Described is a mechanistic study of a diastereoselective nitrone cyclization induced by use of a variety of chiral auxiliaries to afford diastereoselectivities ranging from 60 to 91 %.  In-situ reaction characterization and monitoring via 1D and 2D NMR experiments were used to elucidate the mechanism.  Application of these findings afforded improvements of diastereoselectivity by addition of alcohols and phenols that were able to undergo ligand exchange with the titanium isopropoxide and still retain catalytic behavior in the sterically encumbered transition state.   As a result of these hydroxyl additives, the rate of reaction was increased by 2-3 fold and the diastereoselectivity was increased by >8%.   Spectroscopic studies showed that the increased diastereoselectivity resulted from a fundamental change in the E-Nitrone (geometrically disfavored) to the Z-Nitrone (atropisomers geometrically favored) ratio from ~ 1: 1 to 1: 6 with the hydroxyl additives.  Conversion of the undesired diastereomer to the desired diastereomer by thermal retro-nitrone cyclization of the mother liquors enriched in the undesired diastereomer will also be reported.

Chiral auxiliary control in asymmetric nitrone cycloadditions

246th National Meeting (2013)

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