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
Asymmetric Alpha-Ketoester Alkylation via Bifunctional Catalysis
Synthesis of the Rubromycins via a Convergent Dipolar Cycloaddition
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.
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.
In addition, we have
prepared chiral binaphthyl polymers directly from achiral substrates via
asymmetric oxidative phenolic coupling and tandem asymmetric oxidative phenolic
coupling/Glaser-Hay coupling using our chiral 1,5-diaza-cis-decalin copper catalysts.
Due to high chemoselectivity in the coupling reactions, this approach is
useful for the organized assembly of multifunctional substrates.
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. submitted.
DiVirgilio, E. S.; Dugan, E. C.; Mulrooney, C. A.; Kozlowski, M. C. “Asymmetric Total Synthesis of Nigerone and ent-Nigerone” Org. Lett. submitted.
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
Asymmetric Alpha-Ketoester Alkylation via Bifunctional Catalysis:
We
have recently described the development of 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 alpha-ketoesters. With our
piperidine-derived titanium salen catalyst, completely chemoselective, highly
enantioselective, high yielding alpha-ketoester additions are observed. This method is the first asymmetric version
of this transformation and constitutes the most efficient method for generation
of the alpha-hydroxy ester adducts in enantiomerically pure form.
The products of this transformation, alpha-hydroxy esters,
are valuable synthetic precursors as this component is found in several natural
products (tetronic acids & camptothecin) as well as a host of
pharmaceutical agents. For example, we
have applied this method to an efficient enantioselective synthesis of a Wyeth
opiate antagonist.
Basra, S.; Fennie, M. W.; Kozlowski, M. C. “Catalytic Asymmetric Addition of Dialkylzincs to a-Aldiminoesters” Org. Lett. 2006, 8, 2659-2662.DOI
Fennie, M. W.; DiMauro, E. F.; O’Brien, E. M.; Annamalai, V.; Kozlowski, M. C. “Mechanism and Scope of Salen Bifunctional Catalysts in Asymmetric Aldehyde and a-Ketoester Alkylation” Tetrahedron 2005, 61, 6249-6265; invited contribution to "Catalysis in Industry and Academia" Symposium-in-Print. DOI
Annamalai, V.; DiMauro, E. F.; Carroll, P. J.; Kozlowski, M. C. "Catalysis of the Michael Addition Reaction by Late Transition Metal Complexes of BINOL-Derived Salens" J. Org. Chem. 2003, 68, 1973-1981. DOI
DiMauro, E. F.; Mamai, A.; Kozlowski, M. C. "Synthesis, Characterization, and Metal Complexes of a Salen Ligand Containing a Quinoline Base" Organometallics 2003, 22, 850-855. DOI
DiMauro, E. F.; Kozlowski, M. C. "The First Catalytic Asymmetric Addition of Dialkylzincs to a-Ketoesters" Org. Lett. 2002, 4, 3781-3784. DOI
DiMauro, E. F.; Kozlowski, M. C. "Development of Bifunctional Salen Catalysts: Rapid, Chemoselective Alkylations of a-Ketoesters" J. Am. Chem. Soc. 2002, 124, 12668-12669. DOI
DiMauro, E. F.; Kozlowski, M. C. "Late Transition Metal Complexes of BINOL-Derived Salens: Synthesis, Structure, and Reactivity" Organometallics 2002, 21, 1454-1461. DOI
DiMauro, E. F.; Kozlowski, M. C. "Salen-Derived Catalysts Containing Secondary Basic Groups in the Addition of Diethylzinc to Aldehydes" Org. Lett. 2001, 3, 3053-3056. DOI
DiMauro, E. F.; Kozlowski, M. C. "BINOL-Salen Metal Catalysts Incorporating a Bifunctional Design" Org. Lett. 2001, 3, 1641-1644. DOI
Synthesis of the Rubromycins via a Convergent Dipolar Cycloaddition:
The rubromycins are a distinct group of natural
products with anti-cancer, anti-HIV, and antibiotic activities. These compounds all appear to function by
selectively binding single stranded DNA or RNA, a very unusual mode of
action.
We are engaged in the synthesis of the rubromycins via a highly
convergent [3+2] dipolar cycloaddition strategy. By minor modification of the components the
oxygenation patterns found in all these structures are accessible, providing a
unified approach to the rubromycins. The
development of an asymmetric [3+2] dipolar cycloaddition for the assembly of
such advanced substrates is also a focus.
Waters, S. P.; Fennie, M. W.; Kozlowski, M. C. “Investigation of a Convergent Route to Purpuromycin: Benzofuran Formation vs Spiroketalization” Org. Lett. 2006, in press.
Waters, S. P.; Kozlowski, M. C. “Convergent Route to the Purpuromycin Bisphenolic Spiroketal: Hydrogen Bonding Control of Spiroketalization Stereochemistry” Tetrahedron. Lett. 2006, 47, 5409–5413. DOI
Xie, X.; Kozlowski, M. C. "Synthesis of the Naphthalene Portion of the Rubromycins" Org. Lett. 2001, 3, 2661-2663. DOI
Waters, S. P.; Kozlowski, M. C. "Synthesis of the Isocoumarin Portion of the Rubromycins" Tetrahedron Lett. 2001, 42, 3567-3570. DOI
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.
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. in press.
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
top
Whilst we endeavor to ensure that the information on this website is correct, we do not warrant its completeness or accuracy and accept no liability for its use; nor do we not commit to ensuring that the website remains available or that the material on this website is kept up-to-date.
