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 #
2R01GM069445-09
Application #
8367006
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
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
2013
Total Cost
$320,331
Indirect Cost
$100,331
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

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