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 alpha,beta-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.
Crimmins
Michael T
MT
Department of Chemistry, Venable and Kenan Laboratories of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290, USA. crimmins@email.unc.edu
Stanton
Matthew G
MG
Allwein
Shawn P
SP
D000478:Alkylation; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D006016:Glycolates / Q000737:chemistry*; D018942:Macrolides; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000138:chemical synthesis*; D013237:Stereoisomerism; D043823:Taxoids
D000970:Antineoplastic Agents; D006016:Glycolates; D018942:Macrolides; D043823:Taxoids; C117305:laulimalide; D017239:Paclitaxel