The Laurencia Stereochemical Paradox: Chemical Shift Litmus Test, Asymmetric Total Synthesis, and Structural Reassignment of (+)-Itomanallene B

Red algae of the genus Laurencia are prolific sources of halogenated C₁₅-acetogenins, many of which contain a tetrahydrofuran (THF) ring and a bromoallene terminus. Among them, Itomanallene B-type metabolites have presented a stereochemical paradox, as <i>Laurencia intricata</i> and <i>Laurencia nangii</i> yield epimeric structures despite sharing the same planar connectivity. In this study, we demonstrate that the chemical shift of the diagnostic C-4 proton provides a rapid and reliable indicator of the relative orientation (α,α'-<i>syn</i> vs α,α'-<i>anti</i>) of the THF side chains. Comparative analysis of reported NMR data reveals that <i>anti</i> configurations exhibit systematically more deshielded C-4 proton resonances than their <i>syn</i> counterparts. Applying this "chemical-shift litmus test" shows that Itomanallene B <b>1</b> from <i>L. intricata</i> possesses an α,α'-<i>anti</i> arrangement, whereas the metabolite previously reported as Itomanallene B <b>3</b> from <i>L. nangii</i> is instead the α,α'-<i>syn</i> epimer, 4-epi-Itomanallene B. This reassignment was unambiguously confirmed through the total asymmetric synthesis of the (a<i>S</i>,4<i>S</i>,6<i>R</i>,7<i>R</i>) stereoisomer of (+)-Itomanallene B, whose NMR data matched those of the natural product. The simplicity and diagnostic power of the C-4 proton chemical-shift approach provide an efficient tool for the stereochemical assignment of THF-containing C₁₅-acetogenins, addressing a recurrent source of structural misinterpretation within the <i>Laurencia genus</i>.