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

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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.