4.6 Article

A convenient biomimetic synthesis of optically active putative neurotoxic metabolites of MDMA (ecstasy) from R-(-)- and S-(+)-N-methyl-α-methyldopamine precursors

期刊

ORGANIC & BIOMOLECULAR CHEMISTRY
卷 10, 期 18, 页码 3739-3748

出版社

ROYAL SOC CHEMISTRY
DOI: 10.1039/c2ob25245g

关键词

-

资金

  1. Mission Interministerielle de Lutte contre la Drogue et la Toxicomanie (MILDT)
  2. Institut National de la Sante et de la Recherche Medicale (INSERM)
  3. French MRT

向作者/读者索取更多资源

(+/-)-3,4-Methylenedioxymethamphetamine (MDMA, also known as ecstasy) is a psychoactive drug with selective neurotoxic potential toward brain serotonin (5-HT) neurons. One hypothesis holds that MDMA neurotoxicity may at least partially be a consequence of its metabolism. In most species (including primates), O-demethylenated MDMA metabolites such as N-methyl-alpha-methyldopamine (HHMA) have been postulated to serve as precursors for toxic thioether conjugates. As yet, chirality of MDMA was not considered in previously reported in vivo studies because HHMAwas used as the racemate. Since the stereochemistry of this chiral drug needs to be considered, the total synthesis of enantiomerically pure precursors, R-(-)-HHMA and S-(+)-HHMA, was envisioned with the ultimate goal to prepare substantial amounts of optically active thioether conjugates. Recently, we reported the first total synthesis of the R-enantiomer. In this paper, a novel synthesis of the S-enantiomer is described, in 45% overall yield (six steps) and 99% ee, using commercially available L-Boc-alanine (99% ee) as the chiral source. Having at our disposal suitable amounts of R-(-)-HHMA and S-(+)-HHMA precursors, a straightforward one-pot electrochemical procedure has been further developed for the synthesis of several catechol-thioether conjugates in acceptable yields (40-53%) and high degree of purity (99%), with complete diastereoselectivity. The availability of these newly synthesized optically active catechol-thioether conjugates is crucial for ongoing future in vivo studies about their role in MDMA neurotoxicity.

作者

我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。

评论

主要评分

4.6
评分不足

次要评分

新颖性
-
重要性
-
科学严谨性
-
评价这篇论文

推荐

暂无数据
暂无数据