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Asymmetric Total Synthesis of Spongistatins 1 and 2

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journal contribution
posted on 26.04.2002 by Michael T. Crimmins, Jason D. Katz, David G. Washburn, Shawn P. Allwein, Laura F. McAtee
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 γ-pyrone to a β-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.