Synthetic Studies on Adenine-Diterpene Alkaloids Asmarines A-F, Cytotoxic Metabolites from the Marine Sponge Raspailia Species

为了确定从海绵树状体（Raspailia sp.）中分离的新型腺嘌呤二萜生物碱asmarines a - f的结构和绝对构型，我们进行了手性合成，得到了以下结果。6-氯嘌呤与N-（3-溴丙基）-N-（甲氧基甲氧基）氨基甲酸烯丙酯在共络合物存在下发生烷基化反应，优先生成7-异构体，然后通过分子内6位胺化反应转化为具有[1,4]二氮平[1,2,3-gh]嘌呤骨架的羟胺，该骨架与asmarines a，B的杂环部分相对应。6-氯-7,9-二氢-9-甲基- 8h -purin-8- 1在7位分别与N-（3-溴丙基）氨基甲酸叔丁基酯和N-（3-溴丙基）-N-甲氧基氨基甲酸叔丁基酯烷基化，随后在6位环化，分别得到与asmarines C、D和asmarines E、F的杂环部分相对应的胺和甲氧基胺。不对称罗宾逊环法制得(4aR)-1,4 - A -二甲基-4,4a,7,8-四氢萘-2,5(3H, 6H)-二酮，通过Li/ nh3还原、硅烯醇醚羟甲基化和Ir催化剂催化加氢等高度立体选择性反应，转化为(4'aR,5' s,6' r, 8'aR)-八氢-5',6',8' A -三甲基螺[1，-二氧基烷-2,1'(2'H)-萘]-5'-甲醛，其立体中心与天冬氨酸A，D，E的反式十烷骨架一致。目前正在通过侧链修饰完成两个二萜部分，并随后引入杂环部分。

With a view to confirming the structures and absolute configurations of asmarines A-F, novel adenine-diterpene alkaloids, isolated from the marine sponge Raspailia sp., we have undertaken their chiral syntheses and obtained the following results.1. Alkylation of 6-chloropurine with N-(3-bromopropyl)-N-(methoxymethoxy) carbamic acid allyl ester in the presence of Co-complex provided preferentially the 7-isomer, which was then converted to the hydroxylamine possessing a [1,4]diazepino[1,2,3-gh]purine skeleton corresponding to the heterocyclic portion of asmarines A,B via the intramolecular amination at the 6-position.2. Separate alkylation of 6-chloro-7,9-dihydro-9-methyl-8H-purin-8-one at the 7-position with N-(3-bromopropyl)carbamic acid tert-butyl ester and with N-(3-bromopropyl)-N-methoxycarbamic acid tert-butyl ester and the subsequent cyclization at the 6-position afforded the amine and the methoxyamine corresponding to the heterocyclic moieties of asmarines C,D and asmarines E,F, respectively.3. (4aR)-1,4a-Dimethyl-4,4a,7,8-tetrahydronaphthalene-2,5(3H, 6H)-dione , obtained by asymmetric Robinson annulation, was converted to (4'aR,5'S,6'R,8'aR)-octahydro-5',6',8'a-trimethylspiro[1,-dioxolane-2,1'(2'H)-naphthalene]-5'-carboxaldehyde having all stereogenic centers consistent with the trans-decalin skeleton of asrnarines A,D,E via highly stereoselective reactions (Li/NH_3 reduction, hydroxymethylation of the silyl enol ether, and catalytic hydrogenation using Ir catalyst).Completion of two diterpene portions by side chain modification and subsequent introduction of the heterocyclic moieties are currently under way.