The objective of this research program is the discovery and development of new reaction methodology en route to the synthesis of complex bioactive molecules. Our proposed studies will focus on the advancement of enantioselective palladium- catalyzed oxidation reactions that do not involve oxygen atom transfer. These reactions include the oxidative kinetic resolution of secondary alcohols and new cyclizations that deliver enantiopure heterocycles and carbocycles. The processes that we develop will find utility in the synthesis of a variety of complex biologically active molecules for which there is currently no efficient synthetic roadmap. As a consequence of this approach, we will have a) access to novel, medicinally relevant structures, b) a general method for their synthesis, and c) new synthetic methods that will be beneficial for a host of general applications. Specifically, we plan to target two classes of highly biologically relevant complex alkaloids, the Dragmacidins (1-3) and the Cephalotaxines (e.g., 4). The former have been shown to selectively inhibit brain Nitric Oxide Synthase (bNOS), and may have therapeutic importance for the treatment of Alzheimer's and other neurodegenerative disorders. The latter are potent antitumor agents, and have been used to overcome the Multiple Drug Resistance problems associated with many chemotherapeutic agents. The ultimate impact of our research will resonate across numerous disciplines including synthetic and organometallic chemistry, chemical biology, and human medicine.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM065961-05
Application #
7085437
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Schwab, John M
Project Start
2002-07-01
Project End
2007-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
5
Fiscal Year
2006
Total Cost
$310,075
Indirect Cost
Name
California Institute of Technology
Department
Type
Schools of Engineering
DUNS #
009584210
City
Pasadena
State
CA
Country
United States
Zip Code
91125
Ebner, David C; Bagdanoff, Jeffrey T; Ferreira, Eric M et al. (2009) The palladium-catalyzed aerobic kinetic resolution of secondary alcohols: reaction development, scope, and applications. Chemistry 15:12978-92
Krishnan, Shyam; Bagdanoff, Jeffrey T; Ebner, David C et al. (2008) Pd-catalyzed enantioselective aerobic oxidation of secondary alcohols: applications to the total synthesis of alkaloids. J Am Chem Soc 130:13745-54
Ebner, David C; Trend, Raissa M; Genet, Cedric et al. (2008) Palladium-catalyzed enantioselective oxidation of chiral secondary alcohols: access to both enantiomeric series. Angew Chem Int Ed Engl 47:6367-70
Trend, Raissa M; Stoltz, Brian M (2008) Structural features and reactivity of (sparteine)PdCl2: a model for selectivity in the oxidative kinetic resolution of secondary alcohols. J Am Chem Soc 130:15957-66
Ferreira, Eric M; Zhang, Haiming; Stoltz, Brian M (2008) C-H Bond Functionalizations with Palladium(II): Intramolecular Oxidative Annulations of Arenes. Tetrahedron 64:5987-6001
Liu, Qi; Ferreira, Eric M; Stoltz, Brian M (2007) Convergency and divergency as strategic elements in total synthesis: the total synthesis of (-)-drupacine and the formal total synthesis of (+/-)-cephalotaxine, (-)-cephalotaxine, and (+)-cephalotaxine. J Org Chem 72:7352-8
Tambar, Uttam K; Ebner, David C; Stoltz, Brian M (2006) A convergent and enantioselective synthesis of (+)-amurensinine via selective C-H and C-C bond insertion reactions. J Am Chem Soc 128:11752-3
Ferreira, Eric M; Stoltz, Brian M (2006) The synthesis of C-3beta functionalized indoles via a hydroboration/Suzuki-Miyaura coupling sequence. Tetrahedron Lett 47:8579-8582
Garg, Neil K; Stoltz, Brian M (2006) A unified synthetic approach to the pyrazinone dragmacidins. Chem Commun (Camb) :3769-79
Trend, Raissa M; Ramtohul, Yeeman K; Stoltz, Brian M (2005) Oxidative cyclizations in a nonpolar solvent using molecular oxygen and studies on the stereochemistry of oxypalladation. J Am Chem Soc 127:17778-88

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