Parr Brendan T, Economou Christos, Herzon Seth B
Department of Chemistry, Yale University, New Haven, Connecticut 06520, USA.
Nature. 2015 Sep 24;525(7570):507-10. doi: 10.1038/nature14902. Epub 2015 Sep 16.
Alkaloids, secondary metabolites that contain basic nitrogen atoms, are some of the most well-known biologically active natural products in chemistry and medicine. Although efficient laboratory synthesis of alkaloids would enable the study and optimization of their biological properties, their preparation is often complicated by the basicity and nucleophilicity of nitrogen, its susceptibility to oxidation, and its ability to alter reaction outcomes in unexpected ways--for example, through stereochemical instability and neighbouring group participation. Efforts to address these issues have led to the invention of a large number of protecting groups that temper the reactivity of nitrogen; however, the use of protecting groups typically introduces additional steps and obstacles into the synthetic route. Alternatively, the use of aromatic nitrogen heterocycles as synthetic precursors can attenuate the reactivity of nitrogen and streamline synthetic strategies. Here we use such an approach to achieve a synthesis of the complex anti-HIV alkaloid (+)-batzelladine B in nine steps (longest linear sequence) from simple pyrrole-based starting materials. The route uses several key transformations that would be challenging or impossible to implement using saturated nitrogen heterocycles and highlights some of the advantages of beginning with aromatic reagents.
生物碱是一类含有碱性氮原子的次生代谢产物，是化学和医学领域中一些最为人熟知的具有生物活性的天然产物。尽管通过高效的实验室合成方法能够对生物碱的生物学特性进行研究和优化，但其制备过程常常因氮原子的碱性和亲核性、易氧化性以及以意想不到的方式改变反应结果的能力（例如，通过立体化学不稳定性和邻基参与）而变得复杂。为解决这些问题所做的努力催生了大量用于降低氮原子反应活性的保护基；然而，保护基的使用通常会给合成路线引入额外的步骤和障碍。另外，使用芳香族氮杂环作为合成前体可以减弱氮原子的反应活性并简化合成策略。在此，我们采用这样一种方法，以简单的吡咯基起始原料，经九步反应（最长线性序列）实现了复杂的抗HIV生物碱（+）-巴泽拉汀B的合成。该路线采用了几个关键转化反应，而这些反应若使用饱和氮杂环来实施将会具有挑战性或无法实现，并且突出了以芳香族试剂为起始原料的一些优势。
