The mechanism of cleavage of Evans chiral auxiliaries by LiOOH: origins of the different regioselectivities obtained with LiOH, LiOOH, LiOBn and LiSBn

Oxazolidinones are widely used as chiral auxiliaries in asymmetric synthesis. The chiral auxiliary can be selectively removed using LiOOH, LiOBn or LiSBn, but not LiOH, which instead favours endocyclic cleavage with opening of the oxazolidinone ring. Although Evans originally suggested that the regioselectivity of HO--mediated hydrolysis may be governed by the relative rates of formation of the two tetrahedral intermediates, whereas the regioselectivity of HOO- cleavage might be determined by their relative breakdown rates, it was not clear why this should be the case. Since then, there appear to have been no mechanistic studies that account for the differing selectivities of LiOH v. LiOOH, and the reason for this difference in selectivity has remained somewhat of an enigma in organic chemistry for many years. Herein, we report DFT computations with M06-2X-D3//B3LYP-D3 to examine the origins of the regioselectivities. The computations predict that all four nucleophiles prefer to attack at the endocyclic carbonyl group, which is less hindered. The barrier for decomposition of the initially formed tetrahedral intermediate determines whether or not the reaction continues all the way to the endocyclic cleavage products. For LiOH, the barrier for decomposition of the intermediate is small and the endocyclic cleavage products are formed. For LiOOH, LiOBn and LiSBn, the decomposition barrier is large, and the exocyclic cleavage pathway instead becomes preferred. An alternative mechanism involving formation of a novel cyclic peroxide intermediate was found to involve a relatively high energy pathway and has been excluded.