Efficient syntheses of permethylated derivatives of neolamellarin A, a pyrrolic marine natural product

Abstract

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-BuLi/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.