Synthesis of biologically relevant biflavanoids--a review

Recent investigations show that naturally occurring biflavanoids possess anti-inflammatory, anticancer, antiviral, antimicrobial, vasorelaxant, and anticlotting activities. These activities have been discovered from the small number of biflavanoid structures that have been investigated, although the natural biflavanoid library is likely to be large. Structurally, biflavanoids are polyphenolic molecules comprised of two identical or non-identical flavanoid units conjoined in a symmetrical or unsymmetrical manner through an alkyl or an alkoxy-based linker of varying length. These possibilities introduce significant structural variation in biflavanoids, which is further amplified by the positions of functional groups--hydroxy, methoxy, keto, or double bond--and stereogenic centers on the flavanoid scaffold. In combination, the class of biflavanoids represents a library of structurally diverse molecules, which remains to be fully exploited. Since the time of their discovery, several chemical approaches utilizing coupling and rearrangement strategies have been developed to synthesize biflavanoids. This review compiles these synthetic approaches into nine different methods including Ullmann coupling of halogenated flavones, biphenyl-based construction of biflavanoids, metal-catalyzed cross-coupling of flavones, Wessely-Moser rearrangements, oxidative coupling of flavones, Ullmann condensation with nucleophiles, nucleophilic substitutions for alkoxy biflavanoids, and dehydrogenation-based or hydrogenation-based synthesis. Newer, more robust synthetic approaches are necessary to realize the full potential of the structurally diverse class of biflavanoids.