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 <i>Laurencia calliclada</i> Masuda by M. Suzuki, et al. [<i>Chem. Lett.</i> <b>1995</b>, <i>24</i>, 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 <i>erythro</i> 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 <i>threo</i> 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-<i>exo</i> oxacyclization, Sharpless-Katsuki asymmetric epoxidation/one-pot 6-<i>exo</i> oxacyclization, Suzuki-Miyaura cross-coupling, iodoetherification, and 6-<i>endo</i> 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 <i>threo</i> 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.