Optimizing a synthesis for an active pharmaceutical ingredient (API) or intermediate often requires developing an alternative
catalytic route. Recent developments in chemocatalysis and biocatalysis show several interesting approaches.
Patricia Van Arnum
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).
Hydrogen-mediated C–C bond formation may also allow chemists to use less expensive feedstocks in API synthesis. Two cardiovascular
drugs, for example, "Vasotec" (enalapril) by Merck & Co. (Whitehouse Station) and "Zestril" (lisinopril) by AstraZeneca (London) could be synthesized by hydrogen-mediated C–C bond formation using styrene as a starting material (see Figure 1).
Ibuprofen and naproxen may also be synthesized by hydrogen-mediated C–C bond formation using carbon dioxide as the starting
Figure 1: Enalapril (1) and lisinopril (2) are active ingredients that could potentially be synthesized using hydrogen-mediated
carbon–carbon bond formation. (ALL MOLECULES IN FIGURE ARE COURTESY OF US FOOD AND DRUG ADMINISTRATION)
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