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.