The goals of this research program are to develop computational methods to explore and predict stereoselective organic reactions. The research is to involve the study of the transition states of model reactions with quantum mechanics, and the use of the information obtained from these calculations to parameterize empirical force fields to perform computations on transition states of reactions involving a large numbers of atoms. The calculations are to be used to assist in understanding why stereoselective reactions are successful, and to use this information to design new reagents and reactions. The PI notes that some of the most useful stereoselective processes are under investigation and that these include the Sharpless asymmetric dihydroxylation with OsO4 and chincona alkaloid ligands, and the Jacobsen epoxidation with manganese salen catalysts. New reagents for epoxidation and a new general principle for 1,4 asymmetric induction are to be developed. The goals are to understand how these work, to devise quantitative computational models, and to predict improved ligands. Experimental tests of these predictions are to be made. The results are to be of considerable importance for the development of new methods for synthesis of enantiomerically pure pharmaceuticals.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37GM036700-14
Application #
2872654
Study Section
Medicinal Chemistry Study Section (MCHA)
Project Start
1986-02-01
Project End
2001-01-31
Budget Start
1999-02-01
Budget End
2000-01-31
Support Year
14
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Lam, Yu-Hong; Grayson, Matthew N; Holland, Mareike C et al. (2016) Theory and Modeling of Asymmetric Catalytic Reactions. Acc Chem Res 49:750-62
Hie, Liana; Fine Nathel, Noah F; Hong, Xin et al. (2016) Nickel-Catalyzed Activation of Acyl C-O Bonds of Methyl Esters. Angew Chem Int Ed Engl 55:2810-4
Krenske, Elizabeth H; Houk, K N; Harmata, Michael (2015) Computational analysis of the stereochemical outcome in the imidazolidinone-catalyzed enantioselective (4 + 3)-cycloaddition reaction. J Org Chem 80:744-50
Hooper, Joel F; James, Natalie C; Bozkurt, Esra et al. (2015) Medium-Ring Effects on the Endo/Exo Selectivity of the Organocatalytic Intramolecular Diels-Alder Reaction. J Org Chem 80:12058-75
Hie, Liana; Fine Nathel, Noah F; Shah, Tejas K et al. (2015) Conversion of amides to esters by the nickel-catalysed activation of amide C-N bonds. Nature 524:79-83
Lam, Yu-Hong; Houk, K N (2015) Origins of stereoselectivity in intramolecular aldol reactions catalyzed by cinchona amines. J Am Chem Soc 137:2116-27
Patel, Ashay; Vella, Joseph R; Ma, Zhi-Xiong et al. (2015) Transition State Gauche Effects Control the Torquoselectivities of the Electrocyclizations of Chiral 1-Azatrienes. J Org Chem 80:11888-94
Noey, Elizabeth L; Tibrewal, Nidhi; Jiménez-Osés, Gonzalo et al. (2015) Origins of stereoselectivity in evolved ketoreductases. Proc Natl Acad Sci U S A 112:E7065-72
Krenske, Elizabeth H; Lam, Sarah; Ng, Jerome P L et al. (2015) Concerted Ring Opening and Cycloaddition of Chiral Epoxy Enolsilanes with Dienes. Angew Chem Int Ed Engl 54:7422-5
Osuna, Sílvia; Jiménez-Osés, Gonzalo; Noey, Elizabeth L et al. (2015) Molecular dynamics explorations of active site structure in designed and evolved enzymes. Acc Chem Res 48:1080-9

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