Regioselective reactions for programmable resveratrol oligomer synthesis

• Published in: Nature (London) Vol. 474; no. 7352; pp. 461 - 466
• Main Authors: Snyder, Scott A., Gollner, Andreas, Chiriac, Maria I.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 22.06.2011; Nature Publishing Group
• Subjects: 639/638/403/934; 639/638/549; Biochemistry; Biological Products - biosynthesis; Biological Products - chemical synthesis; Biological Products - chemistry; Bromine - chemistry; Cardiovascular diseases; Chemical properties; Chemical reactions; Chemical reactivity; Chemical research; Chemical synthesis; Chemistry; Chemistry, Pharmaceutical - methods; Diets; Exact sciences and technology; Flavonoids - chemistry; Halogenation; Health aspects; Heart diseases; Humanities and Social Sciences; Indicators and Reagents - chemistry; Isomerism; Mass spectrometry; Materials selection; Methods; multidisciplinary; Natural products; Noncondensed benzenic compounds; Observations; Oligomers; Organic chemistry; Phenols - chemistry; Polycyclic Compounds - chemistry; Polyphenols; Preparations and properties; Production processes; Reactivity and mechanisms; Resveratrol; Science; Science (multidisciplinary); Stilbenes - chemical synthesis; Stilbenes - chemistry; Stilbenes - metabolism; Structure; Substrate Specificity; Synthesis; Terpenes - chemistry; United States; Heart; Chemical reagent; Regioselectivity; Biosynthesis; Selectivity; Natural compound; Saturated fat; Oligomer; Biological activity; Stilbene derivatives; Plant; Polyphenol; Functionalization; Phytoalexin; Heart disease; Plant origin; Resveratrol; Phenols; Benzenic compound; Chemical reactivity; Chemical synthesis
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature10197

Although much attention has been devoted to resveratrol, a unique polyphenol produced by plants and credited as potentially being responsible for the ‘French paradox’—the observation that French people have a relatively low incidence of coronary heart disease, even though their diet is high in saturated fats—the oligomers of resveratrol have been largely ignored despite their high biological activity. Challenges in achieving their isolation in sufficient quantity from natural sources, coupled with an inability to prepare them easily synthetically, are seen as the main obstacles. Here we report a programmable, controlled and potentially scalable synthesis of the resveratrol family via a three-stage design. The synthetic approach requires strategy- and reagent-guided chemical functionalizations to differentiate two distinct cores possessing multiple sites with the same or similar reactivity, ultimately leading to five higher-order natural products. This work demonstrates that challenging, positionally selective functionalizations of complex materials are possible where biosynthetic studies have indicated otherwise, it provides materials and tools with which to unlock the full biochemical potential of this family of natural products, and it affords an intellectual framework within which other oligomeric families could potentially be accessed. Resveratrol oligomers succumb to synthesis The natural plant defence molecule resveratrol has captured the public imagination thanks to its various beneficial effects in mice and its presence in red wine. But it may be the resveratrol oligomers that have more long-term potential as pharmaceuticals. They occur naturally and have a broad range of potent biological activities, but their complexity makes rational synthesis of new drug candidates very challenging. Snyder et al . now present a new three-stage strategy that should improve matters: it is programmable, controlled and potentially scalable. Similar principles should be transferable to other oligomeric families.