Total Synthesis of the Actin-Depolymerizing Agent (−)-Mycalolide A:  Application of Chiral Silane-Based Bond Construction Methodology

A highly convergent asymmetric synthesis of the actin-depolymerizing agent (−)-mycalolide A has been achieved through the assembly and union of the C1−C19 trisoxazole fragment 2 and the C20−C35 aliphatic fragment 3, respectively. The C1−C19 fragment 2 was constructed via a Kishi−Nozaki coupling between the C1−C6 subunit 4 and the C7−C19 subunit 5, which in turn was obtained from a highly stereoselective crotylation reaction of silane (S)-7 with trisoxazole aldehyde 8. The synthesis of the C20−C35 fragment 3 has been accomplished using chiral silane-based bond construction methodology for the introduction of the stereochemical relationships. Union of the advanced intermediates 2 and 3 through a Schlosser−Wittig protocol, macrocyclization utilizing Yamaguchi conditions, and subsequent functional group adjustments completed the total synthesis of (−)-mycalolide A. The synthesis confirms the relative and absolute stereochemistry of (−)-mycalolide A, as well as illustrates the application of chiral silane-based C−C bond construction methodology to the asymmetric synthesis of complex molecules.