Synergy of synthesis, computation and NMR reveals correct baulamycin structures
Synergy of synthesis, computation and NMR reveals correct baulamycin structures
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DOI：
10.1038/nature23265
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发表时间：
2017-07-27
期刊：
影响因子：
64.8
通讯作者：
Aggarwal, Varinder K.
中科院分区：
文献类型：
--
作者：
Wu, Jingjing;Lorenzo, Paula;Aggarwal, Varinder K.
小分子的、具有生物活性的天然产物仍然是我们最有价值的新药物的来源和灵感(1)。有时，我们在独特的、难以到达的、往往转瞬即逝的环境中偶然发现了微量的这种分子，也许永远不会再被发现。在这些情况下，确定一个分子的结构——包括分配它的相对构型和绝对构型——是至关重要的，使人们能够了解它的生物活性。包含立体化学复杂的无环和构象柔性碳链的分子使这项任务极具挑战性(2)。鲍拉霉素（A和B）就是一个当代的例子。少量分离并显示出有希望的抗菌活性，构象柔性分子的结构主要是通过基于j的构型分析确定的（3,4），但已被发现是不正确的。我们随后的运动，以确定鲍拉霉素的真实结构，揭示了一个强大的方法，快速结构阐明这类分子。具体地说，通过密度泛函理论预测核磁共振（NMR）参数，结合硼基合成转化的有效序列，可以制备编码（标记）的天然产物非对映体混合物，使我们能够快速确定和合成正确的结构。
Small-molecule, biologically active natural products continue to be our most rewarding source of, and inspiration for, new medicines(1). Sometimes we happen upon such molecules in minute quantities in unique, difficult-to-reach, and often fleeting environments, perhaps never to be discovered again. In these cases, determining the structure of a molecule-including assigning its relative and absolute configurations-is paramount, enabling one to understand its biological activity. Molecules that comprise stereochemically complex acyclic and conformationally flexible carbon chains make such a task extremely challenging(2). The baulamycins (A and B) serve as a contemporary example. Isolated in small quantities and shown to have promising antimicrobial activity, the structure of the conformationally flexible molecules was determined largely through J-based configurational analysis(3,4), but has been found to be incorrect. Our subsequent campaign to identify the true structures of the baulamycins has revealed a powerful method for the rapid structural elucidation of such molecules. Specifically, the prediction of nuclear magnetic resonance (NMR) parameters through density functional theory-combined with an efficient sequence of boron-based synthetic transformations, which allowed an encoded (labelled) mixture of natural-product diastereomers to be prepared-enabled us rapidly to pinpoint and synthesize the correct structures.