Anthony crasto resveratrol synthesis and benefits

1. RESVERATROLE CHEMISTRY AND
BENEFITS, With a spectroscopy
section
BY
DR ANTHONY MELVIN CRASTO
A SHORT PRESENTATION FOR
ACADEMICS
FEB 2012

2. 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.

3. 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.

4. 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

5. 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.

6. Title: Resveratrol
CAS Registry Number: 501-36-0
CAS Name: 5-[(1E)-2-(4-hydroxyphenyl)ethenyl]-1,3-benzenediol
Additional Names: trans-resveratrol; (E)-5-(p-hydroxystyryl)resorcinol; 3,4¢,5-
stilbenetriol; 3,5,4¢-trihydroxystilbene
Molecular Formula: C14H12O3
Molecular Weight: 228.24
Percent 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°

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

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

10. 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]

11. 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

13. 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.

20. • 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.

21. 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.

22. • 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.

23. • 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.

24. 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.

25. • Wine in history was only drunk by the rich.

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

27. 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

28. Nutra-Resveratrol Summary

29. spectroscopy

30. Complete assignment of the 1H and 13C NMR spectra of
resveratrol derivatives
Dongsoo Koh1,
Kwan Ha Park2,
Jihyun Jung3,
Heejung Yang3,
K.Hun Mok4,
Yoongho Lim3,*
Article first published online: 13 NOV 2001
DOI: 10.1002/mrc.910
http://onlinelibrary.wiley.com/doi/10.1002/mrc.910/abstract

34. 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).

36. 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).

38. 3D STRUCTURE OF RESVERATROLE
http://www.hmdb.ca/structure_viewer

39. • 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).

40. • 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

41. 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.

42. Join my process development group on google
http://groups.google.com/group/organic
-process-development

43. Thanks
DR ANTHONY MELVIN CRASTO Ph.D
amcrasto@gmail.com
MBILE-+91 9323115463
GLENMARK SCIENTIST , NAVIMUMBAI,
INDIA
web link
http://anthonycrasto.jimdo.com/
http://www.anthonymelvincrasto.yolasite.com/
http://www.slidestaxx.com/anthony-melvin-crasto-phd
https://sites.google.com/site/anthonycrastoorganicchemistry/sites---my-
own-on-the-net
http://anthonycrasto.wordpress.com/
http://organicchemistrysite.blogspot.com/
http://www.mendeley.com/profiles/anthony-melvin-crasto/
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