Pure and Applied Chemistry

Abstract: The reactions of N-acyliminium ions with tethered π-bonds are among the most important methods for preparing complex nitrogen-containing heterocycles. Pummerer-based cyclizations are also finding widespread application in both carbo- and heterocyclic syntheses. As part of a program concerned with new methods for alkaloid synthesis, 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. α-Thiocarbocations generated from the Pummerer reaction of β-phenylsulfinylmethyl-α,β-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.