RESVERATROLE CHEMISTRY AND BENEFITS, With a spectroscopy section

BYDR ANTHONY MELVIN CRASTO

A SHORT PRESENTATION FOR ACADEMICS FEB 2012

Would you like to look and feel younger and virile

Resveratrol may help to improve skin elasticity,

slow down skin aging, and rejuvinate brain cells.

As we age skin loses it's elasticity as cell renewal slows down. The production of collagen also decreases and fine lines start to appear on the skin's surface.

Drinking plenty of water can help to rehydrate the skin, but taking resveratrol may help to boost collagen production and may also help reduce the appearance of fine lines. It's a very powerful antioxidant and has been at the centre of ground breaking anti aging research.

Resveratrol is a polyphenolic phytoalexin. It is also classified as a stilbenoid, a derivate of stilbene, and is produced in plants with the help of the enzyme stilbene synthase. The levels of resveratrol found in food varies greatly. Red wine contains between 0.2 and 5.8 mg/L depending on the grape variety, while white wine has much less. The reason for this difference is that red wine is fermented with grape skins, allowing the wine to absorb the resveratrol, whereas white wine is fermented after the skin has been removed. Resveratrol is also sold as a nutritional supplement. A number of beneficial health effects, such as anti-cancer, antiviral, neuroprotective, anti-aging, anti-inflammatory and life-prolonging effects have been reported for resveratrol. The fact that resveratrol is found in the skin of red grapes and as a constituent of red wine may explain the "French paradox". This paradox is based on the observation that the incidence of coronary heart disease is relatively low in southern France despite high dietary intake of saturated fats. Resveratrol is thought to achieve these cardioprotective effects by a number of different routes: (1) Inhibition of vascular cell adhesion molecule expression; (2) Inhibition of vascular smooth muscle cell proliferation; (3) Stimulation of endolethelial nitric oxide synthase (eNOS) Activity; (4) Inhibition of platelet aggregation; and (5) Inhibition of LDL peroxidation

SYNTHESIS &PROPERTIES

Resveratrol (IUPAC: (E)-3,4’,5-trihydroxystilbene) is a the E isomer of atrans stilbene with 3 hydroxyl groups, two in the 3rd and 5th carbon of the first benzene ring and the last third on the 4th carbon on the second benzene ring.

This compound is perfectly conjugated and contains 3 h-bond donors and 3 h-bond acceptors because of the three hydroxyl groups.

Title: ResveratrolCAS Registry Number: 501-36-0CAS Name: 5-[(1E)-2-(4-hydroxyphenyl)ethenyl]-1,3-benzenediolAdditional Names: trans-resveratrol; (E)-5-(p-hydroxystyryl)resorcinol; 3,4¢,5-stilbenetriol; 3,5,4¢-trihydroxystilbeneMolecular Formula: C14H12O3Molecular Weight: 228.24Percent Composition: C 73.67%, H 5.30%, O 21.03%Literature References: Phytoalexin found in a variety of plants; active ingredient of Asian folk medicine "Kojo-Kon" which is the powdered root of the Japanese knotweed. Isoln from white hellebore and structure: M. Takaoka, J. Fac. Sci., Hokkaido Imp. Univ. Ser. 3 3, 1 (1940); C.A. 34, 7887 (1940); from fescue grass: R. G. Powell et al., Phytochemistry 35, 335 (1994). Isoln of monomers, oligomers, isomers and glucosides from wine: F. Mattivi et al., J. Agric. Food Chem. 43, 1820 (1995). GC-MS determn: D. M. Goldberg et al., J. Am. Enol. Viticult. 46, 159 (1995). Produced as stress metabolite in response to fungal infection or injury: G. H. Dai et al., Physiol. Mol. Plant Pathol. 46, 177 (1995); P. Jeandet et al., J. Phytopathol. 143, 135 (1995). Antiplatelet aggregating activity: A. A. E. Bertelli et al., Int. J. Tissue React. 17, 1 (1995); and implications in coronary heart disease: C. R. Pace-Asciak et al., Clin. Chim. Acta 235, 207 (1995).Properties: Off-white powder from MeOH, mp 253-255°.Melting point: mp 253-255°

Chen, Xin; Mei, Yicheng; Yu, Aimin; Wang, Kaiwen. Improved method for preparation of resveratrol. Faming Zhuanli Shenqing Gongkai Shuomingshu (2007), 6pp.

New Efficient Resveratrol Synthesis by Means of Heck Reaction. Adapted from M. Guiso, C. Marra, A. Farina, Tetrahedron Lett. 43 (2002) 597

Guiso et. al.[5] reports various approaches to synthesizing trans-3,4,5-trihydroxy-stilbenes (IUPAC: 5-[2-(4-hydroxyphenyl)ethenyl]benzene-1,3-diol), of which mainly a Wittig reaction was utilized to form the ethylenic bridge. Moreno-Manas et. al. reacted p-hydroxy-benzaldehyde with a phosphonium ylid derived from orcinol; only the E isomer was produced at a yield of 10%. [6] About a decade later, Orsini et. al. performed a novel synthesis via a Wittig reaction between 3,5-bis-(tertbutyldimethylsilyloxy) benzaldehyde and the phosphonium ylid obtained from (4-methoxybenzyl)-triphenyl-phosphonium chloride.[7] Unlike the previous reaction, this formed a Z/E mixture (ratio 2:3:1) of 3,4,5 trimethoxystilbenes. [7] Soon thereafter, a lithiation/condensation reaction of 4-methoxy-benzaldehyde and the silyl derivative of 3,5-dimethoxy-benzyl alcohol produced only the Z isomer at a yield of only 21%. [8] A 1999 report featured the reaction of 3,5-dimethoxy-benzaldehyde with the triethylphosphate; upon deprotection and purification yielded resveratrol at a yield of 45%. [9]

Guiso et. al. proceed to elucidate the Heck reaction as a means of producing the ethylenic bridge of resveratrol and producing only the E isomer. This approach was rather frugal concerning atom economy: 99% pure yield. 3,5-Diacetoxy-stirene was formed by a Wittig reaction between 5,5-dihydroxybenzaldehyde and a methylen-triphenyl-phosphorane solution. [5]

Guiso et. al. concisely summarizes the experiement. 3,5-Diacetoxy-stirene (90 mg) and p-acetoxy-iodobenzene (85 mg) were treated with acetonitrile (2 mL), triethyl amine (1 mL), Pd(OAc)2 (0.7 mg), and PPh3 (5.4 mg). Upon heating (85 oC, 17h) and TLC determination of the extent of reaction, the reaction mixture was frozen and acidified with 1 N HCl (20 mL). As the mixture was extracted with diethyl ether, crude 3,4’,5-Triacetoxy-stilbene was obtained from the organic ether layer; later purified silica gel. The acetyl groups were removed with catalytic sodium methoxide/anhydrous THF-MeOH. The identity of resveratrol and even the intermediates were confirmed via 1H NMR and 13C NMR.

REFERNCES AT THE END OF THIS PRESENTATION

The reaction of 3,5-dihydroxybenzaldehyde (I) with Tbdms-Cl gives the disilylated aldehyde (II), which by a Wittig condensation with methylenetriphenylphosphorane (III) yields the 3,5-dihydroxystyrene (IV). The reaction of (IV) with acetic anhydride and pyridine affords 3,5-diacetoxystyrene (V), which was submitted to a Heck condensation with 4-acetoxyiodobenzene (VI) by means of Pd(OAc)2 and PPh3 in hot acetonitrile to provide 3,4',5-triacetopxy-(E)-stilbene (VII). Finally, this compound is deacetylated by means of NaOMe in THF/methanol to furnish the target resveratrol.

• Red wine has been an important part of many rituals. It has even been called the ‘The Blood of Christ’, and as studies are continually showing the health benefits of drinking red wine, drinking ‘blood’ has never been so good.

Resveratrol can be found in the skin and seeds of grapes, blueberries and cranberries. Red wine is high in the antioxidant resveratrol and a glass a day may help to keep your heart healthy.

• With people who exercise regularly, during the process of metabolizing their food and oxygen, free radicals are released which can cause a lot of damage to existing cells in the body.

• The more exercise a person does, the more free radicals are produced.

• It has been found that antioxidants such as those found in red wine have proven to lower the rate of upper body respiratory infections which are associated with high physical workouts.

• This is done by the antioxidants combining with the free radicals and preventing the oxidative process and as a result reducing cell damage (Friel, 2004).

• Antioxidants such as those of flavonoids are found in many foods but are in very high content in red wine. However, the antioxidant that is having popular interest is that of the molecule resveratrol which is a non-flavonoid.

•In the Middle Ages, in the north and east of Europe, where little or no grapes were grown, beer and ale were the common drink of both commoners and nobility. Wine was imported to the northern regions, but was expensive, and thus only the rich could afford.

•It was a symbol of importance.

Red wine is said to have many advantages, besides the amazing flavour and aromas that come with it, but also health benefits and this is explained by the French paradox which is the idea that red wine is beneficial to human health.

In this presentation the health benefits of red wine will be fully explained.

•Wine in history was only drunk by the rich.

But over the years times have definitely changed with wine being accessible to everyone!!

Nutra-Resveratrol is a natural lab pure, powerful, broad spectrum supplement bio-available through the saliva glands, it is water soluble and may be utilized as either a stand-alone ingredient or as a complementary active ingredient in multi-vitamin/minerals, antioxidant, and gender-specific dietary supplement formulas as well as beverages and such food products as non-baked nutrition bars and cereals, confections, cosmetics and more. All ingredients are naturally occurring, lab pure and FDA Self GRAS certified

Nutra-Resveratrol Summary

spectroscopy

Complete assignment of the 1H and 13C NMR spectra of resveratrol derivativesDongsoo Koh1, Kwan Ha Park2, Jihyun Jung3, Heejung Yang3, K.Hun Mok4,Yoongho Lim3,*

Article first published online: 13 NOV 2001DOI: 10.1002/mrc.910

http://onlinelibrary.wiley.com/doi/10.1002/mrc.910/abstract

The 1HNMR spectrum of resveratrol in DMSO-d6 can be seen in figure 22. The data was: NMR 1H (d-DMSO, 300MHz) δ 9.55 (s, 1H), 9.19 (s, 2H), 7.37 (d, Jtrans=8.52 Hz, 2H), 6.95 (d, J=16.2, 1H), 6.80 (d, J=16.4 Hz, 1H), 6.73 (d, Jtrans=8.52 Hz, 2H), 6.36 (d, 2.2 Hz, 2H), 6.0 (t, J=2.2 Hz, 1H), 5.75 (s).

13C NMR (CD3COCD3) ppm: 159.3 (C3, C5), 158.1 (C4’), 140.6 (C1), 129.8 (C1’), 128.9 (Cβ), 128.5 (C2’, C6’), 126.6 (Cα), 116.2 (C3’, C5’), 105.5 (C2, C6), 102.5 (C4).

3D STRUCTURE OF RESVERATROLE

http://www.hmdb.ca/structure_viewer

• Warning• So as the health benefits of having two glasses of red

wine a day build up, what happens when the suggested amount is overlooked and excessive red wine is drunk?

• Drinking too much red wine can have a very serious effect to human health. Problems such as “high blood pressure, high triglycerides, liver damage, obesity, certain types of cancer, accidents and other problems” (Rodger Harms, 2009, para 5)occur which are obviously very problematic for human health when excessive amounts of alcohol such as red wine is drunk.

• In addition alcohol has a diuretic effect, the more alcohol that is consumed the more fluids the individual loses. This is not ideal for recovery and if an exercise regime is needed to be completed (Nancy Clark, 2008, para 11).

• Reference List

• Website

• Red wine has greater anti-inflammatory action than other alcohols, (2004). Red wine has greater anti-inflammatory action than other alcohols. Retrieved May 20, 2009 from http://www.nutraingredients.com/Research/Red-wine-has-greater-anti-inflammatory-action-than-other-alcohols

• Age-standardised rate of finished consultant episodes for operations for CHD by sex and local authority, all ages and under 75 years, 2001/06, England (Table), (2008). Tab 3.5 RSD web08: Age-standardised rate of finished consultant episodes for operations for CHD by sex and local authority, all ages and under 75 years, 2001/06, England (Table). Retrieved May 21, 2009 from http://www.heartstats.org/datapage.asp?id=744ytfytfy

• LDL and HDL Cholesterol: What's Bad and What's Good?, 2008. LDL and HDL Cholesterol: What's Bad and What's Good?. Retrieved May 20, 2009 from http://www.americanheart.org/presenter.jhtml?identifier=180

• Harms, R.W. (2009). Red wine and resveratrol: Good for your heart?. Retrieved May 22, 2009 from http://www.mayoclinic.com/health/red-wine/HB00089

• Resveratrol, (2008). Resveratrol. Retrieved May 21, 2009 from http://www.vitaminstuff.com/resveratrol.html

• Clark, N., (2008). Alcohol, Athletes, and Pressure to Drink. Retrieved May 20, 2009 from http://www.tritraining.ca/nutart5.html

• Williamson, K., Hamilton, P., (2009). Drink-driving at all-time high. Retrieved May 24, 2009 from http://www.stuff.co.nz/the-press/news/national/2434661/Drink-driving-at-all-time-high

• • Journal

• Renaud, S. (2000). From French paradox to Cretan miracle. The Lancet, 355 , 48 - 48 B

• Books

• Friel, J. (2004). The Triathlete’s Training Bible (2nd ed.). Colorado: VeloPress

References

1.E. Bråkenhielm, R. Cao, Y. The FASEB Journal. 2001, express article 10.1096 / fj.01-0028fje Cao.2.Baur J. A; Sinclair D. A. Therapeutic potential of resveratrol: the in vivo evidence. Nature, 5, 493-506. 2006.3.Siemann, E. H.;, L. L. Concentration of the phytoalexin resveratrol in wine. Am. J. Eno. Vitic. 1992, 43, 49–52.4.Sprouse, Dustin; "Synthesis of Resveratrol." 2010. Oral Roberts University Department of Biology and Chemistry.5.M. Guiso, C. Marra, A. Farina, Tetrahedron Lett. 2002, 43, 597.6.Moreno-Manas, M.; Pleixats, R. An. Quim., Ser. C 1985, 81, 157–161.7.Orsini, F.; Pelizzoni, F.; Bellini, B.; Miglierini, G. Carbohydr. Res. 1997, 301, 95–109.8.Alonso, E.; Ramon, D. J.; Yus, M. J. Org. Chem. 1997, 62, 417–421.9.Wang, M.; Jin, Y.; Ho, C. T. J. Agric. Food Chem. 1999, 47, 3974–3977.10.Liu, Jing. SYNTHESIS OF RESVERATROL AND ITS ANALOGS, PHASE-TRANSFER CATALYZED 11.ASYMMETRIC GLYCOLATE ALDOL REACTIONS, AND TOTAL SYNTHESIS OF 8,9-METHYLAMIDO-GELDANAMYCIN, 12.Brigham Young University, Department of Biochemistry and Chemsitry, 2007.

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