An Improved Route to the Preparation of 6-, 8-, 10-Gingerols

Full text of DOI:10.1080/00304948.2015.1088754

Organic Preparations and Procedures International
The New Journal for Organic Synthesis
ISSN: 0030-4948 (Print) 1945-5453 (Online) Journal homepage: http://www.tandfonline.com/loi/uopp20
An Improved Route to the Preparation of 6-, 8-, 10-
Gingerols
N. Vijendra Kumar, S. C. Santosh Kumar, P. Srinivas & B. K. Bettadaiah
To cite this article: N. Vijendra Kumar, S. C. Santosh Kumar, P. Srinivas & B. K. Bettadaiah
(2015) An Improved Route to the Preparation of 6-, 8-, 10-Gingerols, Organic Preparations and
Procedures International, 47:6, 443-448, DOI: 10.1080/00304948.2015.1088754
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Date: 02 November 2015, At: 01:25

Organic Preparations and Procedures International, 47:443–448, 2015
Copyright Ó Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2015.1088754
An Improved Route to the Preparation
of 6-, 8-, 10-Gingerols
N. Vijendra Kumar, S. C. Santosh Kumar, P. Srinivas,
and B. K. Bettadaiah
Department of Spice and Flavour Sciences, CSIR-Central Food Technological
Research Institute, Mysore 570 020, India
Ginger (Zingiber officinale) is one of the important spices known since ancient times
and has numerous health promoting properties. It is used in the treatment of various
ailments such as catarrh, rheumatism, gingivitis, toothache, asthma, stroke, constipa-
tion, gastric ailments and diabetes and as a spice especially in Indian cuisine. It has
found applications in Ayurvedic, Tibb-Unani and Chinese herbal formulations. The
major constituents of the ginger rhizome are volatile and non-volatile pungent com-
pounds. While the volatile components are mainly terpenoids which contribute to the
aroma of ginger, the non-volatile phenolic compounds such as gingerols, shogaols,
paradols (Figure 1) and zingerone contribute to its pungency. Fresh ginger is rich in
6-, 8-, 10-gingerols with the S-(C)-stereochemical configuration, whereas dry ginger
contains mainly 6-, 8-, 10-shogaols. Both gingerols and shogaols are key pungent
compounds and very important phenolic nutraceuticals possessing various biologically
1–15
useful properties.
The isolation of the individual gingerols (where n D 6, 8 and 10) from ginger extracts
is tedious as they contain homologous compounds that are difficult to separate by normal
chromatography; in addition the spice also contains other phenolic compounds viz., sho-
gaols and paradols (Figure 1). Among these compounds, [6]-gingerol is the most useful
and important because to its biological activity.16–19 Some of its derivatives such as aza-
gingerol, a compound that has the ability to reduce the accumulation of body fat20 and
Figure 1 Structure of Biologically Active Ginger Components
Received December 30, 2014; in final form May 13, 2015.
Address correspondence to B. K. Bettadaiah, Department of Spice and Flavour Sciences,
CSIR-Central Food Technological Research Institute, Mysore 570 020, India. E-mail:
bettadaiah@cftri.res.in
443

444
Bettadaiah et al.
gingerol glucoside, a stable water-soluble compound, have been the focus of much atten-
tion.21 The few methods reported for the preparation of gingerols give low yields or
require stringent reaction conditions which discourages their use.22–30 Thus as 6-gingerol
possesses significant pharmaceutical properties, there is a need for simpler methods for
its preparation which are cost effective, easily scalable and proceed in high yields.31 The
previously reported syntheses of these racemic gingerols from eugenol afforded the
desired products in only 24–28%.32 The present article describes the conversion of
O-protected eugenol 1 to the precursor isoxazolidines (6a–6c) (Scheme 1) from which
7a–c may be prepared.
Scheme 1 Synthesis of Gingerols
Since initial hydroboration-iodination of 1 to the iodoeugenol 2 showed the latter
compound to be unstable and easily degraded during chromatographic purification, it was
thus decided to prepare the O-protected alcohol 3 which was found to be stable and was
obtained in high yields from O-benzyleugenol (1) by hydroboration-oxidation using
NaBH4/I2 and H2O2/NaOH system.33 The conversion to 3 was simple and easy to achieve
in an excellent yield (>85%). In this step, it was initially observed that the sequence of
addition of hydrogen peroxide and sodium hydroxide affected the yield of 3 because
iodoeugenol 2 was present in about 10% yield if hydrogen peroxide was added first
followed by sodium hydroxide, we were able to reduce its formation to about 3% by
reversing the order the addition, sodium hydroxide (first) followed by hydrogen peroxide.
Oxidation of O-protected alcohol 3 to eugenol aldehyde 4 using PCC afforded an 85%
yield after column chromatography.34 Treatment of oxime 5, obtained by reaction of 4
with hydroxylamine hydrochloride in MeOH in the presence of terminal olefins, with 5%
sodium hypochlorite solution generated the nitrile oxides in situ and afforded D2-isoxazo-
lines (6a–c) via 1,3-dipolar cycloaddition in good yields (74–75%).35 Gingerols 7a–c
could be obtained in 42–43% yields via the one-pot removal of the benzyl group using Pd/C

Preparation of 6-, 8-, 10-Gingerols
445
and the reductive cleavage of isoxazolines with Ra/Ni in moist ethanol (94–95% yield).32 Both
hydrogenation steps (not described here) of 6a–c were performed at 20 psi in a Parr apparatus
as described to our published procedure.32
In conclusion, an efficient method for the synthesis of 4-, 6-, 8-gingerols has been
reported. The procedures involved in this sequence have wide scope and proceed in high
yields, and the reagents used are readily available, inexpensive and simple to use under
laboratory conditions. This economically viable sequence of reactions should be easily
amenable to scale-up preparation of gingerols and related compounds.
Experimental Section
All the reagents and solvents were procured from commercial suppliers and used without
further purification unless otherwise stated. Melting points were determined in open
capillaries on a Pathak Electrical Works melting point apparatus and are uncorrected. The
purity of the compounds was checked using TLC plates (TLC silica gel 60 F254 aluminum
sheets, Merck KGaA, 64271 Darmstadt, Germany). 1H and 13C NMR spectra were
recorded on a Bruker 500 Ultrashield spectrometer and are reported in d using TMS as
internal standard (splitting patterns of NMR signal are designated as t-triplet, d-doublet,
s-singlet and bs-broad singlet). Mass spectra were acquired on a Waters Q-Tof Ultima,
(Manchester, UK) mass spectrometer. The reaction mixtures were stirred on a Tarsons
spinot stirrer using a magnetic spin bar.
Synthesis of 3-[4-(Benzyloxy)-3-methoxyphenyl]propan-1-ol (3). To a mixture of
sodium borohydride (0.35 g, 9.14 mmol) in THF (10 mL), iodine (1.15 g, 4.56 mmol) in
THF (15 mL) was added dropwise over a period of 2 hrs at 0ꢀC under a nitrogen atmo-
sphere with constant stirring (magnetic spin bar). After completion of the addition, a solu-
tion of O-benzyleugenol (3.0 g, 18.27 mmol) in THF (5 mL) was added dropwise over
10–15 minutes and the reaction mixture was stirred at RT for 2 hrs. After cooling to 0ꢀC,
water (2 mL) was added cautiously to decompose the excess hydride (10 min). Sodium
hydroxide (3M aqueous, 4.6 mL) was then added slowly so as to keep temperature below
0ꢀC over 10 min, followed by the addition of hydrogen peroxide (30%, 1.6 mL) over
10 min. After the completion of the reaction as monitored by tlc. for the disappearance of
O-benzyleugenol (eluent; petroleum ether 60–80ꢀC and EtOAc in 9.5:0.5 ratio, Rf D 0.8),
a saturated aqueous sodium thiosulfate (10 mL) was added to the reaction mixture. The
organic layer was separated and evaporated under vacuum to afford a syrupy mass which
was dissolved in EtOAc (10 mL) and washed with water (5 mL £ 3). The organic layer
was then dried over anhydrous sodium sulfate and evaporated to afford the crude product.
Purification using column chromatography over silica gel (100–200 mesh) with EtOAc
and petroleum ether mixture (20:80) as eluent gave 2.73 g (85%) of the product as an off-
white powder, mp. 68–69ꢀC; lit.36 67–78ꢀC; 1H NMR (500 MHz, CDCl3): d 7.47 (d, 2H,
J D 7.06 Hz), 7.39 (t, 2 H, J D 7.4), 7.32 (t, 2H, J D 7.3), 6.83 (d, 1H, J D 8.1 Hz), 6.77
(d, 1H, J D 1.8 Hz) 6.69 (dd, 1H, J D 8.1), 5.16(s, 2H), 3.91(s, 3H), 3.19 (t, 2H, J D 6.8),
2.69 (t, 2H, J D 7.3), 2.12 (p, 2H, J D 6.9 Hz); 13C NMR (125 MHz, CDCl3): d 149.3,
146.3, 137.0, 133.3, 128.2, 127.5, 126.9, 120.1, 113.9, 112.1, 70.8, 55.7, 35.4, 34.6, 6.31;
Mass (ESI) : [MCCNa] for C17H20O3Na, Cald: 295.1310. Found: 295.1447.
Anal. Calcd for C17H20O3: C, 74.97; H, 7.40. Found: C, 74.77; H, 6.81.
Synthesis of 3-(4-(Benzyloxy)-3-methoxyphenyl)propanal (4). To a solution of
pyridinium chlorochromate (2.4 g, 11.03 mmol) in dichloromethane (20 mL), O-pro-
tected alcohol 3 (3.0 g, 11.03 mmol) in dichloromethane (20 mL) was added dropwise
using pressure equalizing additional funnel with constant stirring (magnetic spin bar).

446
Bettadaiah et al.
The reaction mixture was then heated at reflux. After the completion of the reaction (1 hr)
as monitored by tlc for disappearance of O-protected alcohol 3 (eluent: petroleum ether
60–80ꢀC and EtOAc in 6:4 ratio, Rf D 0.3), silica gel (5 g, 200–400 mesh) was added to
the mixture and dichloromethane was evaporated under vacuum to afford a crude product
adsorbed on the gel. It was purified by column chromatography over silica gel (100–
200 mesh) using petroleum ether (60–80ꢀC) and EtOAc mixtures (95:5 to 80:20) as elu-
ent. The pure product (2.52 g, 85%) was obtained as a white powder, mp. 64–66ꢀC; lit.36
64–65ꢀC; 1H NMR (500 MHz, CDCl3): d 9.84 (s, 1H), 7.45 (d, 2H, J D 7.5), 7.38 (t, 2H,
J D 7.4), 7.31 (t, 2H, J D 7.3), 5.14 (s, 2H), 3.90 (s, 3H), 2.91 (t, 2H, J D 7.5), 2.77 (t,
2H, J D 7.4); 13C NMR (125 MHz, CDCl3): d 201.4, 149.47, 146.44, 137.01, 133.31,
128.20, 127.47, 126.96, 119.83, 114.17, 112.03, 70.93, 55.72, 45.12, 27.46; Mass (ESI) :
[MCCNa] for C17H18O3Na, Calcd: 293.1154. Found: 293.0597.
Anal. Calcd for C17H18O3: C, 75.53; H, 6.71. Found: C, 75.59; H, 6.72.
Synthesis of 3-(4-(Benzyloxy)-3-methoxyphenyl)propanal Oxime (5). To a solu-
tion of aldehyde 4 (2.5 g, 9.25 mmol) in methanol (25 mL), hydroxylamine hydrochlo-
ride (1.0 g, 13.9 mmol) was added in one portion and the mixture was stirred (spin bar) at
RT for 3 hrs. The progress of reaction was monitored by tlc for the disappearance of alde-
hyde 4 (eluent; petroleum ether 60–80ꢀC and EtOAc in 7:3 ratio, Rf D 0.38). After the
completion of reaction, the mixture was evaporated and the residue was dissolved in
dichloromethane (10 mL) and the solution was washed with water (3£5 mL). The
organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo to afford
the crude material which was purified by column chromatography over silica gel
(100–200 mesh) using petroleum ether and EtOAc (80:20) as eluent. The product oxime
5 (2.24 g, 85%) was obtained as an off-white powder, mp. 117–119ꢀC; 1H NMR
(500 MHz, CDCl3): d 7.48–7.45 (m, 3H), 7.38 (t, 2H, J D 7.4), 7.31 (t, 1H, J D 7.1), 6.83
(d, 1H, J D 8.0), 6.76 (d, 1H, J D 9.7), 6.69 (t, 1H, J D 8.2), 5.15 (s, 2H), 3.90 (s, 3H),
2.80–2.75 (m, 2H), 2.74–2.69 (m, 1H), 2.55–2.49 (m, 1H); 13C NMR (125 MHz, CDCl3):
d 151.04, 149.39, 146.37, 137.03, 133.48, 128.21, 127.47, 126.98, 119.89, 114.02,
111.95, 70.89, 55.70, 32.14, 31.06; Mass (ESI) : [MCCNa] for C17H19NO3Na, Calcd:
308.1263. Found: 308.1299.
Anal. Calcd for C17H19NO3: C, 71.56; H, 6.71; N, 4.91. Found: C, 71.23; H, 6.81; N,
4.60.
3-(4-(Benzyloxy)-3-methoxyphenethyl)-5-pentyl-4,5-dihydroisoxazole (6a). To
a solution of oxime 5 (2 g, 7.01 mmol) and 1-heptene (1.05 g, 10.52 mmol) in
dichloromethane (20 mL), pyridine (0.55 mL, 7.01 mmol) was added. It was
followed by the slow addition of 5% sodium hypochlorite (10 mL, 7.01 mmol) over
10 minutes and the whole mixture was stirred (spin bar) at RT for 4 hrs. After com-
pletion of reaction as monitored by tlc for the disappearance of oxime 5 (eluent:
petroleum ether 60–80ꢀC and EtOAc in 6:4 ratio, Rf D 0.38), water (20 mL) was
added slowly and the organic layer was separated. It was dried over anhydrous sodium
sulfate to afford the crude product as a thick yellow liquid that was purified using col-
umn chromatography over silica gel (100–200 mesh) using petroleum ether and
EtOAc (95:5 to 80:20) mixture as eluent. The product 6a (2.0 g, 75%) was obtained
as a pale yellow solid, mp. 63–65ꢀC; lit.32 mp. 63–65ꢀC; 1H NMR (500 MHz,
CDCl3): d 7.45(d, 2H, J D 7.6 Hz), 7.38(t, 2H, J D 7.4 Hz), 7.31(t, 1H, J D 7.5 Hz),
6.82(d, 1H, J D 8.2 Hz), 6.78(s, 1H), 6.69(d, 1H, J D 8.03 Hz), 5.14(s, 2H), 4.50–
4.54(m, 1H), 3.90(s, 3H), 2.92(dd, 1H, J1 D 16.68 Hz, J2 D 10.25 Hz), 2.85(t, 2H, J
D 7.8 Hz), 2.64(t, 2H, J D 7.7 Hz), 2.50(dd, 1H, J1 D 16.82 Hz, J2 D 8.13 Hz),

Preparation of 6-, 8-, 10-Gingerols
447
1.27–1.50(m, 8H), 0.90(t, 3H, J D 6.8 Hz); Mass (ESI): [MCCNa] for C24H31NaNO3,
Calcd:404.2202; Found: 404.4111.
Anal. Calcd for C24H31NO3: C, 75.56; H, 8.19; N, 3.67. Found: C, 75.06; H, 7.94; N,
4.55.
3-(4-(Benzyloxy)-3-methoxyphenethyl)-5-heptyl-4,5-dihydroisoxazole (6b). Light
yellow solid, mp. 58–61ꢀC; 1H (500 MHz, CDCl3): d 7.45(d, 2H, J D 7.4 Hz), 7.38(t, 2H,
J D 7.5 Hz), 7.31(t, 1H, J D 7.3 Hz), 6.83(d, 1H, J D 8.2 Hz), 6.78(d, 1H, J D 1.7), 6.69
(dd, 1H, J D 1.7, J D 8.1 Hz), 5.14(s, 2H), 4.55–4.48(m, 1H), 3.90(s, 3H), 2.92(dd, 1H,
J1 D 16.7 Hz, J2 D 10.1 Hz), 2.86(t, 2H, J D 7.8 Hz), 2.64(t, 2H, J D 7.7 Hz), 2.50(dd,
1H, J1 D 16.7 Hz, J2 D 8.1 Hz), 1.72–1.63(m, 1H), 1.53–1.45(m, 1H), 1.28–1.44(m,
12H), 0.90(t, 3H, J D 6.8 Hz); Mass (ESI): [MCCNa] for C26H35NaNO3, Calcd:
432.2515; Found: 432.3278.
Anal. Calcd for C26H35NO3: C, 76.25; H, 8.61; N, 3.42. Found: C, 76.64; H, 9.16; N,
3.46.
3-(4-(Benzyloxy)-3-methoxyphenethyl)-5-nonyl-4,5-dihydroisoxazole (6c). Light
yellow solid, m. p. 57–59ꢀC; 1H (500 MHz, CDCl3): d 7.45(d, 1H, J D 7.4 Hz),
7.38(t, 2H, J D 7.5 Hz), 7.31(t, 1H, J D 7.3 Hz), 6.83(d, 1H, J D 8.1 Hz), 6.78(d, 1H, J
D 1.72), 6.69(dd, 1H, J D 1.9 Hz, J D 8.0 Hz), 5.14(s, 2H), 4.47–4.54(m, 1H), 3.89(s,
3H), 2.94–2.83(m, 3H), 2.64(t, 2H, J D 7.7 Hz), 2.50(dd, 1H, J1 D 16.7 Hz, J2 D
8.1 Hz), 1.72–1.63(m, 1H), 1.53–1.46(m, 1H), 1.28–1.41(m, 14H), 0.91(t, 3H, J D
6.8 Hz); Mass (ESI): [MCCNa] for C28H39NaNO3, Calcd: 460.2828; Found: 460.3428
Anal. Calcd for C28H39NO3: C, 76.85; H, 8.98; N, 3.20. Found: C, 75.74; H, 8.79; N,
3.39.
Acknowledgements
Author NVK is grateful to the UGC, New Delhi for the award of Senior Research Fellow-
ship. Funding from the BSC-0202 project for this work is gratefully acknowledged. We
are thankful to Mr. J. R. Manjunatha, Technical Officer, Department of Spice and Flavour
Science, CSIR-Central Food Technological Research Institute, Mysore, for NMR
analysis.
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