Studies On The Synthesis Of New Taxol Analogues

Taxol is one of the most important anticancer drugs and exerts its good anticancer activity through a unique mechanism. For a long time, scientists have paid their attention to taxanes. But some problems (resource, multidrug resistance, low solubility) still limite the wide use of taxol. At present, the study of taxanes focuses on the searching for new second generation taxoids as antitumor drugs. Sinenxan A which is a biosynthetic taxane has the same taxane skeleton and has a 14 β -hydroxy group instead of 13-oxygen functionalities. SIA was obtained from cell culture in good yield(⁵%) without natural resource problems. Therefore, it will be of considerable significance to develop a procedure that would allow for the efficient use of SIA as starting material for the new taxol analogues. Analysis of SAR of taxol shows that lack of groups at C-1, C-7 and C-9 position does not affect activity of taxol. Thus we decided to design and synthesize 1, 7, 9-trideoxytaxol, which may keep the good anticancer activity .Two approaches have been designed to synthesize of 1, 7, 9-trideoxytaxol starting from SIA. In the first synthetic route, we obtained the intermediate 39 by synthesise of the oxetane ring first, deoxygenation at C-14 secondly and introduction of 13-carbonyl group finally(13 steps, 15.3% total yields). But 13-carbonyl group of compound 39 can't be reducted by several reducing agents including H₂/PtO₂, NaBH₄, K-selectride and DIBAH. In the second route, we adjust the sequence of steps and successfully synthesized compound 62(10-deacetyl-7,9-dideoxy-2-hydroxyl-baccatin â…¢) via SIA (17 steps, about 6% total yields), which is a key intermidiate of 1, 7, 9-trideoxytaxol which contains 10 β -OH, 13 α -OH, 2α -OH and oxetane ring.On the chemical synthesis, we focus on the following reactions, methods and achieved some accomplishments:1. Regioselective hydrolysis of SIA at C-14 position was explored.2. Deoxygenation at C -14 by 1 ,1'-Thiocarbonyldiimidazole or 1 -methyldithiocarbonyl-imidazole were accomplished.3. Oxidation at C-13 were studied. CrO₃/t-BuOOH was suitable for this reaction, in which its mild reaction conditions, simplicity in operation and yield were superior to PPC method. Microwave-assisted reaction was also applied to this oxidation.4. Reduction of 13-carbonyl group was studied. Finally reduction of 13-carbonyl group to 13α -OH via 5-OH transannular delivery was achieved by NaBH₄/MeOH/THF at 0℃.5. Factors that caused difficultly in 5-OH methylsulfonylation were dicussed.6. The oxetane ring was built in high yields.7. Many efforts have been made to acylate 4-OH. 4-Acetyl group was successfully introduced after 2-OH was oxidated to 2-carbonyl group.8. Different reducting agents were used to reduce 2-carbonyl group. DIBAH was selected for this reduction.Totally 57 compounds were synthesized, 40 of which are unreported. All structure of them were confirmed by ¹HNMR and MS. Some of them were also indentified by 2D-¹HNMR, ¹³CNMR and HRFABMS/...