Kilogram‐Scale Asymmetric Ruthenium‐Catalyzed Hydrogenation of a Tetrasubstituted Fluoroenamide

Abstract

Ruthenium-catalyzed asymmetric homogeneous hydrogenation (AHH) is used as the key step of a multi-kilogram scale synthesis of an enantiomeric fluoropiperidine. The AHH of a tetrasubstituted b-fluoroenamide is carried out under mild conditions using a Ru/Josiphos catalyst with high ee (98%).

Development of the Convergent, Kilogram-Scale Synthesis of an Antibacterial Clinical Candidate Using Enantioselective Hydrogenation

“…Initial attempts to hydrogenate the pyridine ring suffered from excessive amounts of hydrodefluorination, an issue which plagues even the state-of–the-art dearomatization–hydrogenation method of Nairoukh et al The use of a more easily reduced hydrogenation substrate was sought, with attention turning to the hydrogenation of an olefin bearing a double bond between the two prostereogenic centers. − Providing the exocyclic nitrogen of the hydrogenation substrate with a carbamate protecting group was targeted in the hope that the coordination of its carbonyl to the metal of a chiral hydrogenation catalyst would enable the highly enantioselective delivery of hydrogen. Notably, such behavior has been observed with the enantioselective hydrogenation of structurally related fluoroenamides. , …”

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

“…Hence, the development of new, simple, and efficient methods to access a diverse array of novel chiral fluorinated derivatives, has become a highly prioritized research area[53][54][55][56]. Transition metalcatalyzed AH of alkenyl fluorides is one of the most promising methods[57][58][59][60][61]. The relatively strong electron withdrawing behavior of the fluorine together with the easy-to-break C-F bond, making these types of alkene substrates difficult to be hydrogenated.…”

Large Scale Practical Synthesis of Enantiomerically Pure cis-4-Amino-3-fluoro-1-methylpiperidine via Rhodium-Catalyzed Asymmetric Hydrogenation of a Tetrasubstituted Fluoroalkene

“…Compound 1 was commonly obtained via conventional methods including diastereomeric salt resolution of racemates, 7 enantioselective decarboxylation, 8 and enantioselective fluorination. 9 Enantioselective syntheses of cis-4-amino3-fluoropiperidines were reported recently via ruthenium catalyzed asymmetric hydrogenation of the corresponding tetrasubstituted fluoroencarbamates 10 or fluoroenamides 11 by taking advantage of the required cis-configuration of the substituents on piperidine intermediates. However, asymmetric hydrogenation on fluorocontaining tetrasubstituted alkenes often suffers from unsatisfactory enantioselectivity and diastereoselectivity together with generation of the hydrodefluorination impurity.…”