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
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
Wurm, Thomas; Turnbull, Ben W H; Ambler, Brett R et al. (2017) Thermal Hetero-Diels-Alder Reaction of Benzocyclobutenones with Isatins To Form 2-Oxindole Spirolactones. J Org Chem 82:13751-13755
Haydl, Alexander M; Breit, Bernhard; Liang, Tao et al. (2017) Alkynes as Electrophilic or Nucleophilic Allylmetal Precursors in Transition-Metal Catalysis. Angew Chem Int Ed Engl 56:11312-11325
Sato, Hiroki; Fukaya, Keisuke; Poudel, Binit Sharma et al. (2017) Diols as Dienophiles: Bridged Carbocycles via Ruthenium(0)-Catalyzed Transfer Hydrogenative Cycloadditions of Cyclohexadiene or Norbornadiene. Angew Chem Int Ed Engl 56:14667-14671
Roane, James; Holmes, Michael; Krische, Michael J (2017) Reductive C-C Coupling via Hydrogenation and Transfer Hydrogenation: Departure from Stoichiometric Metals in Carbonyl Addition. Curr Opin Green Sustain Chem 7:1-5

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