New scalable and eco-friendly synthesis of gingerols

Article abstract of DOI:10.1016/j.tetlet.2012.03.092

Synthesis of 6-gingerol and its congeners 7- and 9-gingerols has been achieved from eugenol by a new scalable and eco-friendly protocol. The key steps are functionalization of eugenol to the nitro compound and its reaction under optimized condition with terminal alkenes to afford intermediate isoxazolines. The latter on catalytic hydrogenation in presence of Raney nickel afford corresponding gingerols in good yields.

Full text of DOI:10.1016/j.tetlet.2012.03.092

Tetrahedron Letters 53 (2012) 2993–2995
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Tetrahedron Letters
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New scalable and eco-friendly synthesis of gingerols
⇑
N. Vijendra Kumar, P. Srinivas, B.K. Bettadaiah
Plantation Products, Spices and Flavour Technology Department, Central Food Technological Research Institute, Council of Scientific and Industrial Research, Mysore 570 020, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Synthesis of 6-gingerol and its congeners 7- and 9-gingerols has been achieved from eugenol by a new
scalable and eco-friendly protocol. The key steps are functionalization of eugenol to the nitro compound
and its reaction under optimized condition with terminal alkenes to afford intermediate isoxazolines. The
latter on catalytic hydrogenation in presence of Raney nickel afford corresponding gingerols in good
yields.
Received 3 February 2012
Revised 21 March 2012
Accepted 22 March 2012
Available online 29 March 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
6-Gingerol
Eugenol
Hydroboration
Eugenyl iodide
Isoxazolines
Olefins
Reduction
Ginger (Zingiber officinale Roscoe) is used in food as a spice and
has been an important ingredient in Ayurvedic, Tibb-Unani and
Chinese herbal medicines for the treatment of various ailments like
catarrh, rheumatism, gingivitis, toothache, asthma, stroke, consti-
pation, and diabetes.1 6-Gingerol is the key phenolic compound
of rhizomes of ginger and responsible for the flavor, pungency,
and bio-active attributes like antioxidant,2 anti-inflammatory,3
anti-tumor-promoting,4 anti-platelet aggregation,5 and anti-
bacterial effects.6 As it is present in the rhizomes in a complex mix-
ture of homologues along with other components, its isolation and
purification is difficult. Hence, commercial availability of 6-
gingerol is low and it is highly expensive. In spite of broad and
interesting bioactivities associated with gingerol and its structural
simplicity, only a few synthetic methods have been reported.7,8
Due to its attractive medicinal properties, synthetic methods with
experimental simplicity would be valuable additions when com-
pared to the existing methods, which are either not easily amena-
ble or involving severe experimental conditions, for example, a
protocol involving the condensation of lithium-enolate with 1-
alkanals at À78 °C affords good yield but not easily reproducible.9
Hence, a simple eco-friendly and scalable protocol with the use of
inexpensive starting materials is envisioned in this work. Eugenol
(1), a major phenolic constituent of clove bud essential oil, is used
as starting compound to synthesize 6-gingerol and its higher
homologues.10 Eugenol is widely available, inexpensive and has
4-homoallyl, o-methoxy-substituted phenolic moiety. Structurally,
eugenol is an ideal substrate for the synthesis of gingerols. To our
knowledge this is the first report of synthesis of gingerols starting
from eugenol.
In the synthesis (Scheme 1), phenolic group in eugenol was first
protected as benzyl ether and then converted into eugenyl iodide
(2) by hydroboration followed by iodination.11 This was performed
by addition of iodine to double bond of eugenol via hydroboration
reaction using sodium borohydride and sodium methoxide, which
resulted in anti-Markovnikov’s addition of iodine across the double
bond. Compound 2 was then converted into nitro compound (3) in
water using sodium nitrite and silver nitrate. In the presence of so-
dium nitrite alone, 3 was obtained in low yield as the corresponding
nitrite was competing.12 This was overcome when the reaction was
performed under optimized reaction conditions, wherein silver ni-
trate and sodium nitrite were used in three and four equivalents
respectively to afford good yield of product.13 The compound 3
was then converted into isoxazoline (4) by reaction with 1-heptene
in presence of base triethylamine and acetic anhydride in 40%
yield.14 A few exploratory experiments at this stage were conducted
to improve the yield of isoxazoline. Under the optimized conditions
that employed acetic anhydride (3 equiv) and 4-(dimethyl-
amino)pyridine (1.5 equiv), isoxazoline could be obtained in 60%
yield.15 The experiment on higher scale (1.5 g) also afforded the ni-
tro compound 4 in 60% yield. The isoxazoline, thus prepared was
subjected to reduction using hydrogen at 30 psi in the presence of
Raney nickel in moist ethanol to afford b-hydroxy carbonyl com-
pound. Further, it was filtered and taken directly for benzyl de-pro-
tection of phenolic group by hydrogenolysis at 30 psi pressure in
⇑
Corresponding author.
E-mail address: bettadaiah@cftri.res.in (B.K. Bettadaiah).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.03.092

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N. Vijendra Kumar et al. / Tetrahedron Letters 53 (2012) 2993–2995
O
O
O
I
NO2
a,b
c
HO
BnO
BnO
1
3
2
d
R
N
O
O
OH
O
O
R
R
e
BnO
HO
4; R = (CH2)4-CH3 (60%)
4a
5; R = (CH2)4-CH3 (85%)
5a
; R = (CH2)5-CH3 (58%)
4b; R = (CH2)7-CH3 (55%)
; R = (CH2)5-CH3 (81%)
5b; R = (CH2)7-CH3 (81%)
Scheme 1. Reagents and conditions: (a) benzyl bromide, K2CO3, AcCN, rt, 4 h, 98%; (b) NaBH4, I2, THF, 0 °C, 2.5 h then benzyl protected eugenol, rt, 3 h; NaOMe, I2, 0 °C, 3 h,
75%; (c) AgNO3, NaNO2, H2O, rt, 10 h, 75%; (d) Ac2O, DMAP, DCM, N2, rt, 5–6 h; (e) (i) Ra-Ni, H2, EtOH, ꢀ6 h, (ii) Pd/C, H2, EtOH, ꢀ3 h.
presence of Pd/C (10%) to afford excellent yield of 6-gingerol (5).16
On a small scale run (100 mg) the yield of 6-gingerol was 85%. On
higher scale (1 g), the isolated yield of 5 was 80% from steps e (i)
and e (ii). The isolated yield of 5 over two steps d and e was found
to be in the range of 48–51%.17
4. (a) Lee, H. S.; Seo, E. Y.; Kang, N. E.; Kim, W. K. J. Nutr. Biochem. 2008, 19, 313–319;
(b) Lee, S. H.; Cekanova, M.; Baek, S. J. Mol. Carcino. 2008, 47, 197–208.
5. Hibino, T.; Yuzurihara, M.; Terawaki, K.; Kanno, H.; Kase, Y.; Takeda, A. J.
Pharmacol. Sci. 2008, 108, 89–94.
6. Nagoshi, C.; Shiota, S.; Kuroda, T.; Hatano, T.; Yoshida, T.; Kariyama, R.;
Tsuchiya, T. Biol. Pharm. Bull. 2006, 29, 443–447.
7. (a) Kato, N.; Hamada, Y.; Shioiri, T. Chem. Pharm. Bull. 1984, 32, 1679–1682; (b)
Barco, A.; Benetti, S.; Baraldi, P. G.; Guarneri, M.; Pollini, G. P.; Simoni, D. J.
Chem. Soc., Chem. Commun. 1981, 599–600; (c) Denniff, P.; Macleod, I.; Whiting,
D. A. J. Chem. Soc., Perkin Trans. 1 1981, 82–87; (d) Banno, K.; Mukaiyama, T.
Bull. Chem. Soc. Jpn. 1976, 49, 1453–1454; (e) Hirao, N.; Toyama, T.; Takahata,
A.; Yasui, B. Chem. Pharm. Bull. 1972, 20, 2287–2289.
8. (a) Fukuda, H.; Tetsu, M.; Kitazume, T. Tetrahedron 1996, 52, 157–164; (b)
Solladie, G.; Ziani-Cherif, C. J. Org. Chem. 1993, 58, 2181–2185; (c) Martin, M.;
Guibet, P. Chirality 1991, 3, 151–155; (d) Annunziata, R.; Cardani, S.; Gennari,
C.; Poli, G. Synthesis 1984, 702–703; (e) Cinquini, M.; Cozzi, F.; Gilardi, A. J.
Chem. Soc., Chem. Commun. 1984, 551–552; (f) Gall, T. L.; Lellouche, J. P.;
Beaucourt, J. P. Tetrahedron Lett. 1989, 30, 6521–6524; (g) Baraldi, P. G.; Fabio,
M.; Pollini, G. P.; Simoni, D.; Barco, A.; Benetti, S. J. Chem. Soc., Perkin Trans. 1
1982, 2983–2987; (h) Enders, D.; Eichenauer, H.; Pieter, R. Chem. Ber. 1979, 112,
3703–3714; (i) Hirao, N.; Kawachi, J.; Yasui, B. Chem. Pharm. Bull. 1973, 21,
2569–2571.
Further, synthesis of isoxazolines containing 6 and 8 carbons
[R = (CH2)5CH3 and (CH2)7CH3] was undertaken. Starting from 3,
as a scaffold, isoxazolines 4a and 4b were synthesized by replacing
1-heptene with 1-octene and 1-decene respectively. The isolated
yields of 4a and 4b run on 0.6 g scale of compound 3 were 58%
and 55%, respectively. On continuing the sequence, 7- and 9-ginge-
rols (5a and 5b) were prepared from 4a and 4b in 81% yield.17
The products from various stages were isolated by normal
work-up followed by silica gel chromatography to afford com-
pounds, which gave satisfactory 1H and 13C NMR data. The TLC
(2% EA in hexane) visualization under UV at 254 and 366 nm,
and charring of spots with phosphomolybdic acid indicated single
spot products. They were further confirmed from HRMS data. The
synthesized 6-gingerol was also compared with HPLC of natural
sample isolated from ginger.
In conclusion, we have developed a simple, new synthesis of 6-
gingerol and its homologues from eugenol the main compound
present in clove bud essential oil, which is easily available and
inexpensive. The experimental conditions are easily scalable and
involve an eco-friendly step for conversion into nitro compound
(3). Since 6-gingerol is an important bioactive principle, the pres-
ent protocol is advantageous in preparing this food/pharmaceutical
grade compound in good quantity.
9. Fleming, S. A.; Dyer, C. W.; Eggington, J. Synth. Commun. 1999, 29, 1933–1939.
10. Santos, A. L.; Chierice, G. O.; Alexander, K. S.; Riga, A.; Matthews, E. J. Therm.
Anal. Calorim. 2009, 96, 821–825.
11. Brown, H. C.; Rathke, M. W.; Rogic, M. M.; De Lue, N. R. Tetrahedron 1988, 44,
2751–2762.
12. Kornblum, N. Org. React. 1962, 12, 101–156.
13. Compound 3: To a mixture of 2 (1.5 g, 3.94 mmol) in H2O (50 mL), AgNO3 (2 g,
11.82 mmol) and NaNO2 (1.1 g, 15.76 mmol) were added and the mixture was
stirred in dark at ambient temperature for 10 h. The reaction mixture was
filtered and the filtrate was extracted with DCM (3 Â 50 mL). The combined
organic layer was concentrated to afford the crude product which was purified
by column chromatography on silica gel (200–400 mesh) using mixtures of EA
and petroleum ether (60–80 °C) to afford the pure compound (0.88 g, 75%).
Yellow solid; mp 48–50 °C; 1H NMR (500 MHz, CDCl3): d = 7.45(d, 2H,
J = 7.6 Hz), 7.38(t, 2H, J = 7.5 Hz), 7.32(t, 1H, J = 7.4 Hz), 6.84(d, 1H, J = 8.12
Hz), 6.73(s, 1H), 6.66(d, 1H, J = 8.04 Hz), 5.15(s, 2H), 4.38(t, 2 H, J = 6.9 Hz),
3.91(s, 3H), 2.67(t, 2H, J = 7.4 Hz), 2.31(p, 2H, J = 7.1 Hz); Mass (ESI): [M++Na]
for C17H19NO4Na, Calculated: 324.1211; Found: 324.2504.
Acknowledgments
14. Maugein, N.; Wagner, A.; Mioskowski, C. Tetrahedron Lett. 1997, 38, 1547–1550.
15. General procedure for synthesis of isoxazolines (4, 4a and 4b): To a solution of 3
(0.6 g, 1.99 mmol), under inert atmosphere, in DCM (10 mL), an appropriate
olefin (9.95 mmol) was added at ambient temperature followed by the
addition of acetic anhydride (0.55 g, 5.97 mmol) and DMAP (0.36 g,
2.98 mmol). The reaction mixture was stirred until the disappearance of
nitro compound by TLC (ꢀ5–6 h). Aqueous work-up followed by concentration
and silica gel column chromatography afforded pure compound. Compound 4;
Light yellow solid; mp 63–65 °C; 1H NMR (500 MHz, CDCl3): d = 7.45(d, 1H,
J = 7.13 Hz), 7.38(t, 2H, J = 7.4 Hz), 7.31(t, 1H, J = 7.4 Hz), 6.82(d, 1H,
J = 8.32 Hz), 6.78(s, 1H), 6.69(d, 1H, J = 8.03 Hz), 5.14(s, 2H), 4.50–4.55(m,
1H), 3.90(s, 3H), 2.92(dd, 1H, J1 = 16.72 Hz, J2 = 10.15 Hz), 2.85(t, 2H, J = 7.8 Hz),
2.64(t, 2H, J = 7.8 Hz), 2.50(dd, 1H, J1 = 16.82 Hz, J2 = 8.13 Hz), 1.28–1.50(m,
8H), 0.9(t, 3H, J = 6.6 Hz); Mass (ESI): [M++Na] for C24H31NO3Na, Calculated:
404.2201; Found: 404.4111. Compound 4a; Light yellow solid; mp 58–61 °C;
1H NMR (500 MHz, CDCl3): d = 7.45(d, 2H, J = 7.6 Hz), 7.38(t, 2H, J = 7.4 Hz),
7.31(t, 1H, J = 7.5 Hz), 6.82(d, 1H, J = 8.2 Hz), 6.78(s, 1H), 6.69(d, 1H,
J = 8.03 Hz), 5.14(s, 2H), 4.50–4.54(m, 1H), 3.90(s, 3H), 2.92(dd, 1H,
J1 = 16.68 Hz, J2 = 10.25 Hz), 2.85(t, 2H, J = 7.8 Hz), 2.64(t, 2H, J = 7.7 Hz),
2.50(dd, 1H, J1 = 16.82 Hz, J2 = 8.13 Hz), 1.27–1.50(m, 10H), 0.90(t, 3H,
Author N.V.K. is thankful to UGC, New Delhi for the award of
Junior Research Fellowship. We are grateful to Mr. J. R. Manjunath-
a, Senior Research Fellow, Plantation Products, Spices and Flavour
Technology Department, CFTRI, Mysore for NMR analyses.
References and notes
1. (a) Awang, D. Can. Pharm. J. 1992, 125, 309–311; (b) Tapsell, L. C.; Hemphill, I.;
Cobiac, L.; Patch, C. S.; Sullivan, D. R.; Fenech, M.; Roodenrys, S.; Keogh, J. B.;
Clifton, P. M.; Williams, P. G.; Fazio, V. A.; Inge, K. E. Med. J. Aust. 2006, 185,
S4–S24.
2. (a) Murad, N. A.; Ngah, W. Z. W.; Yusof, Y. A. M.; Abdul Aziz, J. M.; Semarak, J.
Asian J. Biochem. 2007, 2, 4214–4226; (b) Kim, J. K.; Kim, Y.; Na, K. M.; Surh, Y.-J.;
Kim, T. Y. Free Radical Res. 2007, 41, 603–614.
3. Ahui, M. L. B.; Champy, P.; Ramadan, A.; Pham Van, L.; Araujo, L.; Brou Andre,
K.; Diem, S.; Damotte, D.; Kati-Coulibaly, S.; Offoumou, M. A.; Dy, M.;
Thieblemont, N.; Herbelin, A. Int. Immunopharmacol. 2008, 8, 1626–1632.

N. Vijendra Kumar et al. / Tetrahedron Letters 53 (2012) 2993–2995
2995
J = 6.8 Hz); Mass (ESI): [M++1] for C25H33NO3, Calculated: 396.5344; Found:
396.4690. Compound 4b; Light yellow solid; mp 57–59 °C; 1H NMR (500 MHz,
CDCl3): d = 7.45(d, 1H, J = 7.2 Hz), 7.38(t, 2H, J = 7.4 Hz), 7.31(t, 1H, J = 7.3 Hz),
6.82(d, 1H, J = 8.1 Hz), 6.78(s, 1H), 6.69(d, 1H, J = 8.0 Hz), 5.14(s, 2H), 4.51–
4.53(m, 1H), 3.90(s, 3H), 2.92(dd, 1H, J1 = 16.48 Hz, J2 = 10.34 Hz), 2.85(t, 2H,
J = 7.8 Hz), 2.64(t, 2H, J = 7.6 Hz), 2.50(dd, 1H, J1 = 16.76 Hz, J2 = 8.14 Hz), 1.27–
1.49(m, 14H), 0.90(t, 3H, J = 6.5 Hz); Mass (ESI): [M++1] for C25H33NO3,
Calculated: 424.5875; Found: 424.5268.
J = 7.80 Hz), 6.67–6.70(m, 2H), 5.53(s, 1H), 4.02–4.07(m, 1H), 3.89(s, 3H),
2.98(s, 1H), 2.85(t, 2H, J = 7.4 Hz), 2.75(t, 2H, J = 7.3 Hz), 2.51–2.57(m, 2H),
1.27–1.46(m, 8H), 0.90(t, 3H, J = 6.9 Hz); 13C NMR (125 MHz CDCl3): 211.04,
146.12, 143.69, 132.32, 120.43, 114.06, 110.69, 67.37, 55.56, 49.04, 45.10,
36.12, 31.31, 28.97, 24.78, 22.23, 13.64; Mass (ESI): [M+] for C17H24O4,
Calculated: 294.1831; Found: 294.4097. Compound 5a; Yellow oily liquid; 1H
NMR (500 MHz, CDCl3): d = 6.84(d, 1H, J = 7.86 Hz), 6.67–6.70(m, 2H), 5.50(s,
1H), 4.03–4.05(m, 1H), 3.89(s, 3H), 2.85(t, 2H, J = 7.2 Hz), 2.75(t, 2H, J = 7.2 Hz),
2.48–2.61(m, 2H), 1.29–1.45(m, 10H), 0.89(t, 3H, J = 6.8 Hz); 13C NMR
(125 MHz, CDCl3): 211.05, 146.12, 143.69, 132.34, 120.44, 114.07, 110.69,
67.36, 55.57, 49.06, 45.12, 36.18, 31.45, 28.98, 28.87, 25.09, 22.26, 13.72. Mass
(ESI): [M++Na] for C18H28O4Na, Calculated: 331.4125; Found: 331.4143.
Compound 5b; Yellow oily liquid; 1H NMR (500 MHz, CDCl3): d = 6.84(d, 1H,
J = 7.89 Hz), 6.66–6.73(m, 2H), 5.53(s, 1H), 4.03–4.05(m, 1H), 3.89(s, 3H),
2.85(t, 2H, J = 7.3 Hz), 2.75(t, 2H, J = 7.3 Hz), 2.48–2.60(m, 2H), 1.27–1.46(m,
14H), 0.89(t, 3H, J = 6.8 Hz); 13C NMR (125 MHz, CDCl3): 199.44, 147.51,
143.65, 132.34, 120.50, 113.99, 110.82, 67.37, 55.57, 49.06, 45.12, 36.18, 31.50,
29.37, 29.21, 28.84, 28.78, 25.13, 22.32, 13.74; Mass (ESI): [M++Na] for
16. Kozikowski, A. P.; Adamczyk, M. Tetrahedron Lett. 1982, 23, 3123–3126.
17. General procedure for synthesis of gingerols (5, 5a and 5b): To a solution of
isoxazolines (4, 4a and 4b, 0.1 g) in ethanol and water (3:1, 4 mL) Raney nickel
(10 mg) was added and hydrogenated at 30 psi pressure for ꢀ6 h. After
completion of the reaction by TLC analyses, the mixture was filtered. To the
filtrate Pd/C (10%, 10 mg) was added and set for hydrogenolysis at 30 psi
hydrogen pressure for ꢀ3 h. After completion of the reaction, the reaction
mixture was filtered and filtrate was taken into DCM (5 mL) and washed with
brine (10 mL). The organic layer was concentrated to get the crude product
which was purified by column chromatography on silica gel (200–400 mesh)
using EA in petroleum ether (60–80 °C) to afford the pure compounds.
Compound 5; Yellow oily liquid; 1H NMR (500 MHz, CDCl3): d = 6.84(d, 1H,
C20H32O4Na, Calculated: 359.2198; Found: 359.3834.