Synthetic Studies Of Nakadomarin A,Subincanadine C And Fluorine-substitueted Nicotine Analogues

This dissertation mainly focuses on synthetic studies of nakadomarin A,subincanadine C, and fluorinated conformationally restricted nicotine analogues.(-)-Nakadomarin A is a novel manzamine-related alkaloid isolated from a marinesponge Amphimedon sp. by Kobayashi et al in 1997 and consists of an unprecedented8/5/5/5/15/6 ring system, which contains a furan ring. Biological assays indicate thatit is cytotoxic against murine lymphoma L1210 cells, inhibits CDK4, and showsantimicrobial activity. Our synthesis features the construction of the strained ABCDcore involving key transformations such as stepwise reductive amination, Sonogashiracoupling, and a platinum(II)-catalyzed cascade reaction sequence. The 8- and15-membered azacycles (i.e., E and F rings) were both obtained by ring-closingmetathesis (RCM). However, for the formation of the 15-membered azacycle viaRCM, a mixture of two geometrical isomers (Z/E = ca. 2:3, by NMR), with thedesired product as the minor one. Further efforts directed to solve the probleminvolves the attempted formation of the 15-membered azacycle by intermolecularWittig olefination (to synthesize the Z-cycloalkene in higher stereoselectivity)followed by intramolecular SN2 reaction or reductive amination, which is still ongoingin our laboratory.Subincanadines C was isolated by Kobayashi et al in 2002 as a novel quaternaryindole alkaloid from a Brazilian medicinal plant, Aspidosperma subincanum. Thiscompound possesses an unprecedented 1-azoniatricyclo[4.3.3.0～(1,5)]undecaneframework. The tetracyclic ketone was constructed from 1-benzyltryptamine featuringMichael addition, Pictet-Spengler cyclization, and Dieckmann condensation. In orderto form the E ring, further manipulations on the key ketone intermediate included theutilization of Aldol condensation (twice) and stereoselective hydrogenation to attachan appropriate side chain. Finally, subincanadine C was successfully obtained throughreductive debenzylation followed by a sequential sulfonation/cyclization (i.e.,intramolecular ammonium formation) process. However, our spectral data are not infull consistence with those reported for this natural product in the literature. Furtherexperimental evidence (e.g., X-ray crystallographic data) will be required to provideinsight into the relative stereochemistry of C-15 and C-16. (S)-Nicotine, an alkaloid present together with a number of minor alkaloids intobacco and a wide variety of other plants, has various biological activities. On theother hand, introduction of fluorine atoms into organic compounds has beenextensively used to modify the biological activities. We have been engaged indesigning and synthesizing fluorinated nicotine analogues with rigid conformations toseek promising lead compounds for the treatment of central nervous system (CNS)disorders. Two strategies for the incorporation of fluorine atoms into nicotineanalogues have been investigated and they are: (i) application of appropriatefluorine-containing building blocks such as 3-bromo-3,3-difluoropropene and ethylbromodifluoroacetate, and (ii) direct fluorination of alcohols or ketones to affordfluorine-substituted nicotine analogues.