Synthesis Of Oleanolic Acid Derivatives

In recent years, AIDS is a serious threat to human health; the trend is spreading around the world. Current clinical drugs for the treatment of AIDS has a variety of side effects and generats drug resistance gradually. However, the synthesis of novel anti-AIDS drugs with natural products as lead compounds is one of the research direction of recent years.Oleanolic Acid is a Pentacyclic Triterpenes natural compound, which widely exists in almost190species of60branches of food, medicinal herbs and other plants as the form of both free acid and aglycones for triterpenoid saponins. Oleanolic Acid possesses some attractive biological activities including protection of the liver against toxic injury, anti-inflammation, anti-tumor, anti-HIV, anti-diabetic, anti-osteoporosis and so on, and the anti-HIV activity,with characters of EC50=1.7μg/mL, TI=12.8, is considered promising. Studies showed C-3hydroxyl, C-28carboxyl group and C12-C13double bond of oleanolic acid were correlated to anti-HIV activity of compounds. We synthesized a series of derivatives by modification of C-3hydroxy, C-28carboxyl group and other site of oleanolic acid.That would lay the foundation for the further study of activity screening and structure-activity relationship.In the present study, we received a total of39compounds by modifying oleanolic acid.①C-3hydroxyl of oleanolic acid was esterified with acyl chloride or aromatic acids at the presence of DCC-DMAP(s-1,2,4,5,8,11,13-17). Before aromatic acids with phenolic hydroxyl groups was esterified with C-3hydroxyl of oleanolic acid, phenolic hydroxyl groups should be protected with benzyl chloride, then the esterification could be carried out in the presence of DCC-DMAP(z-3,6,7,10). The target compounds were received after benzyl groups being taken off with H2and Pd-C(s-3,6,7,10). Fifteen compounds were synthesized in these esterifications.②C-28carboxyl Group was esterified with saturated dihalide (1,2-dichloroethane and1,4-dibromobutane) with combination use of K2CO3firstly. Then the compound was etherified with piperazidine also at the present of K2CO3to yield compound L-1or L-11. Finally, L-1or L-11was amidated with kinds of aromatic acids in the presence of EDC-HOBT to give a series derivatives (L-1-22). Such reactions have yielded21 compounds.③C-3hydroxyl and C-28carboxyl group of oleanolic acid were protected to give methyl3-O-acetyl-oleanolate(z-14). On oxidation with K2Cr2O7in acetic acid, compound(z-14) afforded methyl3-O-acetyl-11-oxo-oleanolate(z-15). The acetyl of z-15was taken off with NaOH in methanol solution to yield11-oxo-oleanolate (T-1).3.11-dioxo-oleanolate (T-2) was produced through the method that compound(T-1) was oxidized by Jone’s reagent.The structures of these compounds synthesized in this article were confirmed by spectroscopic analysis (ESI-MS, APCI-MS, HRMS,1H-NMR). The33compounds including s-2,3,5,6,8,10,11, s-13～17and L-1～22were never reported.Anti-HIV pharmacological activities of these compounds are testing in Chinese Center for Disease Control.