Formal total synthesis of (-)-exiguolide

The formal total synthesis of (-)-exiguolide through the chiral-pool approach is described. The key reactions involved for formation of the macrocyclic core from two subunits are Julia-Kocienski olefination and Yamaguchi macrolactonization. The major methylene bis-tetrahydropyran fragment was achieved in a convergent manner from L-glutamic acid and L-aspartic acid involving the oxa-Michael reaction and an aldol-driven reductive etherification as key steps for the formation of a tetrahydropyran ring. The other sulfone subunit was prepared via an Evans aldol reaction.