An Enantioselective Hydrogenation of an Alkenoic Acid as a Key Step in the Synthesis of AZD2716

Karlsson, Staffan; Sörensen, Henrik; Andersen, Sebastian; Cruz, Angele; Ryberg, Per

doi:10.1021/acs.oprd.5b00382

Cited by 12 publications

(2 citation statements)

References 18 publications

(11 reference statements)

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“…Asymmetric hydrogenation or transfer hydrogenation of prochiral alkenes with cobalt and nickel catalysts has recently been established with various classes of substrates, including minimally functionalized alkenes, unsaturated esters, enamides, ,, and related derivatives . Unsaturated carboxylic acids are another common class of substrates, and rhodium-catalyzed asymmetric hydrogenation of dehydro -amino acids is among the earliest and most impactful examples of asymmetric catalysis with transition metals. , Ruthenium , and iridium catalysts have also been extensively studied and have provided access to structurally diverse chiral carboxylic acids including pharmaceuticals such as l -DOPA, Pregabalin, and numerous other examples …”

Section: Introductionmentioning

confidence: 99%

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

2020

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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.

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Section: Introductionmentioning

confidence: 99%

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

2020

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“…Despite the importance of these scaffolds, many current methods fail to uphold green chemistry principles: low step count, sustainable and environmentally benign conditions, and minimal associated safety risks . Large-scale syntheses often rely on chiral auxiliaries or kinetic resolution, , approaches that require additional steps or limit the theoretical yield to 50%. Asymmetric hydrogenation protocols, with finely tuned catalyst systems, can be employed to provide chiral acids in excellent yields and enantioselectivities from comparably simple unsaturated substrates. − However, the use of expensive transition metals, safety hazards associated with the use of hydrogen gas and chemoselectivity challenges, render this approach nonideal.…”

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confidence: 99%

Enantioselective Enzymatic Reduction of Acrylic Acids

Shaw

Tharp

et al. 2020

Org. Lett.

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An ene-reductase (ERED 36) with broad substrate specificity was identified, and optimization studies led to the development of an enzymatic protocol for the reduction of α,β-unsaturated acids under mild, aqueous conditions. The substrate scope includes aromatic- and aliphatic-substituted acrylic acids, as well as cyclic α,β-substituted acrylic acids, yielding chiral α-substituted acids with exquisite levels of enantioselectivity (>99% ee).

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New Technologies in Process Development

Sutton

Adams

Wade

et al. 2018

Early Drug Development

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An Enantioselective Hydrogenation of an Alkenoic Acid as a Key Step in the Synthesis of AZD2716

Cited by 12 publications

References 18 publications

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

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

Enantioselective Enzymatic Reduction of Acrylic Acids

New Technologies in Process Development

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An Enantioselective Hydrogenation of an Alkenoic Acid as a Key Step in the Synthesis of AZD2716

Cited by 12 publications

References 18 publications

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

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

Enantioselective Enzymatic Reduction of Acrylic Acids

New Technologies in Process Development

Contact Info

Product

Resources

About

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

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