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
Shin, Inji; Wang, Gang; Krische, Michael J (2014) Catalyst-directed diastereo- and site-selectivity in successive nucleophilic and electrophilic allylations of chiral 1,3-diols: protecting-group-free synthesis of substituted pyrans. Chemistry 20:13382-9
Kasun, Zachary A; Geary, Laina M; Krische, Michael J (2014) Ring expansion of cyclic 1,2-diols to form medium sized rings via ruthenium catalyzed transfer hydrogenative [4+2] cycloaddition. Chem Commun (Camb) 50:7545-7
Feng, Jiajie; Garza, Victoria J; Krische, Michael J (2014) Redox-triggered C-C coupling of alcohols and vinyl epoxides: diastereo- and enantioselective formation of all-carbon quaternary centers via tert-(hydroxy)-prenylation. J Am Chem Soc 136:8911-4
McInturff, Emma L; Nguyen, Khoa D; Krische, Michael J (2014) Redox-triggered C-C coupling of diols and alkynes: synthesis of ?,?-unsaturated ?-hydroxyketones and furans by ruthenium-catalyzed hydrohydroxyalkylation. Angew Chem Int Ed Engl 53:3232-5
Park, Boyoung Y; Nguyen, Khoa D; Chaulagain, Mani Raj et al. (2014) Alkynes as allylmetal equivalents in redox-triggered C-C couplings to primary alcohols: (Z)-homoallylic alcohols via ruthenium-catalyzed propargyl C-H oxidative addition. J Am Chem Soc 136:11902-5
Ketcham, John M; Shin, Inji; Montgomery, T Patrick et al. (2014) Catalytic enantioselective C-H functionalization of alcohols by redox-triggered carbonyl addition: borrowing hydrogen, returning carbon. Angew Chem Int Ed Engl 53:9142-50
Geary, Laina M; Glasspoole, Ben W; Kim, Mary M et al. (2013) Successive C-C coupling of dienes to vicinally dioxygenated hydrocarbons: ruthenium catalyzed [4 + 2] cycloaddition across the diol, hydroxycarbonyl, or dione oxidation levels. J Am Chem Soc 135:3796-9
Sam, Brannon; Montgomery, T Patrick; Krische, Michael J (2013) Ruthenium catalyzed reductive coupling of paraformaldehyde to trifluoromethyl allenes: CF3-bearing all-carbon quaternary centers. Org Lett 15:3790-3
Schmitt, Daniel C; Lee, Jungyong; Dechert-Schmitt, Anne-Marie R et al. (2013) Ruthenium catalyzed hydroaminoalkylation of isoprene via transfer hydrogenation: byproduct-free prenylation of hydantoins. Chem Commun (Camb) 49:6096-8
McInturff, Emma L; Mowat, Jeffrey; Waldeck, Andrew R et al. (2013) Ruthenium-catalyzed hydrohydroxyalkylation of acrylates with diols and ?-hydroxycarbonyl compounds to form spiro- and ?-methylene-?-butyrolactones. J Am Chem Soc 135:17230-5

Showing the most recent 10 out of 82 publications