NHC-Catalyzed Enantioselective Access to β-Nitrile Carboxylic Esters via In Situ Substrate Alternation and Release

Abstract

Abstract A carbene-catalyzed asymmetric access to chiral β-nitrile carboxylic esters is disclosed. The reaction proceeds between β,β-disubstituted enals and aromatic thiols involving enantioselective protonation of the enal β-carbon atoms. Two main factors contribute to the success of this reaction. One involves in situ ultrafast addition of the aromatic thiol substrates to the carbon-carbon double bond of the enal substrate. This reaction converts nearly all the enal substrate to a Thiol-click Intermediate, which dramatically reduces the concentration of the aromatic thiol substrates and suppresses the homo-coupling reaction of enals. Another factor is an in situ facile release of the enal substrate from the Thiol-click Intermediate for the desired reaction to proceed effectively. The optically enriched β-nitrile carboxylic esters from our method can be readily transformed to medicines that include γ-aminobutyric acids derivatives such as Rolipram, Phenibut and Baclofen. In addition to synthetic utilities, our control of reaction outcomes via in situ substrate modulation and release can likely inspire future reaction development.