Pure and Applied Chemistry

Abstract: Tandem methodology for heterocyclic synthesis represents a powerful approach for the rapid buildup of molecular complexity from potentially simple starting materials. Work from our laboratory has shown that the rhodium(II)-catalyzed cyclization cascade of alpha-diazo imides represents an effective method for the synthesis of a variety of heterocyclic systems. As an extension of these studies, we became interested in using a linked Pummerer/N-acyliminium ion cyclization sequence since we felt that this combination offers unique opportunities for the assemblage of complex target molecules. A synthetic method that combines transformations of different reaction types significantly broadens the scope of such procedures in synthetic chemistry. Alpha-thiocarbocations generated from the Pummerer reaction of beta-phenylsulfinylmethyl-alpha, beta-unsaturated amides can be intercepted by the adjacent amido group to produce transient amino-substituted furans which undergo subsequent Diels–Alder cycloadditions. Using this domino amido Pummerer/Diels–Alder cascade, we were able to assemble novel polycyclic systems in a single operation. The key step in the process involves the generation of a reactive N-acyliminium ion by fragmentation of an amino-substituted [4+2]-cycloadduct. The successful synthesis of a number of alkaloids by this sequence of reactions reveals the usefulness and importance of this unique domino cascade. Application of the process for the preparation of the stenoma alkaloid stenine was recently carried out in our laboratory.