On Rational Design of Stereodivergent Organocatalysis Controlled by Selective Hydration

Stereodivergent asymmetric synthesis via slightly tuning the catalytic conditions is very attractive for early-stage drug discovery, because it is a very time efficient and economical method for obtaining all potential biologically active diastereomers/enantiomers. However, the exploration is largely serendipity and no general strategy is available. A predictive hydrogen bonding rearrangement via selective hydration by water is proposed as a potential general strategy for rational design of stereodivergent organocatalysis. With the new concept and the proposed hydrated enamine/imine model, the origin of the divergent mechanism for the two recent successful water-modulated transformations could be very well elucidated.