美国耶鲁大学Seth B. Herzon研究组近日在截短侧耳素类抗生素的全合成中取得了新进展。相关论文发表在2022年9月26日出版的《自然—化学》杂志上。

在该研究中，研究人员开发了一个实现截短侧耳素全合成的平台，可合成在以前无法改造的骨架和周围位点具有各种不同修饰的多样化衍生物。该合成是由偶然发现的插烯Wolff重排实现的，该重排有助于在目标化合物中建立C9的季碳中心，以及α-季碳醛的高度非对映选择性的丁炔化，以形成C14仲醇。通过合成17个结构不同的衍生物，研究者证明了该路线的多功能性，这些衍生物许多具有强大的抗菌活性。

研究人员介绍，耐药细菌病原体的出现使新型抗菌药物的化学全合成重新受到重视。四环素、大环内酯、链霉素和林可酰胺现在都可以通过灵活和通用的合成途径获得。然而，截短侧耳素（一种基于真菌代谢物的抗生素）此前尚无法通过化学全合成获得，这在很大程度上是由于在十氢-3a,9-丙基环戊[8]轮烯骨架的从头构建中遇到的困难。

附：英文原文

Title: Total synthesis of structurally diverse pleuromutilin antibiotics

Author: Goethe, Olivia, DiBello, Mikaela, Herzon, Seth B.

Issue&Volume: 2022-09-26

Abstract: The emergence of drug-resistant bacterial pathogens has placed renewed emphasis on the total chemical synthesis of novel antibacterials. Tetracyclines, macrolides, streptogramins and lincosamides are now accessible through flexible and general synthetic routes. Pleuromutilins (antibiotics based on the fungal metabolite pleuromutilin) have remained resistant to this approach, in large part due to the difficulties encountered in the de novo construction of the decahydro-3a,9-propanocyclopenta[8]annulene skeleton. Here we present a platform for the total synthesis of pleuromutilins that provides access to diverse derivatives bearing alterations at previously inaccessible skeletal and peripheral positions. The synthesis is enabled by the serendipitous discovery of a vinylogous Wolff rearrangement, which serves to establish the C9 quaternary centre in the targets, and the development of a highly diastereoselective butynylation of an α-quaternary aldehyde, which forms the C14 secondary alcohol. The versatility of the route is demonstrated through the synthesis of seventeen structurally distinct derivatives, with many possessing potent antibacterial activity.

DOI: 10.1038/s41557-022-01027-7

Source: https://www.nature.com/articles/s41557-022-01027-7