Diastereo- and enantioselective chemical reactions have become essential for the efficient synthesis of complex chiral targets, including natural products, novel materials, biological probes, and pharmaceuticals. While the conventional approach toward asymmetric processes has relied upon intuitive or random screening approaches, the use of computational techniques to develop novel and improved methods has yet to be exploited. Our overall aim is to develop a series of rational design protocols for the identification of new chiral auxiliaries and catalysts for important synthetic reactions, that proceed through well delineated transition-states. In particular, we are using a process that identified noel ligand families via computational screening of data incorporated within large structural databases such as Cambridge Structural Database. As part of this program, we intend to demonstrate that high level ab initio calculations of transition state energies can be correlated to solution phase reactivity on a regular basis; such a result would provide an invaluable tool in reaction development. The success of this program could dramatically change the way chiral ligands are designed; even in a combinatorial setting, where novel core scaffolds could be selected that had a high probability of success upon optimization.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM059945-05
Application #
6705039
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Schwab, John M
Project Start
2000-03-01
Project End
2006-02-28
Budget Start
2004-03-01
Budget End
2006-02-28
Support Year
5
Fiscal Year
2004
Total Cost
$196,761
Indirect Cost
Name
University of Pennsylvania
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Kozlowski, Marisa C; Ianni, James C (2010) Quantum Molecular Interaction Field Models of Substrate Enantioselection in Asymmetric Processes. J Mol Catal A Chem 324:141-145
Annamalai, Venkatachalam R; Linton, Elizabeth C; Kozlowski, Marisa C (2009) Design of a bisamidinium claisen rearrangement catalyst for monodentate substrates. Org Lett 11:621-4
Basra, Sandeep; Fennie, Michael W; Kozlowski, Marisa C (2006) Catalytic asymmetric addition of dialkylzinc reagents to alpha-aldiminoesters. Org Lett 8:2659-62
Huang, Jian; Ianni, James C; Antoline, Jennifer E et al. (2006) De novo chiral amino alcohols in catalyzing asymmetric additions to aryl aldehydes. Org Lett 8:1565-8
Ianni, James C; Annamalai, Venkatachalam; Phuan, Puay-Wah et al. (2006) A priori theoretical prediction of selectivity in asymmetric catalysis: design of chiral catalysts by using quantum molecular interaction fields. Angew Chem Int Ed Engl 45:5502-5
Phuan, Puay-Wah; Ianni, James C; Kozlowski, Marisa C (2004) Is the A-ring of sparteine essential for high enantioselectivity in the asymmetric lithiation-substitution of N-Boc-pyrrolidine? J Am Chem Soc 126:15473-9
Kozlowski, Marisa C; Panda, Manoranjan (2003) Computer-aided design of chiral ligands. Part 2. Functionality mapping as a method to identify stereocontrol elements for asymmetric reactions. J Org Chem 68:2061-76
Kozlowski, Marisa C; Dixon, Steven L; Panda, Manoranjan et al. (2003) Quantum mechanical models correlating structure with selectivity: predicting the enantioselectivity of beta-amino alcohol catalysts in aldehyde alkylation. J Am Chem Soc 125:6614-5
Panda, Manoranjan; Phuan, Puay-Wah; Kozlowski, Marisa C (2003) Theoretical and experimental studies of asymmetric organozinc additions to benzaldehyde catalyzed by flexible and constrained gamma-amino alcohols. J Org Chem 68:564-71
Annamalai, Venkatachalam; DiMauro, Erin F; Carroll, Patrick J et al. (2003) Catalysis of the Michael addition reaction by late transition metal complexes of BINOL-derived salens. J Org Chem 68:1973-81

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