Total syntheses of the dipyrrolobenzoquinone (+)-terreusinone enabled by an evaluation of 4-methylpent-1-yn-3-ols in the Larock indole synthesis

Abstract

The Larock indolization between 4-methylpent-1-yn-3-ols (alkynols) and ortho-bromo and ortho-iodoanilines has been studied. Although the unprotected alkynol was an unviable substrate for the annulation reaction, protected derivatives did proceed to the indole products. Interestingly, this reaction does not appear to occur by the widely accepted mechanism for the Larock indolization of internal alkynes, but by the initial formation of a cross-coupled arylalkyne followed by 5-endo-dig cyclization. Importantly, when a chiral alkynol is used, the stereochemical integrity is retained in the indole product. Although this methodology could not be successfully extended to a double Larock indolization approach to terreusinone, two separate total syntheses evolved from these studies: A bidirectional, double Sonogashira-hydroamination approach and a one-pot Larock indolization–Sonogashira coupling followed by hydroamination. This work has not only confirmed the gross structure and absolute configuration of the photoprotecting natural product terreusinone, but also uncovered several novel applications of known reaction conditions that should find broad applications in the field of heteroaromatic construction.