StereoselectiveEpimerization of 1,3-Diols Using aChiral Hydrogen Atom Abstraction Catalyst

Abstract The 1,3-diol unit is an extremely important functional group motif, and significant effort has gone into development of methods to access it with definition of relative and absolute stereochemistry. Conventionally, stereochemical complexity is built up in a stepwise manner alongside functional group interconversion. It is interesting to consider an unconventional approach whereby the diol may be synthesized nonselectively and the stereoisomers “descrambled” by a chiral catalyst in a subsequent step. We report studies toward this goal using a cinchona alkaloid-derived hydrogen atom abstraction catalyst. This catalyst permits selective hydrogen atom abstraction from a given stereoisomer out of, in some cases three or four, depending on diol substitution. The relative rates of abstraction from different stereoisomers determine the ultimate product outcome after hydrogen atom delivery from an achiral thiol. Symmetrical 1,3-diols participate in a kinetic resolution process whereby one enantiomer is converted to the meso diastereomer with extremely high selectivity, a rare example of a kinetic resolution involving conversion of one enantiomer to an achiral diastereomer. Nonsymmetrical 1,3-diols exhibit different outcomes depending on substitution, and their behavior is systematically explored. Notably, sterically differentiated substrates can allow high ee of both syn and anti diastereomers to be achieved from racemic starting material. On the basis of mechanistic studies, a unified rationalization of the behavior of 1,3-diols of various types with our catalyst is presented, and we additionally evaluate the analogous chiral 1,2-diols, uncovering promising outcomes with nonsymmetrical diols.