Expanding the scope of allylbis(silane)-imine cyclizations : a concise approach to the synthesis of the azatricyclic core of Stemofoline and Asparagamine A

Abstract

The Mannich cyclization has been utilized for the synthesis of a number of heterocyclic compounds since its discovery. In this dissertation, a silane-based variant of the Mannich cyclization is discussed. This Mannich-like cyclization has proven to be a powerful tool in governing regio- and stereo- control in carbon-carbon bond forming reactions, which benefit from enhanced nucleophilicity of the C=C pi bond derived from the hyperconjugative effect of the adjacent silicon group. Despite the synthetic utility associated with this transformation, there are comparatively few examples that have explored the intramolecular variant containing silane-based nucleophiles. The utility of a 2-propylidene-1,3-bis(silane) nucleophile in synthesis has also received little attention and it is the goal of this project to further develop this concept, and to apply these findings toward the construction of the azatricyclic core found in the stemona alkaloids Asparagamine A and Stemofoline. The use of a 2-propylidene-1,3-bis(silane) nucleophile in N-acyliminium ion chemistry has been successfully applied towards the construction of the azatricyclodecane cores by employing two cationic desilylative cyclization events. Construction of the requisite nucleophile was accomplished in quantitative yield through a Negishi coupling which employed ZnCl 2 x (THF) 2 and 7 mol% PdCl 2(PPh 3) 2. Within this linear synthesis the enantiopure cores were acquired in 16% (36) and 12% (38) overall yield (16 and 17 steps respectively) from 1,1-dibromo-4-amino-1-butene (18).