High Regioselective Synthesis Of Non-natural Lamellarin O

Lamellarins and its derivatives are a group of pyrrole alkaloids which were isolated from marine molluscs with high biological activities.To date,more than 40 species have been found.Some lamellarins exhibit a wide array of interesting and significant biological activities.Many of the naturally-occurring lamellarins have been isolated in a very small amount and for this reason,their synthetic research is significant.We performed a sturcture modification to lamellerin O to discover the potential new drugs.The key to synthesize lamellarins is the construction of pentacyclic pyrroly core with different substitued group.A route was found to synthesize the modification of lamellerin O. We introduced N,N-dimethyl sulfonamide as the protecting group of 3,4-disubstituted-1H-pyrroles which is conducive to the introduction of theα-methoxycarbonyl group.Aromatic ring was introduced to the pyrrole by high regioselective ipso iodination and Suzuki reaction due to the high regioselective substitution of trimethylsilyl group at the 3,4-position of pyrrole after methyl esterification.After using TBAF as the deprotection reagent,we synthesized fourteen unreported polysubstituded pyrroles in all which structures were confirmed by MS and NMR.Some important intermediates have been involved.We also found some interesting results.Frist,when the methyl group was introduced,N-substitued pyrrole andα-substitued pyrrole was obtainted with the ratio of 7:1.Second,when n-BuLi was emplored,we found the position to be lithiated of pyrrole was related to the temperature.N-H was deprived by Li⁺at -78℃andα-H was deprived under higher temperature.Third,when the AgCO₂CF₃ and iodine was used for the second iodination,the iodination happened at H atom of trimethoxyphenyl rather than the trimethylsilyl.The iodination went smoothly in the presence of ICl,and the yield was up to 80%.