3 分子力場計算に基づくタキソール合成中間体の分子設計とその合成研究(口頭発表の部)

概要

論文の詳細を見る
Taxol (1), originally isolated from the Pacific yew (Taxus brevifolia), has shown remarkable potential in recent clinical trials for the treatment of breast and ovarian cancer. Its structural complexity and the limited availability have engendered world-wide intensive studies toward its total synthesis. We describe here 1) biosynthetic approach to taxol BC ring system, 2) convergent approach to taxol skeleton, featuring molecular modeling studies for the rational design of synthetic intermediates. The biosynthetic approach involves the transannular cyclization of 12 membered epoxide 4 for the construction of taxol BC ring system. Rational design of the 12-membered epoxide 4 suitable for providing trans stereochemistry between C-8 methyl and C-3 hydrogen was carried out by applying Monte Carlo conformational search and MM2 force field. The key 12-membered intermediate 4 for the transannular cyclization was constructed by aldol condensation of the 5-membered lactone 7 with aldehyde 8, followed by intramolecular alkylation of the protected cyanohydrin 11. An attempt to construct BC ring system by treatment of 14 with Lewis acid revealed the desired transannular cyclization and additional side reaction leading to bicyclic product 16. Then, a concise method for the formation of C-aromatic taxol system has been developed. In our convergent approach, A, C rings were constructed first and then brought together to form the 8-membered B ring. Construction of A, C rings in the intermediate 19 was carried out by successive Friedel-Crafts reaction and cation-cyclization processes. Formation of B ring was achieved by employing intramolecular alkylation of the protected cyanohydrin 18. X-ray crystallographic analysis of the cyclized product confirmed the stereochemical structure and endo conformation of 26. Next, synthesis of the functionalized C-ring system was carried out based on the intramolecular [3+2] cycloaddition of nitrile oxide derivative 30. MM2 transition state modeling (flexible model) of various nitrile oxide derivatives showed that cycloaddition of oxime 30 having C-2, C-4 six membered acetonide group would give the desired trans stereochemistry between C-8 methyl and C-3 hydrogen. Upon treatment with NaOCl aq., the chiral oxime 30 underwent [3+2] cycloaddition to afford the desired chiral C ring synthon 31.
天然有機化合物討論会の論文
1995-09-01

3 分子力場計算に基づくタキソール合成中間体の分子設計とその合成研究(口頭発表の部)

スポンサーリンク

概要

著者

関連論文

スポンサーリンク