TANDEM BENZANNULATION-CYCLIZATION STRATEGIES FOR THE SYNTHESIS OF HIGHLY SUBSTITUTED INDOLES

Abstract

Tandem benzannulation-cyclization strategies were developed for the synthesis of highly substituted indoles. The benzannulation strategies involved the reaction of vinylketenes (or aryl ketenes) with ynamides or with ynehydrazides to afford highly substituted phenols via a pericyclic cascade mechanism. The vinylketenes were generated via the Wolff rearrangement of diazo enones or via the 4π electrocyclic ring-opening of cyclobutenones. Two cyclization approaches were studied: (1) an intramolecular acid-promoted cyclization, and (2) a Fischer indole cyclization. The first approach required the development of a thermal benzannulation protocol and was applied in a concise total synthesis of (-)-herbindoles A-C and (+)-trans-herbindole A. The second approach required the development of a new benzannulation variant that employed ynehydrazides as the ketenophile.