The goal of this research program is to develop and apply state-of-the-art computation methods to understand stereoselectivity and to design new stereoselective reagents and catalysts. The control of stereoselectivity is an essential feature of efficient synthesis, and this program provides explanations of the origins of these selectivities and builds on these to predict new reagents and catalysts for regioselective and stereoselective reactions. These are critical elements in the synthesis of effective pharmaceutical agents. This renewal of GM36700 is built on the achievements of the last grant period. Collaborations with many synthetic laboratories around the world have kept our attention focused on problems that are central to progress in organic synthesis. The grant has been a training vehicle for a large number of graduate students, postdocs, and visitors to our laboratories from synthetic groups, and these people have become leaders in computational understanding of organic and pharmaceutical chemistry.
The specific aims for the new grant period are:
Aim 1 : Development of computer program and resources to provide accurate predictions of stereoselectivity for large and flexible molecules. To combine the quantum mechanics at various levels, conformational searching with force fields, and analysis tools for the understanding of stereoselectivity and design of new catalysts and ligands, as well as to access the many computers and clusters available to our group, a computer program/interface called DESIGNMAKER will be created.
Aim 2 : Explorations of asymmetric organocatalysis and design of new catalysts. Nucleophilic, hydrogen-bonding, and bifunctional catalysts as well as cascade reactions involving organocatalysts will be studied, and new versions will be designed.
Aim 3 : Exploration of transition metal catalyzed asymmetric reactions. Rh, Mo, Ru, Pd, and Ni-catalyzed hydrogenations, allylic substitutions, and asymmetric coupling reactions will be explored in order to establish the origins of transition metal catalysis of regioselective and stereoselective reactions.
Aim 4 : Collaborative design and testing of new reagents and catalysts for stereoselective reactions. Ongoing collaborations with Carlos Barbas (Scripps), Paul Wender (Stanford), Yonqui Sun, Ian Davies, Thorsten Rosner, Shane Krska (Merck), Samuel Danishefsky (Columbia-SKMI), Timothy Jamison and Stephen Buchwald (MIT), and others will drive the development of new technology and increase our understanding of stereoselectivity of many different types of reactions.
The goal of this research program is to develop and apply state-of-the-art computation methods to understand stereoselectivity and to design new stereoselective reagents and catalysts. The control of stereoselectivity is an essential feature of efficient synthesis, and this program provides explanations of the origins of these selectivities and builds on these to predict new reagents and catalysts for regioselective and stereoselective reactions. These are critical elements in the synthesis of effective pharmaceutical agents.
|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|
|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|
|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|
|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|
|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|
|Osuna, SÃlvia; JimÃ©nez-OsÃ©s, 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|
|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|
|Phillips, Eric M; Mesganaw, Tehetena; Patel, Ashay et al. (2015) Synthesis of ent-ketorfanol via a C-H alkenylation/torquoselective 6Ï€ electrocyclization cascade. Angew Chem Int Ed Engl 54:12044-8|
|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|
|Noey, Elizabeth L; Tibrewal, Nidhi; JimÃ©nez-OsÃ©s, Gonzalo et al. (2015) Origins of stereoselectivity in evolved ketoreductases. Proc Natl Acad Sci U S A 112:E7065-72|
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