Concise and Efficient Synthesis of [6]-Paradol

Article abstract of DOI:10.1021/acs.oprd.0c00553

An efficient synthesis of [6]-paradol (1) has been performed in four steps with a 72.0% overall yield. The present method highlights commercially available materials, convenient isolation with multiple crystallization without involving column chromatography, and a high-purity product (more than 99.2%), and it is amenable to large-scale synthesis.

Full text of DOI:10.1021/acs.oprd.0c00553

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Concise and Efficient Synthesis of [6]-Paradol
Xiang Shi,* TianTian Xia, Brooke E. McKamey, Xian Wu, Yue Sun, Weifeng Zhou,
and Guangyan Zhang*
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ABSTRACT: An efficient synthesis of [6]-paradol (1) has been performed in four steps with a 72.0% overall yield. The present
method highlights commercially available materials, convenient isolation with multiple crystallization without involving column
chromatography, and a high-purity product (more than 99.2%), and it is amenable to large-scale synthesis.
KEYWORDS: synthesis, [6]-paradol, vanillin, Wittig−Horner reaction, Grignard reaction
obtained with high purity (more than 99.2%) and high yield
(72.0% overall yield). In order to protect this valuable
synthetic method, we have applied for a patent in China and
obtained patent protection (CN110937985).
INTRODUCTION
■
[6]-Paradol, one of the bioactive components isolated from
ginger, has been widely used for food and medicines. Among
many ginger ingredients, [6]-paradol exhibits lower pungent
flavor, higher water solubility, and various biological activities
including anti-inflammation, antioxidation, and antibacteria.1 It
can markedly reduce neuroinflammatory responses by reducing
the secretion of iNOS and TNF-α,2 while also protecting the
primary hippocampal cells from beta-amyloid (Αβ) oligomers
and Αβ plaque.3 In addition to neuroprotective effects, several
in vivo and in vitro studies have also demonstrated that [6]-
paradol has a strong effect on diabetes prevention via
promotion of glucose utilization4 and displays significant
cytotoxicity against many human tumor cell lines.5
Because of its wide range of biological activities, several
synthetic protocols for [6]-paradol (1) have been reported
previously. As shown in Scheme 1, Shih et al. devised a concise
route from vanillin (2) using a three-step method with a 13.3%
overall yield.6 Galre et al. also used 2 as a starting material to
produce 1 using a seven-step method with a moderate overall
yield (19.1%).7 Both of these methods resulted in a relatively
low yield of 1. In addition, Choi et al. reported a more concise
protocol to obtain 1 with a satisfactory overall yield (48−58%)
via Claisen−Schmidt condensation and palladium hydrogen
reduction reaction.7 Although this route was easy to operate,
each step of the protocol required column chromatography for
purification; thus, it was not suitable for industrial-scale
production. Hori et al. also described synthetic routes using
a hydrogen borrowing C−C bond formation reaction for
synthesizing phytochemicals and successfully obtained 1 by Pd,
Ir catalysis with an overall yield of 65%.8 This route had a
satisfactory overall yield, but the intermediate compound 12
was not commercially available, and the catalyst Ir/chitin was
very expensive. In addition, every intermediate in this route
needed to be purified by column chromatography, which
significantly elevates the cost of production. Overall, all the
above routes were not suitable for mass production.
RESULTS AND DISCUSSION
■
The retrosynthetic analysis for 1 is shown in Scheme 2. We
anticipated that a reduction reaction and Grignard reaction
could translate 16 into target compound 1. The Wittig−
Horner reaction between 19 and 15 could yield compound 16.
Furthermore, compound 15 could be obtained by heating
vanillin (2) with benzyl bromide, and Weinreb amideb (19)
could be synthesized from 18 via two conventional reactions.
As shown in Scheme 3, the synthesis commenced with
commercially available vanillin (2). Using the reported
protocol (BnBr, K2CO3, MeOH, reflux, 2 h),9 we obtained
15 successfully. Then, the Wittig−Horner reaction of 15 with
compound 19, which was prepared according to the reported
method,10 gave 16 in satisfactory yield (91.5%). Subsequently,
16 underwent a Grignard reaction with heptylmagnesium
bromide to afford 17 in good yield (81.2%). To obtain the
target compound 1, we initially attempted to treat 17 with H2
in the presence of Pd/C according to Choi’s procedure (5%
Pd/C, room temperature, MeOH, 3 h).7 Unfortunately, a
mixture of desired product 1 and byproduct 1a was produced.
To avoid the formation of 1a, which may be closely related
to the amount of Pd/C in the catalytic hydrogenation
reaction,6 different reaction conditions were screened (Table
1), and dichloromethane was used as the solvent to lower the
activity of the catalyst. The yield of 17, 1, and 1a (Figure 1)
showed that the amount of Pd/C and various temperatures did
not have any influence on the production of 1a. Furthermore, a
Received: December 30, 2020
Published: May 20, 2021
To achieve a novel and more efficient method for large-scale
synthesis, a four-step synthetic route was developed in this
study. Through multiple recrystallizations, [6]-paradol was
https://doi.org/10.1021/acs.oprd.0c00553
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© 2021 American Chemical Society
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Scheme 1. Previous Preparations of [6]-Paradol (1)
prolonged reaction time revealed a smaller amount of desired
product 1 along with a larger amount of byproduct 1a, which
may be attributed to the poor selectivity between ketone
carbonyl and ethylenic bonds under the action of hydrogen.
Unsatisfied with the above result along with difficultly
removing byproduct 1a by recrystallization, another synthetic
strategy was designed (shown in Scheme 4). Given that the
carbonyl group on the amide structure is more difficult to
reduce by hydrogen compared with ketones, we turned our
attention to synthesize 20 using 16 via a reduction reaction in
the presence of Pd/C. After overnight reaction at room
temperature in CH2Cl2, a high-purity 20 was successfully
obtained with excellent yield (98%).
To optimize the reaction condition of catalytic hydro-
genation of compound 17 over palladium on charcoal, different
solvents were investigated (Table 2). It is found that the
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Scheme 2. Retrosynthetic Analysis of [6]-Paradol (1)
Scheme 3. Synthesis of Product 1 and Byproduct 1a
(1) in moderate yield (81%). After recrystallization with
petroleum ether and cyclohexane (∼1:1), high-purity 1 was
obtained as a white waxy solid.
Table 1. Product Yield under Various Reaction Conditions
a
b
entry
Pd/C (N)
temp. (°C)
time (h)
yield (17/1/1a)
1
2
3
4
5
6
7
0.005
0.010
0.005
0.005
0.005
0.005
0.005
25
25
0
50
25
25
25
3
3
3
3
1
2
5
-/56/42
-/52/41
-/55/43
-/46/40
24/33/11
13/44/32
CONCLUSION
■
In conclusion, we have demonstrated a concise and efficient
synthesis for the preparation of high-purity [6]-paradol (1)
(more than 99.2%) in four steps with an overall yield of 72.0%.
The isolation of each product was carried out by recrystalliza-
tion. Key steps of the strategy included the Wittig−Horner
reaction, the Grignard reaction, and a reduction reaction. The
proposed synthetic route was straightforward, effective and
meaningful for commercial large-scale production.
-/37/54
a
b
Compound 17 (500 mg, 2.7 mmol), CH2Cl2 (10 mL). Conversion
and ratio of 17/1/1a were determined by HPLC, and the structure
1
was confirmed by H NMR.
reaction could proceed smoothly in methanol, dichloro-
methane, THF, ethanol, and ethyl acetate. Importantly, the
reaction rate was faster with methanol and ethanol.
With compound 20 in hand, we treated it with
heptylmagnesium bromide for 4 h to afford crude [6]-paradol
EXPERIMENTAL SECTION
■
Unless otherwise stated, all the chemicals and reagents were
obtained commercially and used without further purification.
All NMR experiments were carried out on a Mercury 400 or
Figure 1. Structure of compounds 17, 1, and 1a.
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Scheme 4. Synthesis of Product 1
mol, 1.2 equiv) in dry THF (4 L), tert-BuOK (437 g, 3.8 mol,
1.2 equiv) was added in batches and stirred for 1 h. Then, a
solution of 15 in THF (ca. 3 M THF, 1.1 L, 3.24 mol, 1.0
equiv) was added dropwise to the above mixture at 0 °C.
Subsequently, the reaction mixture was allowed to stir
overnight at room temperature. The resulting solution was
poured into water, and the aqueous phase was extracted with
EtOAc. The organic layers were washed with water and brine
and dried over anhydrous Na2SO4. The dried solution was
filtered, and the filtrate was concentrated in vacuo to give crude
16 as a yellow solid, which was purified by recrystallization
(EtOAc/petroleum ether, ∼1:3, 0 °C) to give 16 (white solid,
970 g), yield 91.5%. 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J
= 15.7 Hz, 1H, Ar−H), 7.26−7.44 (m, 5H, Ar−H), 7.08−7.10
(m, 2H, Ar−H), 6.86−6.90 (m, 2H, CH = CH), 5.19 (s, 2H,
CH2), 3.93 (s, 3H, NCH3), 3.76 (s, 3H, OCH3), 3.31 (s, 3H,
OCH3); 13C NMR (100 MHz, CDCl3) δ 167.22, 149.94,
149.76, 143.38, 136.70, 128.60, 127.96, 127.21, 121.89, 113.76,
113.71, 111.05, 71.59, 61.30, 55.95, 32.55; HRMS (ESI): calcd
for C19H22NO4 [M + H]+, 328.1471; found, 328.1541.
Table 2. Product Yield under Various Reaction Solvents
a
b
entry
solvent (N)
time (h)
yield (compound 20)
1
2
3
4
5
6
7
8
9
CH2Cl2
CH2Cl2
MeOH
MeOH
EtOH
EtOH
EtOAc
EtOAc
THF
3 h
6 h
3 h
6 h
3 h
6 h
3 h
6 h
3 h
6 h
46%
61%
78%
98%
72%
94%
32%
67%
51%
10
THF
74%
a
b
Compound 16 (0.5 g, 3.0 mmol), solvent (10 mL). Conversion and
ratio of compound 20 was determined by HPLC, and the structure
1
was confirmed by H NMR.
Bruker AV500 spectrometer using CDCl3 or DMSO-d6 as the
solvent with tetramethylsilane as the internal standard.
Coupling constants were given in Hz, and chemical shifts
were expressed as δ values in ppm. The following multiplicity
abbreviations were used: (s) singlet, (d) doublet, (t) triplet,
(q) quartet, (m) multiplet, (br) broad, (dd) double doublet,
(dt) double triplet. High-resolution mass spectra (HRMS)
were obtained with Thermo Exactive Orbitrap plus spec-
trometer. Thin-layer chromatography was performed using
commercially available HSGF 254 precoated plates.
Diethyl (2-(Methoxy(methyl)amino)-2-oxoethyl)-
phosphonate (19). According to the reported method,10 to
a solution of K2CO3 (731.4 g, 5.3 mol, 1.2 equiv) in water (5
L), N-methyoxymethyl amine hydrochloride aqueous solution
(ca. 5.3 M H2O solution, 1 L, 5.3 mol, 1.2 equiv) was added
slowly under 0 °C and stirred for 1 h. Then, a solution of
chloroacetyl chloride in CH2Cl2 (ca. 2.2 M H2O solution, 2 L,
4.4 mol, 1.0 equiv) was added dropwise to the above reaction
solution. After vigorous stirring for 1 h under 0 °C, the mixture
was allowed to warm to room temperature and continue to stir
for 12 h. The resulting solution was poured into water, and the
aqueous phase was extracted with DCM. The organic layers
were washed with water and brine and dried over anhydrous
Na2SO4. The dried solution was filtered, and the filtrate was
concentrated in vacuo to give a colorless oil (565.7 g, yield
92.9%), which was used directly for the next reaction.
Warming triethyl phosphite (684.1 g, 4.12 mol, 1.0 equiv) to
100 °C, then the above colorless oil (565.7 g, 4.12 mol, 1.0
equiv) was added dropwise and kept stirring for 12 h. After
that, excess triethyl phosphite was removed by vacuum
distillation to give 19 as a yellow oil (940 g), yield 95.4%.
1H NMR (400 MHz, CDCl3) δ 4.21 (m, 4H, CH2 × 2 of
CH3CH2O), 3.78 (s, 3H, NCH3), 3.21 (s, 3H, OCH3), 3.19 (t,
J = 21.9, 2H, CH2P = O), 1.33 (t, J = 7.2 Hz, 6H, CH3 × 2 of
CH3CH2O); 13C NMR (100 MHz, CDCl3) δ 166.13 (CO),
62.52, 61.42, 32.08, 30.69, 16.32, 16.29; HRMS (ESI): calcd
for C8H18NO5P [M + H]+, 240.0923; found, 240.0992.
(E)-3-(4-(Benzyloxy)-3-methoxyphenyl)-N-methoxy-
N-methyl Acrylamide (16). To a solution of 19 (930 g, 3.8
(E)-1-(4-(Benzyloxy)-3-methoxyphenyl)dec-1-en-3-
one (17). To a solution of magnesium (185 g, 7.69 mol, 3.0
equiv) and I2 (40 g) in dry THF/toluene (∼1:1.5, 5 L), 1-
bromoheptane (1.4 kg, 7.69 mol, 3.0 equiv) was added
dropwise at 90 °C under Ar atmosphere. After the mixture was
stirred for 3 h, it was cooled to 0 °C, and a solution of 16 (840
g, 2.56 mol, 1.0 equiv) was added dropwise. Subsequently, the
reaction mixture was heated to room temperature and allowed
to stir for 1 h. The reaction mixture was then poured into
water, and the aqueous phase was extracted with EtOAc. The
organic layers were washed with brine and dried over
anhydrous Na2SO4. The dried solution was filtered, and the
filtrate was concentrated in vacuo to afford 17 (761 g, 81.2%)
as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.31−7.50 (m,
6H, Ar−H), 7.07 (t, J = 8.4 Hz, 2H, Ar−H), 6.87 (d, J = 8.3
Hz, 1H, Ar−H), 6.61 (d, J = 16.4 Hz, 1H, CH = CH), 5.19 (s,
2H, CH2), 3.92 (s, 3H, OCH3), 2.64 (t, J = 7.4 Hz, 2H, CH2),
1.67 (t, J = 6.7 Hz, 2H, CH2), 1.26−1.32 (m, 8H, CH2 × 4),
0.83−0.88 (m, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ
200.57 (C = O),150.45, 149.91, 142.31, 136.59, 128.61,
128.01, 128.00, 127.21, 124.55, 122.65, 113.62, 110.50, 70.93,
63.05, 31.93, 29.70, 29.66, 29.36, 22.68, 14.07; HRMS (ESI):
calcd for C24H31O3[M + H]+, 367.2195; found, 367.2228.
3-(4-Hydroxy-3-methoxyphenyl)-N-methoxy-N-meth-
ylpropanamide (20). A mixture of 16 (900 g, 2.74 mol) and
10% palladium on carbon (50 g) in MeOH (5 L) was stirred
under 1 atm of H2 at room temperature for 8 h. Subsequently,
the catalyst was removed by filtration, and the filtrate was
concentrated in vacuo to give 20 (644 g) as a grayish-white oil,
yield 98.4%, which was used in the next step without further
1
purification. H NMR (400 MHz, CDCl3) δ 6.83 (d, J = 7.9
Hz, 1H, Ar−H), 6.69−6.72 (m, 2H, Ar−H), 5.73 (br, 1H,
OH), 3.86 (s, 3H, NCH3), 3.60 (s, 3H, OCH3), 3.18 (s, 3H,
OCH3), 2.89 (t, J = 7.4 Hz, 2H, CH2), 2.71 (t, J = 7.4 Hz, 2H,
CH2); 13C NMR (100 MHz, CDCl3) δ 207.53 (CO),
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146.55, 144.05, 133.30, 120.93, 114.45, 111.33, 110.00, 61.32,
55.92, 34.19, 30.51; HRMS (ESI): calcd for C12H18NO4 [M +
H]+, 240.1158; found, 240.1217.
Brooke E. McKamey − Department of Kinesiology, Nutrition,
and Health, Miami University, Oxford, Ohio 45056, United
States
Xian Wu − Department of Kinesiology, Nutrition, and Health,
Miami University, Oxford, Ohio 45056, United States;
orcid.org/0000-0002-6805-3737
Yue Sun − Anhui Engineering Laboratory for Agro-products
Processing, School of Tea & Food Science, International Joint
Laboratory on Tea Chemistry and Health Effects, Anhui
Agricultural University, Hefei 230036, China
[6]-Paradol (1). 1-Bromoheptane (1.0 kg, 5.83 mol, 3.0
equiv) was added dropwise to a stirred solution of magnesium
(134 g, 5.83 mol, 3.0 equiv) and I2 (20 g) in dry THF/toluene
(∼1:1.5, 5 L) at 90 °C under Ar atmosphere. The reaction
mixture was allowed to stir for 3 h before being cooled to 0 °C,
and a solution of 20 in THF (ca. 1.9 M THF solution,1 L, 1.88
mol, 1.0 equiv) was added dropwise. Then, the reaction
mixture was allowed to stir for 1 h at room temperature. After
completion of the reaction (monitored by TLC), the mixture
was slowly poured into 5% HCl solution, and the aqueous
phase was extracted with EtOAc. The combined organic layers
were washed with brine and dried over anhydrous Na2SO4.
The dried solution was filtered, and the filtrate was
concentrated in vacuo to give crude compound 1 as a yellow
oil, which was purified by recrystallization (Hexane/petroleum
ether, ∼1:1, 0 °C) to give 1 (white waxy solid, 970 g), yield
81.4%. 1H NMR (400 MHz, CDCl3) δ 6.81 (d, J = 8.0 Hz, 1H,
Ar−H), 6.64−6.68 (m, 2H, Ar−H), 5.54 (br, 1H, OH), 3.86
(s, 3H, OCH3), 2.82 (t, J = 7.4 Hz, 2H, CH2), 2.68 (t, J = 7.6
Hz, 2H, CH2), 2.36 (t, J = 7.4 Hz, 2H, CH2), 1.50−1.58 (m,
2H, CH2), 1.24−1.28 (m, 8H, CH2 × 4), 0.87 (t, J = 6.7 Hz,
3H, CH3); 13C NMR (100 MHz, CDCl3) δ 210.75 (C = O),
146.51, 143.99, 133.15, 120.83, 114.42, 111.15, 55.92, 44.68,
43.21, 31.74, 29.62, 29.25, 29.13, 23.88, 22.67, 14.14; HRMS
(ESI): calcd for C17H27O3 [M + H]+, 279.1182; found,
279.1921.
Weifeng Zhou − Xuchang Yuanzhi Biological Technology Co.,
Ltd. Xuchang, Henan 461000, P. R. China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.oprd.0c00553
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Anhui Province Natural
Science Foundation [Grant No. 1808085QC77].
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Compound 1a as a white solid. 1H NMR (300 MHz,
CDCl3) δ 6.72 (d, J = 7.92 Hz, 1H, Ar−H) 6.55−6.59 (m, 2H,
Ar−H), 3.70 (s, 3H, OCH3), 3.48−3.55 (m, 1H, CH), 2.43−
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31.66, 31.56, 29.51, 29.12, 25.48, 22.48, 13.90; HRMS (ESI):
calcd for C17H29O3 [M + H]+, 281.4080; found, 281.4076.
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NMR spectra of compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Xiang Shi − State Key Laboratory of Bioelectronics, School of
Biological Science and Medical Engineering, Southeast
University, Nanjing, Jiangsu 210096, P. R. China;
Email: 101102029@seu.edu.cn
Guangyan Zhang − State Key Laboratory of Bioactive
Substances and Functions of Natural Medicines, Beijing Key
Laboratory of Active Substances Discovery and Druggability
Evaluation, Institute of Materia Medica, Chinese Academy of
Medical Sciences and Peking Union Medical College, Beijing
100050, China; Email: zhangguangyan@imm.ac.cn
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Liao, Y. R.; Teng, C. M.; Wu, T. S. Synthesis of Analogues of Gingerol
and Shogaol the Active Pungent Principles from the Rhizomes of
Zingiber officinale and Evaluation of Their Anti-Platelet Aggregation
Effects. Int. J. Mol. Sci. 2014, 15, 3926−3951.
Authors
TianTian Xia − State Key Laboratory of Bioelectronics, School
of Biological Science and Medical Engineering, Southeast
University, Nanjing, Jiangsu 210096, P. R. China
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