School of Chemistry, University of Bristol, Cantock's Close, Bristol BS8 1TS, UK.
Nature. 2017 Jul 26;547(7664):436-440. doi: 10.1038/nature23265.
Small-molecule, biologically active natural products continue to be our most rewarding source of, and inspiration for, new medicines. 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. 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, 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.
小分子、生物活性天然产物仍然是我们获得新药的最有价值的来源和灵感。有时，我们会在独特、难以到达且往往转瞬即逝的环境中偶然发现这些分子，而且可能再也找不到了。在这种情况下，确定分子的结构，包括其相对和绝对构型，至关重要，这使我们能够理解其生物活性。包含立体化学复杂的无环和构象灵活的碳链的分子使得这样的任务极具挑战性。巴劳霉素 (A 和 B) 就是一个当代的例子。这些分子的结构通过基于 J 的构型分析来确定，但由于其构象灵活，数量稀少且具有有前景的抗菌活性，因此被证明是不正确的。我们随后开展的确定巴劳霉素真实结构的活动揭示了一种快速阐明此类分子结构的有效方法。具体来说，通过密度泛函理论预测核磁共振 (NMR) 参数——结合一系列高效的基于硼的合成转化，这使得可以制备编码（标记）的天然产物非对映异构体混合物——使我们能够快速确定并合成正确的结构。
