The overall goal of this program is to develop concise, general strategies and methods for the stereoselective synthesis of structurally complex alkaloids. The methods section of the research plan is divided into three broad areas. The first part describes studies directed toward the synthesis of the important anticancer agents vinblastine and vincristine, and their analogs. During the last funding period we developed an efficient, practical synthesis of Aspidosperma alkaloids (""""""""lower"""""""" part of Vinca), based on an enantioselective Diels-Alder (DA) reaction that was specifically developed for this application. Our next objective in this project is to complete a practical chemical synthesis of the Vinca alkaloids. In this context, we will develop new concise, asymmetric syntheses of vindoline, the first asymmetric synthesis of catharanthine, the """"""""upper"""""""" (velbenamine) part, and develop new methods for coupling the two parts to produce bioactive Vinca alkaloids. Structurally diverse analogs of the Vinca alkaloids will also be prepared. The second part describes the application of the newly developed chemistry to a diverse range of bioactive natural products that are derived biogenetically from geissoschizine, including akagerine, pleiocarpamine, and strictamine. The third part describes concise, general routes to Amaryllidaceae alkaloids and hapalindoles. Both families have members that exhibit significant anticancer activity. The proposed synthetic routes make efficient use of the asymmetric DA chemistry that was developed in our labs during the last grant period. Throughout the research plan section, we provide extensive preliminary results to support the proposed new chemistry. Overall, these investigations are expected to result not only in efficient syntheses of a wide range of indole alkaloids, but also in the development of useful new methodologies, particularly palladium-catalyzed processes and asymmetric Diels-Alder reactions. The methods developed through this work should prove useful to other synthetic endeavors. The work is expected to lead to the synthesis of many biologically active natural products (especially anticancer agents) and their analogs. These synthetic compounds, including advanced intermediates, will be submitted for biological testing. ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
9R01CA101438-05
Application #
6619897
Study Section
Special Emphasis Panel (ZRG1-SSS-B (01))
Program Officer
Lees, Robert G
Project Start
1997-05-01
Project End
2008-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
5
Fiscal Year
2003
Total Cost
$311,588
Indirect Cost
Name
University of Chicago
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Reyes, Julius R; Rawal, Viresh H (2016) Reductive Chlorination and Bromination of Ketones via Trityl Hydrazones. Angew Chem Int Ed Engl 55:3077-80
Allan, Kevin M; Kobayashi, Kenichi; Rawal, Viresh H (2012) A unified route to the welwitindolinone alkaloids: total syntheses of (-)-N-methylwelwitindolinone C isothiocyanate, (-)-N-methylwelwitindolinone C isonitrile, and (-)-3-hydroxy-N-methylwelwitindolinone C isothiocyanate. J Am Chem Soc 134:1392-5
Bhat, Vikram; Mackay, James A; Rawal, Viresh H (2011) Lessons Learned while Traversing the Welwitindolinone Alkaloids Obstacle Course. Tetrahedron 67:100997-10104
Bhat, Vikram; Mackay, James A; Rawal, Viresh H (2011) Directed oxidative cyclizations to C2- or C4-positions of indole: efficient construction of the bicyclo[4.3.1]decane core of welwitindolinones. Org Lett 13:3214-7
Bhat, Vikram; Allan, Kevin M; Rawal, Viresh H (2011) Total synthesis of N-methylwelwitindolinone D isonitrile. J Am Chem Soc 133:5798-801
Bhat, Vikram; Rawal, Viresh H (2011) Stereocontrolled synthesis of 20,21-dihydro N-methylwelwitindolinone B isothiocyanate. Chem Commun (Camb) 47:9705-7
Jewett, John C; Rawal, Viresh H (2010) Temporary restraints to overcome steric obstacles: an efficient strategy for the synthesis of mycalamide B. Angew Chem Int Ed Engl 49:8682-5
Okamoto, Kazuhiro; Hayashi, Tamio; Rawal, Viresh H (2008) Simple chiral diene ligands provide high enantioselectivities in transition-metal-catalyzed conjugate addition reactions. Org Lett 10:4387-9
Kagawa, Natsuko; Malerich, Jeremiah P; Rawal, Viresh H (2008) Palladium-catalyzed beta-allylation of 2,3-disubstituted indoles. Org Lett 10:2381-4
Zhong, H Marlon; Sohn, Jeong-Hun; Rawal, Viresh H (2007) Studies toward the asymmetric synthesis of the right part of the mycalamides. J Org Chem 72:386-97

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