Enantioselective Electrophilic Cyanation of Boron Enolates: Scope and Mechanistic Studies

Chiral beta-ketonitriles bearing a stereogenic carbon center at the alpha-position are an important class of compounds, many of which serve as useful synthetic intermediates for the preparation of chiral 1,3-aminoalcohols, beta-hydroxy nitriles, and related derivatives. Although the enantioselective electrophilic cyanation of enolate equivalents is one of the most promising approaches for the synthesis of chiral beta-ketonitriles, the available methods are largely limited to reactions of 1,3-dicarbonyl compounds. Herein, we report on enantioselective electrophilic cyanation of boron enolates, which are readily prepared from alpha,beta-unsaturated ketones and diisopinocampheylborane (Ipc(2)BH) to afford chiral beta-ketonitriles with a high level of enantioselectivity. The present method is scalable and provides facile access to both enantiomers of chiral beta-ketonitriles. Analysis of the in situ generated boron enolates by NMR revealed that hydroboration proceeds in a stereospecific manner, providing alpha,alpha-disubstituted boron enolates in the form of single isomers. Furthermore, the results of DFT calculations suggest that the cyanation of the boron enolates with p-toluenesulfonyl cyanide (TsCN) proceeds in a highly enantioselective manner through a unique six-membered ring transition state.