Zhang Bingbing, Zheng Kuan, Hong Ran
CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, PR China.
University of Chinese Academy of Sciences, Beijing 100049, PR China.
ACS Cent Sci. 2023 Jan 4;9(1):84-92. doi: 10.1021/acscentsci.2c01096. eCollection 2023 Jan 25.
A hypothetical Mannich macrocyclization in the biosynthesis of chejuenolides A-C served as the basis for the synthetic design herein. Using a lactone-based linear precursor constructed via a tactic sequence of aldol-Julia-aldol reactions on a gram scale, the biomimetic total synthesis and structural validation of chejuenolides A-C were successfully achieved for the first time. The β-oxo-δ-lactone unit in the macrocyclized adducts was fragile and readily converted to a series of C2/C18-diastereoisomers via a decarboxylation and protonation pathway. Stereochemical identification of the biosynthetic precursor (O3P2) confirmed structural adherence to the given macrocycles and previously clarified lankacidins. Moreover, the stereovariants of the linear precursor designed for the macrocyclization event highlighted the unparalleled impact of using this biomimetic approach to determine the stereoselectivity in the proposed enzymatic reaction by reviving the lost or unstable intermediate.
在济州内酯A - C生物合成中一种假设的曼尼希大环化反应为本研究的合成设计提供了基础。通过在克级规模上进行羟醛 - 朱利亚 - 羟醛反应的策略性序列构建基于内酯的线性前体，首次成功实现了济州内酯A - C的仿生全合成及结构验证。大环化加合物中的β - 氧代 - δ - 内酯单元很不稳定，通过脱羧和质子化途径很容易转化为一系列C2/C18 - 非对映异构体。对生物合成前体（O3P2）的立体化学鉴定证实了其结构与给定大环以及先前阐明的兰卡杀菌素相符。此外，为大环化反应设计的线性前体的立体变体突出了使用这种仿生方法的独特影响，即通过复活丢失或不稳定的中间体来确定所提出的酶促反应中的立体选择性。
