This proposal is directed towards the development of new approaches to the construction of naturally occurring substances with important biological activity. Three areas of research based on vinylogous amide photochemistry are outlined herein: 1) the extension of the vinylogous amide photocycloaddition/retro-Mannich fragmentation/ring closure sequence to the synthesis of perhydroquinoline ring systems; 2) the application of the photocycloaddition of tertiary vinylogous amides to a construction of the recently discovered manzamine antitumor alkaloids; and 3) a study of the scope and limitations of a novel synthesis of heterocycles based on the photochemistry of vinylogous amides. Taxol (NSC-125973) is an exceptionally promising cancer chemotherapeutic agent with an unusually broad spectrum of potent antileukemic and tumor-inhibiting activity. It is the only plant product known to promote the assembly of microtubules and inhibit the tubulin disassembly process and, thus, appears to be the prototype of a new class of cancer chemotherapeutic agents. Two approaches for the construction of the carbocyclic ring system of the taxane diterpenes are described in this proposal: 1) the application of the intramolecular dioxenone photocycloaddition to the synthesis of taxol analogs and the naturally occurring taxusin; and 2) the development of a highly convergent approach for the synthesis of the taxane diterpenes based on a Grob-like fragmentation of an intramolecular ketene-olefin cycloadduct. The strategies that are outlined herein for the synthesis of biologically active natural products have counterparts in the Diels-Alder reaction, cationic polyene cyclization, and arene-olefin cycloaddition reaction. More than one carbon-carbon bond and considerable stereochemical information is generated in a single synthetic operation. The approaches for the construction of the manzamine alkaloids and the taxane diterpenes outlined in this proposal attest to the considerable potential of this methodology for the synthesis of medicinally important substances.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Medicinal Chemistry Study Section (MCHA)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pennsylvania
Schools of Arts and Sciences
United States
Zip Code
Haimowitz, Thomas; Fitzgerald, Mark E; Winkler, Jeffrey D (2011) STUDIES DIRECTED TOWARD THE SYNTHESIS OF NAKADOMARIN A. Tetrahedron Lett 52:2162-2164
Winkler, Jeffrey D; Lee, Esther C Y; Nevels, LaToya I (2005) A Pauson-Khand approach to the synthesis of ingenol. Org Lett 7:1489-91
Winkler, Jeffrey D; Oh, Kyungsoo; Asselin, Sylvie M (2005) Synthesis of highly functionalized furanones via aldol reaction of 3-silyloxyfurans. Org Lett 7:387-9
Winkler, Jeffrey D; McLaughlin, Emily C (2005) Intramolecular photocycloaddition of dioxenones with alkynes: formation of secondary photoproducts from cyclobutene photoadducts. Org Lett 7:227-9
Winkler, Jeffrey D; Asselin, Sylvie M; Shepard, Stacey et al. (2004) Metathesis approach to the synthesis of polyheterocyclic structures from oxanorbornenes. Org Lett 6:3821-4
Doerksen, Robert J; Chen, Bin; Yuan, Jing et al. (2003) Novel conformationally-constrained beta-peptides characterized by 1H NMR chemical shifts. Chem Commun (Camb) :2534-5
Winkler, Jeffrey D; Rouse, Meagan B; Greaney, Michael F et al. (2002) The first total synthesis of (+/-)-ingenol. J Am Chem Soc 124:9726-8
Kwak, Y S; Winkler, J D (2001) Synthesis of 6-aza-bicyclo[3,2,1]octan-3-ones via vinylogous imide photochemistry: an approach to the synthesis of the hetisine alkaloids. J Am Chem Soc 123:7429-30
Davis, K D; Berrodin, T J; Stelmach, J E et al. (1994) Endogenous retinoid X receptors can function as hormone receptors in pituitary cells. Mol Cell Biol 14:7105-10