A Total Synthesis of Norhalichondrin B.

The halichondrin family of marine polyethers, first defined by the isolation and structure elucidation of norhalichondrin A by Uemura and co-workers in 1985, now numbers ~ 15 compounds.[1] The structures of the halichondrins, as exemplified by norhalichondrin B (Figure 1) are characterized by a 53–55 carbon backbone that is defined by two domains: the spiroketal containing C31-C53/55 region and a C1-C30 macrolactone that also contains a 2,6,9-trioxatricyclo[3.3.2.03,7]decane. The structures, in conjunction with impressive levels of cytotoxicity, have attracted significant scientific attention[2,3] highlighted by the total syntheses of halichondrin B and norhalichondrin B by Kishi in 1992,[3,5] and the current efforts of Eisai Pharmaceuticals to establish E7389,[6] a truncated analog of the macrolactone, as an anti-cancer therapeutic. In this communication we describe our studies that have culminated in the total synthesis of norhalichondrin B.