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 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.

Enantioselective Transformations in the Synthesis of Therapeutic Agents

“…The electron-rich P-chiral bisphosphorus ligand ArcPhos (L18) was developed by Tang and co-workers for Rh-catalyzed enantioselective hydrogenation of heterocyclic tetrasubstituted enamide 120 (Scheme 26b). 81 The use of the conformationally defined Rh-ArcPhos catalyst provided high enantioselectivity at a 0.025 mol % catalyst loading. The asymmetric hydrogenation reaction delivered cis chiral amine derivative 121 in 99% yield and 96% ee, which served as a key transformation in the asymmetric synthesis of Janus kinase inhibitor tofacitinib (122).…”

SNAr Regioselectivity Predictions: Machine Learning Trigger-ing DFT Reaction Modeling through Statistical Threshold

“…Due to its interpretability, accuracy, versatility, and general applicability, DFT has been the major workhorse for in silico reaction predictions in pharmaceutical industries. [3][4][5] Despite those benefits, limitation still exists in process development when DFT reaction modeling is used for prospective predictions, i.e., virtual screening of reaction pathways. Conventional DFT reaction modeling requires a subject-matter expert (SME) to locate key transition states which is usually a tedious trial-and-error process and contains repeated jobs.…”

Palladium‐Catalyzed Regio‐, Diastereo‐, and Enantioselective 1,2‐Arylfluorination of Internal Enamides

“…We set out to explore whether the prefunctionalized alkene, such as internal enamide would be an alternative candidate for synthesis of chiral amine derivatives with the simultaneous formation of vicinal stereocenters. [5] The transition metal-catalyzed asymmetric hydrogenation [6] and hydrofunctionalization [7] of enamide has been proven to be a powerful approach for chiral amine synthesis via the stereoselective insertion of M-H species over the carboncarbon double bond. The chiral phosphoric acid could promote the consecutive functionalization of enamide by the cascade nucleophilic addition.…”