NHC-catalyzed enantioselective access to β-cyano carboxylic esters via in situ substrate alternation and release

The search for efficient methods for the enantioselective synthesis of cyano-containing molecules is important but synthesis methods are often limited by the need of toxic cyano salts or reduction with hydrogen gas. Here the authors report the efficient and selective access to & beta;-cyano carboxylic esters which can be easily converted into & gamma;-aminobutyric acid derivatives with high optical purities. A carbene-catalyzed asymmetric access to chiral & beta;-cyano carboxylic esters is disclosed. The reaction proceeds between & beta;,& beta;-disubstituted enals and aromatic thiols involving enantioselective protonation of enal & beta;-carbon. 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 almost all enal substrate to a Thiol-click Intermediate, significantly reducing aromatic thiol substrates concentration and suppressing the homo-coupling reaction of enals. Another factor is an in situ release of enal substrate from the Thiol-click Intermediate for the desired reaction to proceed effectively. The optically enriched & beta;-cyano carboxylic esters from our method can be readily transformed to medicines that include & gamma;-aminobutyric acids derivatives such as Rolipram. In addition to synthetic utilities, our control of reaction outcomes via in situ substrate modulation and release can likely inspire future reaction development.