Enantioselective Electrophilic Cyanation of Boron Enolates: Scope and Mechanistic Studies

Chiral β-ketonitriles bearing a stereogenic carbon center at the α-position are an important class of compounds, many of which serve as useful synthetic intermediates for the preparation of chiral 1,3-aminoalcohols, β-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 β-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 α,β-unsaturated ketones and diisopinocampheylborane (Ipc₂ BH) to afford chiral β-ketonitriles with a high level of enantioselectivity. The present method is scalable and provides facile access to both enantiomers of chiral β-ketonitriles. Analysis of the in situ generated boron enolates by NMR revealed that hydroboration proceeds in a stereospecific manner, providing α,α-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.