First synthesis of (±)-halichonadins A-D

Described herein is the first total synthesis of a marine isocyanide terpene, (+/-)-halichonadin C. Our synthetic strategy features nitrile-to-isocyanide interconversion utilizing hypervalent iodine-promoted Hofmann rearrangement. This approach led to successful construction of an isocyanide group at the stereochemically encumbered C-6 position in (+/-)-halichonadin C. Furthermore, in accord with a scenario we propose for the biosynthesis of halichonadins A-D, (+/-)-halichonadin C was transformed to halichonadins A and B via the missing link intermediate, halichonadin isocyanate. The first total synthesis of marine isocyanide terpenes, halichonadins A-D has been achieved, featuring nitrile-to-isocyanide interconversion utilizing Hofmann rearrangement.