Efficient Syntheses of Permethylated Derivatives of Neolamellarin A,a Pyrrolic Marine Natural Product  

作　　者：YIN Ruijuan JIANG Long WAN Shengbiao JIANG Tao 

机构地区：[1]Key Laboratory of Marine Drugs of Ministry of Education of China, School of Pharmacy, Ocean University of China

出　　处：《Journal of Ocean University of China》2015年第2期329-334,共6页中国海洋大学学报（英文版）

基　　金：supported by the National Natural Science Foundation of China (21171154 and 91129706);Special Fund for Marine Scientific Research in the Public Interest (01005024)

摘　　要：The pyrrole-derived alkaloids with marine origin, especially their permethyl derivatives, have unique structures and promising biological activities. Marine natural product neolamellarins are a collection of lamellarin-like phenolic pyrrole compounds, which can inhibit hypoxia-induced HIF-1 activation. Many pyrrole-derived lamellarin-like alkaloids show potent MDR reversing activity. In this study, five permethylated derivatives of neolamellarin A were synthesized with their MDR reversing activity studied in order to identify new MDR reversal agents. A convergent strategy was adopted to synthesize the permethylated derivatives of neolamellarin A. Pyrrole was first converted into a corresponding N-trisisopropylsilyl （TIPS）-substituted derivative, then through iodination afforded 3,4-diiodinated pyrrole compound. The key intermediate, 3,4-disubstituent-lH-pyrrole, was obtained through desilylation of 3,4-disubstituent-l-TIPS pyrrole, which was prepared from 3,4-diiodinated pyrrole derivative and aryl boronic acid ester through Suzuki cross-coupling reaction between them. Then, the intermediate, 3,4-disubstituent-lH-pyrrole, reacted with fresh phenylacetyl chloride under n-BuLi/THF condition afforded the target compounds. Finally, we obtained five novel pyrrolic com- pounds, permethylated derivatives ofneolamellarin A 16a-e, in 30%-37% yield through five step reactions. The bioactivity testing of these compounds are in process.The pyrrole-derived alkaloids with marine origin, especially their permethyl derivatives, have unique structures and promising biological activities. Marine natural product neolamellarins are a collection of lamellarin-like phenolic pyrrole compounds, which can inhibit hypoxia-induced HIF-1 activation. Many pyrrole-derived lamellarin-like alkaloids show potent MDR reversing activity. In this study, five permethylated derivatives of neolamellarin A were synthesized with their MDR reversing activity studied in order to identify new MDR reversal agents. A convergent strategy was adopted to synthesize the permethylated derivatives of neolamellarin A. Pyrrole was first converted into a corresponding N-trisisopropylsilyl(TIPS)-substituted derivative, then through iodination afforded 3,4-diiodinated pyrrole compound. The key intermediate, 3,4-disubstituent-1H-pyrrole, was obtained through desilylation of 3,4-disubstituent-1-TIPS pyrrole, which was prepared from 3,4-diiodinated pyrrole derivative and aryl boronic acid ester through Suzuki cross-coupling reaction between them. Then, the intermediate, 3,4-disubstituent-1H-pyrrole, reacted with fresh phenylacetyl chloride under n-Bu Li/THF condition afforded the target compounds. Finally, we obtained five novel pyrrolic compounds, permethylated derivatives of neolamellarin A 16a-e, in 30%–37% yield through five step reactions. The bioactivity testing of these compounds are in process.

关 键 词：neolamellarin A DERIVATIVE SYNTHESIS Suzuki-Miyaura cross-coupling reaction ACYLATION 

分 类 号：TQ464[化学工程—制药化工]