Synthetic Studies of Halichondrin B, an Antitumor Polyether Macrolide Isolated from a Marine Sponge 5. A Highly Concise and Efficient Synthesis of the C37~C54 Tricyclic JKL-Ring Part

Abstract

A concise and efficient synthesis of C37-C54 hicyclic JKL-ring unit (2) of halichondrin B (1) utilizing C2-symmetric spiroketal derivative (5) as a synthetic key intermediate, easily provided from dimethyl L(+)-tartrate, is reported.Halichondrin B (1) is a representative compound of the antitumor polyether macrolides in the halichondrin family, isolated from a marine sponge Halichondria okodai Kadota by Uemura, Huata and co-workers in 1985.1Synthetic challenges toward a total synthesis of halichondrins by synthetic organic chemists2 have been reported due to the highly complex chemical structure as well as important biological activities, the first total synthesis of halichondrin B (1) and norhalichondrin B was achieved by Kishi and co-workers in 1992.2fIn connection with our synthetic program of 1, we reported the stereoselective syntheses of four convenient synthetic subunit^.^In this paper, we describe a highly efficient, concise and stereoselective synthesis of the C37-C54 tricyclic (JKL rings) unit (2) from dimethyl L-(+)-tamate.