Asymmetric total synthesis of (-)-laulimalide: Exploiting the asymmetric glycolate alkylation reaction

A concise total synthesis of the potent antitumor macrolide (-)-laulimalide is described. The observation that homoallylic (or latent homoallylic) C-O bonds are present at C5, C9, C15, C19, and C23 led to the strategic decision to rely heavily on the asymmetric glycolate alkylation to construct both the C1-C14 fragment 3 and the C15-C27 subunit 4. A diastereoselective addition of a C1-C14 allylstannane to a C15-C27 α,β-epoxyaldehyde served to join the two advanced fragments. A Mitsunobu macrolactonization of hydroxy acid 2 avoided isomerization of the sensitive 2,3-Z-enoate, which has been observed in base-catalyzed macrolactonizations. Removal of two TBS protecting groups to reveal the C15 and C20 hydroxyls occurred without rearrangement to isolaulimalide. Copyright © 2002 American Chemical Society.