Total synthesis and biological evaluation of (−)-enigmazole B

Abstract Total synthesis of (−)-enigmazole B, isolated from a Papua New Guinean sponge, Cinachyrella enigmatica, has been achieved for the first time. The macrocyclic skeleton of the target compound was synthesized by exploiting a Sonogashira cross-coupling of an (E)-enol tosylate and a terminal alkyne, a Au-catalyzed intramolecular alkyne hydroalkoxylation, and a Yamaguchi macrolactonization. The (E)-enol tosylate was accessed through an olefin cross-metathesis/hemiacetalization/intramolecular oxa-Michael addition in a stereocontrolled manner. Cytotoxic activity of synthetic (−)-enigmazole B was evaluated against a small panel of human cell lines. It was shown that (−)-enigmazole B was approximately 5- to 7-fold more potent than (−)-enigmazole A in human cancer cell lines. Moreover, (−)-enigmazole A/B hybrid analogs were synthesized and evaluated to investigate the structure–activity relationship, suggesting the importance of the dihydropyran ring of (−)-enigmazole B for potent cytotoxicity.