NEW CYCLIZATION METHODS FOR NATURAL PRODUCT SYNTHESIS

Project: Research project

Project Details

Description

The overall objective of this proposal is the development of new strategies
for the construction of carbocyclic or heterocyclic systems. This new
methodology will facilitate the synthesis of biologically active compounds,
and moreover, provide routes to previously unsynthesized compounds. Two
strategies will be examined.

In the first strategy we will study application of the intramolecular
Diels-Alder reaction in the synthesis of the potent hypocholesterolemic
agents mevinolin and dihydromevinolin. These compounds cause a marked
decrease in serum cholesterol in man by inhibiting the rate-limiting
enzymatic step (HMG-CoA reductase) in the cholesterol biosynthetic
pathway. It is hoped that these agents will be useful for the treatment of
atherosclerosis.

The exploitation of the Claisen-rearrangement-mediated approach to hetero-
and carbocycles in natural product synthesis is the second major topic of
the program. The targeted compounds are primarily comprised of
medium-sized rings. For example, this reaction will play a fundamental
role in the construction of: the seven-membered ring of antitumor
guaianolides (desacetoxymatricarin); as well as the eight-membered ring of
both steganicin, which possesses antileukemic activity, and the cytotoxic
taxane class of compounds, specifically, taxinine. A novel entry to the
cyclodecane framework of the germacranes, a class of sesquiterpenes with a
wide range of biological activities, will be demonstrated in the synthesis
of costunolide and tulipinolide.

Utilization of this process in the synthesis of the heterocyclic, neuronal
excitatory compound, Alpha-kainic acid, will also be examined. Also,
extension of this methodology to the bridged bicycloalkane class of
compounds with possible application to clovene, the antitumor compound
quadrone and an alternate taxane strategy will be pursued.
StatusFinished
Effective start/end date12/31/896/30/99

Funding

  • National Institute of General Medical Sciences

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