Additional Insights into <i>Hypericum perforatum</i> Content: Isolation, Total Synthesis, and Absolute Configuration of Hyperbiphenyls A and B from Immunomodulatory Root Extracts

Phytochemical investigation of the root extracts of <i>Hypericum perforatum</i> led to the isolation of two biphenyl derivatives named hyperbiphenyls A and B (<b>1</b> and <b>2</b>) and four known xanthones (<b>3</b>–<b>6</b>). These structures were elucidated by spectroscopic and spectrometric methods including UV, NMR, and HRMS. The absolute configuration of the biphenyl derivatives was defined by two different approaches: biomimetic total synthesis of racemic hyperbiphenyl A followed by ¹H and ¹⁹F NMR Mosher’s esters analysis and stereoselective total synthesis of hyperbiphenyl B, permitting assignment of the <i>S</i> absolute configuration for both compounds. The bioactivity of compounds <b>1</b>–<b>6</b> toward a set of biomolecules, including major histocompatibility complex (MHC) molecules expressed on vascular endothelial cells, was measured. The results showed that the major xanthone, i.e., 5-<i>O</i>-methyl-2-deprenylrheediaxanthone B (<b>3</b>), is a potent inhibitor of MHC that efficiently reduces HLA-E, MHC-II, and MICA biomolecules on cell surfaces