Identifying catalyst activation modes that exploit one-electron chemistry and overcome associated deactivation pathways will be transformative for developing first-row transition metal catalysts with performance equal or, ideally, superior to precious metals. Here we describe a zinc-activation method compatible with high-throughput reaction discovery that identified scores of cobalt-phosphine combinations for the asymmetric hydrogenation of functionalized alkenes. An optimized catalyst prepared from (,)-Ph-BPE {Ph-BPE, 1,2-bis[(2,5)-2,5-diphenylphospholano]ethane} and cobalt chloride [CoCl·6HO] exhibited high activity and enantioselectivity in protic media and enabled the asymmetric synthesis of the epilepsy medication levetiracetam at 200-gram scale with 0.08 mole % catalyst loading. Stoichiometric studies established that the cobalt (II) catalyst precursor (,)-Ph-BPECoCl underwent ligand displacement by methanol, and zinc promoted facile one-electron reduction to cobalt (I), which more stably bound the phosphine.

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A family of single-component iron precatalysts for the [4+4]-cyclodimerization and intermolecular cross-[4+4]-cycloaddition of monosubstituted 1,3-dienes is described. Cyclooctadiene products were obtained with high regioselectivity, and catalyst-controlled access to either cisor transdiastereomers was achieved using 4-substituted diene substrates. Reactions conducted either with single-component precatalysts or with iron dihalide complexes activated in situ proved compatible with common organic functional groups and were applied on multi-gram scale (up to >100 g). Catalytically relevant, S = 1 iron complexes bearing 2-iminopyridine ligands, (R PI)FeL 2 (R PI = [2-(2,6-R 2-C 6 H 3-N=CMe)-C 5 H 4 N] where R = i PR or Me, L 2 = bis-olefin) were characterized by single-crystal X-ray diffraction, mößbauer spectroscopy, magnetic measurements, and dft calculations. The structural and spectroscopic parameters are consistent with an electronic structure description comprised of a high spin iron(I) center (S fe = 3/2) engaged in antiferromagnetically coupling with a ligand radical anion (S PI = −1/2). Mechanistic studies conducted with these single-component precatalysts-including kinetic analyses, 12 C/ 13 C isotope effect measurements, and in situ mößbauer spectroscopy-support a mechanism involving oxidative cyclization of two dienes that determines regio-and diastereoselectivity. Topographic steric maps derived from crystallographic data provided insights into the basis for the catalystcontrol through stereoselective oxidative cyclization and subsequent, stereospecific allylisomerization and CC bond-forming reductive elimination.

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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.