Research On The Synthesis Of Bioactive Lamellarin D (LMD) From Marine Mollusc

Lamellarins are a group of marine active pyrrole alkaloids isolated from prosobranch mollusks. So far, over 40 lamellarins have been isolated and identified. As the best known member of lamellarins, Lamellarin D (LMD) exhibited a significant cytotoxicity and was a potential non-CPT (camptothecin) topoisomerase 1 poison. Due to the novel structures and biological activities, considerable biological and chemical researchers have devoted into the studies of LMD and its derivatives, and researches on total synthesis of it is more and more active in recent years. This thesis mainly carried on a research from the following aspects.1.We begun with 2-(3,4-dimethoxyphenyl)ethanamine, followed by acylation and cyclization, then Knorr condensation with 2,4,5-trimethoxy-a-halogen acetophenone afforded 8,9-dimethoxy-2-(2,4,5-trimethoxyphenyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline(I). I was treated with ClCOCCl3 in CHCl3 under low temperature giving 2,2,2-trichloro-1-(8,9-dimeth -oxy-2-(2,4,5-trimethoxyphenyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-yl)ethanone(II). Treatment of II in MeONa/MeOH afforded open lactone analogues of LMD—methyl 8,9-di- methoxy-2-(2,4,5-trimethoxyphenyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carboxylate (III).2. We explored the influence of temperature on the structure of III. Under low temperature (-10℃), the hydroxgen of pyrrolo ring at the ortho position of nitrogen atom was more active and we mainly got III. Under high temperature (30℃), the hydroxgen of pyrrolo ring at the meta position of nitrogen atom was more active. I was followed by the same condition under high temperature giving methyl 8,9-dimethoxy-2-(2,4,5-trimethoxyphenyl)- 5,6-dihydropyrrolo[2,1-a]isoquinoline-1-carboxylate(VI). VI was an isomeric compound of III.3. We explored the influence of K2CO3 on reaction product. Treatment of II with K2CO3 afforded 3-chloro-8,9-dimethoxy-2-(2,4,5-trimethoxyphenyl)-5,6-dihydropyrrolo[2,1-a] isoquinoline(VII), which was treated with MeONa/MeOH giving I. It provided a new and convenient way of chlorization and deprivation of chlorine.4. We begun with benzaldehyde and isovanillin, then followed by protection with BnCl, addition with MeNO2, reduction with LiAlH4, cyclazition in the presence of POCl3 and Knorr condensing with 2,4,5-trimethoxy-a-halogen acetophenone afforded 8-benzyloxy-9-methoxy- 2-(2,4,5-trimethoxyphenyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline and 8,9-bis(benzyloxy)-2- (2,4,5-trimethoxyphenyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline.5. We initially brought forward the method of forming lamellarin skelton from 2H- indene-1,3-dione, then bromization with NBS, condensation with 3,4-dihydroisoquinoline, then followed by Baeyer-villiger oxidation. We synthesized 1,2-(3,4-dimethoxyphenyl)-3H- indeno[1,2-b]indolizin-6(4H)-one (X).6. I,II,III,VI,VII,VIII and IX were all new compounds, which were identified by m.p, 1H NMR, 13C NMR, DEPT 13C 135, UV or IR. The products obtained were stable and may be expected to exhibit biological activity to some extend.