Stereoelectronic Effects in Ligand Design: Enantioselective Rhodium‐Catalyzed Hydrogenation of Aliphatic Cyclic Tetrasubstituted Enamides and Concise Synthesis of (R)‐Tofacitinib

• Published in: Angewandte Chemie International Edition Vol. 58; no. 38; pp. 13573 - 13583
• Main Authors: Li, Chengxi, Wan, Feng, Chen, Yuan, Peng, Henian, Tang, Wenjun, Yu, Shu, McWilliams, J. Christopher, Mustakis, Jason, Samp, Lacey, Maguire, Robert J.
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 16.09.2019; Wiley Subscription Services, Inc
• Edition: International ed. in English
• Subjects: Aliphatic compounds; asymmetric hydrogenation; Catalysts; Chemistry; Chemistry, Multidisciplinary; enamides; Enantiomers; Enzyme inhibitors; Hydrogenation; Janus kinase; Kinases; Ligands; Physical Sciences; P ligands; Rhodium; Science & Technology; stereoelectronic effects; tofacitinib; stereoelectronic effects; PRACTICAL SYNTHESIS; MECHANISM; enamides; SCOPE; COMPLEXES; tofacitinib; PHOSPHORUS LIGANDS; KINETIC RESOLUTION; AMINO-ACIDS; P ligands; OLEFINS; asymmetric hydrogenation; P ligands
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.201908089

We herein report the development of a conformationally defined, electron‐rich, C2‐symmetric, P‐chiral bisphosphorus ligand, ArcPhos, by taking advantage of stereoelectronic effects in ligand design. With the Rh‐ArcPhos catalyst, excellent enantioselectivities and unprecedentedly high turnovers (TON up to 10 000) were achieved in the asymmetric hydrogenation of aliphatic carbocyclic and heterocyclic tetrasubstituted enamides, to generate a series of chiral cis‐2‐alkyl‐substituted carbocyclic and heterocyclic amine derivatives in excellent enantiomeric ratios. This method also enabled an efficient and practical synthesis of the Janus kinase inhibitor (R)‐tofacitinib. The conformationally defined, electron‐rich, C2‐symmetric, P‐chiral ligand ArcPhos was designed by taking advantage of stereoelectronic effects. With the Rh‐ArcPhos catalyst, excellent enantioselectivities and high turnovers were achieved in the asymmetric hydrogenation of aliphatic carbocyclic and heterocyclic tetrasubstituted enamides.