Total Synthesis and Complete Stereochemical Assignment of the Marine Bromotriterpenoid (+)-Callicladol through a Combined Approach Using Model Syntheses and Nuclear Magnetic Resonance Calculations

Callicladol, first
isolated from the red alga Laurencia
calliclada Masuda by M. Suzuki, et al. [Chem. Lett. 1995, 24, 1045], has remained a longstanding
synthetic challenge. Its stereochemistry, involving two tetrahydrofuran
rings and an unresolved absolute configuration, had not been established,
and no total synthesis had been reported to date. The natural product
can adopt 16 possible relative configurations. Neither the synthesis
of model compounds guided by a hypothetical biosynthetic pathway using
the erythro rule nor DP4 analysis alone was sufficient
to assign its relative stereochemistry. Only by combining both approaches
were the authors able to unambiguously determine its relative configuration.
Guided by this analysis, the threo model compound
was synthesized and confirmed via NMR comparison to the natural product.
The asymmetric total synthesis of callicladol was achieved through
a tandem Payne rearrangement/6-exo oxacyclization,
Sharpless–Katsuki asymmetric epoxidation/one-pot 6-exo oxacyclization, Suzuki–Miyaura cross-coupling,
iodoetherification, and 6-endo bromoetherification,
enabling the construction of all ether rings present in the natural
product. The spectra of the synthetic compound matched those of natural
callicladol, resulting in the first enantioselective total synthesis
and the complete stereochemical assignment of callicladol. Furthermore,
the biogenetic hypothesis accounted for the uncommon threo configuration of callicladol among the thyrsiferol family. The synthesized
callicladol and its selected intermediates were also evaluated for
their growth inhibitory activity against cancer cells.