We are engaged in the first systematic efforts to exploit hydrogenation in C-C couplings beyond hydroformylation. Using cationic rhodium and iridium catalysts, we have found that diverse ?-unsaturated reactants reductively couple to carbonyl compounds and imines under hydrogenation conditions, offering a byproduct-free alternative to stoichiometric organometallics in a range of classical C=X (X = O, NR) addition processes. This concept is extended further via "C-C bond forming transfer hydrogenation". Here, using ruthenium or iridium catalysts, alcohols serve dually as hydrogen donors and aldehyde precursors, enabling carbonyl addition directly from the alcohol oxidation level in the absence of stoichiometric byproducts. In the proposed funding period, byproduct-free C-C couplings of alcohol and amines with abundant, renewable feedstocks will be developed, including the first hydrogen-mediated Grignard additions of organic halides. Other areas of investigation include redox neutral couplings of ?-olefins to carbonyl partners, and initial explorations into the use of iron-based catalysts for transfer hydrogenative coupling.

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 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 hydrogen-mediated C-C coupling has lain fallow. We are engaged in the first systematic efforts to exploit hydrogenation in C-C couplings beyond hydroformylation. Using cationic rhodium and iridium catalysts, we have found that diverse ?-unsaturated reactants reductively couple to carbonyl compounds and imines under hydrogenation conditions, offering a byproduct-free alternative to stoichiometric organometallics in a range of classical C=X (X = O, NR) addition processes. This concept is extended further via C-C bond forming transfer hydrogenation. Here, using ruthenium or iridium catalysts, alcohols serve dually as hydrogen donors and aldehyde precursors, enabling carbonyl addition directly from the alcohol oxidation level in the absence of stoichiometric byproducts.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
3R01GM069445-09S1
Application #
8748599
Study Section
Program Officer
Lees, Robert G
Project Start
2005-03-15
Project End
2017-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
9
Fiscal Year
2014
Total Cost
$15,130
Indirect Cost
$4,455
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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