Synthesis resveratrol

It is well known that drinking wine and grape juices will reduce cardiovascular, cerebrovascular, and peripheral vascular risks due to the presence of resveratrol. As a natural antioxidant, resveratrol is able to prevent LDL oxidation, scavenge intracellular reactive oxygen species, lower the oxidative stress, and induce NO synthesis. Resveratrol modulates various aspects of cardiovascular diseases and is effective against atherosclerosis, hypertension, ischemia reperfusion injury and heart failure, and many other cardiac dysfunctions [111]. 

Along with these well-defined complexes, other protocols have been developed to directly involve imidazolinm salts with Pd sonrces and form the active catalysts in situ. One of the most popnlar consists of the nse of carbene precursors such as IMes HCl or IPr HCl with PdCOAc) or PdCdba) and a base [40]. A mixture of SIPr HCl and PdCOAc) in a 1 1 ratio was nsed for the synthesis of resveratrol analogues (MOM protected MOM = methoxymethylether) through decarbonylative Mizoroki-Heck coupling [41] (Scheme 6.9). 

Scheme 6.9 An in situ protocol applied to the synthesis of resveratrol analogues...

Andrus and Liu exploited a Pd(NHC) decarbonylative Heck coupling reaction in the total synthesis of resveratrol [59], The catalyst was formed in situ with Pd(OAc), and IPr HCl. 

This protocol could be extended to a range of different ,/i-unsaturated carbonyl compounds and either activated or deactivated aryl iodides [22], An application of related Heck chemistry to the synthesis of methylated resveratrol (3,4, 5-trihydroxy-( )-stilbene) is shown in Scheme 6.4 [23]. The phytoalexin resveratrol exhibits a variety of interesting biological and therapeutic properties, among them activity against several human cancer cell lines. Botella and Najera have shown that the trimethyl ether of resveratrol (Scheme 6.4) can be rapidly prepared by microwave-assisted Heck reaction of the appropriate aryl iodide and styrene derivatives, using the same oxime-derived palladacycle as indicated in Scheme 6.3. 

Scheme 6.4 Synthesis of resveratrol trimethyl ether via Heck arylation.

Not direct gene produa however, gene for enzyme (resveratrol synthase) catalyzing synthesis of stilbene phytoalexin in peanut has been cloned. 

Resveratrol has also been reported to offer protection against cardiovascular disease, such as coronary heart disease. The effects of resveratrol on factors implicated in the development of coronary heart disease - human platelet aggregation and the synthesis of eicosanoids (lipids) from arachidonate by platelets - were investigated and compared with the actions of other wine phenolics - catechin (1.39), epicatechin (7.18a), and quercetin (1.43) - and the antioxidants a-tocopherol (7.10a), hydroquinone and butylated hydroxytoluene. Resveratrol and quercetin demonstrated a dose-dependent inhibition of platelet aggregation, whereas the other compounds tested were inactive. Resveratrol also inhibited the synthesis of the eicosanoids in a dose-dependent manner, whereas the other phenolics were less effective of not effective at all. Removal of the alcohol from the wine did not diminish the effect on platelet aggregation (Pace-Asciak et al., 1995 Goldberg et al., 1995). 

Hain R, Bieseler B, Kindi H, Schroder G, Stocker R. 1990 Expression of a stilbene synthase gene in Nicotiana tabacum results in synthesis of the phytoalexin resveratrol. Plant Mol Biol 15 325-335. 

Kuwajerwala N, Cifuentes E, Gautam S, Menon M, Barrack ER, Reddy GP. 2002. Resveratrol induces prostate cancer cell entry into S phase and inhibits DNA synthesis. Cancer Res 62 2488-2492. 

Scheme 9 Decarbonylative Heck reaction in the synthesis of resveratrol...

Becker, J. V., Armstrong, G. O., van der Merwe, M. J., Lambrechts, M. G., Vivier, M. A., Pretoiius, 1. S. (2003) Metabolic engineering of Saccharomyces cerevisiae for the synthesis of the wine-related antioxidant resveratrol. FFMS Yeast Research, 4, 79-85. 

One of the most relevant and extensively studied stilbene is trani-resveratrol (3,5,4 -trihydroxystilbene), a phytoalexin produced by grapevines in response to fungal infection, particularly Botrytis cinerea. Synthesis of resveratrol in grape berries is mainly located in the skin cells and is absent or low in the fruit flesh. In nature, resveratrol exists in two isomeric forms (cis- and frani -conflgured) in the free as well as in 6-glucoconjugated form. The 3-0-6-D-glucosides of cis- and trans-resveratrol cis-and trans-conflgured are called piceids. The chemical structures of resveratrol and further stilbenes are depicted in Fig. 9C.6. 

Ragione, F.D., Cucciolla, A., Borriello, A., Pietra, V.D., Raciioppi, L., Soldati, G., Manna, C., Galletti, R, and Zappia, V, Resveratrol arrests the cell division cycle at S/G2 phase transition, Biochem. Biophys. Res. Comm., 250, 53-58, 1998. Kuwajerwala, N., Cifuentes, E., Gautam, S., Menon, M., Barrack, E.R., and Reddy, G.P.V., Resveratrol induces prostate cancer cell entry into S phase and inhibits DNA synthesis. Cancer Res. 62, 2488-2492, 2002. 

The synthesis of /raw5-resveratrol oligomers requires the set of enzymes that yield trows-resveratrol from the phenylpropanoid precursor, p-coumaryl-CoA and malonyl-CoA, and then the oxidative coupling of resveratrol units by a phenol oxidase, which is presumably a class HI plant peroxidase [138,139], In fact, class HI plant peroxidases, such as that purified from grapevines, are able to oxidize frvms-resveratrol with values of 17-93 pM for H2O2 concentrations ranging from 0.1 to 5.0 mM at pH 4.0 [58], and with values of 11.9 pM" s, at the same pH [35,58]. 

Both (Mp + Mco) (Scheme XVII) and (Mp + Mc2) (Scheme XX) coupling modes in the synthesis of resveratrol oligomers are totally compatible with the nature of the peroxidase-catalyzed reaction. The reasons why the above coupling modes are favored in vivo (to permit the formation of s-viniferin), whereas the (Mp + Mo4 ) coupling mode (Scheme XVI) is favoured in vitro, is a question which deserves further research. 

Since resveratrol (1) and its derivatives have manifested remarkable bioactivities, a series of methodologies have been developed for then-synthesis. The main ones are as follows ... 

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