Novel and efficient syntheses of four useful shikimate-derived epoxy chiral building blocks via cyclic sulfite intermediates

Article abstract of DOI:10.1002/cjoc.201201000

All of the four stereoisomers of methyl 4,5-epoxy-3-hydroxy-cyclohex-1-ene- carboxylate (1a-1d) are useful chiral building blocks. Novel and efficient syntheses of these four epoxy chiral building blocks from naturally abundant (-)-shikimic acid (2) via c

Full text of DOI:10.1002/cjoc.201201000

FULL PAPER
DOI: 10.1002/cjoc.201201000
Novel and Efficient Syntheses of Four Useful Shikimate-
derived Epoxy Chiral Building Blocks via
Cyclic Sulfite Intermediates†
Quan, Na(全娜)
Nie, Liangdeng(聂良邓)
Shi, Xiaoxin*(施小新)
Zhu, Ruiheng(朱瑞恒)
Lü, Xia(吕霞)
Department of Pharmaceutical Engineering, School of Pharmacy, East China University of Science and Technol-
ogy, Shanghai 200237, China
All of the four stereoisomers of methyl 4,5-epoxy-3-hydroxy-cyclohex-1-ene-carboxylate (1a—1d) are useful
chiral building blocks. Novel and efficient syntheses of these four epoxy chiral building blocks from naturally abun-
dant (－)-shikimic acid (2) via cyclic sulfite intermediates are described in this article. The targeted compound
(3R,4R,5S)-1a was synthesized via four steps from (－)-shikimic acid in 79% overall yield. The other three targeted
compounds (3S,4R,5S)-1b, (3S,4S,5R)-1c and (3R,4S,5R)-1d were synthesized via seven steps from (－)-shikimic
acid in 56%, 64% and 65% overall yields, respectively.
Keywords chiron, cyclic sulfite, epoxide, shikimic acid, synthesis
Introduction
matic natural products via shikimate pathway in plants
and microorganisms.[9-11] (－)-Shikimic acid is also an
important starting material for the synthesis of ose-
talmivir phosphate (Tamiflu®),[12-19] which is an active
prodrug of the potent neuraminidase inhibitor[20-22] and
has been widely used for the therapies of both H5N1
and H1N1 influenza.[23-26]
(－)-Shikimic acid can be readily obtained in a large
quantity by extraction from the Chinese star anise or
other natural plants,[27-31] or could be produced in indus-
try from the fermentation using genetically modified E.
coli.[32-35] Because of the very resemblance between
scaffolds of (－)-shikimic acid and the four targeted
chiral building blocks (1a—1d), the naturally abundant
and commercially available (－)-shikimic acid can be
used as a suitable starting material for syntheses of the
targeted compounds 1a—1d.
The four stereoisomers of methyl 4,5-epoxy-3-hy-
droxy-cyclohex-1-ene-carboxylate (1a—1d, Figure 1)
are important and useful chiral building blocks for the
syntheses of (－)-chorismic acid and its analogues,[1-5]
antitumor alkaloids (＋)-narciclasine and (＋)-pancratis-
tatin,[6] epimers of methyl shikimate,[7] and some other
biologically active compounds.[8] Therefore, easy and
efficient preparations of these four epoxy chiral building
blocks from a commercially available and inexpensive
starting material are highly desirable.
3
HO
CO2CH3 HO
CO2CH3 HO
CO2CH3
S
S
S
R
R
R
4
5
S
R
S
O
O
O
1a
1b
1c
Kim and his colleagues reported a synthesis of
compound 1a from (－)-qunic acid.[21] Berchtold and
his colleague reported a synthesis of compound 1a also
from (－)-shikimic acid.[36] Compounds 1b and 1c have
been prepared by Berchtold via enzyme-catalyzed enan
tioselective hydrolysis of the corresponding racemic
esters.[1] Four methods for synthesis of compound 1d
have been reported,[1-3,7] and Gotor’s synthesis[7] of
compound 1d also started from (－)-shikimic acid.
Herein we want to report novel and efficient syntheses
of the four targeted chiral building blocks (1a—1d)
2
5
HO
HO
3
1 CO2H
6
HO
CO2CH3
R
S
4
R
O
OH
(-)-Shikimic acid 2
1d
Figure 1 Structures of four stereoisomers of methyl 4,5-epoxy-
3-hydroxy-cyclohex-1-ene-carboxylate 1 and (–)-shikimic acid 2.
(－)-Shikimic acid (2, Figure 1) is a pivotal bioge-
netic precursor in the biosynthesis of a variety of aro-
*
E-mail: xxshi@ecust.edu.cn; Tel.: 0086-021-64252052; Fax: 0086-021-64252052
Received October 13, 2012; accepted November 16, 2012; published online December 13, 2012.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201201000 or from the author.
Dedicated to 60th Anniversary of East China University of Science and Technology.
†
Chin. J. Chem. 2012, 30, 2759—2766
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Quan et al.
FULL PAPER
from the naturally abundant (－)-shikimic acid via
highly reactive cyclic sulfite intermediates, which can
be easily prepared according to known methods.[37,38]
86% yield. The subsequent nucleophilic substitution of
OTs group at C-3 allylic position of compound 7 was
performed by treating compound 7 with a mixture of
benzoic acid and triethylamine (BzOH∶Et3N＝3∶2)
at 60 ℃ in toluene,[40] and benzoate 8 was obtained in
85% yield. This nucleophilic substitution occurred via a
typical SN2 mechanism, so the (R)-configuration of C-3
was accordingly inverted into the (S)-configuration.
Notablely, the nucleophile (BzO–) only attacked the
OTs group at C-3 position during the reaction, while
leaving the OMs group at C-5 position intact. It is
probably due to the fact that the OTs group at the allylic
C-3 position was much more reactive than the OMs
group at non-allylic C-5 position. When compound 8
was treated with 1.0 equiv. of potassium carbonate at 0
℃ in anhydrous methanol, epoxide formation and si-
multaneous deblocking of benzoyl group took place
smoothly to give the desired compound (3S,4R,5S)-1b
in 93% yield.
Results and Discussion
As depicted in Scheme 1, compound (3R,4R,5S)-1a
was synthesized via a 4-step synthetic route. Methyl
shikimate 3 was readily prepared in 93% yield from
(－)-shikimic acid 2 according to a known procedure.[39]
Exposure of methyl shikimate 3 to 2.5 equiv. of thionyl
chloride and 2.5 equiv. of triethylamine in ethyl acetate
at 0 ℃ to room temperature efficiently produced
3,4-cyclic sulfite 4 in 98% yield. Treatment of com-
pound 4 with 1.5 equiv. of methanesulfonyl chloride,
1.5 equiv. of triethylamine and catalytic amount of
N,N-dimethylaminopyridine (DMAP) at 0 ℃ in ethyl
acetate produced mesylate 5 in 96% yield. Both
3,4-cyclic sulfite 4 and the corresponding mesylate 5
actually occurred as an epimeric mixture of two epimers
with different configurations of sulfur atoms, however,
separation of the two epimers was unnecessary, because
the two epimers of compound 5 gave the same product
in the next step. When compound 5 was treated with 1.5
equiv. of powdered potassium carbonate at room tem-
perature in anhydrous methanol, cascade methanolysis
of cyclic sulfite and intramolecular SN2-type reaction
took place smoothly to afford the desired compound
(3R,4R,5S)-1a in 90% yield.
Scheme 2 Synthesis of (3S,4R,5S)-1b from compound 5
O
CO2Me
HO
CO2Me
O
TsCl, Py
HCl
S
THF
r.t., 5 h
95%
CH2Cl2
r.t., 8 h
86%
O
HO
OMs
5
OMs
6
TsO
HO
CO2Me
3
BzO
HO
CO2Me
BzOH, Et3N
K2CO3
5
toluene,
CH3OH
60 oC, 4 h
0 oC, 30 min
93%
OMs
7
OMs
8
85%
Scheme 1 Synthesis of (3R,4R,5S)-1a from (－)-shikimic acid
HO
CO2Me
HO
CO2H
HO
CO2Me
Ref.[35]
93%
SOCl2, Et3N
EtOAc, 0 oC
to r.t., 12 h
O
HO
HO
1b
OH
2
OH
3
98%
As depicted in Scheme 3, compound (3S,4S,5R)-1c
was synthesized via a 5-step synthetic route from com-
O
CO2Me
MsCl, Et3N, cat. DMAP
O
O
S
S
pound 4. Cyclic sulfite
4 was obtained from
EtOAc, 0 oC, 1 h
96%
O
(－)-shikimic acid 2 in 91% yield via two steps as per
Scheme 1. Treatment of the compound 4 with 1.2 equiv.
of benzoyl chloride and 2.0 equiv. of triethylamine at
room temperature gave compound 9 in 98% yield. Hy-
drolysis of compound 9 with aqueous HCl at room
temperature in THF afforded compound 10 in 95%
yield.
OH
4
O
O
CO2Me
HO
CO2Me
K2CO3
CH3OH, 0 oC, 30
min
90%
O
OMs
5
1a
Exposure of compound 10 to 3.0 equiv. of methane-
sulfonyl chloride, 3.0 equiv. of triethylamine and cata-
lytic amount of DMAP at 0 ℃ in ethyl acetate pro-
duced bis-mesylated compound 11 in 97% yield. Next,
when compound 11 was treated with 2.0 equiv. of
1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) and 6.0
equiv. of acetic acid (AcOH∶DBU＝3∶1, molar ratio)
at 60 ℃ in toluene,[40] selective SN2-type replacement
of the OMs group at C-3 position of compound 11 by an
OAc group took place smoothly to afford compound 12
in 86% yield. Since the OMs group at the C-3 position
is much more reactive than the OMs group at C-4 posi-
tion, so the nucleophilic substitution at the allylic C-3
As depicted in Scheme 2, compound (3S,4R,5S)-1b
was synthesized via a 4-step synthetic route from com-
pound 5. The cyclic sulfite intermediate 5 was obtained
in 87% yield from (－)-shikimic acid 2 via a 3-step se-
quence as per Scheme 1. After treatment of compound 5
with aqueous concentrated hydrochloric acid at room
temperature in tetrahydrofuran, the cyclic sulfite func-
tional group was removed, and compound 6 was then
obtained in 95% yield. Regioselective mono-tosylation
of compound 6 with 2.0 equiv. of toluenesulfonyl chlo-
ride in the presence of 6.0 equiv. of pyridine at room
temperature in dichloromethane produced tosylate 7 in
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Syntheses of Four Useful Shikimate-derived Epoxy Chiral Building Blocks
Scheme 3 Synthesis of (3S,4S,5R)-1c from compound 4
O
O
CO2Me
O
O
CO2Me
HO
HO
CO2Me
O
O
MsCl, Et3N, cat. DMAP
HCl
BzCl, Et3N
S
S
EtOAc, 0 oC, 1 h
97%
THF, r.t., 5 h
95%
CH2Cl2, r.t., 4 h
98%
OH
OBz
OBz
4
9
10
AcO
MsO
CO2Me
3
MsO
MsO
CO2Me
HO
CO2Me
K2CO3
CH3OH, 0 oC to r.t., 1 h
CH3COOH, DBU
4
toluene, 60 oC, 3 h
86%
O
90%
OBz
12
OBz
11
1c
position was exclusive, and the (R)-configuration of C-3
was inverted into the (S)-configuration via a typical SN2
mechanism. Treatment of compound 12 with 1.0 equiv.
of K2CO3 at 0 ℃ to room temperature in anhydrous
methanol furnished the desired compound (3S,4S,5R)-1c
in 90% yield.
desired compounds (3R,4R,5S)-1a, (3S,4R,5S)-1b,
(3S,4S,5R)-1c and (3R,4S,5R)-1d were efficiently syn-
thesized from the naturally abundant (－)-shikimic acid
in 79%, 56%, 64% and 65% overall yields, respectively.
Characterization data of our synthetic samples of the
four targeted compounds (1a—1d) are consistent with
those data reported in the above-mentioned litera-
tures.[1-3,7,36]
As compared with the known syntheses of com-
pounds 1a—1d,[1,7,36] our syntheses outlined in Schemes
1—4 are obviously more efficient and practical, and
used less expensive reagents. The overall yield of com-
pound (3R,4R,5S)-1a was increased from 70%[36] to
79%, and the overall yield of compound (3R,4S,5R)-1d
was significantly increased from 47%[7] to 65%.
As depicted in Scheme 4, compound (3R,4S,5R)-1d
was synthesized via a 3-step synthetic route from com-
pound 10. The Compound 10 was obtained from
(－)-shikimic acid 2 in 85% yield via four steps as per
Schemes 1 and 3. When compound 10 was exposed to
1.2 equiv. of p-chlorobenzoyl chloride and 2.0 equiv. of
triethylamine at room temperature in ethyl acetate, se-
lective protection of the less hindered hydroxyl at allylic
C-3 position took place smoothly to afford compound
13 in 88% yield. Treatment of compound 13 with 2.0
equiv. of methanesulfonyl chloride, 2.0 equiv. of
triethylamine and catalytic amount of DMAP at 0 ℃ in
ethyl acetate produced compound 14 in 97% yield. Re-
moval of protecting groups (p-Cl-Bz and Bz) on the
both hydroxyls at C-3 and C-5 positions and the simul-
taneous epoxide formation by treating compound 14
with 1.0 equiv. of K2CO3 at 0 ℃ in anhydrous metha-
nol finally furnished the desired compound (3R,4S,5R)-
1d in 90% yield.
Experimental
General methods
1H and 13C NMR spectra were acquired on a Bruker
AM-500 instrument. Chemical shifts were given on the
delta scale as parts per million (ppm) with tetramethyl-
silane (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 2010 or a
Mariner Mass Spectrum equipment. Optical rotations of
chiral compounds were measured on a Perkin-Elmer
polarimeter at room temperature. Melting points were
determined on a Mel-TEMP II melting point apparatus.
Column chromatography was performed on silica gel
(Qingdao Chemical Factory). All reagents and solvents
were analytically pure, and were used as such as re-
ceived from the chemical suppliers. (－)-Shikimic acid
was purchased from a Chinese company. (－)-Methyl
shikimate 3 was prepared in 93% yield according to the
reported procedure.[39]
Scheme 4 Synthesis of (3R,4S,5R)-1d from compound 10
3
HO
HO
CO2Me
p-Cl-BzO
CO2Me
p-Cl-BzCl, Et3N
4
5
EtOAc, r.t., 10 h
88%
HO
OBz
OBz
13
10
p-Cl-BzO
CO2CH3
K2CO3
MsCl, Et3N, cat. DMAP
CH3OH, 0 oC, 1 h
90%
MsO
EtOAc, 0 oC, 1 h
97%
OBz
14
(3R,4S,5R)-Methyl 3,4-O-thionylshikimate (4)
(－)-Methyl shikimate 3 (10.00 g, 53.14 mmol) and
triethylamine (13.44 g, 132.8 mmol) were dissolved in
ethyl acetate (200 mL), and resulting solution was
cooled down to 0 ℃ with an ice bath. A solution of
thionyl chloride (15.81 g, 132.9 mmol) in dichloro-
methane (30 mL) was then dropwise added over 1 h,
and the temperature of the reaction mixture was kept
below 10 ℃ during the addition. After the dropwise
addition was finished, the ice bath was removed, and the
mixture was warmed to room temperature. The reaction
HO
CO2CH3
O
1d
Conclusions
In conclusion, we have successfully developed novel
asymmetric syntheses of four useful chiral building
blocks, i.e. four stereoisomers of methyl 4,5-epoxy-3-
hydroxycyclohex-1-ene-carboxylate (1a—1d). The four
Chin. J. Chem. 2012, 30, 2759—2766
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－
1
mixture was then further stirred at room temperature for
12 h. The reaction was quenched by adding water (60
mL) and an aqueous solution of potassium carbonate
(20% w/v, 110 mL) until pH 8—9. The organic phase
was separated and dried over anhydrous MgSO4, and
then was concentrated under vacuum to afford a pale
yellow oily product that could be directly used for the
next step or purified by flash chromatography to furnish
cyclic sulfite 4 (12.20 g, 52.08 mmol) in 98% yield.
[α]2D0 ＋54.0 (c 2.9, CHCl3). For major diastereomer:
1H NMR (500 MHz, CDCl3) δ: 2.27—2.40 (m, 1H),
2.79—2.95 (m, 2H), 3.81 (s, 3H), 3.97 (dd, J＝12.9, 6.2
Hz, 1H), 4.87 (dd, J＝7.8, 6.2 Hz, 1H), 5.54—5.61 (m,
1H,), 6.86—6.92 (m, 1H); 13C NMR (100 MHz, CDCl3)
δ: 165.77, 133.03, 129.44, 81.20, 75.79, 67.16, 52.60,
992, 968, 921, 829, 779 cm ; MS (EI) m/z (%): 311 (1)
[M]＋, 281 (20), 230 (3), 216 (4), 169 (5), 152 (100), 137
(29), 124 (50), 109 (44), 93 (15), 79 (30), 53 (18);
HR-ESI-MS m/z: 334.9873 [M＋Na]＋ (m/z calcd for
[C9H12O8S2Na]＋ 334.9871).
(3S,4R,5R)-Methyl 4,5-epoxy-3-hydroxycyclohex-
1-ene-carboxylate (1a) To a solution of cyclic sulfite
5 (5.000 g, 16.01 mmol) in anhydrous methanol (50 mL)
was added powdered potassium carbonate (3.319 g,
24.01 mmol). After stirring was continued at room tem-
perature for 1 h, the reaction was complete. The reaction
solution was concentrated under vacuum to remove
methanol, and then ethyl acetate (200 mL) and brine (15
mL) were added. After the mixture was vigorously
stirred for 15 min, organic phase was separated and
dried over anhydrous MgSO4. Removal of the solvent
under a vacuum gave a crude solid product, which was
triturated in a mixed solvent of hexane and ethyl acetate
[V(EtOAc)∶V(hexane)＝1∶4] to afford pure com-
pound 1a (2.452 g, 14.41 mmol) as off-white crystals in
90% yield. m.p. 80.4—81.6 ℃ (lit.[36] 81—82 ℃),
[α]2D0 －56.4 (c 3.8, CHCl3) {lit.[36] [α]D25 －55.4 (c
1
29.66. For minor diastereomer: H NMR (500 MHz,
CDCl3) δ: 2.29—2.45 (m, 1H), 2.82—2.98 (m, 1H),
3.80 (s, 3H), 4.42—4.54 (m, 1H), 4.64 (t, J＝7.1 Hz),
5.22—5.31 (m, 1H), 6.96—7.03 (m, 1H); 13C NMR
(100 MHz, CDCl3) δ: 166.07, 131.67, 131.07, 83.19,
79.00, 68.07, 53.52, 29.66; IR (neat) νmax: 3497, 2958,
1722, 1660, 1440, 1260, 1213, 1060, 989, 865, 780
－
＋
1
1
cm ; HR-EI-MS m/z: 235.0277 [M＋H] (m/z calcd
4.0, CHCl3)}; H NMR (500 MHz, CDCl3) δ: 2.47 (d,
for [C8H12O6S]＋ 235.0276).
J＝19.7 Hz, 1H), 2.88 (d, J＝8.9 Hz, 1H), 3.01 (d, J＝
19.7 Hz, 1H), 3.52—3.57 (m, 2H), 3.76 (s, 3H), 4.56 (d,
J＝8.9 Hz, 1H), 6.70—6.72 (m, 1H); 13C NMR (100
MHz, CDCl3) δ: 167.23, 136.80, 126.91, 66.01, 55.26,
52.72, 52.66, 24.85; IR (KBr) νmax: 3286, 2985, 1718,
(3R,4S,5R)-Methyl 5-methanesulfonyloxy-3,4-O-
thionyl-shikimate (5) To a solution of compound 4
(5.000 g, 21.35mmol) in ethyl acetate (100 mL) was
added methanesulfonyl chloride (3.668 g, 32.02 mmol).
The resulting solution was cooled to 0 ℃ by an ice
bath, and DMAP (0.261 g, 2.136 mmol) was added.
Triethylamine (3.240 g, 32.02 mmol) was then dropwise
added over 15 min. After the addition was finished, the
reaction mixture was further stirred at 0 ℃ for 1 h to
allow the reaction to be complete. The reaction was
quenched by adding water (20 mL). The organic phase
was separated and washed successively with potassium
carbonate aqueous solution (10% w/w, 20 mL) and brine
(20 mL). The organic solution was dried over anhydrous
MgSO4, and then was concentrated under vacuum to
give a pale yellow oily residue that gradually became
solid on standing at room temperature. The crude solid
product was then triturated with a mixed solvent of
hexane and ethyl acetate [V(EtOAc)∶V(hexane)＝1∶5]
to give compound 5 as pale yellow crystals (6.400 g,
20.49 mmol) in 96% yield. m.p. 100.1—101.8 ℃,
[α]2D0 ＋13.6 (c 1.0, CHCl3); For major diastereomer:
1H NMR (500 MHz, CDCl3) δ: 2.57—2.63 (m, 1H),
3.07—3.15 (m, 1H), 3.14 (s, 3H), 3.82 (s, 3H), 4.69—
4.82 (m, 1H), 5.03 (dd, J＝8.3, 5.6 Hz, 1H), 5.65 (t, J＝
5.6 Hz, 1H), 6.96—7.01 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ: 164.75, 132.40, 129.23, 78.05, 76.20, 75.60,
－
1
1437, 1262, 1090, 1026, 873, 747 cm ; MS (EI) m/z
(%): 170 (0.4) [M]＋, 155 (25), 138 (57), 111 (100), 81
(70), 71 (39), 65 (30), 53 (86), 43 (20), 39 (49).
HR-ESI-MS m/z: 193.0474 [M＋Na]＋ (m/z calcd for
[C8H10O4Na]＋ 193.0477).
(3R,4R,5R)-Methyl 5-O-methanesulfonylshikimate
(6) To a solution of compound 5 (5.000 g, 16.01 mmol)
in THF (50 mL) was added concentrated hydrochloric
－
1
acid (12 mol•L , 5 mL). The mixture was stirred at
room temperature and traced by TLC. After stirring was
continued around 5 h, the reaction was complete. Sol-
vents were removed by vacuum distillation and then
ethyl acetate (100 mL) and water (50 mL) were added
and stirred. The organic phase was separated and
washed with potassium carbonate aqueous solution until
pH 8—9. Organic solution was dried over anhydrous
MgSO4, and then concentrated to dryness to give crude
product as pale yellow solid, which was triturated in a
mixed solvent of ethyl acetate and hexane [V(EtOAc)∶
V(hexane)＝1∶3], and then was collected on a Bucher
funnel and rinsed with hexane. Compound 6 (4.050 g,
15.21 mmol) as white crystals was thus obtained in 95%
yield. m.p. 139.1—139.8 ℃, [α]2D0 －125.8 (c 1.0,
1
1
52.75, 38.73, 28.90. For minor diastereomer: H NMR
CHCl3); H NMR (500 MHz, CD3COCD3) δ: 2.51 (dd,
(500 MHz, CDCl3) δ: 2.60—2.65 (m, 1H), 3.12—3.20
(m, 1H), 3.13 (s, 3H), 3.81 (s, 3H), 4.80—4.91 (m, 1H),
5.14—5.27 (m, 1H), 5.25—5.40 (m, 1H), 7.01—7.09 (m,
1H); 13C NMR (100 MHz, CDCl3) δ: 165.01, 131.08,
130.79, 79.34, 79.16, 53.58, 52.69, 38.17, 29.00; IR
(KBr) νmax: 3029, 2985, 1722, 1344, 1257, 1220, 1174,
J＝18.2, 6.1 Hz, 1H), 2.91 (dd, J＝18.2, 5.6 Hz, 1H),
3.19 (s, 3H), 3.74 (s, 3H), 3.94 (dd, J＝7.8, 4.5 Hz, 1H),
4.38—4.46 (m, 1H), 4.85—4.94 (m, 1H), 6.81—6.84 (m,
1H); 13C NMR (100 MHz, DMSO-d6) δ: 165.95, 139.18,
126.57, 77.82, 67.85, 65.03, 51.86, 37.67, 28.78; IR
(KBr) νmax: 3402, 3016, 2962, 2931, 1718, 1660, 1456,
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Syntheses of Four Useful Shikimate-derived Epoxy Chiral Building Blocks
－
1
1345, 1250, 1168, 979, 942, 907, 815, 758, 529 cm ;
HR-ESI-MS m/z: 289.0359 [M＋Na]＋ (m/z calcd for
[C9H14O7SNa]＋ 289.0358).
(d, J＝7.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ:
166.64, 165.43, 134.38, 133.76, 129.94, 129.44, 129.06,
128.59, 78.94, 74.56, 71.88, 52.44, 38.52, 30.73; IR
(neat) νmax: 3513, 2942, 1729, 1699, 1352, 1240, 1172,
(3R,4S,5R)-Methyl 4-hydroxy-5-methanesulfonyl-
－
1
oxy-3-tosyloxy-cyclohex-1-ene-carboxylate
(7)
1095, 958, 715 cm ; HR-ESI-MS m/z: 393.0626 [M＋
Compound 6 (3.000 g, 11.27 mmol) was dissolved in
methylene chloride (60 mL). Pyridine (2.674 g, 33.81
mmol) was added, and then p-toluenesulfonyl chloride
(2.578 g, 12.39 mmol) was added in small portions over
15 min. After stirring was continued at room tempera-
ture for around 8 h, the reaction was complete. Solvents
were removed by vacuum distillation, and then ethyl
acetate (80 mL) and diluted hydrochloric aqueous solu-
Na]＋ (m/z calcd for [C16H18O8SNa]＋ 393.0620).
(3S,4R,5S)-Methyl 4,5-epoxy-3-hydroxy-cyclohex-
1-ene-carboxylate (1b) To a solution of compound 8
(2.000 g, 5.400 mmol) in methanol (20 mL), potassium
carbonate (0.746 g, 5.398 mmol) was added. The mix-
ture was stirred at 0 ℃ and traced by TLC. After stir-
ring was continued at 0 ℃ for 30 min, the reaction was
complete. The reaction solution was concentrated under
vacuum to remove methanol, then ethyl acetate (100 mL)
and brine (8 mL) were added. After the mixture was
vigorously stirred for 10 min, organic phase was sepa-
rated, dried over anhydrous MgSO4, and evaporated
under vacuum to give the crude product, which was pu-
rified by flash chromatography through a short column
of silica gel to afford compound 1b (0.855 g, 5.025
mmol) as off-white crystals in 93% yield. m.p. 65.5—
－
1
tion (2 mol•L , 30 mL) were added. After the mixture
was vigorously stirred for 15 min, the organic phase was
separated and washed successively with potassium car-
bonate aqueous solution (10% w/w, 20 mL) and brine
(20 mL). The organic solution was dried over anhydrous
MgSO4 and then was concentrated under vacuum to
give a pale yellow oily residue, which was purified by
flash chromatography to give compound 7 (4.074 g,
9.690 mmol) in 86% yield. [α]2D0 －109.6 (c 1.6,
66.2 ℃ (lit.[1] 65—67 ℃), [α]2D0 ＋54.1 (c 1.7,
1
1
CHCl3); H NMR (500 MHz, CDCl3) δ: 2.40 (s, 3H),
CHCl3) {lit.[1] [α]25 ＋55.3 (c 4.1, CHCl3)}; H NMR
D
2.50 (dd, J＝18.7, 6.0 Hz, 1H), 2.95 (dd, J＝18.7, 5.5
Hz, 1H), 3.02 (s, 3H), 3.69 (s, 3H), 3.98—4.08 (m, 1H),
4.83—4.92 (m, 1H), 5.20—5.24 (m, 1H), 6.55—6.58 (m,
1H), 7.32 (d, J＝8.1 Hz, 2H), 7.77 (d, J＝8.1 Hz, 2H);
13C NMR (100 MHz, CDCl3) δ: 165.37, 145.67, 132.90,
131.96, 131.27, 130.16, 127.98, 76.45, 75.44, 67.62,
52.46, 38.56, 29.25, 21.74; IR (neat) νmax: 3510, 3040,
2960, 1720, 1670, 1600, 1440, 1365, 1260, 1180, 1100,
965, 930, 890, 815, 750 cm － 1; HR-ESI-MS m/z:
443.0452 [M＋Na]＋ (m/z calcd for [C16H20O9S2Na]＋
443.0446).
(400 MHz, CDCl3) δ: 2.58 (dq, J＝19.8, 2.5 Hz, 1H),
2.73 (d, J＝7.3 Hz, 1H), 2.86 (dq, J＝19.8, 1.2 Hz, 1H),
3.20—3.26 (m, 1H), 3.34—3.42 (m, 1H), 3.69 (s, 3H),
4.51—4.62 (m, 1H), 6.70—6.75 (m, 1H); 13C NMR
(100 MHz, CDCl3) δ: 167.33, 133.84, 126.71, 62.92,
52.76, 51.99, 50.68, 24.57; IR (KBr film) νmax: 3393,
3023, 2954, 1717, 1657, 1438, 1263, 1090, 1026, 872,
747 cm ; MS (EI) m/z (%): 170 (0.5) [M] , 169 (2),
155 (15), 149 (12), 139 (26), 138 (46), 137 (11), 123 (9),
111 (100), 110 (44), 109 (39), 100 (16), 83 (32), 82 (40),
81 (61), 71 (40), 65 (27), 59 (23), 55 (32), 53 (66), 39
(36).
－
＋
1
(3S,4R,5R)-Methyl
3-benzoyloxy–4-hydroxy-5-
methanesulfonyloxy-cyclohex-1-ene-carboxylate (8)
To a solution of triethylamine (1.444 g, 14.27 mmol) in
toluene (20 mL) was added benzoic acid (2.615 g,
21.41mmol). The solution was then stirred at room
temperature for 0.5 h, and compound 7 (3.000 g, 7.135
mmol) was added. The mixture was heated to 60 ℃,
and stirring was then continued at this temperature for 4
h. After being cooled down to room temperature, the
reaction mixture was diluted with toluene (60 mL). The
solution was transferred into aseparatory funnel, and
was washed successively with aqueous HCl solution (2
mol•L , 20 mL), aqueous K2CO3 solution (10% w/w,
25 mL), and brine (10 mL). After the organic solution
was dried over anhydrous MgSO4, the solvent was re-
moved by distillation in vacuo to give the crude product,
which was purified by flash chromatography to afford
compound 8 (2.247 g, 6.067 mmol) as white crystals in
85% yield. m.p. 134.7—135.2 ℃, [α]2D0 ＋46.5 (c 0.8,
CHCl3); 1H NMR (500 MHz, CDCl3) δ: 2.52—2.63 (m,
1H), 3.09 (s, 3H), 3.07—3.15 (m, 1H), 3.28 (d, J＝5.6
Hz, 1H), 3.72 (s, 3H), 3.98—4.12 (m, 1H), 4.73—4.85
(m, 1H), 5.67—5.71 (m, 1H), 6.70—6.73 (m, 1H), 7.41
(t, J＝7.8 Hz, 2H), 7.55 (dd, J＝7.4, 7.8 Hz, 1H), 8.00
(3R,4S,5R)-Methyl 5-O-benzoyl-3,4-O-thionyl-
shikimate (9) To a solution of cyclic sulfite 4 (5.000 g,
21.35 mmol) in dichloromethane (40 mL), triethylamine
(4.320 g, 42.69 mmol) was added, and the resulting so-
lution was then cooled to 0 ℃ with an ice bath. Ben-
zoyl chloride (3.601 g, 25.62 mmol) was added drop-
wise over 10 min. The ice bath was removed, and the
mixture was then further stirred at room temperature for
4 h until the reaction was complete. The reaction solu-
tion was concentrated under vacuum to remove di-
chloromethane, and the residue was dissolved in ethyl
acetate (150 mL), and washed successively with dilute
－
1
－
1
hydrochloric aqueous solution (2 mol•L , 50 mL), po-
tassium carbonate aqueous solution (15% w/w, 50 mL),
and brine (15 mL). The organic solution was dried over
anhydrous MgSO4 and then evaporated under vacuum to
give a crude oil, which could be directly used for the
next step or purified by flash chromatography to furnish
compound 9 (7.078 g, 20.92 mmol) in 98% yield. [α]D20
1
＋15.9 (c 4.1, CHCl3). For major diastereomer: H
NMR (400 MHz, CDCl3) δ: 2.54 (dd, J＝18.1, 7.5 Hz,
1H), 3.05 (dd, J＝18.1, 4.9 Hz, 1H), 3.80 (s, 3H), 5.15
(dd, J＝7.6, 6.2 Hz, 1H), 5.32—5.43 (m, 1H), 5.60—
Chin. J. Chem. 2012, 30, 2759—2766
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
2763

Quan et al.
FULL PAPER
－
1
5.68 (m, 1H), 6.97—7.03 (m, 1H), 7.45 (dd, J＝7.7, 8.0
Hz, 2H), 7.58 (t, J＝7.7 Hz, 1H), 8.03 (d, J＝8.0 Hz,
2H); 13C NMR (100 MHz, CDCl3) δ: 165.43, 165.28,
133.65, 132.43, 129.79, 129.54, 129.17, 128.57, 77.46,
L , 20 mL). The organic phase was separated and
washed successively with potassium carbonate aqueous
solution (10% w/v, 20 mL) and brine (20 mL). The or-
ganic solution was dried over anhydrous MgSO4, and
then was concentrated under vacuum to give a pale yel-
low oily residue that gradually became solid on standing
at room temperature. The crude solid product was then
triturated with a mixed solvent of ethyl acetate and hex-
ane [V(EtOAc)∶V(hexane)＝1∶6] to give pure com-
pound 11 (5.953 g, 13.27 mmol) as pale yellow crystals
in 97% yield. m.p. 85.1—86.2 ℃, [α]2D0 －160.0 (c
1
75.71, 68.96, 52.58, 27.21. For minor diastereomer: H
NMR (400 MHz, CDCl3) δ: 2.75 (dd, J＝18.2, 7.6 Hz,
1H), 2.97 (dd, J＝18.2, 5.0 Hz, 1H), 3.78 (s, 3H), 4.81
—4.91 (m, 1H), 5.32—5.43 (m, 1H), 5.78—5.88 (m,
1H), 7.08—7.12 (m, 1H), 7.39—7.51 (m, 2H), 7.52—
7.64 (m, 1H), 7.91—7.98 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ: 165.77, 165.15, 133.65, 131.48, 130.06,
129.79, 129.17, 128.57, 78.80, 69.35, 53.53, 52.42,
25.66; IR (KBr) νmax: 3067, 2954, 1726, 1660, 1438,
1
6.0, CHCl3); H NMR (500 MHz, CDCl3) δ: 2.60 (dd,
J＝19.0, 5.9 Hz, 1H), 3.09 (s, 3H), 3.18 (s, 3H), 3.23
(dd, J＝19.0, 5.6 Hz, 1H), 3.80 (s, 3H), 5.12—5.22 (m,
1H), 5.58—5.67 (m, 2H), 6.87—6.91 (m, 1H), 7.47 (t,
J＝7.6 Hz, 2H), 7.61 (t, J＝7.6 Hz, 1H), 8.03 (d, J＝7.6
Hz, 2H); 13C NMR (100 MHz, CDCl3) δ: 165.22, 165.15,
133.78, 133.24, 130.42, 129.80, 128.95, 128.68, 74.70,
－
1
1257, 1216, 1102, 992, 712 cm ; HR-ESI-MS m/z:
361.0353 [M＋Na]＋ (m/z calcd for [C15H14O7SNa]＋
361.0358).
(3R,4S,5R)-Methyl 5-O-benzoyl shikimate 10 To
a solution of compound 9 (5.000 g, 14.78 mmol) in THF
(50 mL) was added concentrated hydrochloric acid (12
72.77, 66.74, 52.58, 38.87, 38.72, 29.33; IR (KBr) νmax
3031, 2937, 1720, 1460, 1360, 1180, 1100, 980, 910,
:
－
1
mol•L , 5 mL). The mixture was stirred at room tem-
perature and traced by TLC. After stirring was contin-
ued around 5 h, the reaction was complete. Solvents
were removed by vacuum distillation and then ethyl
acetate (100 mL) and water (50 mL) were added and
stirred. The organic phase was separated and washed
with potassium carbonate aqueous solution until pH 8—
9. Organic solution was dried over anhydrous MgSO4,
and then concentrated to dryness to give crude product
as pale yellow solid, which was triturated in a mixed
solvent of ethyl acetate and hexane [V(EtOAc) ∶
V(hexane)＝1∶2] and was then collected on a Bucher
funnel by suction. Compound 10 (4.103 g, 14.04 mmol)
as off-white crystals was thus obtained in 95% yield.
m.p. 132.7—132.8 ℃, [α]2D0 －120.9 (c 1.4, CHCl3);
1H NMR (500 MHz, CDCl3) δ: 2.49 (d, J＝16.7 Hz, 1H),
2.97 (d, J＝16.7 Hz, 1H), 3.44 (brs, 2H), 3.75 (s, 3H),
3.98—4.11 (m, 1H), 4.47—4.58 (m, 1H), 5.42—5.53 (m,
1H), 6.90—6.96 (m, 1H), 7.37—7.48 (m, 2H), 7.53—
7.61 (m, 1H), 7.93—8.02 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ: 166.71, 166.39, 136.97, 133.38, 129.73,
129.61, 129.25, 128.45, 70.50, 69.05, 66.27, 52.18,
27.97; MS (EI) m/z (%): 292 (0.1) [M＋], 260 (2), 233
(2), 207 (1), 184 (1), 170 (43), 138 (7), 111 (8), 105
(100), 77 (19), 65 (4), 44 (5); IR (KBr) νmax: 3256, 2920,
－
＋
1
845, 715 cm . HR-EI-MS m/z: 448.0497 [M] (m/z
calcd for [C17H20O10S2]＋ 448.0498).
(3S,4S,5R)-Methyl 3-O-acetyl-5-O-benzoyl-4-O-
methanesulfonyl-shikimate 12 To a solution of DBU
(2.716 g, 17.84 mmol) in toluene (20 mL) was added
acetic acid (3.214 g, 53.52 mmol). The solution was
then stirred at room temperature for 0.5 h, and com-
pound 11 (4.000 g, 8.919 mmol) was added. The mix-
ture was heated to 60 ℃, and stirring was then contin-
ued at this temperature for 2 h. After being cooled down
to room temperature, the reaction mixture was diluted
with toluene (50 mL). The solution was transferred into
a separatory funnel, and was washed successively with
－
1
aqueous HCl solution (2 mol•L , 20 mL), aqueous
K2CO3 solution (15% w/v, 30 mL), and brine (10 mL).
After the organic solution was dried over anhydrous
MgSO4, the solvent was removed by vacuum distillation
to give the crude product, which was purified by flash
chromatography to afford 12 (3.311 g, 8.028 mmol) as
white crystals in 90% yield. m.p. 132.5—133.7 ℃,
1
[α]2D0 －62.5 (c1.0, CHCl3); H NMR (500 MHz,
CDCl3) δ: 2.13 (s, 3H), 2.49—2.68 (m, 1H), 2.94 (s, 3H),
3.22 (dd, J＝17.9, 6.8 Hz, 1H), 3.78 (s, 3H), 5.14 (dd,
J＝9.8, 6.8 Hz), 5.41—5.52 (m, 1H), 5.76—5.81 (m,
1H), 6.71—6.74 (m, 1H), 7.47 (t, J＝7.5 Hz, 2H), 7.60
(t, J＝7.5 Hz, 1H), 8.10 (d, J＝7.5 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ: 170.09, 165.39, 165.25, 133.67,
133.55, 129.91, 129.73, 129.10, 128.62, 78.09, 70.45,
68.24, 52.46, 38.83, 29.69, 20.83; IR (KBr) νmax: 3010,
2958, 1750, 1720, 1350, 1255, 1220, 1165, 1112, 1030,
－
1
1725, 1715, 1440, 1280, 1250, 1140, 1100, 710 cm .
HR-ESI-MS m/z: 315.0840 [M＋Na]＋ (m/z calcd for
[C15H16O6Na]＋ 315.0845).
(3R,4S,5R)-Methyl 5-O-benzoyl-3,4-O-dimethane-
sulfonyl-shikimate 11 Compound 10 (4.000 g, 13.69
mmol) was dissolved in ethyl acetate (60 mL), and the
solution was cooled to 0 ℃ by an ice bath. Methane-
sulfonyl chloride (4.703 g, 41.06 mmol) and DMAP
(0.167 g, 1.367 mmol) were added, and then triethyl-
amine (4.155 g, 41.06 mmol) was dropwise added over
15 min. After addition was finished, the stirring was
continued at 0 ℃ for 1 h, and TLC showed that the
reaction was complete. The reaction was quenched by
adding diluted hydrochloric aqueous solution (2 mol•
－
＋
1
710 cm . HR-EIMS m/z: 412.0831 [M] (m/z calcd for
[C18H20O9S]＋ 412.0828).
(3S,4S,5R)-Methyl 4,5-epoxy-3-hydroxy-cyclohex-
1-ene-carboxylate 1c To a solution of compound 12
(1.000 g, 2.425 mmol) in methanol (10 mL), potassium
carbonate (0.335 g, 2.424 mmol) was added. The mix-
ture was stirred at 0 ℃ and traced by TLC. After 30
min, the reaction was complete. The reaction solution
2764
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 2759—2766

Syntheses of Four Useful Shikimate-derived Epoxy Chiral Building Blocks
was concentrated under vacuum to remove methanol,
then the residue was dissolved in ethyl acetate (200 mL).
The undissolvable inorganic salts were removed on
Buchner funnel by suction, and ethyl acetate was then
dried over anhydrous MgSO4 and evaporated to give the
crude product which was purified by flash chromatog-
raphy to afford 1c (0.371 g, 2.180 mmol) as off-white
crystals in 90% yield. m.p. 80.7—81.0 ℃ (lit.[1] 80—
81 ℃). [α]2D0 ＋56.6 (c 1.3, CHCl3) {lit.[1] [α]D25
＋57.0 (c 4.1, CHCl3)}. Spectra data of compounds 1c
and 1a are identical.
vacuum to give a pale yellow oily residue that gradually
became solid on standing at room temperature. The
crude solid product was then triturated with hexane to
give compound 14 (2.286 g, 4.492 mmol) as pale yellow
crystals in 97% yield. m.p. 103.9—104.5 ℃; [α]D20
1
－90.4 (c 0.5, CHCl3); H NMR (400 MHz, CDCl3) δ:
2.68 (dd, J＝19.0, 5.6 Hz, 1H), 3.02 (s, 3H), 3.20 (dd,
J＝19.0, 5.4 Hz, 1H), 3.80 (s, 3H), 5.25—5.31 (m, 1H),
5.67—5.73 (m, 1H), 6.09—6.12 (m, 1H), 6.93—6.96 (m,
1H), 7.43—7.51 (m, 4H), 7.59 (t, J＝7.6 Hz, 1H), 8.01
—8.09 (m, 4H); 13C NMR (100 MHz, CDCl3) δ: 165.54,
165.41, 164.77, 140.24, 133.72, 131.86, 131.68, 131.35,
129.87, 129.02, 128.63, 127.44, 74.27, 67.30, 66.94,
52.42, 38.76, 28.65; IR (KBr film) νmax: 2958, 1725,
(3R,4S,5R)-Methyl 5-O-benzoyl-3-O-(p-chloro-
benzoyl)-shikimate 13 To a solution of compound 10
(2.000 g, 6.843 mmol) in ethyl acetate (20 mL),
triethylamine (1.385 g, 13.69 mmol) was added. The
resulting solution was then cooled to 0 ℃ with an ice
bath, and p-chlorobenzoyl chloride (1.437 g, 8.211
mmol) was dropwise added over 10 min. The ice bath
was removed, and the mixture was then further stirred at
room temperature for 10 h until the reaction was com-
plete. More ethyl acetate (60 mL) was added, and the
solution was transferred into a separatory funnel, and
was washed successively with dilute hydrochloric
－
1
1710, 1595, 1460, 1255, 1175, 1100, 715 cm ; HR-
ESI-MS m/z: 531.0490 [M ＋Na] ＋ (m/z calcd for
[C23H21O9SClNa]＋ 531.0493).
(3R,4S,5R)-Methyl 4,5-epoxy-3-hydroxy-cyclohex-
1-ene-carboxylate 1d To a solution of compound 14
(1.996 g, 3.922 mmol) in anhydrous methanol (40 mL),
potassium carbonate (0.542 g, 3.922 mmol) was added.
The mixture was stirred at 0 ℃ and traced by TLC.
After stirring was continued at 0 ℃ for 1 h, the reac-
tion was complete. The reaction solution was then con-
centrated under vacuum to remove methanol, and ethyl
acetate (100 mL) and brine (10 mL) were added. After
the mixture was vigorously stirred for 15 min, the or-
ganic phase was separated and dried over anhydrous
MgSO4. Removal of solvent by vacuum distillation gave
the crude product, which was purified by flash chroma-
tography to afford compound 1d (0.601 g, 3.532 mmol)
as off-white crystals in 90% yield. m.p. 64.4—65.1 ℃
－
1
aqueous solution (2 mol•L , 30 mL), potassium car-
bonate aqueous solution (15% w/w, 30 mL) and brine
(10 mL). The organic solution was dried over anhydrous
MgSO4, and then was evaporated under vacuum to give
a crude oil, which was purified by flash chromatography
to afford compound 13 (2.595 g, 6.023 mmol) as white
crystals in 88% yield. m.p. 88.4 —89.6 ℃, [α]D20
－178.8 (c 0.6, CHCl3); 1H NMR (400 MHz, CDCl3) δ:
2.59 (dd, J＝18.7, 5.9 Hz, 1H), 3.09 (dd, J＝18.7, 5.2
Hz, 1H), 3.77 (s, 3H), 4.31 (dd, J＝7.9, 4.0 Hz, 1H),
5.54—5.61 (m, 1H), 5.88—5.91 (m, 1H), 6.95—6.98 (m,
1H), 7.38—7.46 (m, 4H), 7.57 (t, J＝7.6 Hz, 1H), 7.97
—8.06 (m, 4H); 13C NMR (100 MHz, CDCl3) δ: 166.31,
166.09, 164.99, 140.02, 133.48, 132.78, 131.72, 131.25,
129.77, 129.49, 128.90, 128.52, 127.80, 70.16, 69.67,
68.12, 52.28, 28.44; IR (KBr film) νmax: 3500, 2958,
(lit.[2] 64—65.5 ℃). [α]20 －52.6 (c 1.9, CHCl3).
D
Spectra data of compounds 1d and 1b are identical.
Supporting Information
Copies of spectra of 1H and 13C NMR of compounds
1a—1d and 4—14.
1725, 1710, 1595, 1440, 1400, 1270, 1095, 1012, 850,
Acknowledgement
－
＋
1
712 cm . HR-ESI-MS m/z: 453.0717 [M＋Na] (m/z
calcd for [C22H19O7ClNa]＋ 453.0721).
We thank the National Natural Science Foundation
of China (No. 20972048) and Shanghai Educational
Development Foundation (The Dawn Program: No.
03SG27) for the financial support of this work.
(3R,4S,5R)-Methyl
5-O-benzoyl-3-O-(p-chloro-
benzoyl)-4-O-methane-sulfonyl-shikimate 14 Com-
pound 13 (1.995 g, 4.631 mmol) was dissolved in ethyl
acetate (50 mL), and the solution was cooled to 0 ℃ by
an ice bath. Triethylamine (0.937 g, 9.260 mmol) and
DMAP (0.057 mg, 0.467 mmol) were added, and then
methanesulfonyl chloride (1.061 g, 9.262 mmol) was
dropwise added over 10 min. After addition was fin-
ished, the stirring was continued at 0 ℃ for 1 h. The
reaction was quenched by adding a diluted hydrochloric
aqueous solution (2 mol•L－1, 20 mL). The organic
phase was separated and washed successively with po-
tassium carbonate aqueous solution (10% w/w, 20 mL)
and brine (15 mL). The organic solution was dried over
anhydrous MgSO4, and then was concentrated under
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
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FULL PAPER
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