抄録
Micronesian marine sponge Lendenfeldia chondrodes contains structurally diverse neuroactive metabolites such as dysiherbaine, neodysiherbaine, dysibetaine, dysibetaine CPa and CPb, and cribronic acid, which have received significant attention from the synthetic community as structural motifs for developing novel neuroactive compounds. It is also of our considerable interest to use these metabolites as a probe for investigating functions of synaptic receptors. In the present study, we established a synthetic route to dysibetaine CPa (1) in racemic form, which is amenable to the analog synthesis, to study the biological function as well as the structure-activity relationships. Dysibetaine CPa (1) is a betaine consists of a quaternary ammonium group and two carboxyl groups, located on a novel 1,2,3-trisubstituted cyclopropane ring. From the synthetic point of view, differentiation of the functional groups on the cyclopropane ring is essential for the total synthesis but proved to be challenging during our study because of the instability of the synthetic intermediates. Upon considerable experimentation, we discovered that the cyclopropane ring was readily constructed by the reaction of N-(4-nitrophenyl)maleimide with sulfonium ylide 3. Reductive opening of the cyclopropane-fused imide 22 with NaBH_4 proceeded chemoselectively, giving rise to hydroxyamide 23. The amide was converted to ethyl ester over two steps, and then quaternary ammonium group was introduced by way of bromide 6'. Finally, acidic hydrolysis of two esters was effected by hydrochloric acid to achieve the total synthesis of dysibetaine CPa ((±ア)-1). Total yield was 4.5% for 12 steps. Furthermore, synthesis of five analogs was performed in the present study. Our route for the racemates, thus established here, will be also expanded to the asymmetric synthesis to determine the absolute stereochemistry of 1. Preliminary study indicated that all synthetic compounds did not induce noticeable behavioral change when 20 μg was administrated in mice intracerebroventricularly, as was observed with natural product.
