Asymmetric Transfer Hydrogenation of α-Substituted-β-Keto Carbonitriles via Dynamic Kinetic Resolution

• DOI: 10.1021/jacs.0c13273
• Publication Date: 2021-02-06T11:50:47Z
• Authors: Fangyuan Wang; Tilong Yang; Ting Wu; Long-Sheng Zheng; Congcong Yin; Yongjie Shi; Xiang-Yu Ye; Gen-Qiang Chen; Xumu Zhang
• Keywords: α-; Evolutionary Biology; Ecology; Chemical Sciences not elsewhere classified; DKR-ATH; Dynamic Kinetic Resolution; Biophysics; Plant Biology; Computational Biology; Biochemistry; DFT; 01 natural sciences; 0104 chemical sciences; -β-keto carbonitriles; Infectious Diseases; Asymmetric Transfer Hydrogenation; enantio; β- hydroxy carbonitrile scaffolds; Cancer; Biological Sciences not elsewhere classified

A catalytic protocol for the enantio- and diastereoselective reduction of α-substituted-β-keto carbonitriles is described. The reaction involves a DKR-ATH process with the simultaneous construction of β-hydroxy carbonitrile scaffolds with two contiguous stereogenic centers. A wide range of α-substituted-β-keto carbonitriles were obtained in high yields (94%-98%) and excellent enantio- and diastereoselectivities (up to >99% ee, up to >99:1 dr). The origin of the diastereoselectivity was also rationalized by DFT calculations. Furthermore, this methodology offers rapid access to the pharmaceutical intermediates of Ipenoxazone and Tapentadol.