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

为了确定从海绵Raspailia sp.中分离得到的新型腺嘌呤二萜生物碱A-F的结构和绝对构型，我们进行了它们的手性合成，得到了以下结果。6-氯嘌呤与N-(3-溴丙基)-N-(甲氧基甲氧基)氨基甲酸烯丙基酯在钴络合物存在下的烷基化反应优先得到7-异构体，然后通过6-位的分子内胺化反应生成具有[1，4]二氮杂环[1，2，3-GH]嘌呤骨架的羟胺，该骨架对应于天冬氨酸A，B的杂环部分。6-氯-7，9-二氢-9-甲基-8H-嘌呤-8-酮与N-(3-溴丙基)氨基甲酸叔丁酯和N-(3-溴丙基)-N-甲氧基氨基甲酸叔丁酯分别在7-位上烷基化，然后在6-位上环合，得到了分别对应于Amarine C、D和Asmarine E、F杂环基团的胺和甲氧基胺。通过高度立体选择性的反应(Li/NH_3还原，硅烯醇醚的羟甲基化，和使用Ir催化剂的催化氢化)。通过侧链修饰和随后引入杂环部分来完成两个二萜部分目前正在进行中。

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.