A New Synthesis of Stilbene Natural Product Piceatannol

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Hydroxylated (E)-stilbene natural products are widely present in nature and show a variety of biological activities including anti-inflamatory, antioxidative, lipid-lowering, radical scavenging, neuroprotection, anticarcinogenic and antiviral activities. (E)-3,3',4,5'-tetrahydroxystilbene (piceatannol, 1, Figure 1) was isolated from Rheum undulatum which has been widely used in China and Korea for the treatment of blood platelet aggregation. It was reported that 0.3 g of pure piceatannol was isolated from 1 kg of dry root of Rheum undulatum. The limited supply of piceatannol from nature has prevented the diverse characterization of its biological activities. Several syntheses of (E)-stilbene have been reported by using Wittig-Horner, Heck and Suzuki coupling reactions. However, the polyhydroxy (E)-stilbenes are difficult to prepare due to oxidizing sensitivity of the polyphenolic groups, and due to inherent difficulties of controlling trans-selectivity. We report herein the new total synthesis of piceatannol (1) in 6 steps from vanillin by using Sonogashira coupling reaction. Vanillin (2) in acetone at reflux with benzyl bromide and potassium carbonate produced 95% yield of benzylated vanillin 3 which was then reacted with trimethylsilyl diazomethane and n-buthyllithium in THF at −78 C to give ethynylbenzene 4 in 99% yield by Colvin rearrangement (Scheme 1). Sonogashira coupling of 4 with 1-iodo-3,5dimethoxybenzene by using PdCl2(PPh3)2/CuI/Et3N in DMF yielded 5 in 97% yield. Direct reduction of 5 to give (E)stilbene produced no reaction (entries 1-6) or afforded only (Z)-stilbene 7b in 80% yield by using Zn/HCl in acetonitrile (entry 7) as shown in Table 1. In order to produce (E)stilbene, 5 was reacted with bromine at −78 C and gave only the desired (E)-dibromostilbene 6 in 80% yield through the cyclic bromoniun intermediate (Scheme 2). Reductive debromination of 6 with Zn/KI/HCl in ethanol (entry 3) yielded 80% of (E)-stilbene 7a as shown in Table 2. However, LAH and n-BuLi (entries 4 and 6) in reductive debromination reaction produced only the acethylene 5 back, and t-BuLi (entry 5) gave the 1:1 mixture of 5 and 7a. Finally, dealkylation of 7a by BBr3 in methylene chloride gave piceatannol (1) in 50% yield. Polymethoxy aryl ether has been known to difficult for demethylation by using BBr3 or other reagents probably due to susceptibility for oxidation of polyphenolic substances.