Catalytic Asymmetric Staudinger–aza-Wittig Reaction for the Synthesis of Heterocyclic Amines

• Published in: Journal of the American Chemical Society Vol. 141; no. 24; pp. 9537 - 9542
• Main Authors: Cai, Lingchao, Zhang, Kui, Chen, Shuming, Lepage, Romain J, Houk, K. N, Krenske, Elizabeth H, Kwon, Ohyun
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 19.06.2019; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Multidisciplinary; Physical Sciences; Science & Technology; GAMMA; ENANTIOSELECTIVE SYNTHESIS; REDUCTION; MECHANISM; ANNULATION; UGI; PHOSPHINE OXIDES
• ISSN: 0002-7863; 1520-5126; 1520-5126
• DOI: 10.1021/jacs.9b04803

Many natural products and medicinal drugs are heterocyclic amines possessing a chiral quaternary carbon atom in their heterocyclic ring. Herein, we report the first catalytic and asymmetric Staudinger–aza-Wittig reaction for the desymmetrization of ketones. This highly enantioselective transformation proceeds at room temperature to provide high yieldseven on multigram scalesof nitrogen heterocycles featuring a chiral quaternary center. The products of this reaction are potential precursors for the synthesis of pharmaceuticals. A commercially available small P-chiral phosphine catalyst, HypPhos, induces the asymmetry and is recycled through in situ reduction of its oxide, mediated by phenylsilane in the presence of a carboxylic acid. The efficiency, selectivity, scalability, mild reaction conditions, and broad substrate scope portend that this process will expedite the syntheses of chiral heterocyclic amines of significance to chemistry, biology, and medicine.