David B. Berkowitz

David B. Berkowitz Ph.D. 1990, Harvard University; Traveling Scholar, ETH-Zurich; 1986-1990; Merck Postdoctoral Fellow, Yale University (1990-1991); Alfred P. Sloan Research Fellow (1997-2001).

Tel. (402) 472-2738. Fax. (402) 472-9402. Internet: dbb@unlserve.unl.edu

Publications

The Berkowitz Group

The Berkowitz group addresses issues at the interface of organic chemistry and enzymatic chemistry. On the one hand, enzymes are used as reagents for organic synthesis. For example (Scheme 1), an enzyme performs a key step in our asymmetric synthesis of the natural product, (-)-podophyllotoxin. This compound serves as the aglycon for Etoposide, a widely used chemotherapeutic drug. Recently, the project has also led to a fundamentally new "reverse Kahne glycosylation" strategy for constructing glycoconjugates with electron rich aglycons. Our synthesis is deliberately modular in ring E, and is being used to better define how the drug binds to its target, topoisomerase II.

The group is also actively developing new classes of mechanism-based enzyme inhibitors and metabolically stable substrate analogues. For example, several new classes of a-branched amino acids, including a-oxiranyl-, a-(2Z-fluoro)vinyl-, a-(1-fluoro)vinyl AA's have been synthesized for the first time, and examined for their ability to inhibit AADC's (amino acid decarboxylases). This project includes a significant component of enantioselective synthesis {(1) chiral auxiliary-mediated (Scheme 2); (2) self-reproduction of chirality; and (3) enzyme-assisted approaches are all being examined}. Students also have the opportunity to purify their target enzymes and characterize the nature of the inhibition with a variety of techniques (including UV- or radiolabel-based kinetics, and heteronuclear NMR).

There is also a significant effort to develop and study novel, metabolically stable phosphate mimics. In recent years, we have focused on the a-mono- and difluorinated phosphonates as both pseudo-substrates (Scheme 3) and slow-binding inhibitors for phosphate-processing enzymes. Through this work, we seek to better define the optimal features required for mimicking either the substrate or the transition state in such active sites.

Selected Recent Publications:

Mohua Bose and Sungjo Choi "ISES: A Tool for Catalyst Discovery and Reaction Development ," Angewandte Chemie 2002, 41, 1603-1607 - selected as a "Hot Paper" by the editors of Angewandte Chemie; and featured in the May 27, 2002 issue of Chemical and Engineering News. Go to: http://pubs.acs.org/isubscribe/journals/cen/80/i21/html/8021sci2.html

David B. Berkowitz and Mohua Bose "(a-Monofluoroalkyl)phosphonates: A Class of Isoacidic and ëTunableí Mimics of Biological Phosphates," Journal of Fluorine Chemistry 2001, 112, 13-33 (invited).

David B. Berkowitz, Esmort Chisowa and Jill M. McFadden, "Stereocontrolled Synthesis of Quaternary, b,g-Unsaturated Amino Acids: Chain Extension of D- & L- a-(2-Tributylstannyl)Vinyl Amino Acids," Tetrahedron Symposia-in-Print 2001, 57, 6329-6343 (invited).

David B. Berkowitz, Mohua Bose and Nathan G. Asher "A Convergent Triflate Displacement Approach to (a-Monofluoroalkyl)phosphonates,"Organic Letters 2001, 3, 2009-2012.

David B. Berkowitz, Jill M. McFadden, Esmort Chisowa and Craig L. Semerad "Organoselenium-Based Entry into Versatile,
a-(2-Tributylstannyl)vinyl Amino Acids in Scalemic Form: A New Route to Vinyl Stannanes," J. Am. Chem. Soc. 2000, 122, 11031-11032.

David B. Berkowitz, Mohua Bose, Travis J. Pfannenstiel and Tzanko Doukov "a-Fluorinated Phosphonates as Substrate Mimics for Glucose 6-Phosphate Dehydrogenase: The CHF Stereochemistry Matters," J. Org. Chem. 2000, 65, 4498-4508.

David B. Berkowitz, Sungjo Choi, Debnath Bhuniya and Richard K. Shoemaker "Novel 'Reverse Kahne-Type Glycosylation': Synthesis of O-, N- and C-Linked Epipodophyllotoxin Conjugates."Org. Lett. 2000, 2, 1149-1152.

David B. Berkowitz "Ring E-Modified Analogues of (-)-Podophyllotoxin and a Method for Their Synthesis," U.S. Patent No. 6,051,721 April 18, 2000.

David B. Berkowitz, Jill M. McFadden and Marianne K. Sloss "Engineering Acyclic Stereocontrol in the Alkylation of Vinylglycine-Derived Dianions: Asymmetric Synthesis of Higher

-Vinyl Amino Acids," J. Org. Chem. 2000, 65, 2907-2918.

David B. Berkowitz, Sungjo Choi and Jun-Ho Maeng "Enzyme-Assisted Asymmetric Total Synthesis of (-)-Podophyllotoxin and (-)-Picropodophyllin." J. Org. Chem.2000,65, 847-860.

David B. Berkowitz and Michelle L. Pedersen, "

-Oxiranyl Amino Acids," U.S. Patent No. 6,008,386 December 28, 1999.

David B. Berkowitz, Ryan Hartung and Sungjo Choi "Enzymatic Hydrolysis of Advanced Synthetic Intermediates: On the Choice of the Organic Cosolvent." Tetrahedron: Asymmetry, 1999, 10, 4513-4520.

David B. Berkowitz, Debnath Bhuniya and Gorka Peris "Facile Installation of the Phosphonate and (

-Difluoromethyl)phosphonate Functionalities Equipped with Benzyl Protection." Tetrahedron Letters, 1999, 40, 1869-1872.

David B. Berkowitz,* Jill McFadden, Marianne K. Smith and Michelle L. Pedersen, "Synthesis of

-Vinyl Amino Acids." Methods in Molecular Medicine, Peptidomimetics Protocols (Wieslaw M. Kazmierski, volume Ed.; John M. Walker, series Ed.; Humana Press, Totowa, NJ), Vol. 23, Chapter 27, 467-488, 1999.

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