Study On The Synthesis Of Lactonamycin And Ascomycone A

The dissertation consists of two parts:Part 1. Synthesis of important intermediates of Lactonamycin. Part 2. Synthesis of pivotal intermediates of Ascomycone A. In this paper, synthetic routes of Lactonamycin and Ascomycone A were designed according to the conventional retrosynthetic analysis. Eventually, important intermediates of lactonamycin and Ascomycone A were synthesized successfully by the designed routes.Part 1. Firstly, the important intermediate 10 (16.8%overall yield) and 21(10.3% overall yield) of Lactonamycin were synthesized via a six-step and ten-step reactions, respectively. The compound 3 was prepared with 84.1%yield by protection of propynol with 3,4-dihydropyran. Diels-Alder and retroDiels-Alder addition of 4 and diene 6, which obtained by Birch reduction of 1,4-dimethoxybenzene, was carried out at 190℃, and the product 8 was obtained in 41.3% yield. Reaction of 8 and ethyl acetate carbanion provided product 9 in 68.9% yield, and oxidation of 9 with CAN offered quinone 10 with 98% yield. Secondly, the other critical intermediate was synthesized with methyl acetoacetate as starting material. Acetylation of methyl acetoacetate provided compound 12 in 89% yield, enolic 12 was protected with TMS to give compound 13, which reacted with bromomaleic anhydride to offer phthalic anhydride derivative 14, regioselective reduction of 14 with L-selectride gave dihydroisobenzofuranone 15, and bromination 15 with NBS gave complexed products 17a,17b and 17c, the usefull 17a was isolated in 56% yield. After several run study, we found that it was readily to synthesize compound 20 with one pot reaction. Product 21 was obtained in 91.5% yield via enolization and protection with TBS.Part 2. Synthesis of Ascomycone A was studied. In this part, two synthetic routes of Ascomycone A were designed according to the conventional retrosynthetic analysis. In the first route, the intermediate 30 was synthesized with 24.5% overall yield from 2,5-dimethoxybenzaldehyde. Bromination of compound 26, before protection of aldehyde with propylene glycol, gave 86% yield. Deprotection and Sonogashira coupling provided 3,6-dimethoxy-2-(prop-1-ynyl)benzaldehyde 29, and then cyclization of 29 offered the intermediate 30 in 95% yield. In order to control the structure of product, the second route was designed. Reaction of 2-chloro-4-methoxyphenol and HCHO gave the product 34, after etherlation, oxidation and pretection of 34 were carried out in turn, the product 37 was obtain in high yield.40 was prepared from 37 according the proceedure of synthesis of product 30. oxidation of 40 with CAN provided quinone, which reacted in on pot with Danishefsky diene 43, prepared with two steps from methyl acetoacetate, to obtain the final target molecule was ongoing in my hand.