Organocatalytic Enantioselective α-Hydroxymethylation of Aldehydes: Mechanistic Aspects and Optimization

Further studies of the direct enantioselective alpha-hydroxymethylation of aldehydes employing the a,alpha-diarylprolinol trimethylsilyl ether class of organocatalysts are described. This process has proven efficient for access to beta-hydroxycarboxylic acids and d-hydroxy-alpha,beta-unsaturated esters from aldehydes in generally good yields, excellent enantioselectivity, and compatibility with a broad range of functional groups in the aldehyde. The goal of these studies was to identify the critical reaction variables that influence the yield and enantioselectivity of the a-hydroxymethylation process such as catalyst structure, pH of the medium, purity of the reactants and reagents particularly with respect to the presence of acidic impurities, and the nature of the buffer, along with the standard variables including solvent, time, temperature and mixing efficiency. The previously identified intermediate lactol has been further characterized and its reactivity examined. These studies have led to identification of the most critical variables translating directly into improved substrate scope, reproducibility, enantioselectivity, and yields.