Lewis acid-mediated alkylations of N,O-acetals and applications to the total syntheses of alkaloids

Abstract

Chapter one describes a literature overview of studies on the cyclic iminium ion chemistry and its use in the synthesis of 2,6-disubstituted piperidine derivatives. Chapter two describes the facile synthesis of cyclic N,O-acetals and Lewis acid-mediated alkylation of thesis acetals with allyltrimethylsilane via acyclic iminium ion chemistry, giving homoallylic amine derivatives efficeintly. In Chapter three, we describe the successful syntheses of porantheridine 3-1 and its C8-epimer 3-59, employing silver-catalyzed allene cyclization to generate a cis-isoxazolidine intermediate and Lewis acid-mediated alkylation of N,O-acetals to generate substituted piperidine rings. The generation of trans and cis-2,6-disubstituted piperidine can be rationalized by consideration of the different conformations of monocyclic N-acyl iminium ion 3-55 and bicyclic N-acyl iminium ion 3-64. In Chapter four, the first asymmetric synthesis of the sedum alkaloid sedinine 4-2 has been successfully achieved, employing silver-catalyzed allene cyclization and ring closing metathesis to form a bicyclic N,O-acetal 4-33. Alkylation of this acetal with silyl enol ether 4-47 under Lewis acidic conditions was exclusively trans selective, leading to the natural product after reduction. On the other hand, conversion of the bicyclic N,O-acetal 4-33 to a semicyclic N,O-acetal 4-17 resulted in no stereoselectivity during such a reaction. Compared to the porantheridine synthesis, the constrasting results also can be rationalized by consideration of the conformation of the iminium ions.