Metal-catalyzed hydrogen-mediated C–C bond formation
Catalytic hydrogenation is widely used in API synthesis, including asymmetric reactions. Catalytic hydrogenation involves the addition of hydrogen to unsaturated organic molecules to form saturated compounds. Conventional hydrogenation involves hydrogen delivery to a single functional group, but the technique of hydrogen delivery across multiple functional groups with concomitant carbon–carbon (C–C) bond formation has been limited.Hydrogen-mediated C–C bond formation has been used for alkene hydroformylation and the Fischer–Tropsch reaction, but these reactions require carbon dioxide as a coupling partner (1). Work by Michael J. Krische, professor of chemistry at the University of Texas at Austin, shows that organometallic intermediates arising transiently under the conditions of catalytic hydrogenation may be captured by conventional electrophiles such as carbonyl compounds and imines. This approach avoids using organometallic reagents such as Grignard and Gilman reagents in carbonyl and imine addition reactions. Instead, under hydrogen-mediated C–C bond formation, the catalytic C–C coupling is achieved by exposing two or more molecules to gaseous hydrogen in the presence of a metallic catalyst (1, 2).
Krische's work in hydrogen-mediated C–C bond formation was recognized last year with the Dowpharma Prize Lecture for Creativity in Chiral Chemistry at Chiral USA and the Environmental Protection Agency's Presidential Green Challenge Award.
For pharmaceutical syntheses, hydrogen-mediated C–C bond formation may achieve high optical purity in enantioselective reactions using various chiral ligands in transition-metal catalysts. In a recent example, Krische reported enantioselective reductive aldol couplings of vinyl ketones through a rhodium catalyst modified by a new monodentate Taddol-like phosphonite ligand (3). In another example, Krische reported on hydrogen-mediated C–C bond formations catalyzed by iridium for the direct regioselective reductive coupling of alkyl-substituted alkynes to activated ketones (1, 4).
Enantioselective iridium-catalyzed imine vinylation is another approach using hydrogen-mediated C–C bond formation. In this method, alkyenes are hydrogenated in the presence of N-arylsulfonyl imines using an iridium catalyst modified by (R)-Cl-MeO-BIPHEP to obtain the corresponding allylic amines in high optical purity (5).
The enantioselective coupling of acetylene, another low-cost feedstock, also shows the promise of hydrogen-mediated C–C bond formation. Krische's work shows that exposing aldehydes or α-ketoesters to equal volumes of acetylene and hydrogen gas in the presence of cationic rhodium catalysts provides products of Z-butadienylation: two molecules of acetylene, a molecule of a vicinal dicarbonyl compound, and one molecule of elemental hydrogren (6).