Stereoselective Synthesis of the Southern Hemisphere Acyclic Domain of Neaumycin B.

A stereocontrolled synthetic entry to the southern hemisphere C3-C17 acyclic domain of neaumycin B, a highly potent cytotoxic macrolide natural product, has been developed. The present synthesis is based on (i) a tandem olefin cross-metathesis/hemiacetalization/intramolecular oxa-Michael addition, (ii) a regioselective reductive acetal opening for differential protection of the C14 hydroxy group, (iii) a Horner-Wadsworth-Emmons reaction for the stereoselective formation of the C8-C9 olefin, and (iv) a Corey-Bakshi-Shibata asymmetric reduction to create the C7 stereogenic center.