Ru-Catalyzed Enantioselective Hydrogenation of 2-Pyridyl-Substituted Alkenes and Substrate-Mediated H/D Exchange

Abstract

A highly efficient and enantioselective asymmetric hydrogenation catalyzed by Ru-DTBM-segphos is reported for a broad range of pyridine−pyrroline trisubstituted alkenes. Kinetic, spectroscopic, and computational studies suggest that addition of H 2 is rate-determining, alkene insertion is enantio-determining, and that the presence and position of the pyridine nitrogen is critical to enantioselectivity. These studies also reveal an intriguing Ru-catalyzed H/D exchange process that is facilitated by a substrate at room temperature and low pressure, where hydrogenation activity is suppressed. These studies lead to a mechanistic proposal that further defines the roles of hydrogen gas, Ru−H species, and protic solvents in this catalytic system.

Kinetic and Thermodynamic Considerations in the Rh-Catalyzed Enantioselective Hydrogenation of 2-Pyridyl-Substituted Alkenes

“…As part of a recent early-stage program at BMS, an enantiopure pyridyl-pyrrolidine was required, and we explored asymmetric hydrogenation of 1a as a potential route. As part of this work, we reported a mechanistic study of the highly enantioselective hydrogenation of these substrates catalyzed by Ru-segphos, in which we also observed an unusual H/D exchange process between the methanol solvent and the substrate . In the current work, we reveal that the H/D exchange does not occur in the Rh-catalyzed hydrogenation reaction and that enantioselectivity is much more sensitive to substitution in the pyridyl substrate compared to Ru.…”

“…As part of this work, we reported a mechanistic study of the highly enantioselective hydrogenation of these substrates catalyzed by Ru-segphos, in which we also observed an unusual H/D exchange process between the methanol solvent and the substrate. 13 In the current work, we reveal that the H/ D exchange does not occur in the Rh-catalyzed hydrogenation reaction and that enantioselectivity is much more sensitive to substitution in the pyridyl substrate compared to Ru. Detailed kinetic, spectroscopic, and computational studies give a comprehensive mechanistic picture of the role of substrate 1 functional groups in this reaction system in achieving both rapid reaction rates and high enantioselectivities at ambient temperature and low pressure.…”

“…In contrast to the Ru system, dihydrofuran instead of pyrroline was active but less selective ( 1t ). Substrates with a 2-pyrroline group, where the olefin double bond is conjugated with the protected amine, gave low ee ( 1x ) and, in one case, a sluggish reaction and a reversal of enantioselectivity to −40% ee ( 1w ).…”

Collaboration as a Key to Advance Capabilities for Earth-Abundant Metal Catalysis

“…Our collaboration with the Yu lab has focused on innovation aimed toward new reaction methodology, mainly mediated by palladium, with a lens toward our discovery team. 80 Multiple transition-metalcatalyzed mechanistic interrogations have been completed with the Blackmond lab, for example impacting the process route to fostemsavir through investigation of an Ullmann coupling 7c and building understanding of stereospecificity in a rhodium- 81 or ruthenium-catalyzed 82 hydrogenation relevant to our portfolio. Further, we reported the importance of catalyst activation of palladium(II) precatalysts in the formation of a bisphosphine monoxide palladium complex for a direct arylation from our JAK2 program.…”

Single-Atom Ru-zeolite isomerization catalysis for a bio-based route towards terephthalates from muconic acid

“…Besides, these findings point out that the Ru-D insertion occurs selectively, whereby the D is incorporated at the C2 while the Ru bond is formed with C3, probably due to electronic or steric effects. [61] The spent catalyst (after 2838 mol/mol) was characterized in order to understand routes to deactivation and thus possible remediation paths. Thermogravimetric analysis shows 4% of 'coke' on the spent catalyst, which corresponds to less than 0.7% of the initial amount of ctDEM (300mM), and this burned between 220 and 500°C (Fig.…”