The synthesis of highly substituted indoles via isonitriles

Abstract

A highly efficient approach to 2,3-disubstituted indoles has been presented. The indole precursors, isonitriles, were used as powerful geminal radical donors/acceptors. The novel isonitrile-alkyne free radical cascade has been efficiently mediated by tin and sulfur. In the case of sulfur, interesting 2,3-dithioindoles were formed. This new class of compounds has exhibited great promise as versatile indole intermediates. In particular, nucleophilic additions at C-10 of the 2,10-dithioindoles were achieved using carbon, sulfur and amine nucleophiles. The versatility of 2,10-dithioindoles was further demonstrated using rhodium-mediated sulfur ylide chemistry. We achieved an intramolecular sulfur ylide reaction which led to a gramine-type addition product 270. Furthermore, sulfur ylides were formed intermolecularly and rearranged to give highly substituted indoles. In studies aimed at the synthesis of the spirotryprostatins, our 2,10-dithioindoles were used in the synthesis of both a simple C-3 spiro-oxindole compound 249 and a diketopiperazine-containing indole derivative 256. This demonstrated the exciting potential of our indole-forming reaction and elaboration methodologies in natural product synthesis.