Marisa C. Kozlowski

Professor of Chemistry
Organic Chemistry

Office: 4002 IAST
Lab: 4010, 4070 IAST
Phone: (215) 898-3048
Email: marisasasupennedu
Research Group Website: http://www.sas.upenn.edu/~marisa

Jump to: Research Statement | Education and Academic History | Selected Publications

Research Statement
The central theme of research in my laboratory is the rational design of new methods and catalysts for use in organic synthesis. As well as using traditional screening and development approaches, we employ several novel computational tools for the discovery and optimization of new reagents and catalysts. These new synthetic methods comprise the key steps in our total synthesis strategies to a variety of important pharmaceutical agents and natural products.

Asymmetric Oxidative C-C Bond Forming Reactions: The development of chiral catalysts for oxidative C-C bond formation is a major focus in our laboratory. In addition to the substantial potential for developing biomimetic synthetic approaches to a variety of natural products, such transformations are appealing in that C-H bonds are directly transformed to C-C bonds with an inexpensive oxidant, molecular oxygen.

To this end, we developed 1,5-diaza-cis-decalin copper complexes, the catalysts of choice for the oxidative asymmetric biaryl coupling of 2-naphthol derivatives. Study of the mechanism has allowed the development of new reaction methods as well as couplings of highly functionalized 2-naphthols. With this ability, we have completed the first asymmetric synthesis of the natural product nigerone. The first total syntheses of the complex natural products cercosporin and hypocrellin have also been accomplished. These structurally novel compounds display promising photodynamic therapy profiles in cancer treatment. Future goals include exploiting the oxidative biaryl coupling method in the synthesis of chiral bisanthraquinone and naphthodianthrone natural products.

Reactions of α-Ketoesters and Derivatives: We have described bifunctional salen-derived catalysts that contain electronically decoupled Lewis acid and Lewis base sites. This electronic decoupling permits generation of optimally active catalysts as both the Lewis acid and Lewis base can be maximized without quenching each other. These catalysts are particularly effective for the very difficult asymmetric alkylation of α-ketoesters and α-iminoesters to yield α-hydroxy and α-amino acid adducts in enantiomerically pure form. Further studies with α-iminoesters have revealed an umpolung addition pathway allowing addition of nucleophiles to imine nitrogens. We have exploited this reactivity pattern to develop a three-component coupling that generates highly functionalized α-amino acid derivatives.

Computer-Aided Design of Chiral Auxiliaries and Catalysts: Diastereo- and enantioselective chemical reactions are essential components for the efficient synthesis of complex chiral targets. We have generated several computational tools to assist researchers in designing and optimizing chiral catalysts including database searching and functionality mapping. In addition, we have developed semi-empirical quantum mechanical quantitative structure selectivity (QSSR) relationships for accurate and precise enantiomeric excess predictions of chiral catalysts. In one example, we correlated the structures of various beta-amino alcohol catalysts to their enantioselectivities in the asymmetric addition of diethylzinc to benzaldehyde. With our method the selectivities of new catalysts were also calculated. Subsequent chemical synthesis and analysis of the new catalysts indicated that the model was very useful and easily distinguished catalysts of low, moderate, and high selectivity.

Education and Academic History

Selected Publications
Kozlowski, M. C.; Morgan, B. J.; Linton, E. C.; “Total Synthesis of Chiral Biaryl Natural Products by Asymmetric Biaryl Coupling” Chem. Soc. Rev. 2009, 38, 3193-3207.

Morgan, B. J.; Dey, S.; Johnson, S. W.; Kozlowski, M. C. “Total Synthesis of Cercosporin and New Photodynamic Perylenequinones:  Inhibition of the Protein Kinase C Regulatory Domain” J. Am. Chem. Soc.  2009, 131, 9413–9425.

Annamali, R.; Linton, E. C.; Kozlowski, M. C. “Design of an Organocatalytic Claisen Rearrangement Catalyst for Monodentate Substrates” Org. Lett. 2009, 11, 621-624.

Linton, E. C.; Kozlowski, M. C. “Catalytic Enantioselective Meerwein-Eschenmoser Claisen Rearrangement: Asymmetric Synthesis of Allyl Oxindoles” J. Am. Chem. Soc. 2008, 130, 16162–16163.

Joshua S. Dickstein, J. S.; Norman, A.; Fennie, Michael W.; Jennifer, B.; Kozlowski, M. C. “Three Component Coupling of α-Iminoesters via Umpolung Addition of Organometals: Synthesis of α,α-Disubstituted α-Amino Acids” J. Am. Chem. Soc. 2008, 130, 15794–15795.

Hewgley, J. B.; Stahl, S. S.; Kozlowski, M. C. “Mechanistic Study of Asymmetric Oxidative Biaryl Coupling: Evidence for Self-Processing of the Copper Catalyst to Achieve Control of Oxidase vs. Oxygenase Activity” J. Am. Chem. Soc. 2008, 130, 12232-12233.

O’Brien, E. M.; Morgan; B. J.; Kozlowski, M. C. “Dynamic Sterochemistry Transfer in a Transannular Aldol Reaction: Total Synthesis of Hypocrellin A” Angew. Chem., Int. Ed. 2008, 47, 6877-6880.

Dickstein, J. S.; Kozlowski, M. C. “Organometal Additions to α-Iminoesters: N-Alkylation via Umpolung” Chem. Soc. Rev. 2008, 37, 1166-1173.

Dickstein, J. S.; Mulrooney, C. A.; O’Brien, E. M.; Morgan; B. J.; Kozlowski, M. C. “Development of a Catalytic Aromatic Decarboxylation Reaction” Org. Lett. 2007, 9, 2441-2444.

DiVirgilio, E. S.; Dugan, E. C.; Mulrooney, C. A.; Kozlowski, M. C. “Asymmetric Total Synthesis of Nigerone” Org. Lett. 2007, 9, 385-388.

Basra, S.; Fennie, M. W.; Kozlowski, M. C. “Catalytic Asymmetric Addition of Dialkylzincs to alpha-Aldiminoesters” Org. Lett. 2006, 8, 2659-2662.

Ianni, J. C.; Annamalai, V.; Phuan, P.-W.; Kozlowski, M. C. “A Priori Theoretical Prediction of Selectivity in Asymmetric Catalysis: Design of New Chiral Catalysts using Quantum Molecular Interaction Fields”Angew. Chem., Int. Ed. 2006, 45, 5502-5505.