An Efficient Enantioselective Synthesis of Natural Gingerols, the Active Principles of Ginger

Article abstract of DOI:10.1002/hlca.201400393

A straightforward synthesis of (S)-gingerols 1-3 has been described. The requisite stereogenic center in the target molecules was introduced by Sharpless asymmetric dihydroxylation using a chiral complex, AD-mix β. This route is simple and efficient to prepare the products in very good yields.

Full text of DOI:10.1002/hlca.201400393

Helvetica Chimica Acta – Vol. 98 (2015)
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An Efficient Enantioselective Synthesis of Natural Gingerols, the Active
Principles of Ginger
by A. Ramesh Reddy, Sachin B. Wadavrao, J. S. Yadav, and A. Venkat Narsaiah*
Organic and Biomolecular Chemistry Division, Indian Institute of Chemical Technology, Hyderabad-
500007, Telangana, India (fax: þ 91-40-27160387; e-mail: vnakkirala2001@yahoo.com)
A straightforward synthesis of (S)-gingerols 1 – 3 has been described. The requisite stereogenic
center in the target molecules was introduced by Sharpless asymmetric dihydroxylation using a chiral
complex, AD-mix b. This route is simple and efficient to prepare the products in very good yields.
Introduction. – The rhizome of ginger (Zingiber officinale Roscoe) is the most
abundant and widely used dietary condiment worldwide, and also has the long history
as an important traditional medicine in Asian countries [1]. The underground stems or
rhizomes of this plant have been used in oriental medicine for the treatment of common
cold, disorders of the gastro intestinal tract, neuralgia, rheumatism, colic and motion
discomfort [2]. The non-volatile pungent ingredients from ginger include (S)-gingerols
1 – 3, zingerone (4), and shogaol (5).
The three natural gingerols, namely (þ)-(S)-[6]-gingerol (1), (þ)-(S)-[8]-gingerol
(2), and (þ)-(S)-[10]-gingerol (3), have been isolated from the rhizome of zingiber and
have been claimed to be the active principles of ginger [3]. Recently, several population
based studies have shown that the gingerols exhibit diverse pharmacological activities
such as anti-inflammatory, cardiotonic, antibacterial, antifungal, antioxidant, and
antitumor, and antiplatelet aggregation effects [4]. The biological importance of
gingerols have attracted researchers to carry out its synthesis via different routes [5][6].
Results and Discussion. – As part of our regular research program in the synthesis
of biologically active natural products [7], herein, we report an efficient stereoselective
synthesis of (S)-gingerols 1 – 3 in excellent yields from epoxide 11 which was obtained
from vanillin (6).
As shown in the retrosynthetic analysis (Scheme 1), the synthesis strategy started
from commercially available 6. The phenolic OH was protected as benzyl ether
ꢀ 2015 Verlag Helvetica Chimica Acta AG, Zürich

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Helvetica Chimica Acta – Vol. 98 (2015)
Scheme 1
followed by Wittig reaction to give the unsaturated ester [8]. The latter was reduced
with Mg followed by LiAlH4 to yield the primary alcohol which was oxidized under
Swern conditions [9] to afford aldehyde 7. The latter was reacted with allyl bromide in
the presence of activated Zn at low temperature to give 1-[4-(benzyloxy)-3-
methoxyphenyl]hex-5-en-3-ol (8) in 90% yield [10a]. The OH group was protected
as benzyl ether by treating with BnBr in the presence of NaH in THF at room
temperature to give 9 in 90% yield. The terminal olefin was subjected to asymmetric
dihydroxylation using AD-mix b in tBuOH/H2O (1:1) at 08 to afford a 1:1 mixture of
diastereoisomeric 1,2-diols 10 [10b] as shown in Scheme 2.
The 1,2-diol 10 was subjected to Mitsunobu reaction [11] using Ph3P and diethyl
azodicarboxylate (DEAD) in benzene under reflux for 18 h to afford (2R)-2-{2-
(benzyloxy)-4-[4-(benzyloxy)-3-methoxyphenyl]butyl}oxirane (11) in 93% yield. The
latter was reacted with appropriate alkyl magnesium bromides in the presence of CuI at
08 to give the corresponding derivatives 12 with a secondary alcohol group in very good
yields.
The OH groups of 12a – 12c were protected as respective (tert-butyl)(dimethyl)silyl
ethers 13a – 13c by reacting with TBDMSÀCl in the presence of 1H-imidazole at room
temperature. The protected compounds 13a – 13c were treated with Pd/C in AcOEt
Scheme 2
a) BnBr, K2CO3, acetone, reflux, 3 h; 90%. b) Ph3P¼CHCOOEt, benzene, reflux, 2 h; 92%. c) Mg,
MeOH, r.t., 4 h; 85%. d) LiAlH4, THF, 08 – r.t., 2 h; 74%. e) (COCl)2, DMSO, Et3N, CH2Cl2, À 788, 1 h;
85%. f) Allyl bromide, activated Zn, THF, aq. NH4Cl soln., 08 – r.t., 3 h; 90%. g) BnBr, NaH, THF,
t
08 – r.t., 6 h; 90%. h) AD-mix b, BuOH/H2O 1:1, 08, 24 h; 90%.

Helvetica Chimica Acta – Vol. 98 (2015)
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Scheme 3
a) Ph3P, DEAD, benzene, reflux, 18 h; 93%. b) Me(CH2)3MgBr, CuI, THF, 08 – r.t., 2 h; 85%,
or Me(CH2)5MgBr, CuI, THF, 08 – r.t., 2 h; 87%, or Me(CH2)7MgBr, CuI, THF, 08 – r.t., 2 h; 90%.
c) TBDMSÀCl, 1H-imidazole, CH2Cl2, 08 – r.t., 3 h; 92%. d) H2 (40 psi), 10% Pd/C, AcOEt, r.t., 5 h;
90 – 92%.
under H2 atmosphere to give the debenzylated products 14a – 14c in very good yields as
shown in the Scheme 3.
The dihydroxy compounds 14 were subjected to oxidation with various oxidative
catalysts to convert the aliphatic OH group to the ketone, but it was not successful.
Then, 14a – 14c were treated with BnBr in the presence of K2CO3 to protect the
phenolic OH group [12] leading to the corresponding derivatives 15 in very good yields,
which were then treated with DessÀMartin periodinane in CH2Cl2 at room temperature
to afford ketone 16 in excellent yields. Subsequent deprotection of the benzyl ether
with Pd/C in AcOEt under H2 atmosphere afforded 17a – 17c in very good yields
(Scheme 4).
Finally, the TBDMS ethers were cleaved by treating with Bu4NF in THF [13] at
room temperature to obtain the target molecules, (5S)-5-hydroxy-1-(4-hydroxy-3-
methoxyphenyl)decan-3-one (1) in 87% yield with [a]2D5 ¼ þ24.3 (c ¼ 1, CHCl3)
([a]2D5 ¼ þ25.1 (c ¼ 1, CHCl3) [5c]), (5S)-5-hydroxy-1-(4-hydroxy-3-methoxyphenyl)-
dodecan-3-one (2) in 90% yield with [a]2D5 ¼ þ25.8 (c ¼ 1, CHCl3) ([a]D25 ¼ þ26.2 (c ¼ 1,
CHCl3) [5c]), and (5S)-5-hydroxy-1-(4-hydroxy-3-methoxyphenyl)tetradecan-3-one
(3) in 90% yield with [a]D25 ¼ 18.9 (c ¼ 1, CHCl3) ([a]2D5 ¼ 19.8 (c ¼ 1, CHCl3) [5c]),
respectively. The products were characterized by their 1H- and 13C-NMR, IR, and MS
data analyses.
Conclusions. – In summary, we have reported an efficient enantioselective synthesis
of (S)-gingerols 1 – 3 in excellent yields. The key intermediate was the epoxide 11,
which was achieved from vanillin (6). All the reactions were very clean in terms of
conversions as well as in isolation of products.

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Scheme 4
a) BnBr, K2CO3, acetone, reflux, 3 h; 90 – 92%. b) DessÀMartin periodinane, NaHCO3, CH2Cl2, 1 h;
87 – 92%. c) H2 (40 psi), 10% Pd/C, AcOEt, r.t., 5 h; 87 – 92%. d) Bu4NF, dry THF, r.t., 6 h; 87 – 90%.
The authors A. R. R. and S. B. W. are thankful to CSIR-New Delhi for providing fellowship.
Experimental Part
All the solvents and chemicals or reagents used were purchased from standard commercial suppliers
and used as such. M.p.: Büchi cap. melting-point (R-535) apparatus. Optical rotations: Rudolph
AUTOPOL IV automatic polarimeter. IR Spectra: PerkinElmer FT-IR 240C spectrophotometer; n˜ in
cmÀ1. 1H- and 13C-NMR spectra: Brucker-300 spectrometer at 300 (1H) and 75 (13C) MHz, resp.; d in ppm
rel. to Me4Si as internal standard, J in Hz. MS: Finnigan-MAT 1020 mass spectrometer operating at
70 eV; in m/z (rel. %).
3-[4-(Benzyloxy)-3-methoxyphenyl]propanal (7). To a soln. of (COCl)2 (3 g, 23 mmol) in CH2Cl2
(40 ml) at À 788 was added DMSO (3.95 g, 50 mmol) over 20 min. The resulting mixture was stirred for
an additional 15 min, and 3-(4-(benzyloxy)-3-methoxyphenyl)propan-1-ol (4.3 g, 15 mmol) dissolved in
CH2Cl2 (10 ml) was added. The mixture was stirred for 30 min, and Et3N (8 g, 79 mmol) was added
dropwise. The mixture was allowed to warm to r.t. and was stirred for 1 h. Then, the reaction was
quenched with H2O and extracted with CH2Cl2 (2 Â 25 ml). The combined org. layers were washed with
brine, dried (Na2SO4), and concentrated under reduced pressure. The crude product was purified by
column chromatography (CC) on silica gel (SiO2, 60 – 120 mesh; AcOEt/hexane 2 :8) to afford 7 (3.7 g,
85%) as colorless solid. 1H-NMR (CDCl3): 2.65 – 2.75 (m, 2 H); 2.80 – 2.85 (m, 2 H); 3.92 (s, 3 H); 5.08 (s,
2 H); 6.65 (d, J ¼ 7.0, 1 H); 6.75 (t, J ¼ 7.0, 2 H); 7.30 – 7.45 (m, 5 H); 9.80 (s, 1 H). EI-MS: 270 (10, Mþ),
268 (20), 246 (30), 229 (20), 201 (10), 150 (10), 104 (10), 90 (100), 76 (25), 64 (30), 51 (25), 43 (35).

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1-[4-(Benzyloxy)-3-methoxyphenyl]hex-5-en-3-ol (8). To a cold and well-stirred mixture of 7 (3.7 g,
13 mmol), Zn dust (1.7 g, 27 mmol), and allyl bromide (2.36 ml, 27 mmol) in THF (50 ml) was added a
sat. aq. soln. of NH4Cl (30 ml) dropwise within 10 min. The mixture was stirred for 4 h at ambient temp.
until the aldehyde was totally consumed (by TLC). The mixture was filtered, and the precipitate was
thoroughly washed with CHCl3. The combined org. layer was washed successively with H2O and brine.
After solvent removal under reduced pressure, the residue was separated by CC (SiO2, 60 – 120 mesh;
AcOEt/hexane 3 :7) to afford 8 (3.8 g, 90%) as colorless oil. IR (KBr): 3432, 2976, 1718, 1650, 1262, 1160,
1
1050. H-NMR (CDCl3): 1.65 – 1.78 (m, 2 H); 2.08 – 2.34 (m, 2 H); 2.53 – 2.77 (m, 1 H); 3.55 – 3.65 (m,
1 H); 3.88 (s, 3 H); 5.05 – 5.14 (m, 4 H); 5.70 – 5.85 (m, 1 H); 6.58 – 6.64 (m, 1 H); 6.68 – 6.76 (m, 2 H);
7.28 – 7.42 (m, 5 H). ESI-MS: 335 ([M þ Na]þ).
1-(Benzyloxy)-4-[3-(benzyloxy)hex-5-en-1-yl]-2-methoxybenzene (9). To a stirred suspension of
freshly activated NaH (0.53 g, 22 mmol) in dry THF (15 ml) at 08 was added dropwise a soln. of 8 (3.5 g,
22 mmol) in dry THF (30 ml). After 30 min, BnBr (2.1 g, 12 mmol) was added, and the mixture was
warmed to r.t. and stirred for 6 h. The reaction was quenched with an aq. NH4Cl soln. (20 ml) and
extracted with AcOEt (2 Â 20 ml). The combined org. layers were washed with brine, dried (Na2SO4),
and concentrated under reduced pressure to afford a crude product, which was purified by CC (SiO2,
60 – 120 mesh; AcOEt/hexane 1.5 :8.5) to afford 9 (4 g, 90%) as colorless liquid. IR (neat): 3064, 3031,
2932, 2861, 1589, 1512, 1456, 1417, 1379, 1345, 1262, 1226, 1139, 1071, 1029, 914, 851, 804, 737, 697.
1H-NMR (CDCl3): 1.70 – 1.85 (m, 2 H); 2.30 – 2.40 (m, 2 H); 2.50 – 2.60 (m, 1 H); 2.63 – 2.74 (m, 1 H);
3.38 – 3.48 (m, 1 H); 3.82 (s, 3 H); 4.42 (d, J ¼ 11.0, 1 H); 4.60 (d, J ¼ 11.0, 1 H); 5.01 – 5.12 (m, 4 H);
5.72 – 5.90 (m, 1 H); 6.58 (d, J ¼ 7.0, 1 H); 6.65 (s, 1 H); 6.71 (d, J ¼ 7.0, 1 H); 7.20 – 7.45 (m, 10 H). EI-MS:
403 (90, Mþ), 312 (10).
(2R)-4-(Benzyloxy)-6-[4-(benzyloxy)-3-methoxyphenyl]hexane-1,2-diol (10). A mixture of AD-mix
t
b (12.6 g) in BuOH/H2O 1:1 (90 ml) was stirred for ca. 30 min at 08, and then the olefin compound 9
(3.6 g, 9 mmol) was added. The resulting mixture was stirred for 24 h at 08. Then, the reaction was
quenched by adding Na2SO3, and the mixture was filtered, the solid was washed with AcOEt (2 Â 50 ml).
The filtrate was washed with brine, dried (Na2SO4), and concentrated under reduced pressure to obtain a
crude product, which was purified by CC (SiO2, 60 – 120 mesh; AcOEt/hexane 5 :5) to afford a 1:1
mixture of diastereoisomers 10 (3.5 g, 90%) as colorless syrup. IR (KBr); 3416, 2925, 2857, 1512, 1456,
1263, 1226, 1030, 739. 1H-NMR (CDCl3): 1.23 – 1.30 (m, 2 H); 1.76 – 2.01 (m, 2 H); 2.50 – 2.60 (m, 2 H);
3.33 – 3.90 (m, 7 H); 4.40 – 4.65 (m, 2 H); 5.05 (s, 2 H); 6.50 – 6.75 (m, 3 H); 7.2 – 7.45 (m, 10 H). ESI-MS:
437 ([M þ H]þ), 459 ([M þ Na]þ).
(2R)-2-{2-(Benzyloxy)-4-[4-(benzyloxy)-3-methoxyphenyl]butyl}oxirane (11). A mixture of 10
(3.3 g, 7 mmol), Ph3P (2.97 g, 11 mmol), and diethyl azodicarboxylate (DEAD; 1.97 g, 11 mmol) in
benzene (35 ml) was heated under reflux for 18 h, and the complete conversion of the starting material
was confirmed by TLC. Then, the solvent was removed under reduced pressure, and the residue was
diluted with Et2O (35 ml) to precipitate Ph3P¼O, which was removed by filtration. The filtrate was
concentrated, and the crude product was purified by CC (SiO2, 60 – 120 mesh; AcOEt/hexane 1:9) to
afford diastereoisomers of epoxide 11 (3 g, 95%) as colorless liquid. IR (KBr): 3032, 2927, 2861, 1593,
1
1512, 1456, 1416, 1380, 1346, 1262, 1226, 1141, 1075, 1029, 916, 849, 806, 742, 698. H-NMR (CDCl3):
1.70 – 2.01 (m, 4 H); 2.40 – 2.45 (m, 1 H); 2.55 – 2.75 (m, 3 H); 2.97 – 3.02 (m, 1 H); 3.52 – 3.65 (m, 1 H);
3.83 (s, 3 H); 4.51 – 4.60 (m, 2 H); 5.05 (s, 2 H); 6.50 – 6.75 (m, 3 H); 7.20 – 7.40 (m, 10 H). EI-MS: 418 (10,
Mþ), 401 (20), 383 (15), 375 (25), 357 (10), 343 (30), 321 (100), 311 (15), 308 (10), 277 (12), 249 (10), 225
(10), 192 (15), 181 (12), 165 (20), 153 (10).
(5S)-3-(Benzyloxy)-1-[4-(benzyloxy)-3-methoxyphenyl]decan-5-ol (12a). To a suspension of Mg
turnings (0.28 g, 11 mmol) in dry THF (5 ml) was added BuBr (0.98 g, 7 mmol) dropwise under N2
atmosphere at 08. The mixture was allowed to stir for 30 min at r.t. Catalytic amount of CuI was then
added at 08, the mixture was stirred at r.t. for another 30 min, then a soln. of epoxide 11 (1 g, 2 mmol) in
dry THF (10 ml) was added dropwise at 08, and the mixture was stirred at r.t. Progress of the reaction was
monitored by TLC. After completion of the reaction, an aq. NH4Cl soln. (10 ml) was added, and the
mixture was extracted with Et2O. The combined org. extracts were washed with brine (10 ml), dried
(Na2SO4), and the solvent was removed under vacuum to give a crude product, which was purified by CC
(SiO2, 60 – 120 mesh; AcOEt/hexane 1.5 :8.5) to afford the distereoisomeric product 12a (0.96 g, 85%) as

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pale-yellow liquid. IR (KBr): 3442, 3031, 2925, 2856, 1591, 1512, 1457, 1418, 1380, 1263, 1227, 1144, 1068,
1
1029, 852, 804, 741. H-NMR (CDCl3): 0.88 (t, J ¼ 6.0, 3 H); 1.22 – 1.35 (m, 5 H); 1.75 – 1.98 (m, 3 H);
2.10 – 2.20 (m, 1 H); 2.55 – 2.65 (m, 2 H); 3.35 (t, J ¼ 6.0, 2 H); 3.60 – 3.75 (m, 1 H); 3.88 (s, 3 H); 3.90 –
3.96 (m, 1 H); 4.10 – 4.20 (m, 1 H); 4.40 – 4.60 (m, 2 H); 5.12 (s, 2 H); 6.58 (d, J ¼ 7.0, 1 H); 6.65 (s, 1 H);
6.70 – 6.80 (m, 1 H); 7.20 – 7.45 (m, 10 H). EI-MS: 477 (100, Mþ), 474 (20), 441 (25), 433 (10), 412 (10),
358 (10), 329 (10), 291 (10), 279 (15), 277 (10), 222 (15), 205 (10), 201 (15), 159 (20), 139 (12), 116 (20).
(5S)-3-(Benzyloxy)-1-[4-(benzyloxy)-3-methoxyphenyl]dodecan-5-ol (12b). Yield: 87%. IR (KBr):
3454, 3031, 2925, 2855, 1716, 1592, 1512, 1457, 1263, 1030, 850, 737, 697. 1H-NMR (CDCl3): 0.88 (t, J ¼ 5.85,
3 H); 1.23 – 1.43 (m, 16 H); 2.43 – 2.64 (m, 2 H); 3.62 – 3.72 (m, 1 H); 3.82 – 3.92 (m, 4 H); 4.40 – 4.65 (m,
2 H); 5.10 (s, 2 H); 6.55 – 6.80 (m, 3 H); 7.22 – 7.45 (m, 10 H). ESI-MS: 505 ([M þ H]þ), 527 ([M þ
Na]þ).
(5S)-3-(Benzyloxy)-1-[4-(benzyloxy)-3-methoxyphenyl]tetradecan-5-ol (12c). Yield: 90%. IR
1
(KBr): 3459, 3031, 2924, 2854, 1719, 1591, 1511, 1263, 1029, 849, 736, 696. H-NMR (CDCl3): 0.88 (t,
J ¼ 6.9, 3 H); 1.22 – 1.50 (m, 20 H); 2.50 – 2.65 (m, 2 H); 3.63 – 3.74 (m, 1 H); 3.75 – 3.90 (m, 4 H); 4.42 –
4.68 (m, 2 H); 5.10 (s, 2 H); 6.55 – 6.80 (m, 3 H); 7.22 – 7.50 (m, 10 H). ESI-MS: 533 ([M þ H]þ), 555
([M þ Na]þ).
({(5S)-3-(Benzyloxy)-1-[4-(benzyloxy)-3-methoxyphenyl]decan-5-yl}oxy)(tert-butyl)dimethylsilane
(13a). To a soln. of 12a (0.9 g, 1 mmol) and 1H-imidazole (0.5 g, 7 mmol) in dry CH2Cl2 (5 ml) at 08 under
N2 atmosphere, TBDMSÀCl (0.56 g, 3.7 mmol) was added, and the mixture was stirred for 3 h and
allowed to warm to r.t. The mixture was diluted with H2O (3 ml) and extracted with CH2Cl2 (2 Â 5 ml).
The combined org. layers were washed with brine (5 ml), dried (Na2SO4), filtered, and concentrated
under vacuum to afford a crude product, which was purified by CC (SiO2, 60 – 120 mesh; AcOEt/hexane
1:9) afforded distereoisomeric product 13a (1.17 g, 92%) as colorless liquid. IR (KBr): 3032, 2929, 2857,
1592, 1512, 1460, 1417, 1378, 1258, 1139, 1076, 1037, 835, 774, 735. 1H-NMR (CDCl3): 0.21 (s, 6 H); 0.85 (s,
9 H); 0.90 (t, J ¼ 6.0, 3 H); 1.20 – 1.45 (m, 10 H); 1.68 – 1.90 (m, 3 H); 2.55 – 2.70 (m, 2 H); 3.50 – 3.70 (m,
1 H); 3.80 (s, 3 H); 4.40 – 4.58 (m, 2 H); 5.10 (s, 1 H); 6.60 (d, J ¼ 7.0, 1 H); 6.68 (s, 1 H); 6.75 (d, J ¼ 7.0,
1 H); 7.20 – 7.45 (m, 10 H). EI-MS: 590 (100, Mþ), 460 (15), 441 (10), 351 (10), 299 (15), 274 (10), 252
(20), 218 (12), 168 (10), 91 (12).
({(5S)-3-(Benzyloxy)-1-[4-(benzyloxy)-3-methoxyphenyl]dodecan-5-yl}oxy)(tert-butyl)dimethylsi-
lane (13b). Yield: 92%. IR (KBr): 3450, 2926, 2855, 1212, 1460, 1257, 1075, 835, 773, 697. 1H-NMR
(CDCl3): 0.01 – 0.06 (m, 6 H); 0.86 – 0.96 (m, 12 H); 1.22 – 1.48 (m, 14 H); 1.70 – 1.91 (m, 2 H); 2.53 – 2.69
(m, 2 H); 3.45 – 3.75 (m, 1 H); 3.83 – 3.91 (m, 4 H); 4.42 – 4.57 (m, 2 H); 5.11 (s, 2 H); 6.58 – 6.78 (m,
3 H); 7.24 – 7.48 (m, 10 H). ESI-MS: 619 ([M þ H]þ), 641 ([M þ Na]þ).
({(5S)-3-(Benzyloxy)-1-[4-(benzyloxy)-3-methoxyphenyl]tetradecan-5-yl}oxy)(tert-butyl)dimethyl-
silane (13c). Yield: 92%. IR (KBr): 3446, 2924, 2854, 1731, 1460, 1258, 1075, 773, 697. 1H-NMR (CDCl3):
0.01 – 0.06 (m, 6 H); 0.87 – 0.94 (m, 12 H); 1.22 – 1.48 (m, 18 H); 1.73 – 1.95 (m, 2 H); 2.52 – 2.72 (m, 2 H);
3.44 – 3.77 (m, 2 H); 3.85 – 3.89 (d, J ¼ 4.9, 3 H); 4.44 – 4.56 (m, 2 H); 5.10 (s, 2 H); 6.59 – 6.79 (m, 3 H);
7.20 – 7.48 (m, 10 H). ESI-MS: 669 ([M þ Na]þ).
4-[(5S)-5-{[tert-Butyl(dimethyl)silyl]oxy}-3-hydroxydecyl]-2-methoxyphenol (14a). To a stirred
soln. of 13a (1.1 g, 1 mmol) in AcOEt (15 ml) was added 10% Pd/C (100 mg), and the stirring was
continued under H2 atmosphere at r.t. for 5 h. The progress of reaction was monitored by TLC, then, the
mixture was filtered, and the catalyst was washed with AcOEt (2 Â 10 ml). The solvent was concentrated
under reduced pressure. The residue was separated by CC (SiO2, 60 – 120 mesh; AcOEt/hexane 1.5 :8.5)
to afford a mixture of diastereoisomeric product 14a (0.68 g, 90%) as colorless liquid. IR (KBr): 3449,
1
2931, 2858, 1610, 1515, 1462, 1373, 1261, 1152, 1038, 834, 768. H-NMR (CDCl3): 0.20 (s, 6 H); 0.70 (s,
9 H); 0.90 (t, J ¼ 6.0, 3 H); 1.12 – 1.30 (m, 8 H); 1.34 – 1.48 (m, 2 H); 1.50 – 1.70 (m, 2 H); 2.48 – 2.75 (m,
2 H); 3.55 – 3.70 (m, 1 H); 3.85 (s, 3 H); 3.88 – 3.98 (m, 1 H); 5.30 (s, 1 H); 6.60 – 6.70 (m, 2 H); 6.75 (d,
J ¼ 7.0, 1 H). EI-MS: 411 (100, Mþ), 391 (10), 319 (12), 286 (10), 279 (12), 261 (40), 163 (15), 137 (15).
4-[(5S)-5-{[tert-Butyl(dimethyl)silyl]oxy}-3-hydroxydodecyl]-2-methoxyphenol (14b). Yield: 90%.
IR (KBr): 3435, 2927, 2856, 1726, 1515, 1460, 1262, 1078, 1037, 834, 774. 1H-NMR (CDCl3): 0.04 – 0.10 (m,
6 H); 0.84 – 0.92 (m, 12 H); 1.16 – 1.43 (m, 14 H); 1.48 – 1.74 (m, 2 H); 2.48 – 2.76 (m, 2 H); 3.62 – 3.77 (m,
1 H); 3.84 – 4.01 (m, 4 H); 5.30 (s, 1 H); 6.62 – 6.78 (m, 3 H). ESI-MS: 439 ([M þ H]þ), 461 ([M þ Na]þ).

Helvetica Chimica Acta – Vol. 98 (2015)
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4-[(5S)-5-{[tert-Butyl(dimethyl)silyl]oxy}-3-hydroxytetradecyl]-2-methoxyphenol (14c). Yield:
1
92%. IR (KBr): 3448, 2926, 2855, 1515, 1463, 1261, 1080, 1037, 835, 776. H-NMR (CDCl3): 0.05 – 0.10
(m, 6 H); 0.84 – 0.94 (m, 12 H); 1.20 – 1.36 (m, 16 H); 1.35 – 1.78 (m, 4 H); 2.44 – 2.76 (m, 2 H); 3.62 – 3.74
(m, 1 H); 3.82 – 3.97 (m, 4 H); 5.30 (s, 1 H); 6.62 – 6.78 (m, 3 H). ESI-MS: 467 ([M þ H]þ), 489 ([M þ
Na]þ).
(5S)-1-[4-(Benzyloxy)-3-methoxyphenyl]-5-{[tert-butyl(dimethyl)silyl]oxy}decan-3-ol (15a). To a
stirred soln. of 14a (0.6 g, 1 mmol) and K2CO3 (0.4 g, 2 mmol) in acetone (20 ml) was added BnBr (0.25 g,
1 mmol) at r.t., and the mixture was stirred under reflux for 3 h. The progress of the reaction was
monitored by TLC, then, the solvent was removed under reduced pressure, and the residue was dissolved
in H2O and extracted with AcOEt (2 Â 15 ml). The org. layers were washed with brine, dried (Na2SO4),
and concentrated under reduced pressure to afford a crude product, which was purified by CC (SiO2,
60 – 120 mesh; AcOEt/hexane 1:9) to obtain a mixture of diastereoisomers 15a (0.65 g, 90%) as colorless
liquid. IR (KBr): 3451, 2926, 2855, 1672, 1512, 1461, 1378, 1258, 1138, 1074, 1036, 835, 771, 697. 1H-NMR
(CDCl3): 0.20 (s, 6 H); 0.85 (s, 9 H); 0.92 (t, J ¼ 6.0, 3 H); 1.20 – 1.40 (m, 10 H); 1.45 – 1.80 (m, 2 H); 2.50 –
2.70 (m, 2 H); 3.60 – 3.75 (m, 1 H); 3.85 (s, 3 H); 3.88 – 3.98 (m, 1 H); 5.10 (s, 2 H); 6.62 (d, J ¼ 7.0, 1 H);
6.75 (d, J ¼ 7.0, 2 H); 7.20 – 7.42 (m, 5 H). EI-MS: 501 (100, Mþ), 369 (15), 351 (60), 253 (10), 227 (10),
130 (10).
(5S)-1-[4-(Benzyloxy)-3-methoxyphenyl]-5-{[tert-butyl(dimethyl)silyl]oxy}dodecan-3-ol (15b).
1
Yield: 92%. IR (KBr): 3512, 3924, 2854, 1461, 1259, 1078, 1033, 836, 775. H-NMR (CDCl3): 0.05 –
0.14 (m, 6 H); 0.84 – 0.97 (m, 12 H); 1.32 – 1.45 (m, 14 H); 1.48 – 1.76 (m, 2 H); 2.51 – 2.77 (m, 2 H);
3.66 – 3.74 (m, 1 H); 3.84 – 3.95 (m, 4 H); 5.07 (s, 2 H); 6.59 – 6.82 (m, 3 H); 7.20 – 7.45 (m, 5 H). ESI-MS:
529 ([M þ H]þ), 551 ([M þ Na]þ).
(5S)-1-[4-(Benzyloxy)-3-methoxyphenyl]-5-{[tert-butyl(dimethyl)silyl]oxy}tetradecan-3-ol (15c).
1
Yield: 90%. IR (KBr): 3511, 2928, 2856, 1512, 1460, 1259, 1033, 836, 776. H-NMR (CDCl3): 0.04 –
0.11 (m, 6 H); 0.84 – 0.94 (m, 12 H); 1.16 – 1.33 (m, 16 H); 1.34 – 1.75 (m, 4 H); 2.52 – 2.73 (m, 2 H);
3.65 – 3.74 (m, 1 H); 3.83 – 3.97 (m, 4 H); 5.08 (s, 2 H); 6.60 – 6.78 (m, 3 H); 7.22 – 7.41 (m, 5 H). ESI-MS:
557 ([M þ H]þ).
(5S)-1-[4-(Benzyloxy)-3-methoxyphenyl]-5-{[tert-butyl(dimethyl)silyl]oxy}decan-3-one (16a). To a
stirred soln. of 15a (0.6 g, 1 mmol) in dry CH2Cl2 (10 ml) were added sequentially NaHCO3 (0.3 g,
3 mmol) and DessÀMartin periodinane (0.76 g, 1 mmol), and the mixture was stirred for 1 h at 08. The
completion of reaction was confirmed by TLC, and the mixture was extracted with CH2Cl2 (2 Â 10 ml).
The combined org. layers were washed with brine, dried (Na2SO4), and concentrated under reduced
pressure to afford a crude product, which was purified by CC (SiO2, 60 – 120 mesh; AcOEt/hexane 5 :95)
to afford the pure product 16a (0.5 g, 85%) as colorless liquid. IR (KBr): 2926, 1738, 1677, 1609, 1547,
1457, 1371, 1301, 1213, 1155, 1090, 1053, 854, 754. 1H-NMR (CDCl3): 0.20 (s, 6 H); 0.75 (s, 9 H); 0.90 (t,
J ¼ 6.0, 3 H); 1.20 – 1.38 (m, 8 H); 2.35 – 2.42 (m, 1 H); 2.50 – 2.60 (m, 1 H); 2.65 – 2.85 (m, 4 H); 3.88 (s,
3 H); 4.10 – 4.20 (m, 1 H); 5.10 (s, 2 H); 5.60 (d, J ¼ 7.0, 1 H); 6.70 (s, 1 H); 6.75 (d, J ¼ 7.0, 1 H); 7.28 – 7.45
(m, 5 H). EI-MS: 499 (100, Mþ), 481 (20), 367 (50), 269 (10), 227 (15), 215 (50).
(5S)-1-[4-(Benzyloxy)-3-methoxyphenyl]-5-{[tert-butyl(dimethyl)silyl]oxy}dodecan-3-one (16b).
Yield: 87%. IR (KBr): 2927, 2856, 1714, 1513, 1461, 1258, 1077, 1032, 836, 775. 1H-NMR (CDCl3):
0.01 – 0.08 (m, 6 H); 0.83 – 0.93 (m, 12 H); 1.24 – 1.34 (m, 12 H); 2.34 – 2.58 (m, 2 H); 2.65 – 2.85 (m, 4 H);
3.88 (s, 3 H); 4.10 – 4.17 (br. s, 1 H); 5.08 (s, 2 H); 5.58 – 5.75 (m, 3 H); 7.26 – 7.43 (m, 5 H). ESI-MS: 527
([M þ H]þ), 549 ([M þ Na]þ).
(5S)-1-[4-(Benzyloxy)-3-methoxyphenyl]-5-{[tert-butyl(dimethyl)silyl]oxy}tetradecan-3-one (16c).
Yield: 85%. IR (KBr): 2925, 2855, 1715, 1640, 1460, 1256, 1141, 1135, 855, 771. 1H-NMR (CDCl3):
0.01 – 0.08 (m, 6 H); 0.82 – 0.94 (m, 12 H); 1.22 – 1.34 (m, 16 H); 2.34 – 2.59 (m, 2 H); 2.65 – 2.85 (m, 4 H);
3.87 (s, 3 H); 4.05 – 4.18 (s, 1 H); 5.08 (s, 2 H); 5.58 – 5.76 (m, 3 H); 7.26 – 7.43 (m, 5 H). ESI-MS: 555
([M þ H]þ), 577 ([M þ Na]þ).
(5S)-5-{[tert-Butyl(dimethyl)silyl]oxy}-1-(4-hydroxy-3-methoxyphenyl)decan-3-one (17a). To a
soln. of 16a (0.4 g, 8 mmol) in AcOEt (10 ml) was added 10% Pd/C (100 mg), and the mixture was
stirred under H2 atmosphere at r.t. for 5 h. The progress of the reaction was monitored by TLC, then, the
mixture was filtered, and the catalyst was washed with AcOEt (2 Â 10 ml). The combined org. layers
were dried (Na2SO4) and concentrated under reduced pressure. The residue was separated by CC (SiO2,

1016
Helvetica Chimica Acta – Vol. 98 (2015)
60 – 120 mesh; AcOEt/hexane 1:9) to obtain the pure product 17a (0.3 g, 92%) as colorless liquid.
1
IR (KBr): 3449, 2922, 2853, 1714, 1516, 1462, 1371, 1262, 1149, 1074, 835, 776, 722. H-NMR (CDCl3):
0.20 (s, 6 H); 0.82 (s, 9 H); 0.90 (t, J ¼ 6.0, 3 H); 1.18 – 1.35 (m, 8 H); 2.30 – 2.40 (m, 1 H); 2.48 – 2.58 (m,
1 H); 2.65 – 2.85 (m, 4 H); 3.88 (s, 3 H); 4.06 – 4.20 (m, 1 H); 5.32 (s, 1 H); 6.62 (d, J ¼ 7.0, 2 H); 6.78 (d,
J ¼ 7.0, 1 H). EI-MS: 409 (90, Mþ), 381 (20), 367 (10), 309 (10), 277 (60), 215 (100), 179 (50), 141 (40),
137 (50).
(5S)-5-{[tert-Butyl(dimethyl)silyl]oxy}-1-(4-hydroxy-3-methoxyphenyl)dodecan-3-one (17b). Yield:
90%. IR (KBr): 3448, 2924, 2854, 1705, 1660, 1515, 1460, 1271, 1034, 764. 1H-NMR (CDCl3): 0.02 – 0.08
(m, 6 H); 0.82 – 0.93 (m, 12 H); 1.22 – 1.34 (m, 12 H); 2.34 – 2.56 (m, 2 H); 2.66 – 2.88 (m, 4 H); 3.88 (s,
3 H); 4.10 – 4.15 (m, 1 H); 5.32 (s, 1 H); 6.60 – 6.78 (m, 3 H). ESI-MS: 437 ([M þ H]þ), 459 ([M þ Na]þ).
(5S)-5-{[tert-Butyl(dimethyl)silyl]oxy}-1-(4-hydroxy-3-methoxyphenyl)tetradecan-3-one (17c).
Yield: 87%. IR (KBr): 3428, 2924, 2854, 1715, 1461, 1372, 1257, 1082, 835, 772. 1H-NMR (CDCl3):
0.01 – 0.08 (m, 6 H); 0.82 – 0.95 (m, 12 H); 1.20 – 1.35 (m, 16 H); 2.32 – 2.55 (m, 2 H); 2.65 – 2.88 (m, 4 H);
3.89 (s, 3 H); 4.10 – 4.17 (m, 1 H); 5.32 (s, 1 H); 6.62 – 6.78 (m, 3 H). ESI-MS: 465 ([M þ H]þ), 487
([M þ Na]þ).
(þ)-(S)-[6]-Gingerol (¼(5S)-5-Hydroxy-1-(4-hydroxy-3-methoxyphenyl)decan-3-one; 1). To a stir-
red soln. of 27 (0.25 g, 0.6 mmol) in dry THF (5 ml) under N2 atmosphere at 08 was added Bu4NF (1m,
THF, 0.60 ml) dropwise, and the mixture was allowed to be stirred at r.t. The progress of the reaction was
monitored by TLC, after completion of the reaction, the solvent was removed under reduced pressure,
and the residue was dissolved in H2O and extracted with AcOEt (2 Â 5 ml). The combined org. layers
were washed with brine, dried (Na2SO4), and concentrated under reduced pressure to afford a crude
product, which was purified by CC (SiO2, 60 – 120 mesh; AcOEt/hexane 2 :8) to obtain the pure product
1 (0.15 g, 87%) as colorless oil. [a]D25 ¼ þ24.3 (c ¼ 1, CHCl3) ([a]2D5 ¼ þ25.1 (c ¼ 1, CHCl3) [5c]). IR
(KBr): 3362, 2925, 2855, 1712, 1659, 1516, 1462, 1273, 1124, 653. 1H-NMR (CDCl3): 0.89 (t, J ¼ 6.5, 3 H);
1.12 – 1.38 (m, 8 H); 2.42 – 2.48 (m, 2 H); 2.69 (t, J ¼ 6.5, 2 H); 2.80 (t, J ¼ 6.5, 2 H); 3.88 (s, 3 H); 3.90 –
4.02 (m, 1 H); 5.32 (s, 1 H); 6.62 (d, J ¼ 7.0, 2 H); 6.78 (d, J ¼ 7.0, 1 H). 13C-NMR (75 MHz, CDCl3): 14.0;
22.6; 25.1; 29.3; 29.7; 31.7; 33.7; 36.3; 45.4; 49.3; 55.8; 110.9; 114.0; 114.3; 120.7; 132.5; 143.9; 211.5. ESI-
MS: 295 ([M þ H]þ), 317([M þ Na]þ).
(þ)-(S)-[8]-Gingerol (¼(5S)-5-Hydroxy-1-(4-hydroxy-3-methoxyphenyl)dodecan-3-one; 2). Yield:
90%. [a]2D5 ¼ þ25.8 (c ¼ 1, CHCl3) ([a]D25 ¼ þ26.2 (c ¼ 1, CHCl3) [5c]). IR (KBr): 3450, 2923, 2854, 1715,
1462, 1264, 1075, 835, 776. 1H-NMR (CDCl3): 0.89 (t, J ¼ 6.7, 3 H); 1.22 – 1.36 (m, 12 H); 2.34 – 2.55 (m,
2 H); 2.69 (t, J ¼ 6.7, 2 H); 2.81 (t, J ¼ 6.7, 2 H); 3.88 (s, 3 H); 3.92 – 4.02 (m, 1 H); 5.32 (s, 1 H); 6.58 – 6.79
(m, 3 H). 13C-NMR (75 MHz, CDCl3): 14.2; 22.5; 25.3; 29.1; 29.4; 29.8; 31.7; 36.4; 45.3; 49.2; 55.8; 67.6;
110.9; 114.3; 120.6; 132.5; 143.9; 146.4; 211.4. ESI-MS: 323 ([M þ H]þ), 345 ([M þ Na]þ).
(þ)-(S)-[10]-Gingerol (¼(5S)-5-Hydroxy-1-(4-hydroxy-3-methoxyphenyl)tetradecan-3-one; 3).
Yield: 90%. [a]2D5 ¼ þ18.9 (c ¼ 1, CHCl3) ([a]D25 ¼ þ19.8 (c ¼ 1, CHCl3) [5c]). IR (KBr): 3449, 2924,
2854, 1635, 1463, 1217, 1019, 766. 1H-NMR (CDCl3): 0.88 (t, J ¼ 5.0, 3 H); 1.24 – 1.40 (m, 16 H); 2.43 – 2.49
(m, 2 H); 2.68 (t, J ¼ 6.8, 2 H); 2.80 (t, J ¼ 7.5, 2 H); 3.87 (s, 3 H); 3.92 – 4.01 (m, 1 H); 5.34 (s, 1 H); 6.59 –
6.78 (m, 3 H). 13C-NMR (75 MHz, CDCl3): 14.1; 22.6; 24.6; 25.4; 28.7; 29.2; 29.3; 29.5; 29.6; 29.7; 29.8;
31.4; 31.8; 31.9; 33.7; 36.4; 45.4; 49.3; 55.8; 67.6; 110.9; 114.3; 120.7; 125.0; 132.6; 143.9; 211.4. ESI-MS:
351 ([M þ H]þ), 373 ([M þ Na]þ).
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Received December 18, 2014