55332-37-1

Chiral carboxylic acids are important compounds because of their prevalence in pharmaceuticals, natural products and agrochemicals. Asymmetric hydrogenation of α,β-unsaturated carboxylic acids has been widely recognized as one of the most efficient synthetic approaches to afford such compounds. Although related asymmetric hydrogenation of di- and trisubstituted unsaturated acids with noble metals is well established, asymmetric hydrogenation of challenging tetrasubstituted α,β-unsaturated carboxylic acids is rarely reported. We demonstrate enantioselective hydrogenation of cyclic and acyclic tetrasubstituted α,β-unsaturated carboxylic acids via cobalt(II) catalysis. This protocol showed broad substrate scope and gave chiral carboxylic acids in good yields with excellent enantiocontrol (up to 98 % yield and 99 % ee). Combined experimental and computational mechanistic studies support a CoII catalytic cycle involving migratory insertion and σ-bond metathesis processes. DFT calculations reveal that enantioselectivity may originate from the steric effect between the phenyl groups of the ligand and the substrate.

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.

We have extended the methodology developed for the preparation of atropisomeric chiral ligands derived from the MeOBIPHEP ligand to water-soluble ones. The hydrophilic ligands bearing sodium carboxylate and methylammonium chloride moieties were easily synthesized under mild conditions in a short sequence and in high yields. Their solubility and acid/base properties were also determined. The ruthenium(II) catalysts contain- ing 4-CO2Na- and 3,5-(CO2Na)2-substituted MeOBIPHEP analogues showed excellent activities and led to the desired hydrogenated products derived from dimethyl itaconate and 2-(4-fluorophenyl)-3-methylcrotonic acid in ees≥92%. An investigation of the asymmetric hydrogenation of the latter substrate in D2O as solvent afforded an insight into the mechanism. Copyright

α, β-Unsaturated acids of the formula STR1 wherein R1 signifies C1 -C5 -alkyl and Ar signifies an aryl group which is optionally substituted by one or more substituents selected from the group consisting of halogen, phenyl, C1 -C5 -alkyl, C1 -C5 -alkoxy, perfluorinated C1 -C5 -alkyl or perfluorinated C1 -C5 -alkoxy can be obtained from new or known compounds of the formula STR2 Compounds I can be converted by asymmetric hydrogenation into corresponding optically active saturated acids.

A kinetic model and simulation as well as a continuous stirred tank reactor (CSTR) system for the synthesis of (S)-2-(4-fluorophenyl)-3-methylbutanoic acid, an important optically active intermediate in the synthesis of inibefradil (POSICOR, a new type of calcium antagonist), by asymmetric hydrogenation of 2-(4-fluorophenyl)-3-methylbut-2-enoic acid under high pressure (270 bar) are described. It was demonstrated that a continuous, homogeneous metal complex catalyzed, enantioselective hydrogenation under high pressure is not only feasible but also a very attractive possibility. Using such a CSTR system one may achieve a space-time yield of 5.0 kg/L/day. Compared to a batch mode under high pressure, the CSTR reactor system has a more favourable space-time yield, is safer, would need less investment, and allows easier temperature control.

A short, technically feasible route was developed for the synthesis of (S)-2-(4-fluorophenyl)-3-methylbutanoic acid (S)-2 with an overall yield of 80% starting from 4-fluorophenylacetic acid. Asymmetric hydrogenation of the easily accessible unsaturated acid 3 in the presence of ruthenium(II) carboxylato complexes containing chiral atropisomeric diphosphines afforded (S)-2 in up to 94% ee. The ee of (S)-2 was upgraded to 98% by crystallization of its sodium salt. The same protocol was also applied to the synthesis of (S)-2-(4-chlorophenyl)-3-methylbutanoic acid.