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

Abstract

We herein report the development of ac onformationally defined, electron-rich, C 2 -symmetric, P-chiral bisphosphorus ligand, ArcPhos,b yt aking 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,t og enerate as eries of chiral cis-2-alkylsubstituted carbocyclic and heterocyclic amine derivatives in excellent enantiomeric ratios.T his method also enabled an efficient and practical synthesis of the Janus kinase inhibitor (R)-tofacitinib.

Inside Perspective of the Synthetic and Computational Toolbox of JAK Inhibitors: Recent Updates

“…Due to the pharmaceutical importance, and to overcome the synthetic constraints reported by Pfizer Inc., the synthesis of tofacitinib was extensively studied and several procedures were published [ 119 , 120 , 121 , 122 , 123 , 124 , 125 ]. Usually, the key compound implicated in the synthesis of tofacitinib is the (3 R ,4 R )-1-benzyl- N ,4-dimethylpiperidin-3 amine, which is obtained from 3-amino-4-methylpyridine ( Scheme 4 A,B) [ 119 , 120 ] or 4-methyl-picoline ( Scheme 4 C).…”

“…Recently, the development of protocols describing the conditions for catalytic asymmetric reductive amination for the preparation of chiral amines as key intermediates in the synthesis of tofacitinib was also documented [ 124 , 125 ].…”

Recent Developments in Transition-Metal-Catalyzed Asymmetric Hydrogenation of Enamides

“…The hydrogenation was carried out under 34 bar of hydrogen in MeOH for 6 hours at room temperature (Scheme 46). 49…”

Asymmetric hydrogenation of γ‐branched allylamines for the efficient synthesis of γ‐chirogenic amines

“…Therefore, the development of general and efficient methods to prepare chiral amines has been a major focus in both academia and industry [1–6]. In the process of pursuing this goal, catalytic asymmetric hydrogenation (AH) has gradually emerged as the most industrially feasible option due to its high efficiency, cost competitiveness, and environmental friendliness [7–18]. Until now, hundreds of chiral transition metal catalysts have been developed and successfully applied in the AH of thousands of structurally different N ‐containing substrates.…”