Biomimetic Synthesis of Chejuenolides A–C by a Cryptic Lactone-Based Macrocyclization: Stereochemical Implications in Biosynthesis

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.

本研究以chejuenolides A–C（济州内酯A–C）生物合成中的假想曼尼希大环化反应（Mannich macrocyclization）为合成设计依据。通过经策略性羟醛反应-Julia烯化反应-羟醛反应（aldol–Julia–aldol reactions）序列构建的克级规模内酯型线性前体，本研究首次成功实现了济州内酯A–C的仿生全合成与结构确证。大环化加合物中的β-氧代-δ-内酯单元（β-oxo-δ-lactone unit）性质不稳定，可通过脱羧质子化途径转化为一系列C2/C18位非对映异构体。对生物合成前体O3P2的立体化学鉴定证实，其结构与所获得的大环化合物及此前已阐明的兰卡菌素（lankacidins）相符。此外，为大环化过程设计的线性前体立体变体表明，通过复苏丢失或不稳定的中间体，该仿生方法在确定所提出的酶促反应的立体选择性方面具有无与伦比的作用。