Synthetic Studies Of Nakadomarin A, Subincanadine C And Fluorine-substituted 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 marine sponge Amphimedon sp. by Kobayashi et al in 1997 and consists of an unprecedented 8/5/5/5/15/6 ring system, which contains a furan ring. Biological assays indicate that it is cytotoxic against murine lymphoma L1210 cells, inhibits CDK4, and shows antimicrobial activity. Our synthesis features the construction of the strained ABCD core involving key transformations such as stepwise reductive amination, Sonogashira coupling, and a platinum(II)-catalyzed cascade reaction sequence. The 8- and 15-membered azacycles (i.e., E and F rings) were both obtained by ring-closing metathesis (RCM). However, for the formation of the 15-membered azacycle via RCM, a mixture of two geometrical isomers (Z/E = ca. 2:3, by NMR), with the desired product as the minor one. Further efforts directed to solve the problem involves the attempted formation of the 15-membered azacycle by intermolecular Wittig olefination (to synthesize the Z-cycloalkene in higher stereoselectivity) followed by intramolecular SN2 reaction or reductive amination, which is still ongoing in our laboratory.Subincanadines C was isolated by Kobayashi et al in 2002 as a novel quaternary indole alkaloid from a Brazilian medicinal plant, Aspidosperma subincanum. This compound possesses an unprecedented 1-azoniatricyclo[4.3.3.01,5]undecane framework. The tetracyclic ketone was constructed from 1-benzyltryptamine featuring Michael addition, Pictet-Spengler cyclization, and Dieckmann condensation. In order to form the E ring, further manipulations on the key ketone intermediate included the utilization of Aldol condensation (twice) and stereoselective hydrogenation to attach an appropriate side chain. Finally, subincanadine C was successfully obtained through reductive debenzylation followed by a sequential sulfonation/cyclization (i.e., intramolecular ammonium formation) process. However, our spectral data are not in full consistence with those reported for this natural product in the literature. Further experimental evidence (e.g., X-ray crystallographic data) will be required to provide insight into the relative stereochemistry of C-15 and C-16. (S)-Nicotine, an alkaloid present together with a number of minor alkaloids in tobacco and a wide variety of other plants, has various biological activities. On the other hand, introduction of fluorine atoms into organic compounds has been extensively used to modify the biological activities. We have been engaged in designing and synthesizing fluorinated nicotine analogues with rigid conformations to seek promising lead compounds for the treatment of central nervous system (CNS) disorders. Two strategies for the incorporation of fluorine atoms into nicotine analogues have been investigated and they are: (i) application of appropriate fluorine-containing building blocks such as 3-bromo-3,3-difluoropropene and ethyl bromodifluoroacetate, and (ii) direct fluorination of alcohols or ketones to afford fluorine-substituted nicotine analogues.