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Cobalt-catalyzed asymmetric hydrogenation of enamides enabled by single-electron reduction

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Science  25 May 2018:
Vol. 360, Issue 6391, pp. 888-893
DOI: 10.1126/science.aar6117
  • Fig. 1 Catalyst-activation strategies for alkene hydrogenation catalysts.

    (A) Activation of Wilkinson’s catalyst (Ph3P)3RhCl is limited by unfavorable PPh3 dissociation equilibrium and strongly coordinating Cl. (B) Schrock-Osborn–type catalysts are paired with a weakly coordinating anion such as PF6 and rely on irreversible hydrogenation of diene ligands to open coordination sites. (C) Wilkinson’s ruthenium catalyst is activated by base in H2 to form ruthenium monohydride but suffers from limited coordination sites. (D) Cationic ruthenium catalysts are designed to open coordination sites. (E) Previous work on cobalt catalysts relied on activation by alkyl lithium reagents and posited formation of cobalt dihydride as an active catalyst. S, solvent molecule; L, neutral ligand; cat., catalyst.

  • Fig. 2 High-throughput evaluation of chiral phosphine ligands.

    (A) Comparing results of 192 chiral ligands for the asymmetric hydrogenation of dehydro-levetiracetam by using LiCH2SiMe3 (top, table S9) and Zn (bottom, table S8). (B) Ligand compatibility with LiCH2SiMe3 (top; see also table S19) and Zn (bottom; see also table S20) for hydrogenation of a representative alkene methyl-2-acetamidoacrylate. (C) Ligands in the expanded 216-ligand library that give highest enantioselectivity for dehydro-levetiracetam hydrogenation. Catalyst loadings were 10 mol % unless otherwise noted. Positive and negative ee values correspond to (S) and (R) enantiomers, respectively. Me, methyl; tBu, tert-buty.

  • Fig. 3 Cobalt-catalyst activation enabled by single-electron reduction.

    (A) Properties and reactivity of Co(II), Co(I), and Co(0) species; (P,P)CoCl2; [(P,P)CoCl]2; and (P,P)CoCOD under catalytic conditions (Zn-MeOH). (B) Single-component, Zn-free Co(I) and Co(0) precatalysts are competent for hydrogenation.

  • Fig. 4 Applications at large scale.

    (A) Previous work on cobalt-catalyzed asymmetric hydrogenation of dehydro-α–amino acid derivatives. (B) Patented route for asymmetric hydrogenation for levetiracetam synthesis by a rhodium catalyst in dichloromethane solvent. (C) Industrially relevant cobalt-catalyzed asymmetric hydrogenation for levetiracetam synthesis in MeOH solvent.

Supplementary Materials

  • Cobalt-catalyzed asymmetric hydrogenation of enamides enabled by single-electron reduction

    Max R. Friedfeld, Hongyu Zhong, Rebecca T. Ruck, Michael Shevlin, Paul J. Chirik

    Materials/Methods, Supplementary Text, Tables, Figures, and/or References

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    • Materials and Methods 
    • Figs. S1 to S54
    • Tables S1 to S30
    • References 

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