Jeffrey D. Winkler
Merriam Professor of Chemistry
Office: 449 N
Lab: 432, 434 N
Phone: (215) 898-0052
Fax: (215) 573- 6329
New Synthetic Pathways Based on the Intramolecular
Dioxenone and Vinylogous Amide Photocycloaddition Reactions We have developed these methods and have
applied them to the first total syntheses of several molecules of biological
importance, including manzamine A, 1,
saudin, 2 , and ingenol, 3.
Total Synthesis of Manzamine-Related Structures Current efforts in our laboratory are focused toward the synthesis of nakadomarin, 4, a structurally complex hexacyclic alkaloid that displays a range of promising biological activities including cytotoxic activity against murine lymphoma L1210 cells, inhibitory activity against cyclin dependent kinase 4, and anti-microbial activity against a fungus and a Gram-positive bacterium. We have also demonstrated that manipulation of the structure of 1 via Grubbs metathesis leads to the formation of novel structures, i.e., 5, with antibacterial properties comparable to those of ciprofloxacin. Finally, we have embarked on a program directed toward the synthesis of neokauluamine, 6, a dimeric manzamine with highly potent immunosuppressive properties.
Transformations Using Organic Photochemistry We have recently discovered a novel approach to the synthesis of substituted thiophenes 8 from arylsulfide enone precursors 7. The study of the mechanism of this unusual transformation (9 is a byproduct) as well as its application to the synthesis of more complex structures is currently underway in our laboratory.
Development of Novel Inhibitors of Hedgehog Signaling Based on Cyclopamine Aberrant activation of the Sonic Hedgehog (Hh) signaling pathway has been associated with numerous malignancies in the brain, breast, pancreas and other organs. In vivo evidence suggests the antagonism of excessive Hh signaling may provide a route to unique mechanism-based therapies for the treatment of cancer. The steroidal alkaloid cyclopamine 10 suppresses the Hh signaling pathway, and has recently been been shown to be effective in the treatment of cancer using a variety of mouse models. Human cells are also sensitive, supporting the promising use of this natural product. However, the metabolic instability of cyclopamine precludes its clinical use. A significant demand exists for more stable cyclopamine-like structures. This project is directed toward the synthesis of cyclopamine-like structures, i.e., 11, from readily available metabolically-stable steroidal precursors, i.e., estrone.
Total Synthesis of Cortistatin A The development of specific anti-angiogenic agents that could serve as anticancer chemotherapeutic agents is an important goal. In 2006, Kobayashi isolated the cortistatins from the marine sponge Corticium simplex. Cortistatin A 12 is the most active member of this family. It exhibits antiproliferative activity against human umbilical vein endothelial cells at nM concentrations. The total synthesis of the cortistatins and designed materials with cortistatin-like properties is one of the goals of our laboratory.
Education and Academic History
- A.B. Harvard College (1977)
- M.A., M.Phil., Ph.D. Columbia University (1981-83)
- American Cyanamid Young Faculty Award, 1989-1992
- NIH-NCI Research Career Development Award, 1988-1993
- Alfred P. Sloan Research Fellow, 1987-1989
- American Chemical Society Arthur C. Cope Scholar, 2000
- Lindback Award for Distinguished Teaching, 2007
- Philadelphia Organic Chemists’ Club Award, 2006
- Founding Member, University of Pennsylvania Center for Cancer Pharmacology
- Member, University of Pennsylvania Cancer Center
- Associate Editor, Organic Letters
Selected PublicationsJ. Winkler, A. Londregan, M. Hamann, “Synthetic Modification of Manzmaine A via Grubbs Metathesis. Novel Structures with Enhanced Antibacterial and Antiprotozoal Properties,” Org. Lett. 2007, 9, 4467-4469.
J. Winkler, E. Lee, “Photochemical Route to the Synthesis of Thiolane 1-Oxides,” J. Am. Chem. Soc. 2006, 128, 9040-9041.
J. Ragains, J. Winkler, “Pseudosymmetry in azabicyclo[2.1.1.]hexanes. A Stereoselective Construction of the Bicyclic Core of the Ring System of Peduncularine,” Org. Lett., 2006, 8, 4437-4440.
J. Winkler, J. Ragains, “Intramolecular Photocycloaddition of Vinylogous Amides with Allenes: A Novel Approach to the Synthesis of Pyrroles,” Org. Lett., 2006, 8, 4031-33.
S. Choi, D. Clements, V. Pophristic, I. Ivanov, S. Vemparala, J. Bennett, M. Klein, J. Winkler, W. DeGrado, “The Design and Evaluation of Heparin-Binding Foldamers,” Angew. Chem. Int. Ed. 2005, 44, 6685-6689.
J. Winkler, M. Rouse, M. Greaney, S. Harrison, Y. Jeon, “The First Total Synthesis of Ingenol, J. Am. Chem. Soc. 2002, 124, 9726-9728.
Educational InterestsChemistry 241-Organic Chemistry I
Chemistry 242-Organic Chemistry II
Chemistry 441-Organic Mechanism and Structure
Chemistry 443-Organic Reactions
Chemistry 700-Special Topics