Temperature‐Controlled Stereodivergent Synthesis of 2,2′‐Biflavanones Promoted by Samarium Diiodide

Abstract

In this work,t he first exampleo faradical stereodivergent reactiond irected towardst he stereoselective synthesis of both (R*,R*)-and (R*,S*)-2,2'-biflavanones promoted by samarium diiodide is reported. Control experiments showedt hat the selectivity of this reaction was exclusively controlled by the temperature. It was possible to generate av ariety of 2,2'-biflavanones bearing different substitution patterns at the aromatic ring in good-toquantitative yields, being both stereoisomerso ft he desired compounds obtained with total or high control of selectivity.Amechanismt hat explains both the generation of the corresponding 2,2'-biflavanones and the selectivity is also discussed. The structure ands tereochemistry determination of each isomer was unequivocally elucidatedb y single-crystal X-ray diffraction experiments.Flavonoid-derivedc ompounds are gainingi ncreasinga ttention owing to their interesting biological activity,i ncluding their anticarcinogenic, antifungal, antiviral,a ntibacterial,a ntimicrobial, antioxidant, anxiolytic and anti-inflammatory properties. For this reason, several methodsd irected towards the stereoselective synthesis of flavonoid-related compounds, includingb iflavonoids, have been recently published. [1] Despite the large number of biflavonoids that are suggestedt oe xist in nature, only ac ouple of dozen naturalb iflavonoidsh ave been explored for biological activity studies. In this respect, it has also been shown that, in general terms, the dimerization of flavonoid units is av aluable protocol for the synthesis of biflavonoids, being the bioactivity of these compounds remarkably increased when compared with that shown by the flavonoid monomer. [2] For all these reasons, the developmento fn ew stereoselectives ynthetic proceduresa imed the synthesis of bifla-vonoidsa re of great interesti no rganic synthesis. Moreover,a s part of an ongoing project on the synthesis and biological evaluation of phenolic compounds, we became also interested in the efficient preparation of 2,2'-biflavonoids. For this purpose,w ee nvisioned the reductive coupling of 4-oxo-4H-1-benzopyrans,t hrough their 2-positions,b ym eans of samarium diiodideasasingle-electron transfer (SET) reagent.Samarium diiodide [3] is unique when compared with other SET reagents given its well-known high versatility in providing different radicals in organic synthesis.I nfact, the use of samarium diiodide has been widely covered in the literature in different reductivep rocesses, [4] including homo-or heterocoupling reactions. [5] Our group has accumulated aw idee xperience in the use of samarium diiodidei nb oth ionic and radicalr eactions,i ncluding its application in 1,2-elimination processes, [6] cyclopropanation reactions [7] reduction of multiple bonds [8] and the stereoselective synthesis of compounds of high value derived from naturalp roducts such as carbohydrates [9] or aaminoa cids. [10] Encouraged by the pharmacological interest in biflavonoids, [1f] hereinw er eport the use of different easily availablef l...

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