Corey-Itsuno Reduction - Mechanism

Mechanism

Corey and coworkers originally proposed the following reaction mechanism to explain the selectivity obtained in the catalytic reduction.

The first step of the mechanism involves the coordination of BH₃ to the nitrogen atom of the oxazaborolidine CBS catalyst 1. This coordination serves to activate the BH₃ as a hydride donor and to enhance the Lewis acidity of the catalyst’s endocyclic boron. X-ray crystal structures and 11B NMR spectroscopic analyses of the coordinated catalyst-borane complex 2 have provided support for this initial step. Subsequently, the endocyclic boron of the catalyst coordinates to the ketone at the sterically more accessible electron lone pair (i.e. the lone pair closer to the smaller substituent, Rs). This preferential binding in 3 acts to minimize the steric interactions between the ketone (the large R_L substituent directed away) and the R’ group of the catalyst, and aligns the carbonyl and the coordinated borane for a favorable, face-selective hydride transfer through a six-membered transition state 4. Hydride transfer yields the corresponding, chiral boron enolate 5, which upon acidic workup yields the chiral alcohol 6. The last step to regenerate the catalyst may take place by two different pathways (Path 1 or 2).

The predominant driving force for this face-selective, intramolecular hydride transfer is the simultaneous activation of the borane reagent by coordination to the Lewis basic nitrogen and the enhancement of the Lewis acidity of the endocyclic catalyst boron for coordination to the ketone.