Enantioselective hydrogenation accounts for over half the chiral drugs produced industrially, withstanding physical or enzymatic resolution. Whereas conventional hydrogenation involves C-H bond formation, our research breaks dogma by establishing hydrogenation as a method for C-C bond formation. In the prior funding period, we demonstrated that hydrogenation could be used to couple diverse p-unsaturated reactants to carbonyl compounds and imines, constituting a byproduct-free alternative to stoichiometrically preformed organometallics in a range of classical C=X (X = O, NR) addition processes. In the proposed funding period, we seek to continue these first systematic efforts to exploit catalytic hydrogenation in C-C couplings beyond hydroformylation.

Public Health Relevance

Over 50% of the world's top-selling drugs are single enantiomers and it is estimated that 80% of all drugs currently entering development are chiral and will be marketed as single-enantiomer entities. In 1994, the chiral drug market grossed over """"""""45.2 billion US dollars worldwide, which corresponds to an increase of 27% in a single year!"""""""" In 1999, the chiral drug market topped 100 billion US dollars in sales. In 2002, world-wide sales of single enantiomer drugs reached more than 159 billion US dollars. Notably, enantioselective hydrogenation accounts for over half the chiral drugs produced industrially, withstanding physical or enzymatic resolution. The enormous impact of hydrogenation vis-?-vis chiral drugs portends an equally powerful approach to reductive C-C bond formations mediated by hydrogen. However, since the discovery of alkene hydroformylation and the parent Fischer-Tropsch reaction, processes restricted to the use of carbon monoxide, the field of hydrogenative coupling has lain fallow. In this proposal, we report the first systematic efforts to exploit hydrogenation in C-C couplings beyond hydroformylation. Our efforts have led to the development of a broad new family """"""""hydrogenative C-C couplings"""""""" - byproduct-free alternatives to stoichiometrically preformed organometallics in an ever-increasing range classical C=X (X = O, NR) addition processes.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Synthetic and Biological Chemistry A Study Section (SBCA)
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Hagan, Ann A
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University of Texas Austin
Schools of Arts and Sciences
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Guo, Yi-An; Liang, Tao; Kim, Seung Wook et al. (2017) Nickel-Catalyzed Cross-Coupling of Vinyl Dioxanones to Form Enantiomerically Enriched Cyclopropanes. J Am Chem Soc 139:6847-6850
Zhang, Wandi; Chen, Weijie; Xiao, Hongde et al. (2017) Carbonyl anti-(?-Amino)allylation via Ruthenium Catalyzed Hydrogen Autotransfer: Use of an Acetylenic Pyrrole as an Allylmetal Pronucleophile. Org Lett 19:4876-4879
Sato, Hiroki; Fukaya, Keisuke; Poudel, Binit Sharma et al. (2017) Diols as Dienophiles: Bridged Carbocycles via Ruthenium(0)-Catalyzed Transfer Hydrogenative Cycloadditions of Cyclohexadiene or Norbornadiene. Angew Chem Int Ed Engl 56:14667-14671
Haydl, Alexander M; Breit, Bernhard; Liang, Tao et al. (2017) Alkynes as Electrophilic or Nucleophilic Allylmetal Precursors in Transition-Metal Catalysis. Angew Chem Int Ed Engl 56:11312-11325
Holmes, Michael; Nguyen, Khoa D; Schwartz, Leyah A et al. (2017) Enantioselective Formation of CF3-Bearing All-Carbon Quaternary Stereocenters via C-H Functionalization of Methanol: Iridium Catalyzed Allene Hydrohydroxymethylation. J Am Chem Soc 139:8114-8117
Roane, James; Wippich, Julian; Ramgren, Stephen D et al. (2017) Synthesis of the C(1)-C(13) Fragment of Leiodermatolide via Hydrogen-Mediated C-C Bond Formation. Org Lett 19:6634-6637
Wurm, Thomas; Turnbull, Ben W H; Ambler, Brett R et al. (2017) Thermal Hetero-Diels-Alder Reaction of Benzocyclobutenones with Isatins To Form 2-Oxindole Spirolactones. J Org Chem 82:13751-13755
Kim, Seung Wook; Lee, Wonchul; Krische, Michael J (2017) Asymmetric Allylation of Glycidols Mediated by Allyl Acetate via Iridium-Catalyzed Hydrogen Transfer. Org Lett 19:1252-1254
Luong, Tom; Chen, Shujie; Qu, Ke et al. (2017) Ruthenium(0)-Catalyzed C-C Coupling of Alkynes and 3-Hydroxy-2-oxindoles: Direct C-H Vinylation of Alcohols. Org Lett 19:966-968
Feng, Jiajie; Holmes, Michael; Krische, Michael J (2017) Acyclic Quaternary Carbon Stereocenters via Enantioselective Transition Metal Catalysis. Chem Rev 117:12564-12580

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