, 2H, OCHHx 2), 3.12 (d, J = 5.1 Hz, 2H, O=CCHa), 2.05 (m, 1H, CHH), 1.34 (dd, J = 13.3, 1.1 Hz, 1H, CHH); NMR (75 MHz, CDCI3 , 1H decoupled) 5 169.22, 97.37, 66.93, 52.18, 25.23. 5-[2-(1,3-dioxany l)acetyl]-4-[1-(trimethy Isily Imethy l)etheny I]- 3,4-dihydro-2H-pyrrole (48e). To a 5 mL tear-dropped flask containing a solution of 2-(1,3-dioxolanyl)acetyl chloride (61 mg, 0.37 mmol) in CHgCIg (200 gL) was added isonitrile 46a (94 mg, 0.37 mmol) via syringe. The flask was sealed and the reaction mixture was stirred at 40 °C for 14h. Upon cooling the mixture to room temperature, 1:1 CHgCIg/CICHgCHgCI (0.5 mL) was added and the resulting solution of the crude ketoimidoyl chloride was treated with AgOTf (143 mg, 0.56 mmol) as described in the general procedure used for the preparation of 48a. Isolation and purification of the crude product was achieved by the methods described for 48a to furnish 48e (105 mg, 91%) as a colorless viscous oil: 1H NMR (300 MHz, CDCI3) 8 5.05 (dd, J = 5.6, 5.2 Hz, 1H, 1 9 5 OCHO), 4.47 (s, IH, C=CHH), 4.20 (s, IN, C=CHH), 4.03 (m, 4H, C=NCH2 and OCHH x 2), 3.74 (ddd, J = 12.8, 2.3, 1.1 Hz, 2H, OCHHx 2), 3.53 (dt, J = 10.1, 2.9 Hz, IH, C=CCH), 3.27 (dd, J = 15.7, 5.8 Hz, 1H, O=CCHH), 3.10 (dd, J = 15.8, 4.7 Hz, IH, O=CCHH), 2.11 (m, 2H, C=NCH2CHH and OCH2CHH), 1.80 (dddd, J = 12.7, 11.2, 7.4, 3.6 Hz, 1H, NCH2CHH), 1.66 (d, J = 13.5 Hz, 1H, SiCHH), 1.47 (d, J = 13.6 Hz, IH 1SiCHH), 1.27 (app dt, J = 13.5, 1.1 Hz, 1H, OCH2CHH), 0.04 (s, 9H, (CH3)3Si); 13C NMR (75 MHz, CDCI3, 1H decoupled) 5 195.02, 175.22, 146.87, 107.17, 98.99, 66 .86 , 60.81, 53.19, 44.63, 31.31, 27.79, 25.50, -1.34; IR (film) 3075, 2954, 2855, 1739, 1702, 1631, 1248, 1136, 1017, 847 cm"1; HRMS calcd for C16H27NO3Si (M+) 309.1760, found 309.1754. 7ra/7s-3-methyl-5-trimethylacetyl-4-[1-(trimethylsilylmethyl)- ethenyl]-3,4-dihydro-2/V-pyrrole (49a). The procedure previously described for the preparation of 48a was followed employing isonitrile 46b (144 mg, 0.54 mmol) and trimethylacetyl chloride (83 pL, 0.67 mmol). This provided 49a (61 mg, 41%) as a colorless oil after purification by silica gel chromatography (1% EtOAc/hexane for elution): 1H NMR (300 MHz, CDCI3) 8 4.47 (s, 1H, C=CHH), 4.29 (s, 1H, C=CHH), 4.15 (ddd, J = 17.1,7.1,2.2 Hz, 1H, CHHN=C), 3.67 (dd, J = 17.1,3.0 Hz, 1H, CHHN=C), 3.20 (t, J = 2.7 Hz, 1H, C=CCH), 2.11 (m, IH 1CHCH3), 1.59 (d, J = 13.7 Hz, 1 H1SiCHH), 1.43 (d, J = 13.7 Hz, IH, SiCHH), 1.29 (s, 9H, (CH3)3C), 0.99 (d, J = 7.0 Hz, 3H, CH3), 0.05 (s, 9H, (CH3)3Si); 13C NMR (75 MHz, CDCI3, 1H decoupled) S 205.06, 173.41, 196 146.26, 107.24, 68.76, 63.92, 44.10, 38.32, 27.34, 27.08, 20.92, -1.19; IR (film) 3075, 2956, 2871, 1683, 1631, 1482, 1419, 1249, 1161, 1093, 955, 846, 696 cm"1; HRMS calcd for C16H29NOSi (M+) 279.2018, found 279.2011. Tra/?s-3-methy l-4-[1-(tr imethy Isi Iy Imethy i)ethenyl]-5- propanoyl-3,4-dihydro-2H-pyrrole (49b). The previously described procedure was followed employing isonitrile 46b (241 mg, 0.87 mmol) and propionyl chloride (84 pL, 0.96 mmol) to provide 49b (86 mg, 40%) as a colorless oil after purification by silica gel chromatography (1% - 5% EtOAc/hexane for elution): 1H NMR (300 MHz, CDCI3) 5 4.44 (s, 1H, C=CHH), 4.16 (s, 1H, C=CHH), 4.12 (ddd, J = 17.4, 6.9, 2.4 Hz, 1H, CHHN=C), 3.67 (dd, J = 17.5, 2.4 Hz, 1H, CHHN=C), 3.17 (t, J = 2.1 Hz, 1H, C=CCH), 3.05 (dq, J = 18.1,7.5 Hz, IH, CHHCH3), 2.78 (dq, J = 18.8, 7.4 Hz, 1H, CHHCH3), 2.19 (m, IH, CH3CH), 1.64 (d, J = 13.5 Hz, 1H, SiCHH), 1.45 (d, J = 13.7 Hz, 1H, SiCHH), 1.08 (t, J = 7.4 Hz, 3H, CH2CH3), 1.00 (d, J = 7.5 Hz, 3H, CH3), 0.07 (s, 9H, (CH3)3Si); 13C NMR (75 MHz, CDCI3, 1H decoupled) 5 200.07, 174.60, 146.03, 106.77, 68.22, 62.07, 39.12, 32.00, 27.27, 21.30, 7.58, -1.24; IR (film) 3076, 2956, 1700, 1631, 1460, 1377, 1249, 1159, 1096, 950, 848, 698 cm"1; HRMS calcd for C14H25NOSi (M+) 251.1705, found 251.1705. 197 Cis- and f r a n s -2 -m e th y l- 5 - t r im e th y la c e ty l - 4 - [ 1 - ( t r im e th y l- s i ly lm e th y l) -e th e n y l ] -3 ,4 -d ih y d ro -2 H -p y r r o le (SOatrans and 5 0 a c#s). Utilizing isonitrile 46c (200 mg, 0.75 mmol) and trimethylacetyl chloride (110 gL, 0.90 mmol) in the procedure outlined for the preparation of 48a, a mixture of pyrrolines 5 0 c /s and SOtrans (189 mg, 90%, 4.4 : 1.0 by NMR) was obtained as a light yellow oil after filtration of the crude product mixture through a plug of silica gel (5% EtOAc/hexane for elution). The mixture of diastereomeric pyrrolines was subjected to column chromatography on silica gel (1% - 5% EtOAc/hexane for elution) to afford the major pyrroline SOac is (131 mg, 63% from 46c) as a colorless oil. 50c/s: 1H NMR (300 MHz, CDCI3) 5 4.56 (s, 1H, C=CHH), 4.39 (s, 1H, C=CHH), 4.19 (sx, J = 6.7 Hz, 1H, CH3CHN=C), 3.58 (dt, J = 9.6, 1.5 Hz, 1H, C=CCH), 2.41 (ddd, J = 18.0, 9.9, 8.1 Hz, 1H, CHH), 1.65 (d, J = 13.5 Hz, 1H, SiCHH), 1.52 (d, J = 13.4 Hz, 1H, SiCHH), 1.35 (d, J = 6.9 Hz, 3H, CH3), 1.29 (m, IH, CHH), 1.27 (s, 9H, (CH3)3C), 0.03 (s, 9H, (CH3)3Si); 13C NMR (75 MHz, CDCI3, 1H decoupled) 5 206.31, 172.10, 149.32, 108.23, 68.77, 56.67, 43.99, 38.34, 28.47, 27.06, 22.16, -1.28; IR (film) 3077 ,2957, 2871, 1685, 1630, 1482, 1457, 1364, 1249, 1161, 1050, 841,695, cm"1; HRMS calcd for C16H29NOSi (M+) 279.2018, found 279.2012. SOtrans 1H NMR (300 MHz, CDCI3) 6 4.47 (s, 1H, C=CHH), 4.32 (m, 1H, CH3CHN=C), 4.31 (s, 1H, C=CHH), 3.66 (dt, J = 9.9, 2.9 Hz, IH, C=CCH), 1.91 (ddd, J = 12.9, 7.2, 3.5 Hz, IH, CHH), 1.64 (d, J = 13.0 Hz, IH, SiCHH), 198 1.63 (ddd, J = 17.7, 9.9, 7.3 Hz, 1H, CHAT), 1.48 (d, J = 13.0 Hz, 1H, SiCHH), 1.29 (s, 9H, (CH3)3C), 0.04 (s, 9H, (CH3)3Si); 13C NMR (75 MHz, CDCI3, 1H decoupled) 5 205.25, 171.74, 147.43, 106.95, 68.78, 55.90, 44.19, 38.67, 29.87, 27.66, 21.63, -1.27; IR (film) 3077, 2954, 2858, 1687, 1630, 1472, 1463, 1361, 1250, 1161,1125, 1004, 840, 777, 696 cm"1. Cis- and f r a n s -3 -m e th y l- 4 - [ 1 - ( t r im e th y ls i ly lm e th y l ) e th e n y l ] - 5 - p ro p a n o y l-3 ,4 -d ih y d ro -2 H -p y r ro le (5 0 b c#s and SObfr a n s ). The general procedure employed for the preparation of 48a was followed using isonitrile 46c (215 mg, 0.78 mmol) and propionyl chloride (80 pL, 0.92 mmol) to furnish a mixture of pyrrolines 5 0 b c/s and SObfran s (152 mg, 78%, 3.9 : 1.0 by NMR) which was isolated as a light yellow-green oil after elution of the crude material through a silica gel plug (5% EtOAc/hexane for elution). The mixture of isomeric pyrrolines was subjected to chromatography on silica gel (1% - 5% EtOAc/ hexane for elution) to provide the major diastereomer SObczs (95 mg, 49% from 46c) as a colorless oil. 5 0 b czs: 1H NMR (300 MHz, CDCI3) 8 4.52 (s, 1H, C=CHH), 4.26 (s, 1H, C=CHH), 4.21 (sx, J = 7.0 Hz, 1H, CH3CHN=C), 3.53 (dd, J = 9.5, 6.9 Hz, 1H, C=CCH), 3.05 (dq, 18.1,7.3 Hz, 1H, CHHCH3), 2.72 (dq, J = 18.1, 7.4 Hz, 1H, CHHCH3), 2.48 (ddd, J = 18.6, 10.4, 8.6 Hz, 1H, CHH), 1.68 (d, J = 13.5 Hz, 1H, SiCHH), 1.51 (d, J = 13.5 Hz, IH, SiCHH), 1.35 (q, J = 6.3 Hz, IH, CHH), 1.33 (d, J = 6.9 Hz, 3H, CH3), 1.06 (t, J = 7.4 Hz, 3H, CH2CH3), 0.04 (s, 9H, 199 (CH3)3Si); 13C NMR (75 MHz, CDCI3, 1H decoupled) 5 200.73, 173.34, 149.69, 107.78, 68.41,54.76, 38.80, 32.48, 28.27, 22.10, 7.50, -1.30; IR (film) 3074, 2967, 2896, 1701, 1631, 1451, 1410, 1374, 1321, 1249, 1159, 1111,919, 854, 696 cm"1; HRMS calcd Io rC 14H25NOSi (M+) 251.1705 found 251.1701. 50bfrans; 1H NMR (300 MHz- CDCI3) 5 4.46 (s, 1H, C=CHH), 4.26 (dsx, J = 6.7, 1.8 Hz, 1H, CH3CHN=C), 4.21 (s, 1H, C=CHH), 3.64 (dt, J = 9.9, 2.3 Hz, 1H, C=CCH), 3.06 (dq, J = 18.2, 7.2 Hz, 1H, CHHCH3), 2.77 (dq, J = 18.1, 7.4 Hz, 1H, CHHCH3), 2.00 (ddd, J = 12.6, 6.9, 2.6 Hz, 1H ,CHH), 1.67 (dd, J = 18.3, 12.8 Hz, 1H, CHH), 1.67 (d, J = 13.1 Hz, 1H, SiCHH), 1.49 (d, J = 13.8 Hz, 1H, SiCHH), 1.35 (d, J = 6.9 Hz, 3H, CH3), 1.08 (t, J = 7.3 Hz, 3H, CH2CH3), 0.06 (s, 9H, (CH3)3Si); 13C NMR (75 MHz, CDCI3, 1H decoupled) 5 200.30, 173.47, 146.96, 106.65, 68.14, 54.18, 39.37, 32.13, 27.90, 21.46, 7.53, -1.33; IR (film) 3075, 2960, 2890, 1701, 1654, 1631, 1449, 1376, 1308, 1249, 1158, 1099, 854, 695 cm"1. Me3Si T B SO ^ C /s -a n d - f r a n s -2 - ( f -b u ty ld im e th y ls i ly lo x y )m e th y l-5 - t r im e th y l- a c e ty l - 4 - [1 - ( t r im e th y Is i ly Im e th y l )e th e n y l] -3 ,4 -d ih y d r o -2 H -p y r r o le (5 0 c c/-s and SOcfran s ). Isonitrile 46d (205 mg, 0.51 mmol) and trimethylacetyl chloride (76 pL, 0.62 mmol) were used in the general procedure outlined for the preparation 48a to yield a mixture of diastereomeric pyrrolines 5 0 c c /s and SOcfrans (184 mg, 87%, 2.8 : 1.0 by NMR) as a light gold oil after 200 purification of the crude material via filtration through a silica gel plug (5% EtOAc/hexane for elution). Separation of the mixture by column chromatography on silica gel (1% - 5% EtOAc/hexane for elution) furnished the major diastereomer 50cc/-s (118 mg, 56% from 46d) as a light yellow oil. 50cc/s: 1H NMR (300 MHz, CDCI3) 5 4.57 (s, 1H, C=CHH), 4.49 (s, 1H, C=CHH), 4.17 (m, 1H, CHN=C), 3.86 (d, J =4.8 Hz, 2H, CH2O), 3.59 (dt, J = 10.7,2.1 Hz, 1H, C=CCH), 2.26 (ddd, J = 18.1, 9.2, 8 .2 , 1H, CHH), 1.65 (dd, J = 16.2, 12.8 Hz, IH, CHH), 1.59 (ABq, Av = 33.4 Hz, J = 13.6 Hz, 2H, SiCH2), 1.27 (s, 9H, (CH3)3C), 0.87 (s, 9H, (CH3)3CSi), 0.05 (s, 3H, CH3SiC(CH3)3), 0.04 (s, 3H, CH3SiC(CH3)3), 0.03 (s, 9H, (CH3)3Si); 13C NMR (75 MHz, CDCI3, 1H decoupled) 5 206.53, 173.95, 148.88, 108.83, 74.86, 65.52, 56.35, 43.88, 32.75, 28.43, 27.04, 25.94, 18.38, -1.26, -5.34; IR (film) 3077, 2954, 2859, 1687, 1630, 1482, 1472, 1463, 1391, 1361, 1250, 1160, 1123, 1037, 1001, 940, 837, 776 cm '1; HRMS calcd for C22H43NO2Si2 (M+) 409.2832, found 409.2826. 50ctrans- 1H NMR (300 MHz, CDCI3) 5 4.49 (s, 1H, C=CHH), 4.38 (m, 1H, CHN=C), 4.34 (s, 1H, C=CHH), 3.80 (dd, J = 4.2, 2.4 Hz, 2H, OCH2), 3.66 (ddd, J = 9.8, 4.2, 2.3 Hz, TH, C=CCH), 2.04 (ddd, J = 16.4, 1.0.0, 6.4 Hz, 1H, CHH), 1.75 (ddd, J = 12.5, 7.8, 4.6 Hz, 1H, CHH), 1.65 (d, J = 13.5 Hz, 1H, SiCHH), 1.50 (d, J = 13.3 Hz, 1H, SiCHH), 1.29 (s, 9H, (CH3)3C), 0.84 (s, 9H, (CH3)3CSi), 0.06 (s, 3H, CH3SiC(CH3)3), 0.04 (s, 9H, (CH3)3Si), 0.02 (s, 3H, CH3SiC(CH3)3); 13C NMR (75 MHz, CDCI3, 1H decoupled) 5 205.27, 173.63, 148.25, 107.17, 75.15, 65.51, 56.11, 44.07, 33.24, 28.18, 27.08, 25.85, 18.26, - 1.25, -5.39; IR (film) 3076, 2954, 2858, 1686, 1630, 1482, 1472, 1463, 1391, 1361,1250,1161,1125,1004, 840, 777, 696, 627 cm'1. 201 CO2CH3 TBSO"" C /s -a n d - f r a /7 s -2 - ( f -b u ty ld im e th y ls i ly lo x y )m e th y l-5 - (3 -c a rb o - m e th o x y p ro p a n o y l ) -4 - [1 - ( t r im e th y Is i ly Im e th y l )e th e n y l] -3 ,4 -d ih y d ro - 2H -p y rro le (5 0 d c /s and SOdfran s ). Using the procedure outlined for the preparation of 48a , isonitrile 46d (188 mg, 0.47 mmol) and 3-carbomethoxy- propionyl chloride (85 mg, 0.57 mmol) were converted into a mixture of diastereomeric pyrrolines SOdcfs and SOdfran s (160 mg, 77%, 4.3 : 1.0 by NMR). In this instance, exposure of the crude ketoimidoyl chloride to AgOTf was performed at -78 °C for 2 h followed by an abbreviated reaction time of 2 h at - 25 °C. Isolation of the major pyrroline SOdcfs (99 mg, 48% from 46d ) was achieved by separation of the mixture by silica gel chromatography (5% EtOAc /hexane for elution). SOdc fs : 1H NMR (300 MHz, CDCI3) 5 4.55 (s, 1H, C=CHH), 4.33 (s, 1H, C=CHH), 4.24 (m, 1H, C=NCH), 3.88 (dd, J = 10.1,4.6 Hz, 1H, SiOCHH), 3.77 (dd, J = 10.2, 6.1 Hz, 1H, SiOCHH), 3.64 (s, 3H, CH3O), 3.54 (ddd, J = 9.5, 7.3, 1.5 Hz, IH, C=CCH), 3.44 (dt, J = 18.8, 6.8 Hz, 1H, O=CCHH), 2.97 (dt, J = 18.9, 6.6 Hz, IH, O=CCHH), 2.61 (t, J = 6.7 Hz, 2H, O=CCH2CH2), 2.35 (ddd, J = 18.7, 10.0, 8.7 Hz, 1H, CHH), 1.70 (dd, J = 19.9, 6.8 Hz, 1H, CHH), 1.68 (d, J = 13.9 Hz, 1H, SiCHH), 1.52 (d, J = 13.6 Hz, 1H, SiCHH), 0.88 (s, 9H, (CH3)3CSi), 0.06 (s, 3H, (CH3)3CSiCH3), 0.05 (s, 3H, (CH3)3CSiCH3), 0.04 (s, 9, (CH3 )3Si); 13C NMR (75 MHz, CDCI3, 1H decoupled) 5 197.81, 174.56, 172.88, 149.14, 108.40, 74.70, 65.66, 54.45, 51.63, 34.26, 33.63, 28.16, 27.60, 202 25.95, 18.43, -1.28, -5.24; IR (film) 2954, 2929, 2857, 1744, 1705, 1632, 1472, 1437, 1361, 1250, 1212, 1162, 1123, 1006, 841, 777 cm"1; HRMS calcd for C22H41NO4Si2 (M+) 439.2574, found 439.2563. 50dtrans 1H NMR (300 MHz, CDCI3) 5 5.20 (d, J = 1.0 Hz, 1H, C=CHH), 4.08 (m, 1H, C=NCH), 3.93 (m, 4H, SiOCH2, C=CCH and C=CHH), 3.63 (s, 3H, OCH3), 3.34 (dt, J = 19.0, 6.8 Hz, 1H, O=CCHH), 3.01 (dt, J = 18.9, 6.8 Hz, IH, O=CCHH), 2.60 (dt, J = 7.0, 1.8 Hz, 2H, O=CH2CH2), 2.08 (ddd, J = 16.5, 9.5, 8.6 Hz, 1H, CHH), 1.70 (ddd, J = 19.4, 9.8, 9.8 Hz, 1H, CHhi), 1.39 (dd, J = 15.1, 1.3 Hz, IH, SiCHH), 1.10 (d, J = 15.2 Hz, 1H, SiCHH), 0.89 (s, 9H, (CH3)3CSi), 0.11 (s, 6H, (CH3)3CSi(CH3)2), -0.01 (s, 9H, (CH3)3Si); 13C NMR (75 MHz, CDCI3, 1H decoupled) 6 197.31, 174.37, 172.87, 152.84, 126.25, 73.76, 65.45, 57.21, 51.61,33.97, 31.50, 27.53, 25.96, 23.99, 18.46, -0.53, - 5.20; IR (film) 2954, 2898, 2858, 1744, 1705, 1599, 1472, 1438, 1373, 1360, 1249, 1168,1125, 1047, 1015, 837, 779, 734, 690 cm"1. Me3Si TBSO ^ C /s -a n d - f r a n s -2 - ( f -b u ty ld im e th y ls i ly lo x y )m e th y l- 5 - (E -3 - c a rb o m e th o x y -2 -m e th y Ip ro p e n o y l ) - 4 - [1 - ( t r im e th y Is i ly Im e th y I)- e th e n y l] -3 ,4 -d ih y d ro -2 H -p y r ro le (5 0 e c /s and SOetrans). Employing isonitrile 46d (259 mg, 0.65 mmol) and (E)-3-carbomethoxy-2-methyipropenoyl chloride (127 mg, 0.78 mmol) in the general procedure used for 48a provided a mixture of diastereomeric pyrrolines 5 0 e c /s and SOetrans (225 mg, 76%, 3.0 : 203 1.0 by NMR) after elution of the crude material through a silica gel plug (5% EtOAc/hexane for elution). Separation of the diastereomers was achieved by subjecting the mixture to column chromatography on silica gel (1% - 5% EtOAc/hexane for elution) to afford 50ecys (138 mg, 47% from 46d) as a light yellow oil. 50ec/s: 1H NMR (300 MHz, CDCI3) 5 6.92 (d, J = 1.3 Hz, 1H, C=CH), 4.57 (s, 1H, C=CHH), 4.52 (s, 1H, C=CHH), 4.18 (m, 1H, C=NCH), 4.06 (dd, J = 10.2,4.1 Hz, 1H, SiOCHH), 3.81 (dd, J = 10.2, 3.5 Hz, 1H, SiOCHH), 3.73 (dt, J = 9.3, 2.5 Hz, 1H, C=CCH), 3.72 (s, 3H, OCH3), 2.34 (ddd, J = 17.9, 9.7, 8.3 Hz, 1H, CHH), 2.25 (d, J = 1.5 Hz, 3H, C=CCH3), 1.81 (ddd, J = 17.0, 8 .6 , 8.6 Hz, 1H, CHhf), 1.56 (ABq, Av = 28.6 Hz, J = 13.6 Hz, 2H, SiCH2), 0.88 (s, 9H, (CH3)3CSi), 0.06 (s, 6H, (CH3)3CSi(CH3)2), 0.03 (s, 9H, (CH3 )3Si); 13C NMR (75 MHz, CDCI3, 1H decoupled) 8 193.60, 174.02, 166.41, 148.81, 148.10, 130.23, 109.26, 74.81,64.88, 56.39, 51.43, 32.62, 28.16, 25.93, 18.37, 13.23, - 1.32, -5.48; IR (film) 3076, 2953, 2897, 2858, 1729, 1667, 1635, 1472, 1436, 1361, 1251, 1206, 1119,1041, 840, 111 cm"1; HRMS calcd for C23H41NO4Si2 (M+) 451.2574, found 451.2571.' SOetrans. 1H NMR (300 MHz, CDCI3) 5 6.88 (d, J = 1.3 Hz, 1H, C=CH), 4.53 (s, 1H, C=CHH), 4.44 (m, 1H, C=NCH), 4.38 (s, 1H, C=CHH), 3.80 (m, 3H, SiOCH2 and C=CCH), 3.74 (s, 3H, OCH3), 2.26 (d, J = 1.2 Hz, 3H, C=CCH3), 2.23 (ddd, 15.3, 9.9, 5.4 Hz, 1H, CHH), 1.84 (ddd, J = 13.4, 8.1,5.8 Hz, 1H, CHhf), 1.55 (ABq, Av = 37.1 Hz, J = 13.5 Hz, 2H, SiCH2), 0.83 (s, 9H, (CH3)3CSi), 0.03 (s, 9H, (CH3)3Si), 0.00 (s, 3H, (CH3)3CSiCH3), -0.02 (s, 3H, (CH3)3CSiCH3); 13C NMR (75 MHz, CDCI3, 1H decoupled) 5 193.07, 174.15, 166.42, 149.27, 147.81, 129.21, 107.69, 75.01,65.21, 56.22, 51.55, 33.54, 204 27.97, 25.83, 18.22, 13.64, -1.33, -5.49; IR (film) 3075, 2954, 2858, 1727, 1667, 1631, 1472, 1436, 1361, 1251, 1203, 1119, 1035, 1005, 837, 777 cm"1. ( 2 a ,3 a ,5 a ) - /V -T o s y l - 5 - ( f -b u ty ld im e th y ls i ly lo x y )m e th y l - 2 - t r im e th y Ia c e ty l-3 - [1 - ( t r im e th y ls i ly lm e th y l)e th e n y l]p y r ro lid in e (5 3 ). A 5.0 ml_, single-necked, round-bottomed flask was charged with pyrroline 5 0 c c/-s (66 mg, 0.16 mmol) and MeOH (1.1 mL). To the solution was added NaBHgCN (41 mg, 0.65 mmol) in one portion and the mixture was immediately cooled to -78 °C. Trifluoroacetic acid (13 pL, 0.17 mmol) was added dropwise via a syringe and the mixture was stirred for 1h at -78 °C. The cold reaction mixture was poured into pH 7 buffer (3 mL) and the aqueous solution was stirred for 30 min at rt. The solution was saturated with NaCI and extracted with three portions of CHgCIg (1.5 mL). The combined CHgCIg extracts were thoroughly dried over NagSO^, filtered through a pad of celite (CHgCIg for elution) and concentrated to afford the crude pyrrolidine as a viscous, colorless oil which was used immediately in the next step. A 5.0 mL, single-necked, round-bottomed flask containing a solution of DMAP (24 mg, 0.19 mmol) in CHgCIg (1.0 mL) was cooled to 0 °C and TsCI (34 mg, 0.18 mmol) was added in one portion. The mixture was stirred at 0 °C for 30 min, cooled to -78 °C and treated dropwise with a solution of the crude pyrrolidine in CHgCIg (0.20 mL) via syringe. The reaction mixture was stirred 205 for 2h at -78 °C then for an additional 12h at -20 °C. Water (2.0 mL) was added to the cold mixture and the resulting diphasic mixture was stirred for 1h at rt. The organic layer was separated and the aqueous layer was extracted with CHgCIg (3 x 1.0 mL). The organic phases were combined and dried over IX^SO^. Removal of solvent in vacuo afforded the crude product which was purified by chromatography on silica gel (5% EtOAc/hexane for elution) to provide the title compound (60 mg, 67% from 50cc/s) as a colorless, viscous oil: 1H NMR (300 MHz, CDCI3) 5.7.75 (d, J = 8.2 Hz, 2H, ArH), 7.35 (d, J = 8.1 Hz, 2H, ArH), 4 .86 (d, J = 7.4 Hz', O=CCHN), 4.55 (d, J = 5.3 Hz, 2H, C=CH2), 4.08 (dd, J = 9.0, 4.7 Hz, 1H, SiOCHH), 3.91 (dd, J = 9.7, 9.3 Hz, 1H, SiOCHH), 3.60 (m, 1H, SiOCH2CHN), 2.42 (s, 3H, ArCH3), 2.27 (dt, J = 13.1, 8.8 Hz, TH, CHH), 1.85 (ddd, J = 12.8, 6.5, 6.5 Hz, 1H, CHH), 1.54 (ddd, J = 13.6, 7.7, 7.7 Hz, 1H, C=CCH), 1.53 (d, J = 13.2 Hz, SiCHH), 1.10 (s, 9H, (CH3)3CC=O), 1.03 (d, J = 12.5 Hz, SiCHH), 0.89 (s, 9H, (CH3)3CSi), 0.09 (s, 6H, (CH3)3CSi(CH3)2), -0.23 (s, 9H, (CH3)3Si); 13C NMR (75 MHz, CDCI3, 1H decoupled) 8 213.45, 143.88, 140.97, 134.79, 129.90, 127.56, 110.49, 67.12, 62.32, 61.81,49.28, 44.64, 33.58, 29.71,26.30, 25.98, 21.44, 18.33, -1.93, - 5.23; IR (film) 2956, 2929, 2887, 2857, 1711, 1633, 1597, 1473 ,1354, 1250, 1165, 1090, 991, 838, 776 cm"l; HRMS calcd for C28H48NO4SSi2 (M+-CH3) 550.2843 found 550.2842. 206 C#s-/V-Tosyl-2-trimethylacetyl-3-[1-(trimethylsilylmethyl) ethenylj-pyrrolidine (51). Utilizing pyrroline 48a (100 mg, 0.38 mmol) in the procedure described for the preparation of 53 furnished the title compound (87 mg, 55% from 48a) which was obtained as a white, crystalline solid: mp 112.3-114.7 °C; 1H NMR (300 MHz, CDCI3) 8 7.68 (d, J = 8.2 Hz, 2H, ArH), 7.30 (d, J = 8.1 Hz, 2H, ArH), 5.02 (d, J = 7.4 Hz, 1H, O=CCHN), 4.60 (d, J = 7.0 Hz, 2H, C=CH2), 3.59 (dt, J = 9.9, 1.4 Hz1 1H, NCHH), 3.36 (ddd, J = 16.9, 9.6, 7.4 Hz, 1H, NCHH), 2.45 (ddd, J = 15.8, 12.6, 3.3 Hz, 1H, C=CCH), 2.40 (s, 3H, ArCH3), 2.06 (ddd, J = 13.5, 6 .8 , 6.8 Hz, 1H, CHH), 1.72 (ddd, J = 12.1,6.0, 6.0 Hz, 1H, CHH), 1.61 (d, J = 13.1 Hz, 1H, SiCHH), 1.24 (d, J = 13.0 Hz, 1H, SiCHH), 1.10 (s, 9H, (CH3)3C), -0.13 (s, 9H, (CH3)3Si); 13C NMR (75 MHz, CDCI3, 1H decoupled) 5 214.24, 143.49, 141.34, 135.89, 129.69, 127.26, 110.84, 61.67, 50.31,47.51, 44.39, 29.81,28.44, 26.39, 21 .44, -1.76; IR (film) 2956, 2922, 1709, 1631, 1595, 1478, 1351, 1248, 1163, 1093, 992, 849, 663 cm '1; HRMS calcd for C22H36NO3SSi (MH+) 422.2185, found 422.2167. Me3Si H3 (2a,3a,4p)-/V-Tosyl-4-methyl-3-[1-(trimethylsilylmethyl) ethenyl]-2-trimethyl acetylpyrrolidine (52). The procedure used for the preparation of 53 was employed using pyrroline 49a (109 mg, 0.39 mmol) and a reaction time of 2 hr at -78 °C for the reduction with NaBH3CN/ TFA to provide 207 a mixture of diastereomeric AZ-tosyl pyrrolidines (106 mg, 63% from 49a, 4.0 : 1.0 by NMR) which was obtained as a white solid after filtration of the crude material through a silica gel plug (5% EtOAc/hexane for elution). Recrystallization of the mixture (petroleum ether) provided a pure sample of the major, AMosyIpyrroIidine isomer 52 as a crystalline white solid: m.p. 136.0 - 137.2 °C; 1H NMR (300 MHz, CDCI3) 5 7.68 (d, J = 8.1 Hz, 2H, ArH), 7.30 (d, J = 8.0 Hz, 2H, Ar hi), 5.09 (d, J = 7.4 Hz, 1H, O=CCAVN), 4.66 (s, 1H, C=CAVH), 4.52 (s, 1H, C=CHAV), 3.69 (t, J = 7.5 Hz, 1H, NCAVH), 2.91 (dd, J = 15.8, 7.4 Hz, 1H, NCHAV), 2.90 (m, 1H, NCh2CAVCH3), 2.40 (s, 3H, ArCAV3), 1.70 (dd, J = 11.4, 7.6 Hz, 1H, C=CCAV), 1.63 (d, J = 13.2 Hz, 1H, SiCAVH), 1.23 (d, J = 13.1 Hz, 1H, SiCHAV), 1.10 (s, 9H, (CAV3)3CC=O), 0.80 (d, J = 6.2 Hz, 3H, CAV3), -0.11 (s, 9H, (CAV3)3Si); 13C NMR (75 MHz, CDCI3, 1H decoupled) 5 214.21, 143.51, 139.92, 135.70, 129.65, 127:30, 111.11, 62.78, 57.00, 54.79, 44.30, 34.43, 30.38, 26.52, 21.44, 15.66, -1.37; IR (film) 3068, 2958, 2884, 1706, 1631, 1596, 1481, 1343, 1243, 1154, .1058, 1041, 852, 661 cm-1; HRMS calcd for C23H33NO3SSi (MH+) 436.2342, found 436.2340. 208 Stereocontrolled Synthesis of Piperidines General Information: Titanium tetrachloride was distilled under an atmosphere of nitrogen and was stored as a stock solution in toluene (1.0 M) under an argon atmosphere. All aldehydes were provided by commercial suppliers and were distilled under argon prior to use. Molecular sieves (4 A) were activated by flame drying under high vacuum. 7rans-/V-tosyl-2-phenyl-3-[(3-trimethylsilyl)isopropenyl] piperidine (65c). The following serves as the general experimental procedure used for the preparation of AMosyIpiperidines from amine 54. A 5.0 ml_, single-necked, round-bottomed flask was charged with THF (2.5 mL) and activated 4A molecular sieves (200 mg). Amine 54 (129 mg, 0.50 mmol) and freshly distilled benzaldehyde (61 pL, 0.60 mmol) were sequentially added via syringe and the mixture was stirred for 12h at rt. The reaction mixture was diluted with hexane (2.5 mL) and filtered through a Celite pad into a 10 mL, single-necked, round-bottomed flask. Evaporation of solvents and excess aldehyde in vacuo afforded the crude imine as a colorless oil which was used immediately in the next step. To the flask containing the freshly prepared imine was added CHgCIg (5 mL) and the resulting solution was cooled to -78 °C. Titanium tetrachloride (500 pL, 0.50 mmol of a 1.0 M toluene solution) was added dropwise over 2 min via a syringe and the resulting, deep orange solution was allowed to gradually 209 warm to room temperature (2-3h). Stirring was maintained for an additional 3h after which the reaction mixture was transferred dropwise via cannula into vigorously stirred, saturated aqueous KHCOg (10 m l) at 0 °C. The resulting diphasic mixture was stirred for 30 min at rt. The organic layer was removed and the aqueous layer was extracted with CHgCIg ( 2x5 mL). The combined organic phases were then dried with NagSO^ filtered and concentrated. The residual oil was dissolved in pentane (10 mL), filtered through a Celite pad and concentrated to furnish a diastereomeric mixture of crude piperidines which was directly converted into the corresponding AMosyI derivatives. To a 10 mL, single-necked, round-bottomed flask containing a solution of the crude piperidines in CHgCIg (3.0 mL) was added pyridine (145 |iL, 1.80 mmol) and the solution was cooled to 0 °C. Tosyl chloride (114 mg, 0.60 mmol) was added in one portion and the reaction mixture was stirred at 0 °G for 2h followed by an additional 2h at rt. Distilled HgO (3.0 mL) was added and the resulting biphasic mixture was stirred for 1h. The organic layer was removed and the aqueous phase was extracted with CHgCIg (3 x 1 mL). The combined organic phases were dried (NagSO^.), filtered and concentrated. The residue was purified of flash chromatography on silica gel (0%-1 %-5% EtOAc/hexanes for elution) to furnish an inseparable mixture of the title compound and the minor diastereomer (9.5 : 1.0 by NMR, 178 mg, 83% from 54) as a colorless, viscous oil: 1H NMR (300 MHz, C6D6) 5 7.73 (d, J = 8.0 Hz, 2H, CHgArH), 7.30 (dd, J = 7.5, 1.4 Hz, 2H, ArH), 7.09 (m, 3H, ArH), 6.74 (d, J = 8.1 Hz, 2H, CHgArH), 5.44 (d, J = 5.3 Hz, 1H, NCH), 5.19 (s, 1H, C=CHH), 4.85 (s, 1H, C=CHH), 3.83 (ddd, J = 13.1,6.2, 3.1 Hz, 1H, NCHH), 3.25 (ddd, J = 15.7, 11.0, 4.7 Hz, TH, NCHH), 2.39 (ddd, J = 11.5, 5.1, 5.1 Hz, 1H, C=CCH), 1.95 (s, 3H, 210 CHsAr), 1.87 (m, 1H, CHH), 1.50 (m, 2H, CH2), 1.37 (s, 2H, SiCHg), 1.24 (m, 1H, CHH), 0.00 (s, 9H, Si(CHs)S): 13C NMR (75 MHz, CDCI3, 1H decoupled) 5 147.70, 142.49, 141.29, 137.30, 128.98, 127.99, 127.44, 127.20, 126.81, 659 Cm'1; HRMS calcd for C24H33NO2SSi (M+) 427.2001, found 427.1989. 7rans-A/-tosyl-2-(4-methoxyphenyl)-3-[(3-trimethylsilyl)- isopropenyljpiperidine (65b). Using the above procedure outlined for the preparation of AMosyI piperidine 65c, amine 54 (150 mg, 0.58 mmol) and 4- anisaldehyde (78 pL, 0.64 mmol) were converted into an inseparable mixture of the title compound and the minor diastereomer (6.3 ; 1.0 by NMR, 194 mg, 73% from 54) which was isolated as a viscous, colorless oil upon purification by chromatography on silica gel (0%-1%-5% EtOAc/hexanes for elution): 1H NMR (300 MHz, C6D6) 5 7.64 (d, J = 8.2 Hz, 2H, ArH), 7.23 (d, J = 8.4 Hz, 2H, ArH), 6.76 (d, J = 8.1 Hz, 2H, ArH), 6.69 (d, J = 8.7 Hz, 2H, ArH), 5.37 (d, J = 5.5 Hz, 1H, NCH), 5.18 (s, 1H, C=CHH), 4.85 (s, 1H, C=CHH), 3.79 (ddd, J = 13.0, 6.0, 3.4 Hz, IH, NCHH), 3.35 (s, 3H, CHsOAr), 3.29 (ddd, J = 15.4, 10.7, 4.6 Hz, 1H, NCHH), 2.40 (ddd, J = 11.9, 4.9, 4.9 Hz, IH, C=CCH), 1.94 (s, 3H, CHsAr), 1.88 (m, IH, CHH), 1.53 (m, 2H, CH2), 1.41 (s, 2H, SiCHg), 1.30 (m, IH, CHH), 0.02 (s, 9H, Si(CHs)S); 13C NMR (75 MHz, CDCI3, 1H decoupled) 6 158.43,147.85, 142.39, 137.39, 133.24, 128.94, 128.69, 127.19, 113.28, 109.80, 61.58, 55.16, 109.92, 61.78, 46.77, 42.42, 26.46, 23.63, 21.33, -1.28; IR (film) 3089, 3063, 3033, 2952, 1631, 1599, 1495, 1454, 1341, 1248, 1161, 1092, 941, 853, 699, 211 46.92, 42.45, 26.52, 23.93, 21.55, 21.38, -1.25; IR (film) 3070, 3035, 2952, 680, 659 cm'1; HRMS calcd for C2SH35NO3SSi (M+) 457.2107, found 457.2099. 7>ans-/V-tosyl-2-(4-nitrophenyl)-3-[(3-trimethylsilyl)- isopropenyl]piperidine (65d). Using the above procedure outlined for the preparation of AMosyI piperidine 65c, amine 54 (150 mg, 0.58 mmol) and 4- nitrobenzaldehyde (92 mg, 0.61 mmol) were converted into an inseparable mixture of the title compound and the minor diastereomer (21 ; 1.0 by NMR, 110 mg, 40% from 54) which was isolated as white solid upon purification by chromatography on silica gel (20% EtOAc/hexanes for elution): m.p. 104.5 - 107.6 °C; 1H NMR (300 MHz, C6D6) 6 7.77 (d, J = 8.5 Hz, 2H, ArH), 7.49 (d, J = 8.2 Hz, 2H, ArH), 7.02 (d, J = 8.7 Hz, 2H, ArH), 6.69 (d, J = 8.1 Hz, 2H, ArH), 5.03 (d, J = 6.4 Hz, IH, NCH), 4.94 (s, 1H, C=CHH), 4.74 (s, 1H, C=CHH), 3.64 (ddd, J = 13.1,4.3, 4.3 Hz, IH, NCHH), 3.20 (ddd, J = 13.4, 10.2, 4.7 Hz, 1H, NCHH), 2.11 (ddd, J = 7.4, 4.1,4.1 Hz, IH, C=CCH), 1.94 (s, 3H, CHsAr), 1.73 (m, IH, CHH), 1.30 (m, 3H, CH2 and CHH), 1.19 (ABq, Av = 26.7 Hz, J = 14.1 Hz, 2H, SiCHz), -0.03 (s, 9H, Si(CHs)S); 13C NMR (75 MHz, CDCI3, 1H decoupled) 5 149.02,147.10, 146.74, 143.42, 136.40, 129.64, 129.30, 128.41, 127.24, 110.50, 62.74, 48.27, 43.30, 26.61,25.17, 21.85, 21.43, -1.28; IR (film) 3072, 3035, 2952, 1631, 1598, 1522, 1344, 1248, 1160, 1092, 1037, 1013, 974, 937, 2836, 1631, 1611, 1513, 1463, 1340, 1248, 1160, 1091, 1036, 975, 942, 852, Ts 212 852, 738, 763, 680 cm'1; HRMS calcd for C2^ 32NaO4SSi (M+) 472.1852, found 472.1859. 213 Synthesis of Isotropane Alkaloids and Azabicyclononanes OpCCF 4-Methylidene-1-azabicyclo[3.2.1]octane, trifluoracetate salt (67a). A 25 m l, single-necked, round-bottomed flask containing a solution of amine 1a (300 mg, 1.23 mmol) in CHgCN (6 m l) was treated with aqueous CH2O (400 |iL, 4.92 mmol, 37% in H2O) dropwise over 1 min via syringe. The resulting cloudy mixture was stirred for 2h after which TFA (95 pL, 1.23 mmol, freshly distilled from KMnOz*) was added dropwise via syringe. The resulting homogeneous solution was stirred for 8h, basified with NaOH (3 mL, 2 M) and partitioned with brine (6 mL). The organic phase was removed, washed with brine (3 mL), dried (MgSO^) and filtered into a 25 mL, single-necked, round- bottomed flask. The resulting solution of the crude, volatile isotropane (97% by GC) was cooled to 0 °C and TFA (95 pL, 1.23 mmol) was added dropwise. After stirring for 1h at 0 °C, the reaction mixture was concentrated in vacuo and the resulting viscous oil was washed with hexane ( 3x5 mL). The residue was dissolved in Et2O and filtered through a Celite plug to furnish the title compound (257 mg, 88%) as a colorless, viscous oil which solidified upon cold storage: 1HNMR (300 MHz, CDCI3) 5 9.98 (brs, 1H, +NH), 4.89 (d, J = 2.1 Hz, 1H, C=CHH), 4.82 (d, J = 2.0 Hz, 1H, C=CHH), 3.72 (ddd, J = 13.4, 7.4, 5.2 Hz, 1H, +NHCHH), 3.40 (brt, J = 10.6 Hz, 3H, +NHCH2 and +NHCHH), 3.29 (dq, J = 13.4, 5.5 Hz, 1H, +NHCHH), 3.17 (unresolved, 1H, +NHCHH), 3.15 (dd, J = 10.7, 4.4 Hz, IH, CM), 2.67 (m, 1H, C=CCHH), 2.47 (dd, J = 16.0, 5.4 Hz, 1H, CHCHH), 2.32 (m, 1H, C=CCHH), 1.97 (dddd, J = 14.4, 6.9, 5.2, 1.7Hz, 1H, 2 1 4 CHCH/-/); 13C NMR (75 MHz, CDCI3, 1H decoupled) 6 162.02, 142.57, 119.05, 110.55, 58.96, 52.68, 49.78, 42.22, 28.23, 25.15; IR (film) 3414, 3072, 2993, 1680, 1654, 1470, 1173, 1012,911, 798, cm'1; HRMS (-HO2CCF3 ) calcd for C8H13N (M+) 123.1048, found 123.1047. exo-6-Methyl-4-methylidene-1-azabicyclo[3.2.1 ]octane, trifluoracetate salt (67b). Following the procedure used for the preparation of isotropane salt 67a, amine Ib (129 mg, 0.50 mmol) was converted into the title compound (103 mg, 82%) which was isolated as a colorless gelatinous material: 1H NMR (300 MHz, CDCI3) 5 12.17 (brs, 1H, HN+), 4.85 (d, J = 1.9, 1H, C=CHH), 4.80 (d, J = 1.7 Hz, C=CHH), 3.51 (m, 2H, HN+CH2), 3.34 (dd, J = 12.6, 7.2 Hz, IH, HN+CHH), 3.23 (ddd, J = 18.3, 12.0, 6.0 Hz, 2H, HN+CH2), 3.05 (d, J = 11.1 Hz, 1H, CH), 2.71 (d, J = 3.9 Hz, 1H, HN+CHH), 2.62 (m, 1H, C=CCHH), 2.45 (dd, J = 16.2, 5.5 Hz, 1H, C=CCHH), 2.38 (sx, J = 7.2 Hz, IH 1 CH3CH), 1.17 (d, J = 7.0 Hz, 3H, CH3); 13C NMR (75 MHz, CDCI3, 1H decoupled) 5 161.35(g), 142.12, 115.77(g), 110.70, 57.69, 56.96, 52.45, 49.77, 35.86, 25.43, 19.88; IR (film) 3415, 2971, 1674, 1467, 1173, 1025, 910, 798, 706 cm"1; HRMS (-HO2CCF3) calcd for C9H15N (M+) 137.1204, found 137.1207. 215 OoCCF e x o -7 -M e th y l - 4 -m e th y l id e n e -1 - a z a b ic y c lo [3 .2 .1 ]o c ta n e , tr if lu o ra c e ta te sa lt (67c ). Employing amine 1c (129 mg, 0.50 mmol) in the procedure outlined for the preparation of 67a yielded an inseparable mixture of the title isotropane and a minor diastereoisomer (94 mg, 75%, 6.0:1.0) which was isolated as a clear viscous material: 1H NMR (300 MHz, CDCI3) 8 11.45 (br s, 1H, +NH), 4.86 (d, J = 1.8 Hz, IH, C=CHH), 4.80 (d, J = 1.7 Hz, IH, C=CHH), 3.85 (sx, J = 6.8 Hz, 1H, H+NCHCH3), 3.49 (m, 2H, H+NCH2), 3.21 (dddd, J = 14.2, 13.0, 5.7, 1.5 Hz, 1H, H+NCHH), 3.10 (unresolved, 2H, H+NCHHand CH), 2.62 (m, 1H, C=CCHH), 2.44 (dd, J = 16.0, 5.5 Hz, 1H, C=CCHH), 2.21 (ddd, J = 13.5, 8.1, 1.4 Hz, 1H, CHH), 1.85 (dt, J = 13.1,6.0 Hz, 1H, CHH), 1.47 (d, J = 6.8 Hz, 3H, CH3); 13C NMR (75 MHz, CDCI3, 1H decoupled) 5 160.69(g), 141.72, 115.75(g), 111.05, 60.62, 56.60, 53.20, 42.69, 37.57, 25.32, 20.00; IR (film) 3402, 2989, 1676, 1455, 1175, 911,799, 706 cm"1; HRMS (-HO2CCF3) calcd for C9H15N (M+) 137.1204, found 137.1201. OTBDMS exo-7-(ferf-Butyldimethylsilyloxy)methyl-4-methylidene-1- azabicyclo[3.2.1 Joctane (67d). To a 10 mL, single-necked, round- bottomed flask containing a solution of amine 1d (194 mg, 0.50 mmol) in 216 CH3CN (2.5 mL) was added aqueous CH2O (163 juL, 2.0 mmol, 37% in H2O) dropwise over 1 min via syringe. The resulting cloudy mixture was stirred vigorously for 2h and was cooled to 5 0C. Ttrifluoroacetic acid (39 pL, 0.50 mmol, freshly distilled from KMn0 4 ) was added via syringe and the resulting homogeneous solution was stirred for 5 minutes at 5 0C followed by 10h at room temperature. Aqueous NaOH (0.5 mL, 2 M) was added and stirring was continued for 5 minutes. The mixture was diluted with H2O (2.5 mL) and the aqueous mixture was extracted with Et2O (3x2 mL). The Et2O extracts were combined, dried (IVIgSOj.), filtered and concentrated. The residue was passed through a plug of Florisil (Et2O for elution) to furnish isotropane 67d (127 mg, 95%) as a colorless oil: 1H NMR (300 MHz, CDCI3) 5 4.51 (d, J = 2.1 Hz, 1H, C=CHH), 4.44 (d, J = 2.0, Hz, 1H, C=CHH), 3.62 (ddd, J = 11.9, 6.2, 1.9 Hz, 1H, SiOCHH), 3.32 (ddd, J = 11.7,1.5, 1.8 Hz, 1H, SiOCHH), 3.11 (p, J = 6.6 Hz, 1H, NCH), 2.90-2.71 (m, 4H, NCH2 x 2), 2.59 (d, J = 11.1 Hz, TH, CM), 2.33 (m, IH, C=CCHH), 1.97 (dd, J = 14.9, 4.4 Hz, 1H, C=CCHH), 1.76 (dd, J = 13.1, 8.0 Hz, 1H, CHH), 1.62 (ddd, J = 13.1. 5.6, 1.9 Hz, 1H, CHH), 0.85 (s, 9H, (CH3)3CSi), 0.02 (s, 6H, (CH3)2Si); 13C NMR (75 MHz, CDCI3, 1H decoupled) 5 150.90, 103.89, 66.55, 63.94, 59.95, 56.22, 45.41,35.16, 29.04, 25.95, 18.33, -5.24, - 5.32;. IR (film) 3071,2935, 2857, 1646, 1472, 1253, 1114, 1082, 837, 776 Cm"1; HRMS calcd for C15H29NOSi (M+) 267.2018, found 267.2026. 217 H a/7f/-8-lsopropyl-4-methylidene-1-azabicyclo[3.2.1]octane (71a). To a 10 ml_, single-necked, round-bottomed flask containing a heterogeneous mixture of pyrrolidine 14a (203 mg, 0.90 mmol) in 3:1 H2O / THF (4.5 mL) was added aqueous CH2O (146 |iL, 1.80 mmol, 37% in H2O) over 1 min via syringe. The resulting cloudy mixture was stirred vigorously for 1.5h. Upon cooling the reaction mixture to 0 °C, TFA (73 |iL, 0.94 mmol, freshly distilled from KMn0 4 ) was added dropwise via syringe and the resulting homogeneous solution was stirred for 10 min at 0 0C followed by 2h at room temperature. Aqueous NaOH (2 mL, 2 M) was added dropwise and stirring was continued for an additional 30 min. The mixture was diluted with H2O (2 mL) and was extracted with Et2O (3x4 mL). The extracts were washed with brine (2 x 4 mL), dried over MgSO4, filtered and concentrated. Purification of the residue by silica gel chromatography (10% IPA/EtOAc) afforded isotropane 71a (115 mg, 77%) as a colorless oil: 1H NMR (300 MHz, CDCI3) 6 4.51 (t, J = 2.2 Hz, 1H, C=CHH), 4.24 (t, J = 2.2 Hz, IH, C=CHH), 2.92 (dt, J = 13.1, 7.1 Hz, 2H, NCH2), 2.78 (d, J = 6.2, 1H, CH), 2.75 (dt, J = 13.0, 7.0 Hz, 2H, NCH2), 2.28 (m, IH 1 CHHC=C), 2.19 (d, J = 10.3 Hz, 1H, NCH), 1.92 (dd, J = 14.8, 5.1 Hz, 1H, CHCHH), 1.80 (m, 1H, CHHC=C), 1.56 (ddd, J = 13.5, 8.9, 5.1 Hz, 1H, CHCHH), 1.33 (m, 1H, CH(CH3)2), 0.92 (d, J = 6.5 Hz, 3H, CH3CHCH3), 0.86 (d, J = 6.6 Hz, 3H, CH3CHCH3); 13C NMR (75 MHz, CDCI3, 1H decoupled) 5 152.64, 103.02, 80.00, 57.17, 48.99, 45.76, 30.23, 28.45, 27.68, 20.17, 19.95; IR (film) 218 3070, 2956, 2873, 1644, 1469, 1457, 1090, 1078, 1030, 1013, 920, 879 cm"1; HRMS calcd for C11H19N 165.1517, found 165.1516. anf/-8-lsobutyl-4-methylidene-1 -azabicyclo[3.2.1 ]octane (71b). Using the procedure described for the preparation of 71a, pyrrolidine 14b (174 mg, 0.73 mmol) was converted into isotropane 71b (97 mg, 74%) which was obtained as a colorless oil: 1H NMR (300 MHz, CDCI3) 8 4.48 (t, J = 2.2 Hz, 1H, C=CHH), 4.41 (t, J = 2.2 Hz, 1H, C=CHH), 2.69 - 3.01 (m, 5H, NCH2 x 2 and NCH), 2.52 (d, J = 6.4 Hz, 1H, CH), 2.26 (m, 1H, C=CCHH), 1.89 (dd, J = 14.9, 5.0 Hz, 1H, CHCHH), 1.85 (m, 1H, C=CCHH), 1.60 (m, 1H, (CH3)2CH), 1.56 (ddd, J = 13.5, 8.9, 5.0 Hz, 1H, CHCHH), 1.45 (dt, J = 13.8, 7.1 Hz, 1H, CHHCH(CH3)2), 0.98 (dt, J = 13.7, 7.4 Hz, 1H, CHHCH(CH3)2); 0.87 (d, J = 2.3 Hz, 3H, CH3CHCH3), 0.85 (d, J = 2.4 Hz, 3H, CH3CHCH3); 13C NMR (75 MHz, CDCI3, 1H decoupled) 5 152.44, 103.01, 70.92, 57.00, 49.05, 47.84, 40.50, 30.07, 28.30, 25.41, 22.94, 22.57; IR (film) 3071, 2954, 2871, 1652, 1456, 1095, 1080, 1028, 922, 879, 743, 734 crrf1; HRMS calcd for C12H21N (M+)179.1674, found 179.1681. 219 exo-anf/--6-Methyl-4-methylidene-8-isopropyl-1-azabicyclo [3.2.1 ]octane (72a). The procedure outlined for the preparation of 71a was carried out utilizing pyrrolidine 24a (100 mg, 0.42 mmol) and a reaction time of 8h at room temperature following the addition of TFA to furnish the title compound (51 mg, 68%) as a colorless oil: 1H NMR (300 MHz, CDCIg) 8 4.47 (t, J = 2.2 Hz, 1H, C=CHH), 4.37 (t, J = 2.3 Hz, 1H, C=CHH), 3.00 (dd, J = 12.8, 8.4 Hz, IH, NCHH), 2.92 (dd, J = 13.2, 7.7 Hz, NCHH), 2.74 (dt, J = 12.3, 5.6 Hz, 1H, NCHH), 2.59 (dd, J = 13.0, 6.0 Hz, 1H, NCHH), 2.53 (s, 1H, CM), 2.28 (m, 1H, C=CCHH), 2.11 (d, J = 10.7 Hz, 1H, NCH), 1.98 (sx, J = 7.4 Hz, 1H, CH3CH), 1.92 (dd, J = 15.0, 5.5 Hz, 1H, C=CCHH), 1.56 (m, 1H, CH(CH3)2), 1.04 (d, J = 7.4 Hz, 3H, CH3CH), 0.92 (d, J = 6.4 Hz, 3H, CH3CHCH3), 0.86 (d, J = 6.7 Hz, 3H, CH3CHCH3); 13C NMR (75 MHz, CDCI3, 1H decoupled) 5 153.27, 102.28, 81.16, 58.53, 56.86, 53.38, 39.15, 28.96, 28.24, 21.04, 21.00, 19.60; IR (film) 3070, 2957, 2872, 1646, 1469, 1385, 1201, 1056, 1005, 878, 772 cm"1; HRMS calcd for C12H2IN (M+) 179.1674, found 179.1668. O9CCF 4-Methylidene-1-Azabicyclo[3.3.1]nonane, trifluoroacetate salt (75). Utilizing the standard condensation-bicyclization protocol previously 220 used for the preparation of isotropane 67a, amine 54 (387 mg, 1.50 mmol) was converted into the title compound (353 mg, 94%) which was secured as a gold tinted, viscous oil which solidified upon slight cooling: 1H NMR (300 MHz, CDCI3) 511.90 (hr s, 1H, +NH), 4.99 (s, 2H, C=CAVa), 3.54 (m, IH, NCAVH), 3.37 (m, 3H, NCAVa and NCHAV), 3.27 (s, 2H, NCHa), 2.84 (m, 1H, C=CCAVH), 2.76 (s,. TH, CM), 2.60 (ddd, J = 16.4, 6.9, 3.2 Hz, 1H, C=CCHAV), 2.14 (m, 1H, CAVH), 1.89, (m, 3H, CHHand CHa); 13C NMR (75 MHz, CDCI3 , 1H decoupled) 5 162.22 (q, J = 34.9 Hz), 142.13, 116.81 (q, J = 292 Hz), 114.01, 52.56, 52.05, 50.65, 34.25, 28.91, 28.76, 18.84; IR (film) 3389, 3070, 2948, 1663, 1475, 1417, 1163, 1055, 1021, 978, 909, 832, 799, 721 cnrr1; HRMS calcd for CgHTgN (M+) 137.1204, found 137.1203. 221 Model Synthesis of the Tricyclic Core of Stemofoline General Information: Ethyl Ievulinate was used as purchased from Aldrich Chemical Company, Inc. Lawesson's reagent was freshly prepared using reported procedures.85 Triethyloxonium tetrafluoroborate was prepared following known procedures89 and was stored as a CHgCIg solution (1.24 M) at low temperatures (0 0C) under argon. (5a,6(3)-5-Methyl-6-[1-(trimethy Isily Imethy l)ethenyl]-1- azabicyclo[3.3.0]octa-2-one (85). Applying the method outlined previously for the preparation of imine 11a, condensation of amine 1a (4.02 g, 16.5 mmol) and ethyl Ievulinate (2.58 mL, 18.1 mmol) over a 24h period afforded imine 83 (6.15 g, 100%) as a clear oil: 1H NMR (300 MHz, CDCI3) 5 4.76 (t, J = 7.1 Hz, 1H, C=CH), 4.07 (q, J = 7.3 Hz, 2H, CH3CH2), 3.14 (t, J = 7.6 Hz, 2H, NCH2), 2.51 (br s, 4H, CH2CH2C=O), 2.14 (q, J = 7.3 Hz, 2H, CH2C=C), 1.77 (s, 3H, CH3), 1.44 (s, 2H, SiCH2), 1.35 (s, 2H, SiCH2), 1.20 (t, J = 7.2 Hz, 3H, CH3CH2), -0.02 (s, 9H, (CH3)3Si), -0.06 (s, 9H, (CH3)3Si); 13C NMR (75 MHz, CDCI3, 1H decoupled) 8 173.51, 166.33, 135.28, 117.29, 60.07, 51.89, 36.37, 30.52, 30.37, 29.43, 23.81, 17.69, 14.21, -0.71,-1.20. Imine 83 was immediately subjected to the general cyclization conditions used for the preparation of 14a to yield pyrrolizidine 85 (3.31 g, 80%) as a colorless, crystalline solid upon purification by silica gel chromatography (90% O 222 EtOAc/ hexane for elution): mp 74.2 - 75.9°C (light pet. ether); 1H NMR (300 MHz, C6D6) 5 4.56 (s, IH, C=CHH), 4.38 (s, 1H, C=CHH), 3.82 (ddd, J = 13.5, 8.4, 5.3 Hz, IH, NCHH), 2.65 (ddd, J = 11.9, 8.0, 7.0 Hz, 1H, NCHH), 2.41 (dt, J = 16.3, 9.9 Hz, 1H, O=CCHH), 2.19 (ddd, J = 16.3, 9.8, 2.4 Hz, 1H, O=CCHH), 1.99 (app t, J = 6.4 Hz, IH, CHC=C), 1.83 (dt, J = 12.4, 10.1 Hz, IH, O=CCH2CHH), 1.61 (m, 2H, CH2CHC=C), 1.43 (d, J = 13.4 Hz, 1H, SiCHH), 1.26 (app tt, J = 9.2, 2.2 Hz, IH, O=CCH2CHH), 1.08 (d, J = 13.4 Hz, 1H, SiCHH), -0.06 (s, 9H, (CH3)3Si); 13C NMR (75 MHz, CDCI3, 1H decoupled) 5 174.38, 147.61, 107.70, 69.99, 53.20, 39.83, 33.47, 31.77, 29.36, 29.16, 28.10, - 1.54; IR (film) 3082, 2956, 2926, 2855, 1696, 1630, 1457, 1402, 1248, 1170, 856 cm"1; HRMS calcd Io rC 14H25NOSi (M+) 251.1705, found 251.1708. (5a,6(3)-5-Methyl-6-[1-(trimethy Isily Imethy l)ethenyl]-1- azabicyclo[3.3.0]octa-2-thione (88). To a 25 ml_, single-necked, round- bottomed flask containing a vigorously stirred solution of lactam 85 (2.09 g, 8.31 mmol) and diisopropylethyl amine (362 pL, 2.08 mmol) in toluene (8 mL) was added Lawesson’s reagent (1.85 g, 4.57 mmol) in one portion. Vigorous stirring was maintained for 1h after which the reaction mixture was concentrated in vacuo. The residue was triturated with 20% EtOAc/hexane (3x10 mL) and the resulting solution was filtered through a silica gel pad (20% EtOAc / hexane elution) to afford thiolactam 88 (2.07 g, 93%) as a white crystalline solid upon evaporation of solvents in vacuo: mp 86.0 - 88.3 °C; 1H NMR (300 MHz, 223 CDCI3) 5 4.63 (s, IN, C=CHH), 4.33 (s, 1H, C=CHH), 3.85 (dt, J = 14.0, 8.2 Hz, 1H, NCHH), 3.22 (m, 2H, S=CCH2), 2.95 (dd, J = 17.3, 9.1 Hz, 1H, C=CCH), 2.44 (m, IH, NCHH), 2.29 (dd, J = 7.9, 2.1 Hz, CHH), 2.10 (m, 2H, CH2), 1.70 (dd, J = 12.3, 8.0 CHH), 1.58 (d, J = 13.3 Hz, 1H, SiCHH), 1.34 (s, 3H, CH3), 1.14 (d, J = 13.3 Hz, 1H, SiCHH), -0.05 (s, 9H, (CH3)3Si); 13C NMR (75 MHz, CDCI3, 1H decoupled) 5 196.77, 147.35, 108.28, 77.98, 52.47, 47.00, 43.37, 31.67, 31.17, 29.35, 26.10, -1.51; IR (film) 3081,2961,2914, 2887, 1632, 1498, 1475, 1322, 1245, 1169, 1119, 1080, 845 cm"1; HRMS calcd for C14H25NSSi (M+) 267.1477, found 267.1466. 2-Ethylthio-5-methyl-2,6-[2-(methylidene)ethano]-1- azabicyclo[3.3.0]octane (97a). A 10 mL, single-necked, round-bottomed flask containing a solution of thiolactam 88 (200 mg, 0.75 mmol) in CH3CN (3.0 mL) was cooled to 0 °C and treated dropwise over I min with triethyloxonium tetrafluoroborate (700 p i, 0.87 mmol of a 1.24 M CH2CI2 solution) via syringe. The reaction mixture was stirred for 2h at 0 °C, diluted with CH3CN (3.0 mL) and allowed to reach ambient temperature. Stirring was continued for 8h after which the reaction mixture was poured into cold aqueous LiOH (10 mL, 2 M). After the biphasic mixture was stirred for 30 min at rt, the organic layer was removed and the aqueous phase was extracted with Et2O (3x4 mL). The combined organic phases were washed with brine (2x10 mL) and dried over MgSO4. Filtration and evaporation of solvents followed by chromatographic 224 purification of the resulting oil on basic alumina (20% Et2OZpentane) furnished tricyclic pyrrolizidine 97a (152 mg, 90%) as a clear oil: 1H NMR (300 MHz, . C6D6) 5 4.48 (d, J = 1.9 Hz, 2H, C=CH2), 3.28 (ddd, J = 13.8, 9.1,5.4 Hz, 1H, NCHH), 2.73 (ddd, J = 14.3, 9.5, 4.3 Hz, 1H, NCHH), 2.71 (dq, J = 12.3, 7.6 Hz, 1H, SCHHCH3), 2.48 (dq, J = 12.5, 7.5, 1H, SCHHCH3), 2.16 (m, 2H, SCCH2), 2.14 (d, J = 13.9 Hz, 1H, CHHC=C), 1.95 (d, J = 14.1 Hz, 1H, CHHC=C), 1.77 (m, 2H, CH2), 1.66 (dq, J = 11.5, 2.6 Hz, 1H, CHCHH), 1.36 (m, 2H, CH and CHCHH), 1.18 (t, J = 7.5 Hz, 3H, CH3CH2S), 0.96 (s, 3H, CH3); 13C NMR (75 MHz, C6D6, 1H decoupled) 5 149.54, 106.24, 77.44, 71.44, 53.44, 42.59, 40.69, 36.46, 31.65, 31.19, 23.92, 21.01, 15.48; IR (film) 3070, 2964, 1648, 1459, , 1372, 1257, 1227, 1121, 1103, 1024, 981,932, 885, 743 cm"1; HRMS calcd for C13H21NS (M+) 223.1395, found 223.1393. 225 REFERENCES 1) Johnson, W. S. Angew. Chem. Int, Ed. Eng. 1976, 15, 9. 2) Johnson, W. S.; Jensen, NP.; Hooz, J.; Leopold, E. J. J. Am. Chem. Soc. 1968, 90, 5872. 3) Denmark, S ’ E.; Jones, T. K. J: Am. Chem. Soc. 1982, 104, 2642. 4) Evans, D. A.; Thomas, E. W. 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