Cobalt-Catalyzed Asymmetric Hydrogenation of α,β-Unsaturated Carboxylic Acids by Homolytic H₂ Cleavage

Abstract

The asymmetric hydrogenation of α,β-unsaturated carboxylic acids using readily prepared bis­(phosphine) cobalt(0) 1,5-cyclooctadiene precatalysts is described. Di-, tri-, and tetra-substituted acrylic acid derivatives with various substitution patterns as well as dehydro-α-amino acid derivatives were hydrogenated with high yields and enantioselectivities, affording chiral carboxylic acids including Naproxen, (S)-Flurbiprofen, and a d-DOPA precursor. Turnover numbers of up to 200 were routinely obtained. Compatibility with common organic functional groups was observed with the reduced cobalt(0) precatalysts, and protic solvents such as methanol and isopropanol were identified as optimal. A series of bis­(phosphine) cobalt­(II) bis­(pivalate) complexes, which bear structural similarity to state-of-the-art ruthenium­(II) catalysts, were synthesized, characterized, and proved catalytically competent. X-band EPR experiments revealed bis­(phosphine)­cobalt­(II) bis­(carboxylate)­s were generated in catalytic reactions and were identified as catalyst resting states. Isolation and characterization of a cobalt­(II)–substrate complex from a stoichiometric reaction suggests that alkene insertion into the cobalt hydride occurred in the presence of free carboxylic acid, producing the same alkane enantiomer as that from the catalytic reaction. Deuterium labeling studies established homolytic H2 (or D2) activation by Co(0) and cis addition of H2 (or D2) across alkene double bonds, reminiscent of rhodium­(I) catalysts but distinct from ruthenium­(II) and nickel­(II) carboxylates that operate by heterolytic H2 cleavage pathways.

Cobalt-catalyzed highly enantioselective hydrogenation of α,β-unsaturated carboxylic acids

“…Coordination of Co(acac) 2 with (S,S)-Ph-BPE generates Co(II) complex A, which then undergoes ligand exchange with more acidic substrate 1b to produce complex B, complex B and B′ are in equilibrium with each other. Heterolysis of H 2 by complex B′ produces the key catalytic species E via transition state C. Intermediate E may be also produced through protonation 76 of dihydride complex D 65,73 with 1b when employing one-electron reductant. Chirik and coworkers 73 reported an alternative mechanism which involved the migratory insertion of the dihydride complex and the subsequent reduction elimination as key step.…”

“…Heterolysis of H 2 by complex B′ produces the key catalytic species E via transition state C. Intermediate E may be also produced through protonation 76 of dihydride complex D 65,73 with 1b when employing one-electron reductant. Chirik and coworkers 73 reported an alternative mechanism which involved the migratory insertion of the dihydride complex and the subsequent reduction elimination as key step. Note that the addition of one-electron reductant is beneficial for obtaining full conversions with low catalyst loading (vide supra).…”

“…2b). After the first submission of our paper, the asymmetric hydrogenation of α,βunsaturated carboxylic acids is reported by Chirik and coworkers 73 with a cobalt catalytic system, and high yields and enantioselectivities are achieved for a wide range of acrylic acid derivatives.…”

1,3,2‐Diazaphospholenes Catalyze the Conjugate Reduction of Substituted Acrylic Acids

“…Non‐steroidal anti‐inflammatory drugs (NSAIDs) of the aryl propionic acid class such as ibuprofen, naproxen or flurbiprofen are important drugs and could be accessed by a conjugate reduction of corresponding substituted acrylic acids (Scheme ). Generally, a variety of homo‐ and heterogeneous transition‐metal catalyzed processes are reported for the direct hydrogenation of substituted acrylic acids . However, the inherent acidic nature of a carboxylic acid presents a challenge for the development of hydridic, metal‐free alternatives.…”

Enantioselective Hydrogenation of Tetrasubstituted α,β‐Unsaturated Carboxylic Acids Enabled by Cobalt(II) Catalysis: Scope and Mechanistic Insights

“…[10] Especially,c atalysts based on cobalt are highly attractive for asymmetric hydrogenation, [11] and appreciable progress has been made in recent years. [12] Very recently,w ea nd the Chirik group independently reported cobalt-catalyzed enantioselective hydrogenation of a,b-unsaturated carboxylic acids. [12a,b] Thec atalytic system worked well for both di-and trisubstituted unsaturated acids (Scheme 1b).…”