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.