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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM069445-08
Application #
8247831
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Lees, Robert G
Project Start
2003-10-01
Project End
2013-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
8
Fiscal Year
2012
Total Cost
$316,451
Indirect Cost
$98,645
Name
University of Texas Austin
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
170230239
City
Austin
State
TX
Country
United States
Zip Code
78712
Nguyen, Khoa D; Park, Boyoung Y; Luong, Tom et al. (2016) Metal-catalyzed reductive coupling of olefin-derived nucleophiles: Reinventing carbonyl addition. Science 354:
Nguyen, Khoa D; Herkommer, Daniel; Krische, Michael J (2016) Enantioselective Formation of All-Carbon Quaternary Centers via C-H Functionalization of Methanol: Iridium-Catalyzed Diene Hydrohydroxymethylation. J Am Chem Soc 138:14210-14213
Wang, Gang; Krische, Michael J (2016) Total Synthesis of (+)-SCH 351448: Efficiency via Chemoselectivity and Redox-Economy Powered by Metal Catalysis. J Am Chem Soc 138:8088-91
Perez, Felix; Oda, Susumu; Geary, Laina M et al. (2016) Ruthenium-Catalyzed Transfer Hydrogenation for C-C Bond Formation: Hydrohydroxyalkylation and Hydroaminoalkylation via Reactant Redox Pairs. Top Curr Chem (J) 374:35
Nguyen, Khoa D; Herkommer, Daniel; Krische, Michael J (2016) Ruthenium-BINAP Catalyzed Alcohol C-H tert-Prenylation via 1,3-Enyne Transfer Hydrogenation: Beyond Stoichiometric Carbanions in Enantioselective Carbonyl Propargylation. J Am Chem Soc 138:5238-41
Liang, Tao; Woo, Sang Kook; Krische, Michael J (2016) C-Propargylation Overrides O-Propargylation in Reactions of Propargyl Chloride with Primary Alcohols: Rhodium-Catalyzed Transfer Hydrogenation. Angew Chem Int Ed Engl 55:9207-11
Xiao, Hongde; Wang, Gang; Krische, Michael J (2016) Regioselective Hydrohydroxyalkylation of Styrene with Primary Alcohols or Aldehydes via Ruthenium-Catalyzed C-C Bond Forming Transfer Hydrogenation. Angew Chem Int Ed Engl 55:16119-16122
Park, Boyoung Y; Luong, Tom; Sato, Hiroki et al. (2016) Osmium(0)-Catalyzed C-C Coupling of Ethylene and α-Olefins with Diols, Ketols, or Hydroxy Esters via Transfer Hydrogenation. J Org Chem 81:8585-94
Garza, Victoria J; Krische, Michael J (2016) Hydroxymethylation beyond Carbonylation: Enantioselective Iridium-Catalyzed Reductive Coupling of Formaldehyde with Allylic Acetates via Enantiotopic π-Facial Discrimination. J Am Chem Soc 138:3655-8
Jo, H H; Gao, X; You, L et al. (2015) Application of a High-Throughput Enantiomeric Excess Optical Assay Involving a Dynamic Covalent Assembly: Parallel Asymmetric Allylation and Ee Sensing of Homoallylic Alcohols. Chem Sci 6:6747-6753

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