The objective of the proposed research is the enantioselective total synthesis of (-)-xestocyclamine A. This natural product belongs to the manzamine family of marine alkaloids and is a potent inhibitor of protein kinase C (PKC). Recent findings show that PKC plays an important role in cellular regulatory functions and is a possible target for cancer treatment. The initial goal of this research is the novel synthesis of a chiral 3-piperidinol containing a tetra-substituted olefin. This intermediate will play a vital role in the establishment of the core ring system stereochemistry and the incorporation of macrocycle precursors. An intramolecular alkyne-azadiene Diels-Alder reactions will simultaneously form three rings, which include a macrocycle and a complex [2,2,2] bridged bicyclic systems. The face- and regioselectivity of the Diels-Alder reaction can be controlled by the tether length of the dienophile and the conformation of the azadiene. The regio-chemistry may also be influenced by electron donating alkynyl auxiliaries, which are easily incorporated into the synthesis. The final macrocycle of xestocyclamine A will be formed by a ring-closing olefin metathesis reaction. The xestocyclamine A will be formed by a ring-closing olefin metathesis reaction. The development of this convergent synthesis of xestocyclamine A will ultimately lead to the synthesis of analogs to probe the biological activities of this alkaloid.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32GM019972-01
Application #
2861474
Study Section
Medicinal Chemistry Study Section (MCHA)
Project Start
1999-04-05
Project End
Budget Start
1999-04-05
Budget End
2000-04-04
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
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