Regulated-Stereoselective Construction of Thirteen Stereogenic Centers Necessary for the Frame of (+)-Discodermolide, Based on Iterative Lewis Acid-Promoted Aldol Reactions

Abstract

The segments C(1)-C(13) and C(15)-C(21) containing the 13 stereogenic centers required for the frame of (+)-discodermolide were synthesized in good to excellent enantio- and diastereoselectivities from a common racemic aldehyde, derived from 2-methyl-1,3-propanediol. The enantioselective aldol reactions of the racemic aldehyde with a silylketene acetal, derived from ethyl 2-bromopropionate, in the presence of chiral oxazaborolidinones, prepared in situ with N-p-toluenesulfonyl-(R)- and -(S)-valine and BH(3).THF, proceeded under kinetic control to give the stereotriads with a high degree of enantioselectivity. Enantioselective (chiral borane) and diastereoselective (BF(3).OEt(2) and TiCl(4)) aldol reactions with the silylketene acetal, coupled with diastereoselective radical debrominations (Bu(3)SnH, Et(3)B, with or without MgBr(2)), were used iteratively. This aldol reaction strategy for the construction of the polypropionate frame dramatically shortened the steps needed for the construction of the final segments.