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 #
5R01GM069445-10
Application #
8638017
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
2014-04-01
Budget End
2015-03-31
Support Year
10
Fiscal Year
2014
Total Cost
$366,104
Indirect Cost
$114,081
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
Cabrera, James M; Tauber, Johannes; Zhang, Wandi et al. (2018) Selection between Diastereomeric Kinetic vs Thermodynamic Carbonyl Binding Modes Enables Enantioselective Iridium-Catalyzed anti-(?-Aryl)allylation of Aqueous Fluoral Hydrate and Difluoroacetaldehyde Ethyl Hemiacetal. J Am Chem Soc 140:9392-9395
Meza, Arismel Tena; Wurm, Thomas; Smith, Lewis et al. (2018) Amphiphilic ?-Allyliridium C,O-Benzoates Enable Regio- and Enantioselective Amination of Branched Allylic Acetates Bearing Linear Alkyl Groups. J Am Chem Soc 140:1275-1279
Kim, Seung Wook; Wurm, Thomas; Brito, Gilmar A et al. (2018) Hydroamination versus Allylic Amination in Iridium-Catalyzed Reactions of Allylic Acetates with Amines: 1,3-Aminoalcohols via Ester-Directed Regioselectivity. J Am Chem Soc 140:9087-9090
Holmes, Michael; Schwartz, Leyah A; Krische, Michael J (2018) Intermolecular Metal-Catalyzed Reductive Coupling of Dienes, Allenes, and Enynes with Carbonyl Compounds and Imines. Chem Rev 118:6026-6052
Cabrera, James M; Tauber, Johannes; Krische, Michael J (2018) Enantioselective Iridium-Catalyzed Phthalide Formation through Internal Redox Allylation of Phthalaldehydes. Angew Chem Int Ed Engl 57:1390-1393
Brito, Gilmar A; Della-Felice, Franco; Luo, Guoshun et al. (2018) Catalytic Enantioselective Allylations of Acetylenic Aldehydes via 2-Propanol-Mediated Reductive Coupling. Org Lett 20:4144-4147
Guo, Yi-An; Lee, Wonchul; Krische, Michael J (2017) Enantioselective Synthesis of Oxetanes Bearing All-Carbon Quaternary Stereocenters via Iridium-Catalyzed C-C Bond-Forming Transfer Hydrogenation. Chemistry 23:2557-2559
Kim, Seung Wook; Zhang, Wandi; Krische, Michael J (2017) Catalytic Enantioselective Carbonyl Allylation and Propargylation via Alcohol-Mediated Hydrogen Transfer: Merging the Chemistry of Grignard and Sabatier. Acc Chem Res 50:2371-2380
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
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

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