The Synthesis Of Marine Alkaloid Aaptamine

Aaptamine and its natural congeners are marine alkaloids, which contain a benzo [de][1,6]-naphthyridine framework. Studys have shown that these compounds display significant antimicrobial, cytotoxic, antifungal, antituberculous, antimalarial acitivities. In this paper, intermediates in the synthesis of natural products and their analogues were studied.According to the accumulated experience of the preparation of nitro olefins in the prophase work, we explored the synthetic method of the key intermediate. Isoquinoline aldehyde compound was condensed with nitromethane via Henry reaction to nitroethanol compound. Based on the kinds and dosage of bases, reaction temperature, reaction solvent after optimization, it was found that using potassium t-butoxide as the base and two equivalent of CH3NO2 in the mixed solvents dioxane and tertiary butanol(v/v = 1: 1) was beneficial to promote the transformation at 25 °C for 12 hours. Then nitroethanol compound was dehydrated using DMAP as catalyst in the present of acetic anhydride with excelent yield.In conclusion, an improved and efficient methord for synthesis of aaptamine hydrochloride, in eight steps from homoveratrylamine, has been successfully established. 6,7-Dimethoxy-1-methylisoquinoline(2-5) was obtained from homoveratrylamine by acylation, Bischler-Napieralski reaction, dehydrogenation, oxidation. Compound(2-5) was condensed with nitromethane using t BuOK as base via Henry reaction to give 1-(6,7-dimethoxyisoquinolin-1-yl)-2-nitroethanol(3-1), dehydration in the present of Ac2 O using DMAP as catalyst, and then nitrated with 2M HNO3-H2SO4 solution in moderate yield at 0 °C. Finally, iron-acetic acid treatment of(E)-6,7-dimethoxy-8-nitro-1-(2-nitrovinyl)isoquinoline produced aaptamine, the total yield was 31%. The aaptamine was confirmed by 1H NMR, 13 C NMR and HRMS, and the other intermediates were confirmed by 1H NMR, 13 C NMR. At the same time, we synthesized a series of intermediate compounds of aaptamine analogues and confirmed their structures by NMR.