Welcome to the Kozlowski Group Homepage
University of Pennsylvania             Department of Chemistry

Members' Documents

Research Interests

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

Reaction Development and Optimization via High Throughput Experimentation Laboratory

Computer-Aided Design of Chiral Auxiliaries and Catalysts

 

             

Asymmetric Oxidative C-C Bond Forming Reactions:

The development of chiral catalysts for oxidative C-C bond formation has become 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.  Under these circumstances, additional activation of the coupling centers (i.e., as halides) is not necessary and the main byproduct of the reaction is water.

 With this motivation, we developed 1,5-diaza-cis-decalin copper catalysts which have proven to be the catalyst of choice for the oxidative asymmetric biaryl coupling of 2-naphthol derivatives.  The novel chiral diamine utilized in this catalyst was identified using database mining.

 

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The application of the oxidative biaryl coupling to the first synthesis and the first asymmetric synthesis of the natural product nigerone has recently been completed.  The synthesis of cercosporin, hypocrellin, and elsinochrome, members of the perylenequinone class of natural products, that display promising photodynamic therapy profiles in cancer treatment, is currently underway.  Future goals include exploiting the oxidative biaryl coupling method in the synthesis of chiral bisanthraquinone and naphthodianthrone natural products.

 

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Podlesny, E. E.; Kozlowski, M. C. "A Divergent Approach to the Bisanthraquinone Natural Products: Total Synthesis of (S)-Bisoranjidiol and Derivatives from Binaphtho-para-quinones" J. Org. Chem. 2013, 78, 466-476.DOI

Podlesny, E. E.; Carroll, P. J.; Kozlowski, M. C.“Selective Oxidation of 8,8'-Hydroxylated Binaphthols to Bis-spironaphthalenones or Binaphto-para- and Binaphto-ortho-quinones.” Org. Lett. 2012, 14, 4862-4865. DOI

Podlesny, E. E.; Kozlowski, M. C. “Structural Reassignment of a Marine Metabolite from a Binaphtalenetetrol to a Tetrabrominated Diphenyl Ether.” J. Nat. Prod. 2012, 75, 1125–1129. DOI

Podlesny, E. E.; Kozlowski, M. C. “Enantioselective Total Synthesis of (S)-Bisoranjidiol, an Axially Chiral Bisanthraquinone” Org. Lett. 2012, 14, 1408–1411.DOI

Morgan, B. J.; Mulrooney, C. A.; Kozlowski, M. C. “Perylenequinone Natural Products: Evolution of the Total Synthesis of Cercosporin” J. Org. Chem. 2010, 75, 44-56. DOI

Hewgley, J. B.; Stahl, S. S.; Kozlowski, M. C. “Mechanistic Study of a Synthetic Copper Oxidase Reaction for Asymmetric Biaryl Coupling: Evidence Against a Ping-Pong Mechanism”J. Am. Chem. Soc. 2008, 130, 12232-12233.  DOI.

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

Kozlowski, M. C.; DiVirgilio, E. S.; Malolanarasimhan, K.; Mulrooney, C. A. “Oxidation of Chiral a-Phenylacetate Derivatives: Formation of Dimers with Contiguous Quaternary Stereocenters versus Tertiary Alcohols” Tetrahedron: Asymmetry 2005, 16,3599–3605; invited contribution to "Asymmetric Oxidations" Symposium-in-Print.  DOI

Li, X.; Hewgley, J. B.; Mulrooney, C.; Yang, J.; Kozlowski, M. C. "Enantioselective Oxidative Biaryl Coupling Reactions Catalyzed by 1,5-Diazadecalin Metal Complexes:  Efficient Formation of Chiral Functionalized BINOL Derivatives" J. Org. Chem. 2003, 68, 5500-5511.  DOI

Mulrooney, C. A.; Li, X.; DiVirgilio, E. S.; Kozlowski, M. C. "General Approach for the Synthesis of Chiral Perylenequinones via Catalytic Enantioselective Oxidative Biaryl Coupling"  J. Am. Chem. Soc. 2003, 125, 6856-6857.  DOI


Xie, X.; Phuan, P.-W.; Kozlowski, M. C. "Novel Pathways for the Formation of Chiral Binaphthyl Polymers:  Oxidative Asymmetric Phenolic Coupling and Tandem Glaser/Oxidative Asymmetric Phenolic Coupling"  Angew. Chem., Int. Ed. 2003, 42, 2168-2170.  DOI

Kozlowski, M. C.; Li, X.; Carroll, P. J.; Xu, Z. "Copper(II) Complexes of Novel 1,5-Diaza-cis-decalin Diamine Ligands:  An Investigation of Structure and Reactivity"  Organometallics 2002, 21, 4513-4522.  DOI

Li, X.; Xu, Z.; DiMauro, E. F.; Kozlowski, M. C. "Unusual Oxidative Rearrangement of 1,5-Diazadecalin"  Tetrahedron Lett. 2002, 43, 3747-3750.  DOI

Li, X.; Yang, J.; Kozlowski, M. C. "Enantioselective Oxidative Biaryl Coupling Reactions Catalyzed by 1,5-Diazadecalin MetalComplexes"  Org. Lett. 2001, 3, 1137-1140.  DOI


 

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Reaction Development and Optimization via High Throughput Experimentation Laboratory:

In Progress...

 

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Metz, A. E.; Berritt, S.; Dreher, S. D.; Kozlowski, M. C. “Efficient Palladium-Catalyzed Cross-Coupling of Highly Acidic Substrates, Nitroacetates” Org. Lett. 2012, 14, 760–763t.  DOI

Walvoord, R. R.; Berritt, S.; Kozlowski, M. C. “Palladium-Catalyzed Nitromethylation of Aryl Halides: An Orthogonal Formylation Equivalent.” Org. Lett. 2012, 14, 4086-4089. DOI

 

 

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    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 developed 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.

     

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    Huynh, P. N. H.; Walvoord, R. R.; Kozlowski, M. C. "Rapid Quantification of the Activating Effects of Hydrogen Bonding Catalysts with a Calorimetric Sensor." J. Am. Chem. Soc. 2012, 134, 15621-15623. DOI

    Allen, S. E.; Mahatthananchai, J.; Bode, J. W.; Kozlowski, M. C. “Oxyanion-Steering and CH-π Interactions as Key Elements in a N-Heterocyclic Carbene-Catalyzed [4+2] Cycloaddition.” J. Am. Chem. Soc. 2012, 134, 12098–12103. DOI

    Kozlowski, M. C., Ianni, J. C. “Quantum Molecular Interaction Field Models of Substrate Enantioselection in Asymmetric Processes” J. Mol. Cat. A 2010, 324, 141-145. DOI

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

    Huang, J.; Ianni, J. C.; Antoline, J. E.; Hsung, R. P; Kozlowski, M. C. “De Novo Chiral Amino Alcohols in Catalyzing Asymmetric Additions to Aryl Aldehydes” Org. Lett. 2006, 8, 1565-1568. DOI

    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. DOI


    Phuan, P.-W.; Ianni, J. C.; Kozlowski, M. C. "Is the A-Ring of Sparteine Essential for High Enantioselectivity in the Asymmetric
    Lithiation-Substiution of N-Boc-pyrrolidine? J. Am. Chem. Soc. 2004, 126, 15473-15479.  DOI

    Lipkowitz, K. B.; Kozlowski, M. C. "Understanding Stereoinduction in Catalysis via Computer: New Tools for Asymmetric Synthesis" Synlett 2003, 1547-1565.  DOI

    Kozlowski, M. C.; Dixon, S.; Panda, M.; Lauri, G. "Quantum Mechanical Models Correlating Structure with Selectivity: Predicting the Enantioselectivity of b-Amino Alcohol Catalysts in Aldehyde Alkylation" J. Am. Chem. Soc. 2003, 125, 6614-6615.  DOI


    Kozlowski, M. C.; Panda, M. "Computer-Aided Design of Chiral Ligands.  Part II.  Functionality Mapping as a Method to Identify Stereocontrol Elements for Asymmetric Reactions"  J. Org. Chem. 2003, 68, 2061-2076.  Featured on the cover, March 21, 2003 (issue #6).  DOI


    Kozlowski, M. C.; Waters, S. P.; Skudlarek, J. W.; Evans, C. A. "Computer-Aided Design of Chiral Ligands.  Part III.  A Novel Ligand for Asymmetric Allylation Designed Using Computational Techniques"  Org. Lett. 2002, 4, 4391-4393.  DOI
     

    Panda, M.; Phuan, P.-W.; Kozlowski, M. C. "Theoretical and Experimental Studies of Asymmetric Organozinc Additions to Benzaldehyde Catalyzed by Flexible and Constrained g-Aminoalcohols" J. Org. Chem. 2003, 68, 564-571.  DOI
     

    Kozlowski, M. C.; Panda, M. "Computer-Aided Design of Chiral Ligands. Part I.  Database Search Methods to Identify Chiral Ligand Types for Asymmetric Reactions" J. Mol. Graphics Modell. 2002, 20, 399-409.  DOI
     

    Ganguly, B.; Freed, D. A.; Kozlowski, M. C. "Relevance of Torsional Effects to the Conformational Equilibria of 1,5-Diaza-cis-decalins:  A Theoretical and Experimental Study"  J. Org. Chem. 2001, 66, 1103-1108.  DOI
     

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