Paclitaxel and its close structural relatives represent very demanding targets for the implementation of de novo synthetic tactics. This is a consequence of their high structural complexity and abundant stereochemical detail. The routes developed to the present time were designed primarily to demonstrate that paclitaxel can be prepared in the laboratory and cannot be categorized as particularly efficient. The primary goal of the present effort is to develop a more abbreviated route to paclitaxel by addressing at least two central rearrangements, which we have demonstrated in highly functionalized settings to be capable of meeting the stated needs. The approach is therefore one designed around the tactic of elaborating the entire taxane ring system early by submitting simple 1,2-adducts of D-camphor derivatives to sequential charge-accelerated oxy- Cope and alpha-ketol rearrangements alongside new, specifically tailored reactions. A synthesis of taxusin, which takes advantage of some of these concepts, has already been completed. Our protocol will rely on D-camphor, an inexpensive enantiomerically pure commodity chemical, to produce the targeted compounds in their proper absolute configuration. Emphasis is to be placed on brevity; consequently, very reasonable regiocontrol and the minimum number of protection/deprotection maneuvers are to be developed. Flexibility shall also be paramount, such that minor changes in methodology will allow for the adaptation of our intermediates to arrival at several targeted end-products. Our first priority is to arrive at paclitaxel. As the most expeditious route is being made evident, real time will be concurrently devoted to preparing important congeners not available by degradation of the natural product. These include, but are not limited to, the 1-deoxy, D-homo-, 2-desmethyl, and 12-methylene derivatives, in addition to the D-ring invertomer and the C-nor isomer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA083830-03
Application #
6497941
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Lees, Robert G
Project Start
2000-03-01
Project End
2004-01-31
Budget Start
2002-02-01
Budget End
2003-01-31
Support Year
3
Fiscal Year
2002
Total Cost
$268,017
Indirect Cost
Name
Ohio State University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
098987217
City
Columbus
State
OH
Country
United States
Zip Code
43210