Synthetic Study on Taxol via a New Route Inspired by Its Biogenesis

Research Project

Project/Area Number	12672072
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Single-year Grants
Section	一般
Research Field	Chemical pharmacy
Research Institution	Waseda University
Principal Investigator	NAKADA Masahisa Waseda University, School of Science and Engineering, Professor, 理工学部, 教授 (50198131)
Project Period (FY)	2000 – 2001
Project Status	Completed (Fiscal Year 2001)
Budget Amount *help	¥2,900,000 (Direct Cost: ¥2,900,000) Fiscal Year 2001: ¥1,100,000 (Direct Cost: ¥1,100,000) Fiscal Year 2000: ¥1,800,000 (Direct Cost: ¥1,800,000)
Keywords	taxol / asymmetric synthesis / pinacol coupling / samarium (II) iodide / lowvalent titanium / 二ヨウ化サマリウム / 全合成研究 / 不斉全合成 / 生合成経路 / ピナコールカップリング
Research Abstract	In the synthetic study on taxol arose from the interest in its biosynthetic pathway found was the condition for the coupling reaction of the Left-Wing with the Right-Wing model compound, and the transformation of the coupled products to the substrate for the designed transannular reaction. Though the undesired product was the major product, the desired 10-membered ring formed in 10 % yield by the intramolecular pinacol coupling between C-9 and C-10. Hence, another position should be selected if the ring closure is to be carried out by the intramolecualr pinacol coupling. The B-ring closure by the intramolecular alkylation of the cyanohydrin was examined, too. Though its yield was not determined because the reaction was run in a small scale, almost no side products formed in this reaction. Hence, this method will be a promising one if the reaction condition is optimized. In the synthetic study on taxol directed towards its efficient synthesis found was that two model keto-aldehydes afforded the desired products in 12 % and 20 % (at 91 % conversion) yields. The keto-aldehyde possessing acetonide between C-9 and C-10 diol, which was designed to make the reaction points come closer, was also examined, but the corresponding diol was a sole product in this case. Another keto-aldehyde possessing sp^2 C-11 carbon was prepared and subjected to the intramolecular pinacol coupling, but no desired product was obtained. From the results obtained in this study, we recognized that a proper devise to promote the intramolecular pinacol coupling between C-9 and C-10 must be set in the substrate to achieve the efficient construction of B-ring. Hence, we are now investigating the intramolecular pinacol coupling of the substrate possessing a hydroxy group at C-16, because this hydroxy group would aid the substrate to take an endo boat-chair conformation in the transition state to afford the desired product.