New directions in stereocontrolled synthesis: Approach to cytotrienin A

Novel synthetic methods in stereocontrolled synthesis have been developed using chiral E-crotyl silane reagents. Lewis acid promoted C-glycosidation reactions of activated glycals with chiral ( E)-crotylsilanes were found to be highly regio- and diastereoselective. The stereochemical relationship between the methyl bearing stereogenic center at the C1′ position and the anomeric center of the pyran is defined by the silane reagent as the configuration of the C-Si bond determines the stereochemistry of the C1′-methyl group. The topological bias is principally controlled by stereoelectronic effects of the pyran oxonium ion and by the facial bias of the silane reagent. Levels of diastereoselectivity ranged from 10 to 30:1 (α:β ratio) in the presence of BF₃ •OEt₂, which was found to be with TMSOTf, the most effective Lewis acid to promote the reactions. Consistent with the behavior of these silane reagents and an anti-S_E′ mechanism, is that of the four possible diastereomers only the two isomers derived from the C1′ stereochemical relationship are detectable.; Enantioselective syntheses of functionalized homoallylic amines and silyl functionalized pyrrolidines through the Lewis acid promoted condensation of chiral (E)-crotylsilanes with in situ generated N-acyl imines were found to be highly diastereoselective.; Trifloyl oxazoles have been used as coupling partners with alkyne derived vinyl metallic intermediates in Stille and Negishi-type couplings to assemble the corresponding oxazoles in good isolated yield. This strategy takes advantage of transition metal catalyzed coupling reactions for the synthesis of highly functionalized oxazoles. The results obtained provide a good precedent to employ this strategy in the synthesis of the substituted oxazoles of phorboxazole A.; A convergent stereocontrolled approach toward the synthesis of cytotrienin A has been developed. Determination of the absolute and relative stereochemistry of cytotrienin A is described via the synthesis of all cytotrienin epimers. This approach has been implemented in the preparation of the sixteen epimeric macrocyclic precursors. The synthetic route highlights the use of a stereocontrolled aldol reaction to install the C11–C12 stereocenters and a stereoselective hydride reduction or Felkin addition of a lithium anion to an aldehyde to install both possible C13 epimers.