A novel stereoselective synthesis of (-)-quinic acid starting from the naturally abundant (-)-shikimic acid

Article abstract of DOI:10.1016/j.tetasy.2015.10.008

A new stereoselective synthesis of (-)-quinic acid from the naturally abundant (-)-shikimic acid is described. Ethyl shikimate 2 was first prepared in 97% yield via esterification of (-)-shikimic acid according to a previous report. Ester 2 was then transformed into an epimeric mixture of 3,4-O-benzylidene shikimate 3, which was directly converted into compound 4 in 90% yield (over 2 steps from ester 2) via an NBS-mediated acetal ring-opening reaction. Acetylization of the hydroxyl group at the C-5 position of compound 4 gave compound 5 in 98% yield. Compound 5 was transformed into compound 6 in 91% yield via a highly stereoselective Ru-catalyzed dihydroxylation. Subsequently, compound 6 was converted into epoxide 7 in 82% yield via an intramolecular S_N2 type substitution. A regioselective epoxide-opening of compound 7 by PPh₃-I₂ complex furnished an iodo compound 8 in 79% yield. Removal of the iodine atom in compound 8 by Pd/C-catalyzed hydrogenation produced compound 9 in 92% yield. Methanolysis of compound 9 gave methyl quinate 10 in 92% yield. Finally, hydrolysis of compound 10 afforded the targeted compound (-)-quinic acid 1 in 90% yield. The title compound (-)-quinic acid 1 was stereoselectively synthesized through 10 steps starting from (-)-shikimic acid in 38% overall yield.

Full text of DOI:10.1016/j.tetasy.2015.10.008

Tetrahedron: Asymmetry xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A novel stereoselective synthesis of (ꢀ)-quinic acid starting
from the naturally abundant (ꢀ)-shikimic acid
⇑
Wei Zhang, Xing-Liang Zhu, Wei Ding, Xiao-Xin Shi
Department of Pharmaceutical Engineering, School of Pharmacy, East China University of Science and Technology, 130 Mei-Long Road, Shanghai 200237, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A new stereoselective synthesis of (ꢀ)-quinic acid from the naturally abundant (ꢀ)-shikimic acid is
described. Ethyl shikimate 2 was first prepared in 97% yield via esterification of (ꢀ)-shikimic acid accord-
ing to a previous report. Ester 2 was then transformed into an epimeric mixture of 3,4-O-benzylidene
shikimate 3, which was directly converted into compound 4 in 90% yield (over 2 steps from ester 2)
via an NBS-mediated acetal ring-opening reaction. Acetylization of the hydroxyl group at the C-5 position
of compound 4 gave compound 5 in 98% yield. Compound 5 was transformed into compound 6 in 91%
yield via a highly stereoselective Ru-catalyzed dihydroxylation. Subsequently, compound 6 was con-
Received 30 August 2015
Accepted 13 October 2015
Available online xxxx
verted into epoxide 7 in 82% yield via an intramolecular S
N
2 type substitution. A regioselective epox-
ide-opening of compound 7 by PPh –I complex furnished an iodo compound 8 in 79% yield. Removal
3
2
of the iodine atom in compound 8 by Pd/C-catalyzed hydrogenation produced compound 9 in 92% yield.
Methanolysis of compound 9 gave methyl quinate 10 in 92% yield. Finally, hydrolysis of compound
1
0 afforded the targeted compound (ꢀ)-quinic acid 1 in 90% yield. The title compound (ꢀ)-quinic
acid 1 was stereoselectively synthesized through 10 steps starting from (ꢀ)-shikimic acid in 38% overall
yield.
Ó 2015 Elsevier Ltd. All rights reserved.
1
. Introduction
ꢀ)-Quinic acid 1 (Scheme 1) is an important natural cyclitol
Due to the pharmaceutical importance of (ꢀ)-quinic acid and its
derivatives as well as the wide utility of (ꢀ)-quinic acid in
(
asymmetric synthesis, the ready availability of (ꢀ)-quinic acid is
(
cyclic polyol). (ꢀ)-Quinic acid is ubiquitous in the plant kingdom,
highly desirable. Although (ꢀ)-quinic acid can be isolated from
1
and exists in many different plants such as cinchona bark, coffee
beans, tobacco leaves, carrot leaves, apples, peaches, pears, plums,
Nature,
synthetic
preparations
from
the
inexpensive
starting materials are enormously helpful. Several syntheses of
1
vegetables, and so forth. (ꢀ)-Quinic acid was first isolated by
racemic (±)-quinic acid and enantiomerically pure (ꢀ)-quinic acid
2
9
Hofmann in 1790, and its structure and stereochemistry were
have been reported, while the development of a new efficient
3
established by Fisher and Dangschart in 1932 and 1937. The abso-
and practical synthesis of (ꢀ)-quinic acid remains considerable
lute stereochemistry of (ꢀ)-quinic acid was further confirmed by
interest.
means of X-ray analysis of a single crystal by Allen et al. in
(ꢀ)-Shikimic acid (see Scheme 1) can be readily obtained in
large quantities by extraction from Chinese star anise or other nat-
1
988.4 (ꢀ)-Quinic acid is known to exhibit antioxidative, anti-
5
10
inflammatory effects, as well as the ability to chelate transition
ural plants, and has been recently used as a starting material for
6
11
12
metals in vitro. Many derivatives of (ꢀ)-quinic acid, which exhibit
the syntheses of oseltamivir phosphate, (+)-valiolamine, (+)-
1
3
14
various bioactivities, have also been isolated from natural
valienamine, and some chiral building blocks. Due to the wide
availability of (ꢀ)-shikimic acid, (ꢀ)-shikimic acid being less
expensive than (ꢀ)-quinic acid, and the structural resemblance
between (ꢀ)-shikimic acid and (ꢀ)-quinic acid, (ꢀ)-shikimic acid
could be accordingly used as an appropriate starting material for
the synthesis of (ꢀ)-quinic acid. In 1991, Tamm et al. reported
the synthesis of (ꢀ)-quinic acid from (ꢀ)-shikimic acid; herein
we report a new stereoselective synthesis of (ꢀ)-quinic acid
starting from the naturally abundant (ꢀ)-shikimic acid.
7
resources. Moreover, (ꢀ)-quinic acid is a versatile chiral synthon
in organic synthesis, and it has been widely used as a starting
material for the synthesis of natural products and bioactive
8
compounds.
9e
⇑
Corresponding author.
E-mail address: xxshi@ecust.edu.cn (X.-X. Shi).
http://dx.doi.org/10.1016/j.tetasy.2015.10.008
957-4166/Ó 2015 Elsevier Ltd. All rights reserved.
0
Please cite this article in press as: Zhang, W.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.10.008

2
W. Zhang et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
2
HO
HO
CO2H
HO
HO
CO2Et
3
1
CO2Et
Br
2
CO Et
O
O
a
b
c
Ph
4
5
6
97%
90% from 2
BzO
(over 2 steps)
OH
-)-Shikimic acid
OH
OH
OH
(
2
3
4
OH
O
2
OH
CO2Et
2
1
OH
CO2Et
Br
CO2Et
Br
3
d
e
f
3
g
4
98%
91%
5
82%
BzO
79% for 8
BzO
BzO
1
2% for 8'
OAc
OAc
OAc
5
6
7
I
OH
OH
CO2Et
OH
CO2Et
OH
CO2Et
OH
CO Me
2
HO
I
HO
HO
HO
h
i
BzO
BzO
92%
BzO
92%
OAc
(major)
OAc
8' (minor)
OAc
OH
10
8
9
OH
CO2H
HO
HO
j
9
0%
OH
-)-Quinic acid 1
(
Scheme 1. A new stereoselective synthesis of (ꢀ)-quinic acid 1 starting from (ꢀ)-shikimic acid. Reagents and conditions: (a) see Ref. 15. (b) 1.1 equiv of PhCHO, 0.01 equiv of
TsOH, reflux for 6 h in CH CN. (c) 1.1 equiv of NBS, 0 °C for 1 h in CH CN. (d) 1.2 equiv of Ac O, 1.2 equiv of Et N, 0.1 equiv of DMAP, 0 °C–rt for 2 h in CH Cl . (e) 1.5 equiv of
NaIO , 1.0 equiv of H SO , 0.002 equiv of RuCl , 0 °C to 5 °C for 8 h in a mixed solvent (EtOAc/CH CN/H O = 3:3:1). (f) 1.5 equiv of NaH, 15–25 °C for 0.5 h in PhCH /DMSO
2:1). (g) 1.05 equiv of Ph P–I Cl . (h) Pd/C, 1.0 equiv of Et N, H (1.01 atm.), reflux for 3 h in EtOAc. (i) 10 equiv of Et N, reflux
(1:1), 1.1 equiv of DIPEA, ꢀ10 °C for 3 h in CH
for 12 h in MeOH. (j) 2.0 equiv of NaOH, rt for 5 h in a mixed solvent of THF/H O (1:1); then 2.0 equiv of HCl.
3
3
2
3
2
2
4
2
4
3
3
2
3
(
3
2
2
2
3
2
3
2
2
. Results and discussion
Our synthetic route for the new stereoselective synthesis of
N-bromosuccinimide (NBS) at 0 °C in acetonitrile to afford com-
pound 4 in 90% yield over two steps from 2. A plausible mechanism
for the cascade benzylic oxidation and allylic bromination is pro-
1
6
(
ꢀ)-quinic acid 1 starting from (ꢀ)-shikimic acid is depicted in
posed in Figure 1 according to Hanessian et al. As can be seen
from Figure 1, acetal 3 first underwent benzylic bromination to
form an unstable intermediate I-A, which quickly transformed into
intermediate I-B via cleavage of C–Br bond. The bromide anion
then attacked the C-3 position to form compound 4. Since the
allylic C-3 position is much more reactive than the non-allylic
C-4 position, the regioselectivity of the above reaction is exclusive.
Compound 4 was treated with 1.2 equiv of acetic anhydride,
Scheme 1. Ethyl shikimate 2 was first prepared in 97% yield accord-
ing to a known procedure.15 Compound 2 was then treated with
1
.1 equiv of benzaldehyde at reflux in acetonitrile in the presence
of a catalytic amount of para-toluenesulfonic acid (TsOH) to fur-
nish an epimeric mixture of ethyl 3,4-O-benzylidene shikimate 3,
which was used as such for being exposed to 1.1 equiv of
1
.2 equiv of trimethylamine and a catalytic amount of 4-N,
4
4
N-dimethylaminopyridine (DMAP) in dichloromethane at 0 °C to
room temperature to produce compound 5 in an almost quantita-
tive yield. Compound 5 was transformed into compound 6 via a
highly stereoselective Ru-catalyzed dihydroxylation. When com-
pound 5 was treated with 0.002 equiv of ruthenium trichloride,
3
COOEt
OH
3
COOEt
OH
NBS
O
O
O
O
Ph
17
Ph
Br
3
I-A
1
5
.5 equiv of sodium periodate and 1.0 equiv of sulfuric acid at 0–
°C in a mixed solvent of ethyl acetate, acetonitrile, and water
(
3 2
EtOAc/CH CN/H O = 3:3:1), a highly stereoselective dihydroxyla-
4
4
Br
O
tion smoothly took place to afford dihydroxy compound 6 in 91%
yield. The bulkiness of the bromine atom at the C-3 position ren-
dered the ruthenium catalyst to approach the double bond from
the opposite side of the bromine atom during the stereoselective
dihydroxylation, thus the two hydroxyl groups at the C-1 and C-
3
COOEt
OH
Br
3
COOEt
OH
O
O
O
Ph
Ph
4
I-B
2
positions of compound 6 have the orientation trans to the bro-
Figure 1. A plausible mechanism for the conversion of 3 into 4.
mine atom at the C-3 position, meaning that the two stereogenic
Please cite this article in press as: Zhang, W.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.10.008

W. Zhang et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
3
centers at the C-1 and C-2 positions should have (R,R) absolute
configurations. The stereoselectivity of the dihydroxylation was
very high; almost none of other diastereomer was detected by
palladium on carbon as the catalyst in the presence of 1.0 equiv of
triethylamine under hydrogen gas, compound 9 was thus obtained
in 92% yield. Next, compound 9 was treated with 10 equiv of tri-
ethylamine at reflux in methanol for 12 h to furnish methyl qui-
nate 10 in 92% yield. During this reaction, both the Bz and Ac
groups were removed, and the ethyl ester group at the C-1 position
was simultaneously changed to the methyl ester group.
Finally, compound 10 was treated with 2.0 equiv of sodium
hydroxide in a mixed solvent of tetrahydrofuran and water (THF/
2
H O = 1:1) at room temperature, which allowed hydrolysis of the
1
careful TLC and H NMR monitoring of crude product.
Subsequently, compound 6 was converted into epoxide 7 via an
intramolecular S
ted with 1.5 equiv of sodium hydride in a mixed solvent of toluene
and dimethyl sulfoxide (PhCH /DMSO = 2:1) at 15–25 °C, com-
N
2 type substitution. When compound 6 was trea-
3
pound 7 was obtained in 82% yield. The formation of epoxide 7
proved the trans relationship between the vicinal bromine atom
and the hydroxy group on the six-membered ring.
ester group to take place smoothly. After neutralization with
2.0 equiv of hydrochloric acid, the crude product was purified by
chromatography through a column of acidic resin to afford (ꢀ)-
quinic acid 1 in 90% yield.
When compound 7 was treated with 1.05 equiv of the complex
3 2
of triphenylphosphine and iodine (Ph P/I
= 1:1)18 in the presence
of 1.1 equiv of diisopropylethylamine (DIPEA) in dichloromethane
at ꢀ10 °C, a regioselective epoxide-opening smoothly took place
0
to afford compound 8 in 79% yield and its regioisomer 8 (see
3
. Conclusion
Fig. 2) in 12% yield. A plausible mechanism for the regioselective
epoxide-opening of compound 7 is proposed in Figure 2. As can
be seen from Figure 2, epoxide 7 first reacted with PPh –I and
3 2
In conclusion, we have successfully developed a new stereose-
lective synthesis of (ꢀ)-quinic acid 1. By using the naturally abun-
dant and commercially available (ꢀ)-shikimic acid as the starting
material, the target compound (ꢀ)-quinic acid 1 was synthesized
via 10 steps in 38% overall yield. In particular, the overall yield of
DIPEA to form a chelate intermediate compound shown in the
square parenthesis. The iodide ion then underwent a favorable
axial attack at C-2 via path a to produce intermediate I-C, which
was subject to hydrolysis to afford compound 8 as the major pro-
duct; iodide ion could also undergo a disfavorable equatorial attack
at C-3 via path b to produce intermediate I-D, which was subject to
9e
our synthesis is significantly better than Tamm et al. report
(
21–25% overall yield).
Three characteristic reactions in the above-described stereose-
0
hydrolysis to afford compound 8 as the minor product. Here, the
lective synthesis of (ꢀ)-quinic acid 1 are noteworthy. The first
intermediate compound I-C with two six-membered and bridge-
linked chair rings is probably more stable than the intermediate
compound I-D with six-membered and five-membered fused rings.
The iodide atom in compound 8 was removed via Pd-catalyzed
16
one is the NBS-mediated acetal ring-opening reaction of 3,4-O-
benzylidene shikimate 3, the exclusive regioselectivity of the reac-
tion is based on the fact that the allylic C-3 position is much more
reactive than the non-allylic C-4 position. The second one is the
ruthenium-catalyzed highly stereoselective dihydroxylation of
compound 5; the presence of sulfuric acid is crucial for low cata-
lyst-loading (0.002 mol %) for this stereoselective dihydroxyla-
hydrogenation under an atmosphere of H
2
(1.01 atm). Hydrogena-
tion of compound 8 was performed at reflux in ethyl acetate with
1
7
tion. The third one is the regioselective epoxide-opening of
compound 7, chelation of the active intermediate rendered the
favorable axial attack of iodide ion on C-2 to afford the desired
compound 8 as the major product.
AcO
1
4
5
OBz
3
EtO2C
2
OH
O
7
DIPEA PPh3-I2
4. Experimental
4
.1. General
AcO
5
OBz
4
1H and 13C NMR spectra were acquired on a Bruker AM-400
1
EtO2C
3
I
2
instrument. Chemical shifts are given on the delta scale as parts
per million (ppm) with tetramethylsilane (TMS) as the internal
standard. IR spectra were recorded on a Nicolet Magna IR-550
spectrometer. MS spectra were recorded on a Shimadzu GC–MS
O
O
P
Ph3
path a
path b
(disfavorable)
2
010 (EI) or a Mariner Mass Spectrum (ESI) equipment. The optical
(
favorable)
rotations of chiral compounds were measured on WZZ-1S
polarimeter at room temperature. Melting points were determined
on a Mel-TEMP II melting point apparatus. Column chromatogra-
phy was performed on silica gel. All chemicals are analytically
pure, and were used as received from the chemical suppliers. Ethyl
shikimate 2 was prepared via esterification of (ꢀ)-shikimic acid
AcO 5
1
I
4
AcO 5
1
4
OBz
3
OBz
EtO2C
EtO2C
I
2
2
3
O
O
O
O
P
P
Ph3
I-C
Ph3
1
5
I-D
according to a previous report.
H2O
H2O
4
.2. (3R,4S,5R)-Ethyl 3,4-O-benzylidene shikimate 3
I
OH
Ethyl shikimate 2 (10.00 g, 49.45 mmol) was dissolved in
OH
CO2Et
OH
CO2Et
HO
I
acetonitrile (120 mL). Benzyl aldehyde (5.780 g, 54.46 mmol) and
a catalytic amount of p-toluenesulfonic acid (86.10 mg, 0.50 mmol)
were then added to the solution. The mixture was then stirred and
heated at reflux for 6 h with continuous removal of the water by
azeotropic distillation. After the reaction was complete (checked
BzO
BzO
OAc
8
OAc
8'
Figure 2. A plausible mechanism for the epoxide-opening of 7.
2 2
by TLC, eluent: CH Cl /MeOH = 10:1), the solvent was removed
Please cite this article in press as: Zhang, W.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.10.008

4
W. Zhang et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
by vacuum distillation. The residue was then partitioned between
two phases of ethyl acetate (150 mL) and an aqueous solution of
sodium bicarbonate (30 mL, 5% w/w). Two phases were separated,
and the organic phase was washed with brine (15 mL). The organic
7.41 (dd, J
= 3.0 Hz, J
1H, H-4), 4.84 (dd, J
J = 7.1 Hz, 2H, CH in COOEt), 3.93–4.03 (m, 1H, H-5), 3.39 (br s,
1H, OH), 2.93 (dd, J = 17.9 Hz, J = 5.3 Hz, 1H, H-6), 2.52 (ddd,
= 17.9 Hz, J = 5.3 Hz, J = 1.0 Hz, 1H), 1.34 (t, J = 7.1 Hz, 3H, CH
in COOEt) ppm. C NMR (100 MHz, CDCl ) d 166.31 (PhCO),
165.40 (COOEt), 135.90 (Ar–C), 133.48 (Ar–C), 129.91 (Ar–C),
129.70 (Ar–C), 129.29 (C-1), 128.47 (C-2), 78.70 (C-4), 68.45 (CH
in COOEt), 61.39 (C-5), 46.14 (C-3), 32.05 (C-6), 14.16 (CH in
[M+H] : 369.0338;
= 3420, 2982, 1725, 1717, 1271,
1
= 7.2 Hz, J
= 1.0 Hz, 1H, H-2), 5.53 (dd, J
= 3.0 Hz, J = 7.5 Hz, 1H, H-3), 4.27 (q,
2
= 7.3 Hz, 2H, meta protons in Ph), 6.89 (dd,
J
1
2
1
= 7.4 Hz, J = 7.5 Hz,
2
1
2
2
solution was dried over anhydrous MgSO
4
, and then filtered.
1
2
Evaporation of solvent under vacuum gave an epimeric mixture
of compound 3 as a pale yellow oil, which could be used directly
for the next step without separation. Some of the crude oily
product was purified by flash chromatography (eluent: EtOAc/
hexane = 1:4) to give two pure isomers of compound 3 for charac-
terization. The characterization data of the two pure isomers are as
follows:
J
1
2
3
3
1
3
3
2
3
+
COOEt) ppm. HRMS (ESI) calcd for C16
found: 369.0331. IR (neat):
H18BrO
5
m
ꢀ1
One isomer of 3 (upper spot, R
f
= 0.525 on TLC with CH
2
Cl
2
/
H
1102, 1070, 713 cm .
2
5
1
MeOH = 15:1 as the eluent): [
NMR (400 MHz, CDCl
Ph), 7.35–7.43 (m, 3H, aromatic protons in Ph), 6.93 (dd,
= 3.5 Hz, J = 1.2 Hz, 1H, H-2), 5.97 (s, 1H, PhCH in the acetal moi-
ety), 4.86 (dd, J = 3.5 Hz, J = 6.4 Hz, 1H, H-3), 4.34 (dd, J = 6.5 Hz,
= 6.4 Hz, 1H, H-4), 4.24 (q, J = 7.1 Hz, 2H, CH in COOEt),
.07–4.16 (m, 1H, H-5), 3.35 (br s, 1H, OH), 2.82 (dd, J = 17.5 Hz,
= 4.5 Hz, 1H, H-6), 2.35 (ddd, 1H, = 17.5 Hz, = 4.5 Hz,
= 1.2 Hz, 1H, another H-6), 1.32 (t, J = 7.1 Hz, 3H, CH in COOEt)
): d = 166.21 (COOEt), 137.84 (Ar–
C), 133.27 (Ar–C), 131.46 (Ar–C), 129.34 (Ar–C), 128.43 (C-1),
a
]
D
= ꢀ41.7 (c 1.30, CHCl
3
).
3
) d 7.44–7.51 (m, 2H, aromatic protons in
4
.4. (3S,4S,5R)-Ethyl 5-acetoxy-3-bromo-4-benzoyloxy-cyclo-
hex-1-ene carboxylate 5
J
1
2
1
2
1
Compound 4 (10.00 g, 27.16 mmol), triethylamine (3.300 g,
J
2
2
3
2.61 mmol), and a catalytic amount of 4-N,N-dimethylaminopy-
ridine (330 mg, 2.701 mmol) were dissolved in dichloromethane
150 mL). The resulting solution was cooled to 0 °C by an ice bath,
4
1
J
J
2
J
1
J
2
(
3
3
1
3
after which acetic anhydride (3.330 g, 32.62 mmol) was added
dropwise over 5 min. After the addition was completed, the ice
bath was removed, and the mixture was further stirred at room
temperature for 2 h. After the reaction was complete (checked by
TLC, eluent: EtOAc/hexane = 1:4), the solution was transferred into
a separatory funnel. The organic phase was washed successively
ppm. C NMR (100 Hz, CDCl
3
1
26.36 (C-2), 102.61 (PhCH in the acetal moiety), 77.91 (C-3),
2.56 (CH in COOEt), 67.02 (C-4), 61.21 (C-5), 28.95 (C-6), 14.17
in COOEt) ppm. HRMS (EI) calcd for C16
91.1232; found: 291.1235. IR (neat): = 3469, 2911, 1715,
459, 1402, 1251, 1065, 756 cm . The other isomer of 3 (lower
= 0.510 on TLC with CH Cl /MeOH = 15:1 as the eluent):
). H NMR (400 MHz, CDCl ) d 7.39–
.49 (m, 2H, aromatic protons in Ph), 7.31–7.41 (m, 3H, aromatic
protons in Ph), 6.98 (dd, J = 3.5 Hz, J = 1.2 Hz, 1H, H-2), 5.92 (s,
H, PhCH in the acetal moiety), 4.77 (dd, J = 3.5 Hz, J = 7.4 Hz,
H, H-3), 4.22 (q, J = 7.1 Hz, 2H, CH in COOEt), 4.15 (dd,
= 7.5 Hz, J = 7.4 Hz, 1H, H-4), 3.83–3.93 (m, 1H, H-5), 3.00 (br
s, 1H, OH), 2.80 (dd, J = 17.4 Hz, J = 4.7 Hz, 1H, H-6), 2.26 (ddd,
= 17.4 Hz, J = 4.7 Hz, J = 1.2 Hz, 1H, another H-6), 1.29 (t,
J = 7.1 Hz, 3H, CH in COOEt) ppm. C NMR (100 MHz, CDCl
66.02 (COOEt), 136.45 (Ar–C), 132.55 (Ar–C), 131.82 (Ar–C),
29.73 (Ar–C), 128.48 (C-1), 126.87 (C-2), 104.33 (PhCH in the
in COOEt), 68.99 (C-4),
in COOEt) ppm. HRMS (ESI)
[M+H] : 291.1232; found: 291.1228. IR (neat):
7
2
+
(CH
3
19 5
H O [M+H] :
2
1
m
ꢀ
1
with aqueous HCl solution (2 M, 30 mL), aqueous K
2
CO
3
(2 M,
3
0 mL) solution and brine (20 mL). The organic solution was dried
spot R
f
2
2
2
5
1
4
over anhydrous MgSO , and then filtered. Evaporation of the sol-
vent under vacuum gave a crude product, which was purified by
flash chromatography (eluent: EtOAc/hexane = 1:4) to furnish pure
[a
]
D
= ꢀ127.6 (c 0.9, CHCl
3
3
7
1
2
2
5
compound 5 (10.93 g, 26.58 mmol) in 98% yield. [
a
]
D
= +87.6 (c
) d 8.02 (d, J = 7.2 Hz, 2H,
ortho protons in Ph), 7.62 (t, J = 7.3 Hz, 1H, para proton in Ph),
.45 (dd, J = 7.2 Hz, J = 7.3 Hz, 2H, meta protons in Ph), 6.99 (dd,
= 3.2 Hz, J = 1.2 Hz, 1H, H-2), 5.73 (dd, J
1H, H-4), 5.22–5.29 (m, 1H, H-5), 4.85 (dd, J
H, H-3), 4.26 (q, J = 7.1 Hz, 2H, CH
1
1
1
2
1
1
3 3
.30, CHCl ). H NMR (400 MHz, CDCl
2
J
1
2
7
1
2
1
2
J
1
2
1
= 6.8 Hz, J
1
= 6.8 Hz, J
2
2
= 6.4 Hz,
= 3.2 Hz,
J
1
2
3
1
3
3
3
) d
1
2
in COOEt), 2.93 (dd,
= 5.4 Hz, 1H, H-6), 2.64 (ddd, = 16.7 Hz,
= 1.0 Hz, 1H, another H-6), 1.96 (s, 3H, CH in Ac),
in COOEt). C NMR (100 MHz, CDCl
1
1
J
J
1
1
= 16.7 Hz,
= 5.4 Hz, J
.33 (t, J = 7.1 Hz, 3H, CH
J
2
J
1
2
3
3
acetal moiety), 78.69 (C-3), 74.09 (CH
1.21 (C-5), 29.52 (C-6), 14.18 (CH
2
1
3
3
3
)
6
3
+
d 170.11 (PhCO), 165.18 (COOEt), 165.13 (MeCO), 135.49 (Ar–C),
133.60 (Ar–C), 129.85 (Ar–C), 129.04 (Ar–C), 129.02 (C-1), 128.57
19 5
calcd for C16H O
m
ꢀ1
= 3468, 2912, 1716, 1459, 1405, 1251, 1065, 758 cm
.
(
2
C-2), 73.77 (C-4), 68.01 (C-5), 61.47 (CH
8.44 (C-6), 20.85 (CH in Ac), 14.19 (CH
calcd for C18 20BrO
neat): = 2982, 1729, 1725, 1711, 1449, 1366, 1246, 1112,
2
in COOEt), 43.93 (C-3),
in COOEt). HRMS (ESI)
6
[M+H] : 411.0443; found: 411.0438. IR
3
3
4
.3. (3S,4S,5R)-Ethyl 3-bromo-4-benzoyloxy-5-hydroxyl-cyclo-
+
H
hex-1-ene carboxylate 4
(
7
m
ꢀ
1
10 cm .
The above-obtained epimeric mixture of compound 3 was dis-
solved in acetonitrile (150 mL), and the resulting solution was
cooled to 0 °C by an ice bath. After N-bromosuccinimide (9.700 g,
4.5. (1R,2R,3S,4S,5R)-Ethyl 5-acetoxy-4-benzoyloxy-3-bromo-
5
4.50 mmol) was added in portions over 10 min, the mixture was
1,2-dihydroxy-cyclohexane carboxylate 6
stirred at 0 °C for 1 h, and then the reaction was complete (checked
by TLC, eluent: EtOAc/hexane = 1:4). Acetonitrile was removed by
vacuum distillation, and the residue was partitioned between
two phases of ethyl acetate (180 mL) and an aqueous solution of
sodium sulfite (30 mL, 10% w/w). The two phases were separated,
and the organic phase was washed with brine (20 mL). The organic
An aqueous solution of H
2 4
SO (5.0 mL, 1 M, 5.000 mmol) and
powdered NaIO (1.600 g, 7.480 mmol) were added into
4
a
100-mL round-bottomed flask equipped with a magnetic stirring
bar. The mixture was stirred at room temperature for 10 min,
and then a dilute aqueous solution of RuCl
3
(1.0 mL, 0.01 M,
solution was dried over anhydrous MgSO
4
, and then filtered.
0.01 mmol) was added. The resulting solution was stirred at
room temperature until the color turned bright yellow, after
which the temperature was cooled down to 0 °C by an ice-bath.
A solution of compound 5 (2.056 g, 5.000 mmol) in a mixed sol-
vent of ethyl acetate (18 mL) and CH CN (18 mL) was added at
3
0 °C. The mixture was then vigorously stirred at 0–5 °C for
Evaporation of the solvent under vacuum gave a crude product,
which was purified by flash chromatography (eluent: EtOAc/
hexane = 1:4) to furnish pure compound 4 (16.39 g, 44.51 mmol)
25
as a colorless oil in 90% yield (over 2 steps from 2). [
a
]
D
= +58.8
) d 8.02 (d, J = 7.1 Hz, 2H,
ortho protons in Ph), 7.55 (t, J = 7.3 Hz, 1H, para proton in Ph),
1
(
c 1.32, CHCl
3
). H NMR (400 Hz, CDCl
3
approximately 8 h. When TLC (eluent: EtOAc/hexane = 1:2)
Please cite this article in press as: Zhang, W.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.10.008

W. Zhang et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
5
showed the reaction was complete, a saturated aqueous Na
solution (35 mL) and a saturated aqueous NaHCO solution
25 mL) were added and the mixture was vigorously stirred for
2
S
2
O
3
4.7. (1S,2R,3S,4R,5R)-Ethyl 5-acetoxy-4-benzoyloxy-1,3-dihy-
droxy-2-iodo-cyclohexane carboxylate 8
3
(
1
5 min. The mixture was then transferred into a separatory fun-
Triphenylphosphine (0.795 g, 3.031 mmol) and iodine (0.769 g,
3.030 mmol) were dissolved in dichloromethane (15 mL), the mix-
ture was stirred at room temperature for 0.5 h to give a clear solu-
tion, which was immediately used in the following procedure.
Compound 7 (1.050 g, 2.882 mmol) and N,N-diisopropyl ethy-
lamine (0.410 g, 3.172 mmol) were dissolved in dichloromethane
(15 mL). The resulting solution was cooled to ꢀ10 °C by a salt-ice
nel and extracted three times with ethyl acetate (3 ꢁ 30 mL). The
combined organic extracts were then washed with brine (20 mL),
dried over anhydrous MgSO
filtrate under vacuum gave a crude product which was purified
by flash chromatography (eluent: EtOAc/CH Cl /hexane = 1:2:4)
to afford compound 6 (2.026 g, 4.550 mmol, 91%) as white crys-
4
and filtered. Concentration of the
2
2
2
5
1
tals, mp 149–150 °C. [
400 MHz, CDCl ) d 8.05 (d, J = 7.6 Hz, 2H, ortho protons in Ph),
.59 (t, J = 7.4 Hz, 1H, para protons in Ph), 7.46 (dd, J
a]
D
= ꢀ11.6 (c 2.11, CHCl
3
). H NMR
3 2
bath. The above-prepared solution of Ph P–I was then added
(
7
3
dropwise over 5 min. After the addition was finished, the mixture
was stirred at ꢀ10 °C for approximately 3 h, and the reaction was
monitored by TLC (eluent: EtOAc/hexane = 1:3). When the reaction
was complete, an aqueous solution of sodium sulfite (2 M, 10 mL)
was added, and the mixture was vigorously stirred for 5 min. The
mixture was then transferred into a separatory funnel, and two
phases were separated. The organic phase was dried over anhy-
1
1
2
= 7.6 Hz,
= 7.8 Hz,
= 6.9 Hz,
J
J
J
2
= 7.4 Hz, 2H, meta protons in Ph), 5.60 (dd,
= 7.9 Hz, 1H, H-4), 5.37 (ddd, = 7.9 Hz,
= 5.0 Hz, 1H, H-5), 4.32 (q, J = 7.1 Hz, 2H, CH
= 7.8 Hz, J
J
J
2
3
J
1
2
in COOEt), 4.30
2
= 6.5 Hz, 1H, H-
(
d, J = 6.5 Hz, 1H, H-2), 4.17 (dd, J
1
3
), 3.76 (br s, 1H, OH), 2.73 (br s, 1H, OH), 2.30 (dd,
= 13.4 Hz, = 5.0 Hz, 1H, H-6), 2.06 (dd, = 13.4 Hz,
= 6.9 Hz, 1H, another H-6), 1.89 (s, 3H, CH in Ac), 1.34 (t,
C NMR (100 MHz, CDCl ) d
J
J
1
J
2
J
1
drous MgSO
vacuum gave a crude product which was purified by flash chro-
matography (eluent: EtOAc/CH Cl /hexane = 1:2:6) to afford com-
4
, and then filtered. Concentration of the filtrate under
2
3
13
J = 7.1 Hz, 3H, CH
3
in COOEt).
3
2
2
1
1
72.38 (PhCO), 169.86 (MeCO), 165.42 (COOEt), 133.49 (Ar–C),
29.94 (Ar–C), 129.16 (Ar–C), 128.53 (Ar–C), 75.55 (C-4), 75.51
pound 8 (1.121 g, 2.277 mmol) as a colorless oil in 79% yield and
compound 8 (0.170 g, 0.345 mmol) as white crystals in 12% yield.
0
2
5
(
C-5) 74.72 (CH
2
in COOEt), 69.25 (C-1), 63.13 (C-2), 54.54 (C-
), 35.31 (C-6), 20.78 (CH in Ac), 14.12 (CH in COOEt). HRMS
Na [M+Na] : 467.0317; found:
= 3485, 2984, 1730 (br), 1367, 1271,
Characterization data for compound 8 are as follows: [
(c 1.72, CHCl ). H NMR (400 MHz, CDCl
3 3
a]
D
= ꢀ19.6
) d 8.04 (d, J = 7.8 Hz, 2H,
ortho protons in Ph), 7.58 (t, J = 7.6 Hz, 1H, para proton in Ph), 7.46
(dd, J = 7.8 Hz, J = 7.6 Hz, 2H, meta protons in Ph), 5.81 (dd,
= 9.7 Hz, J = 3.6 Hz, 1H, H-4), 5.73–5.58 (m, 1H, H-5), 4.63 (dd,
= 3.8 Hz, 1H, H-3), 4.56 (dd, J = 3.8 Hz, J = 1.6 Hz,
in COOEt), 2.67 (dd,
1
3
3
3
+
(
ESI) calcd for
C
18
H
21BrO
8
4
1
67.0327. IR (neat):
m
1
2
240, 1117, 710 cm 1.
ꢀ
J
J
1
2
1
= 3.6 Hz, J
2
1
2
1
H, H-2), 4.29 (q, J = 7.1 Hz, 2H, CH
2
4
.6. (1R,2S,3S,4S,5R)-Ethyl 5-acetoxy-4-benzoyloxy-2,3-epoxy-1-
J1 = 14.2 Hz, J2 = 10.7 Hz, 1H, H-6), 2.50 (ddd, J1 = 14.2 Hz,
J = 5.3 Hz, J = 1.6 Hz, 1H, another H-6), 2.00 (s, 3H, CH in Ac),
hydroxy-cyclohexane carboxylate 7
2
3
3
1
3
1
3 3
.36 (t, J = 7.1 Hz, 3H, CH in COOEt). C NMR (101 MHz, CDCl )
Compound 6 (2.000 g, 4.492 mmol) was dissolved in a mixed
solvent of toluene (20 mL) and dimethyl sulfoxide (10 mL). The
resulting solution was cooled to 15 °C by a cooled-water bath.
A dispersion of sodium hydride (0.270 g, 60% w/w, 6.751 mmol)
in mineral oil was added in portions over 10 min. After the addi-
tion was finished, the mixture was stirred at 15–25 °C for 0.5 h.
After the reaction was completed (checked by TLC, eluent: ace-
tone/hexane = 1:3), the mixture was diluted by ethyl acetate
d 172.39 (PhCO), 169.95 (MeCO), 165.37 (COOEt), 133.50 (Ar–C),
129.96 (Ar–C), 129.21 (Ar–C), 128.54 (Ar–C), 78.86 (C-4), 74.76
(C-5), 71.99 (CH in COOEt), 67.30 (C-1), 62.52 (C-3), 35.36 (C-2),
2
33.86 (C-6), 20.81 (CH in Ac), 14.11 (CH in COOEt). HRMS (ESI)
3
3
+
calcd for C18H21IO Na [M+Na] : 515.0179; found: 515.0173. IR
8
(neat):
m
= 3376, 2985, 1744 (br), 1722, 1365, 1297, 1110, 1094,
ꢀ
1
0
712 cm . Characterization data for compound 8 are as follows:
mp 164–165 °C. [
2
5
1
3
a
]
D
= ꢀ6.52 (c 1.50, CHCl ). H NMR (400 MHz,
(
50 mL). A dilute aqueous solution of HCl (1 M, 15 mL) was then
CDCl ) d 8.03 (d, J = 7.6 Hz, 2H, ortho protons in Ph), 7.60 (t,
3
added dropwise, after which the mixture was transferred into a
separatory funnel. Two phases were separated, and the aqueous
phase was extracted once more with ethyl acetate (20 mL). The
organic extracts were combined and washed with brine
J = 7.4 Hz, 1H, para proton in Ph), 7.47 (dd, J = 7.6 Hz, J = 7.4 Hz,
1
2
2H, meta protons in Ph), 5.61 (dd, J = 10.8 Hz, J = 9.6 Hz, 1H, H-
1
2
4), 5.33 (ddd, J = 10.8 Hz, J = 9.1 Hz, J = 5.0 Hz, 1H, H-5), 4.39
1
2
3
(d, J = 11.0 Hz, 1H, H-2), 4.32 (q, J = 7.1 Hz, 2H, CH2 in COOEt),
4.18 (dd, J = 11.0 Hz, J = 9.6 Hz, 1H, H-3), 3.67 (s, 1H, OH), 2.52
(
4
20 mL). The organic solution was dried over anhydrous MgSO ,
1
2
and then filtered. Concentration of the filtrate under vacuum
gave a crude product which was purified by flash chromatogra-
1 2
(s, 1H, OH), 2.28 (dd, J = 14.4 Hz, J = 5.0 Hz, 1H, H-6), 2.06 (dd,
J = 14.4 Hz, J = 9.1 Hz, 1H, another H-6), 1.88 (s, 3H, CH in Ac),
1
2
3
1
3
phy (eluent: acetone/CH
2
Cl
2
/hexane = 1:2:5) to afford compound
1.35 (t, J = 7.1 Hz, 3H, CH in COOEt). C NMR (100 MHz, CDCl3)
3
2
5
7
(1.345 g, 3.692 mmol) in 82% yield, mp 89–90 °C. [
a]
D
= ꢀ125
) d 8.07 (d, J = 7.6 Hz,
H, ortho protons in Ph), 7.61 (t, J = 7.8 Hz, 1H, para protons in
= 7.6 Hz, J = 7.8 Hz, 2H, meta protons in Ph),
.45–5.55 (m, 2H, H-4 and H-5), 4.35 (q, J = 7.1 Hz, 2H, CH in
= 1.2 Hz, 1H, H-3), 3.53 (d,
d 172.39 (PhCO), 169.95 (MeCO), 165.37 (COOEt), 133.50 (Ar–C),
129.96 (Ar–C), 129.21 (Ar–C), 128.54 (Ar–C), 76.10 (C-4), 75.37
1
(c 1.62, CHCl
3
). H NMR (400 MHz, CDCl
3
2
(C-5), 75.20 (CH in COOEt), 68.90 (C-1), 63.11 (C-2), 35.36 (C-3),
2
Ph), 7.47 (dd, J
5
1
2
33.45 (C-6), 20.81 (CH in Ac), 14.11 (CH in COOEt). HRMS (ESI)
3
3
+
2
8
calcd for C18H21IO Na [M+Na] : 515.0179; found: 515.0174. IR
COOEt), 3.74 (dd,
J = 3.8 Hz, 1H, H-2), 2.17 (dd, J
.09 (dd, J = 13.2 Hz, J
CH in Ac), 1.38 (t, J = 7.1 Hz, 3H, CH
100 MHz, CDCl 172.45 (PhCO), 169.81 (MeCO), 166.21
COOEt), 133.50 (Ar–C), 129.94 (Ar–C), 129.22 (Ar–C), 128.54
Ar–C), 72.70 (C-4), 72.37 (C-5), 66.56 (CH in COOEt), 62.83
C-1), 57.05 (C-2), 55.44 (C-3), 38.83 (C-6), 20.83 (CH
J
1
= 3.8 Hz,
J
2
(KBr film):
1092, 708 cm .
m = 3489, 2987, 1726 (br), 1705, 1367, 1269, 1242,
ꢀ
1
1
= 13.2 Hz, J
2
= 3.6 Hz, 1H, H-6),
2
1
2
= 5.1 Hz, 1H, another H-6), 1.96 (s, 3H,
1
3
3
3
in COOEt).
C NMR
4.8. (1S,3R,4R,5R)-Ethyl 5-acetoxy-4-benzoyloxy-1,3-dihydroxy-
cyclohexane carboxylate 9
(
(
(
(
3
)
d
2
A solution of compound 8 (0.700 g, 1.422 mmol) in ethyl acetate
(20 mL) was transferred into a three-necked round bottom flask,
which was equipped with a magnetic stirrer bar, an inlet and an
outlet of hydrogen gas. Palladium on carbon (100 mg, 10% w/w)
and trimethylamine (0.144 g, 1.424 mmol) were added. The flask
3
in Ac),
Na [M
1
4.13 (CH
3
in COOEt). HRMS (ESI) calcd for C18
H
20
O
8
+
+Na] : 387.1056; found: 387.1048. IR (KBr film):
m
= 3448,
ꢀ
1
2
918, 1729 (br), 1702, 1367, 1256, 1237, 1122, 710 cm
.
Please cite this article in press as: Zhang, W.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.10.008

6
W. Zhang et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
was purged several times with hydrogen gas. The suspension was
heated at reflux, and was stirred at reflux for approximately 3 h
under an atmosphere of hydrogen gas (1.01 atm.). After the reac-
tion was complete (checked by TLC, eluent: EtOAc/hexane = 1:2),
the mixture was passed through a thin layer of Celite to remove
the catalyst. Evaporation of the solvent gave a crude product,
which was purified by flash chromatography (eluent: EtOAc/
hexane = 1:2) to furnish pure compound 9 (0.480 g, 1.310 mmol)
68.06 (C-3), 42.44 (C-6), 38.45 (C-2). HRMS (ESI) calcd for
+
C
m
8 14 6
H O Na [M+Na] : 229.0688; found: 229.0481. IR (KBr film):
= 3408, 2965, 1726, 1646, 1440, 1267, 1085, 709 cm .
ꢀ1
Acknowledgment
We are grateful to the National Natural Science Foundation of
China (No. 20972048) for the financial support of this work.
25
1
as a colorless oil in 92% yield. [
NMR (400 MHz, CDCl ) d 8.06 (d, J = 7.3 Hz, 2H, ortho protons in
Ph), 7.57 (t, J = 7.5 Hz, 1H, para proton in Ph), 7.45 (dd,
a]
D
3
= ꢀ93.6 (c 1.51, CHCl ). H
3
References
1.
(a) Tuyun, A. F.; Uslu, H. J. Chem. Eng. Data 2012, 57, 190–194; (b) Tuyun, A. F.;
Uslu, H. J. Chem. Eng. Data 2012, 57, 2143–2146.
J
J
J
2
2
1
1
2
= 7.3 Hz,
= 10.4 Hz, J
= 4.2 Hz, 1H, H-4), 4.41–4.49 (m, 1H, H-3), 4.29 (q, J = 7.1 Hz,
in COOEt), 2.35 (dd, J = 13.2 Hz, J = 4.6 Hz, 1H, H-6),
.14–2.27 (m, 2H, two H-2 protons), 2.06 (dd, = 13.2 Hz,
= 9.6 Hz, 1H, another H-6), 1.95 (s, 3H, CH in Ac), 1.33 (t,
J = 7.1 Hz, 3H, CH ) d 173.90
in COOEt). 13C NMR (100 MHz, CDCl
J
2
= 7.5 Hz, 2H, meta protons in Ph), 5.77 (ddd,
2
= 9.2 Hz, J = 4.9 Hz, 1H, H-5), 5.14 (dd, J = 10.4 Hz,
3
1
2.
Hofmann, F. C. Crell’s Chem. Ann. 1790, 2, 314.
3. (a) Fischer, H. O. L.; Dangschat, G. Chem. Ber. 1932, 65, 1009; (b) Fischer, H. O. L.;
Dangschat, G. Helv. Chim. Acta 1937, 20, 705.
H, CH
2
1
2
4.
Christopher, A.; Allen, F. H.; Bugg, T. D. H.; Doyle, M. J.; Raithby, P. R. Acta
Crystallogr. 1988, C44, 1287.
J
1
J
2
3
5. (a) Landolfi, R.; Mower, R. L.; Steiner, M. Biochem. Pharmacol. 1984, 33, 1525–
530; (b) Pietta, P. G. J. Nat. Prod. 2000, 63, 1035–1042; (c) Robak, J.;
1
3
3
Gryglewski, R. J. Biochem. Pharmacol. 1988, 37, 837–841.
(
(
PhCO), 170.28 (MeCO), 166.10 (COOEt), 133.33 (Ar–C), 129.88
Ar–C), 129.65 (Ar–C), 128.50 (Ar–C), 75.88 (C-4), 75.41 (C-5),
6.
(a) Menelaou, M.; Konstantopai, A.; Mateescu, C.; Zhao, H.; Drouza, C.; Lalioti,
N.; Salifoglou, A. Inorg. Chem. 2009, 48, 8092–8105; (b) Cood, R.; Lay, P. A. J. Am.
Chem. Soc. 1999, 121, 7864–7876; (c) Menelaou, M.; Mateescu, C.; Salifoglou, A.
J. Agroaliment. Proc. Technol. 2011, 17, 344–347.
6
(
8.78 (CH
C-2), 20.96 (CH
for C18 Na [M+Na] : 389.1212; found: 389.1214. IR (neat):
= 3449, 2959, 2921, 1731 (br), 1724, 1451, 1367, 1275, 1233,
2
in COOEt), 66.87 (C-1), 62.73 (C-3), 39.10 (C-6), 37.27
3
in Ac), 14.12 (CH in COOEt). HRMS (ESI) calcd
3
7.
(a) Liu, Z.; Feng, Z.; Yang, Y.; Jiang, J.; Zhang, P. Fitoterapia 2014, 99, 109–116;
+
22 8
H O
(
b) Chen, J.; Mangelinckx, S.; Ma, L.; Wang, Z.; Li, W.; Kimpe, N. D. Fitoterapia
m
1
2014, 99, 1–6; (c) Lee, S. Y.; Moon, E.; Kim, S. Y.; Lee, K. R. Bioorg. Med. Chem.
Lett. 2013, 23, 2140–2144; (d) Nakamura, S.; Fujimoto, K.; Matsumoto, T.;
Nakashima, S.; Ohta, T.; Ogawa, K.; Matsuda, H.; Yoshikawa, M. Phytochemistry
ꢀ1
114, 1040, 715 cm .
2013, 92, 128–136; (e) Wu, S.-B.; Meyer, R. S.; Whitaker, B. D.; Litt, A.; Kennelly,
E. J. J. Nat. Prod. 2012, 75, 2246–2250; (f) Xu, J.-G.; Hu, Q.-P.; Liu, Y. J. Agric. Food
Chem. 2012, 60, 11625–11630; (g) Yang, M.; Cai, L.; Shen, X.; Zhao, M.; Yin, T.;
Ding, Z. Chin. J. Chem. 2012, 30, 1323–1326; (h) Ela, Aboul. Helv. Chim. Acta
4
.9. (1S,3R,4S,5R)-Methyl 1,3,4,5-tetrahydroxycyclohexane car-
boxylate 10
2012, 95, 61–66; (i) Huang, Y.-L.; Tsujita, T.; Tanaka, T.; Matsuo, Y.; Kouno, I.; Li,
D.-P.; Nonaka, G.-I. Phytochemistry 2011, 72, 2006–2014; (j) Song, S.; Li, Y.;
Feng, Z.; Jiang, J.; Zhang, P. J. Nat. Prod. 2010, 73, 177–184; (k) Jiang, J.; Zhang, B.
B.; Liao, Z. X. Chin. Chem. Lett. 2010, 21, 203–205; (l) Kahle, K.; Huemmer, W.;
Kempf, M.; Scheppach, W.; Erk, T.; Richling, E. J. Agric. Food Chem. 2007, 55,
Compound
9 (0.440 g, 1.200 mmol) and trimethylamine
(
(
1.220 g, 12.05 mmol) were dissolved in anhydrous methanol
15 mL). The mixture was heated at reflux, and was stirred at reflux
10605–10614; (m) Tsevegsuren, N.; Edrada, R.; Lin, W.; Ebel, R.; Torre, C.;
for 12 h. Methanol was removed by vacuum distillation, and the
residue was purified by flash chromatography (eluent: CH Cl
CH OH = 5:1) to furnish pure compound 10 (0.228 g, 1.106 mmol)
as white crystals in 92% yield, mp 125–126 °C (lit. 126–127 °C).
Ortlepp, S.; Wray, V.; Proksch, P. J. Nat. Prod. 2007, 70, 962–967; (n) Kim, H. J.;
Kim, E. J.; Seo, S. H.; Shin, C.-G.; Jin, C.; Lee, Y. S. J. Nat. Prod. 2006, 69, 600–603;
2
2
/
(
o) Grael, C. F. F.; Albuquerque, S.; Lopes, J. L. C. Fitoterapia 2005, 76, 73–82; (p)
3
Teramachi, F.; Koyano, T.; Kowithayakorn, T.; Hayashi, M.; Komiyama, K.;
Ishibashi, M. J. Nat. Prod. 2005, 68, 794–796.
19
2
5
19
19
[
lit.
4
3
a
]
D
= ꢀ31.2 (c 1.60, CH
3
OH) {lit.
= ꢀ31.6 (c 1.45, CH OH)}. H NMR (400 MHz, CD
.07 (dd, J = 6.6 Hz, J = 5.4 Hz, 1H, H-4), 3.92–4.02 (m, 1H, H-5),
.73 (s, 3H, OCH ), 3.38–3.46 (m, 1H, H-3), 1.95–2.12 (m, 3H, two
[
a
]
D
= ꢀ30.9 (c 1.86, CH
3
OH);
OD) d
8. (a) Sibilska, I. K.; Sicinski, R. R.; Ochalek, J. T.; Plum, L. A.; DeLuca, H. F. J. Med.
Chem. 2014, 57, 8319–8331; (b) Sinisi, V.; Boronova, K.; Colomban, S.; Navarini,
L.; Berti, F.; Forzato, C. Eur. J. Org. Chem. 2014, 1321–1326; (c) Laplace, D. R.;
Overschelde, M. V.; De Clercq, P. J.; Verstuyf, A.; Winne, J. M. Eur. J. Org. Chem.
2013, 728–735; (d) Shih, T.-L.; Gao, W.-L. Tetrahedron 2013, 69, 1897–1903; (e)
Jaiswal, R.; Dickman, M. H.; Kuhnert, N. Org. Biomol. Chem. 2012, 10, 5266–
9
g
30
1
[
a]
D
3
3
1
2
3
1
3
H-6 and one H-2), 1.87 (dd, J
NMR (100 MHz, CD OD) d 175.92 (COOMe), 76.81 (C-1), 76.50 (C-
), 71.38 (C-5), 68.22 (C-3), 52.90 (CH in COOMe), 41.94 (C-6),
8.31 (C-2). HRMS (ESI) calcd for C
1
= 13.2 Hz, J
2
= 9.2 Hz, 1H, H-2).
C
5277; (f) Usami, Y.; Suzuki, K.; Mizuki, K.; Ichikawa, H.; Arimoto, M. Org.
3
Biomol. Chem. 2009, 7, 315–318; (g) Altemoller, M.; Podlech, J. Eur. J. Org. Chem.
2009, 2275–2282; (h) Mulzer, J.; Drescher, M.; Enev, V. S. Curr. Org. Chem. 2008,
12, 1613–1630; (i) Prazeres, V. F. V.; Castedo, L.; Gonzalez-Bello, C. Eur. J. Org.
Chem. 2008, 3991–4003; (j) Smarrito, C. M.; Munari, C.; Robert, F.; Barron, D.
Org. Biomol. Chem. 2008, 6, 986–987; (k) Hong, A.-W.; Cheng, T.-H.;
Raghukumar, V.; Sha, C.-K. J. Org. Chem. 2008, 73, 7580–7585; (l) Shan, M.;
O’Doherty, G. A. Org. Lett. 2008, 10, 3381–3384; (m) Zhang, W.; Baranczak, A.;
Sulikowski, G. A. Org. Lett. 2008, 10, 1939–1941; (n) Metaferia, B. B.; Chen, L.;
Baker, H. L.; Huang, X.-Y.; Bewley, C. A. J. Am. Chem. Soc. 2007, 129, 2434–2435;
4
3
3
+
7
H
12
O
6
Na [M+Na] : 215.0532;
found: 215.0528. IR (KBr film):
m
= 3426, 2958, 1721, 1648, 1437,
.
ꢀ
1
1
323, 1266, 1112, 1085, 710 cm
4
.10. (ꢀ)-Quinic acid 1
(
o) Marchart, S.; Mulzer, J.; Enev, V. S. Org. Lett. 2007, 9, 813–816; (p) Wan, X.;
Doridot, G.; Joullie, M. M. Org. Lett. 2007, 9, 977–980; (q) Garg, N. K.; Caspi, D.
D.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, 5970–5978; (r) Shih, T.-L.; Lin, Y.-L.;
Kuo, W.-S. Tetrahedron 2005, 61, 1919–1924; (s) Shing, T. K. M.; Kwong, C. S. K.;
Cheung, A. W. C.; Kok, S. H.-L.; Yu, Z.; Li, J.; Cheng, C. H. K. J. Am. Chem. Soc. 2004,
Compound 10 (0.220 g, 1.066 mmol) was dissolved in a mixed
solvent of tetrahydrofuran (2 mL) and water (2 mL). Powdered
sodium hydroxide (0.086 g, 2.150 mmol) was then added, and
the mixture was stirred at room temperature for 5 h. An aqueous
solution of HCl (2.000 M, 1.1 mL, 2.200 mmol) was then added.
The mixture was passed through a column of acidic resin (10 cm)
with a mixed solvent of methanol and water (1:1) as the eluent.
Evaporation of the solvents under vacuum afforded (ꢀ)-quinic acid
1
26, 15990–15992; (t) Jiang, S.; Singh, G.; Boam, D. J.; Coggins, J. R. Tetrahedron:
Asymmetry 1999, 10, 4087–4090; (u) Barco, A.; Benetti, S. Tetrahedron:
Asymmetry 1998, 9, 2857–2864; (v) Barco, A.; Benetti, S.; Benetti, S.; Benetti,
S.; Marchetti, P.; Zanirato, V. Tetrahedron: Asymmetry 1997, 8, 3515–3545.
(a) Grewe, R.; Lorenzen, W.; Vinig, L. Chem. Ber. 1954, 87, 793–802; (b)
Smissman, E. E.; Oxman, M. A. J. Am. Chem. Soc. 1963, 85, 2184–2185; (c)
Wolinsky, J.; Novak, R.; Vasileff, R. J. Org. Chem. 1964, 29, 3596–3598; (d)
Bestmann, H. J.; Heid, H. A. Angew. Chem., Int. Ed. Engl. 1971, 10, 336–337; (e)
Meier, R.-M.; Tamm, C. Helv. Chim. Acta 1991, 74, 807–818; (f) Suemune, H.;
Matsuno, K.; Uchida, M.; Sakai, K. Tetrahedron: Asymmetry 1992, 3, 297–306; (g)
Hiroya, K.; Ogasawara, K. Chem. Commun. 1998, 2033–2034; (h) Draths, K. M.;
Knop, D. R.; Frost, J. W. J. Am. Chem. Soc. 1999, 121, 1603–1604; (i) Pansare, S.
V.; Adsool, V. A. Org. Lett. 2006, 8, 2035–2037.
9
.
1
1
(0.184 g, 0.958 mmol) as white crystals in 90% yield, mp 166–
9
g
25
9g
67 °C (lit.
D
167–168 °C). [
= ꢀ43.6 (c 2.03, H
O)}. 1H NMR (400 MHz, CD
dd, J = 6.5 Hz, J = 5.2 Hz, 1H, H-4), 3.95–4.05 (m, 1H, H-5),
.35–3.42 (m, 1H, H-3), 2.00–2.15 (m, 3H, two H-6 and one H-2),
.86 (dd, J = 13.4 Hz, J
= 9.8 Hz, 1H, H-2). 13C NMR (100 MHz,
OD) d 177.64 (COOH), 77.11 (C-1), 76.90 (C-4), 71.99 (C-5),
a]
D
= ꢀ43.2 (c 1.80, H
2
O) {lit.
3
0
[a
]
2
3
OD) d 4.09
(
3
1
1
2
1
0. (a) Ghosh, S.; Chisti, Y.; Banerjee, V. C. Biotechnol. Adv. 2012, 30, 1425–1431; (b)
Ohira, H.; Torii, N.; Aida, T. M.; Watanabe, M.; Smith, R. L. Sep. Purif. Technol.
2009, 69, 102–108; (c) Enrich, L. B.; Scheuermann, M. L.; Mohadjer, A.;
1
2
CD
3
Please cite this article in press as: Zhang, W.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.10.008

W. Zhang et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
7
Matthias, K. R.; Eller, C. F.; Newman, M. S.; Fujinaka, M.; Poon, T. Tetrahedron
Lett. 2008, 49, 2503–2505; (d) He, X.-H.; Liu, L.; Liu, X.-G.; Liu, Z.-P.; Zhao, G.-
M.; Li, H.-Y. Nat. Prod. Res. Dev. (in Chin.) 2008, 20, 914–917.
15. Federspiel, M.; Fischer, R.; Hennig, M.; Mair, H.-J.; Oberhauser, T.; Rimmler, G.;
Albiez, T.; Bruhin, J.; Estermann, H.; Gandert, C.; Gockel, V.; Gotzo, S.;
Hoffmann, U.; Huber, G.; Janatsch, G.; Lauper, S.; Rockel-Stabler, O.;
Trussardi, R.; Zwahlen, A. G. Org. Process Res. Dev. 1999, 3, 266–274.
16. (a) Hanessian, S.; Plessas, N. R. J. Org. Chem. 1969, 34, 1035–1044; (b)
Hanessian, S. Carbohydr. Res. 1966, 2, 86–88.
1
1. (a) Nie, L.-D.; Ding, W.; Shi, X.-X.; Quan, N.; Lu, X. Tetrahedron: Asymmetry
2
012, 23, 742–747; (b) Kim, H.-K.; Park, K.-J. Tetrahedron Lett. 2012, 53, 1561–
1
563; (c) Nie, L.-D.; Shi, X.-X.; Quan, N.; Wang, F.-F.; Lu, X. Tetrahedron:
Asymmetry 2011, 22, 1692–1699; (d) Nie, L.-D.; Shi, X.-X.; Ko, K. H.; Lu, W.-D. J.
Org. Chem. 2009, 74, 3970–3973; (e) Nie, L.-D.; Shi, X.-X. Tetrahedron:
Asymmetry 2009, 20, 124–129; (f) Karpf, M.; Trussardi, R. Angew. Chem., Int.
Ed. 2009, 48, 5760–5762.
17. (a) Plietker, B.; Niggemann, M. Org. Lett. 2003, 5, 3353–3356; (b) Shing, T. K. M.;
Tam, E. K. W.; Tai, V. W.-F.; Chung, I. H. F.; Jang, Q. Chem. Eur. J. 1996, 2, 50–57;
(c) Shing, T. K. M.; Tai, V. W.-F.; Tam, E. K. W. Angew. Chem., Int. Ed. Engl. 1994,
33, 2312–2313.
1
1
1
2. Quan, N.; Nie, L.-D.; Zhu, R.-H.; Shi, X.-X.; Ding, W.; Lu, X. Eur. J. Org. Chem.
18. (a) Back, T. G.; Gladstone, P. L.; Parvez, M. J. Org. Chem. 1996, 61, 3806–3814;
(b) Garcia-Granados, A.; Lopez, P. E.; Melguizo, E.; Moliz, J. N.; Parra, A.; Simeo,
Y. J. Org. Chem. 2003, 68, 4833–4844.
2
013, 6389–6396.
3. Ding, W.; Yu, J.-P.; Shi, X.-X.; Nie, L.-D.; Quan, N.; Li, F.-L. Tetrahedron:
Asymmetry 2015, 26, 1037–1042.
4. Quan, N.; Nie, L.; Shi, X.; Zhu, R.; Xia, L. Chin. J. Chem. 2012, 30, 2759–2766.
19. Banwell, M. G.; Hungerford, N. L.; Jolliffe, K. A. Org. Lett. 2004, 6, 2737–2740.
Please cite this article in press as: Zhang, W.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.10.008