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

[Image: see text] 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.