Asymmetric total synthesis of spongistatins 1 and 2.
The total synthesis of spongistatin 1 (1) and spongistatin 2 (2) has been achieved through an advanced-stage intermediate. The synthesis is highlighted by a highly convergent assembly of the four key fragments (the C1-C15 AB fragment 2, the C16-C28 CD fragment 3, the C29-C43 EF fragment 4, and the C44-C51 side chain 5) at a very advanced stage of the synthesis with minimal functional group interconversion. The CD fragment 3 functions as the central building block to which the other fragments are attached. The synthesis of the AB and CD spiroketal fragments is accomplished through the addition of a metalated gamma-pyrone to a beta-alkoxy aldehyde followed by spiroketalization. The EF subunit was assembled with high diastereoselectivity relying on asymmetric aldol reactions of chlorotitanium enolates of N-propionyl oxazolidinethiones and a double diastereoselective boron aldol to join the E and F fragments. Wittig coupling of the CD and EF fragments followed by a diastereoselective aldol reaction between the CDEF ketone and an AB aldehyde set the stage for attachment of the C44-C51 side chains and final macrolactonization and deprotection.
Crimmins
Michael T
MT
Department of Chemistry, Venable and Kenan Laboratories of Chemistry, University of North Carolina at Chapel Hill, 27599-3290, USA. crimmins@email.unc.edu
Katz
Jason D
JD
Washburn
David G
DG
Allwein
Shawn P
SP
McAtee
Laura F
LF
D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D004988:Ethers, Cyclic / Q000138:chemical synthesis*; D007783:Lactones / Q000138:chemical synthesis*; D018942:Macrolides; D000095702:Polyether Toxins
D000970:Antineoplastic Agents; D004988:Ethers, Cyclic; D007783:Lactones; D018942:Macrolides; C409088:altohyrtin C; D000095702:Polyether Toxins; C083856:spongistatin 1