Tropane alkaloids are an important class of biologically active small molecules characterized by their 8-azabicyclo[3.2.1]octane core. Because of their numerous medicinal applications, microbial biosynthesis and a variety of chemical syntheses have been designed for individual family members. However, current approaches are not amenable to late-stage structural diversification at N8, C3, C6, or C7, positions that are critical for modulating the biological properties of these molecules. Here, we describe a general approach to the synthesis of tropane alkaloids and their analogues that relies on the construction of the 8-azabicyclo[3.2.1]octane core through aziridination of a cycloheptadiene intermediate, followed by vinyl aziridine rearrangement. Using this strategy, we synthesized six tropane alkaloids and several analogues in only 5–7 steps. Given that the tropane alkaloid scopolamine has been reported to promote structural neuroplasticity and produce antidepressant effects, we tested five tropane-containing compounds for their ability to promote dendritic spine growth in cultured cortical neurons. We found that the orientation of the C3 substituent may play a role in the psychoplastogenic effects of tropane alkaloids. Our work provides a robust platform for producing tropane analogs for future structure–activity relationship studies.

中文翻译：

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精神质体托烷生物碱的快速合成


托烷生物碱是一类重要的生物活性小分子，其特征在于其 8-氮杂双环[3.2.1]辛烷核心。由于其众多的医学应用，微生物生物合成和各种化学合成是为各个家庭成员设计的。然而，目前的方法不适合 N8、C3、C6 或 C7 的后期结构多样化，这些位置对于调节这些分子的生物特性至关重要。在这里，我们描述了托烷生物碱及其类似物的合成的一般方法，该方法依赖于通过环庚二烯中间体的氮丙啶化，然后进行乙烯基氮丙啶重排来构建8-氮杂双环[3.2.1]辛烷核心。利用这种策略，我们仅用 5-7 个步骤就合成了六种托烷生物碱和几种类似物。鉴于托烷生物碱东莨菪碱已被报道可促进结构神经可塑性并产生抗抑郁作用，我们测试了五种含托烷的化合物促进培养的皮质神经元树突棘生长的能力。我们发现 C3 取代基的方向可能在托烷生物碱的精神塑性作用中发挥作用。我们的工作为生产托烷类似物以用于未来的结构-活性关系研究提供了一个强大的平台。