Stereodivergent Syntheses of All Stereoisomers of (?)-Shikimic Acid: Development of a Chiral Pool for the Diverse Polyhydroxy-cyclohexenoid (or -cyclohexanoid) Bioactive Molecules

Article abstract of DOI:10.1002/ejoc.202100653

Novel stereodivergent total syntheses of all the seven stereoisomers of (?)-shikimic acid [(?)-SA 1] have been systematically performed. (+)-ent-SA ent-1 was synthesized from (?)-SA 1 via 9 steps in 31 % overall yield; (?)-3-epi-SA 2 was synthesized from (?)-SA 1 via 5 steps in 66 % overall yield; (+)-3-epi-ent-SA ent-2 was synthesized from (?)-SA 1 via 7 steps in 43 % overall yield; (?)-4-epi-SA 3 was synthesized from (?)-SA 1 via 11 steps in 32 % overall yield; (+)-4-epi-ent-SA ent-3 was synthesized from (?)-SA 1 via 7 steps in 42 % overall yield; (?)-5-epi-SA 4 was synthesized from (?)-SA 1 via 6 steps in 56 % overall yield; and (+)-5-epi-ent-SA ent-4 was synthesized from (?)-SA 1 via 12 steps in 29 % overall yield. The stereochemistry of all the above seven stereoisomers of (?)-SA 1 were further studied by two dimensional (2D) ¹H NMR technique.

Full text of DOI:10.1002/ejoc.202100653

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Stereodivergent Syntheses of All Stereoisomers of
(À )-Shikimic Acid: Development of a Chiral Pool for the
Diverse Polyhydroxy-cyclohexenoid (or -cyclohexanoid)
Bioactive Molecules
Yun-Gang He,[a] Yong-Kang Huang,[a] Zhang-Li Xu,[a] Wen-Jing Xie,[a] Yong-Qiang Luo,[a]
Feng-Lei Li,[a] Xing-Liang Zhu,[a] and Xiao-Xin Shi*[a]
Novel stereodivergent total syntheses of all the seven stereo-
isomers of (À )-shikimic acid [(À )-SA 1] have been systematically
performed. (+)-ent-SA ent-1 was synthesized from (À )-SA 1 via
9 steps in 31% overall yield; (À )-3-epi-SA 2 was synthesized
from (À )-SA 1 via 5 steps in 66% overall yield; (+)-3-epi-ent-SA
ent-2 was synthesized from (À )-SA 1 via 7 steps in 43% overall
yield; (À )-4-epi-SA 3 was synthesized from (À )-SA 1 via 11 steps
in 32% overall yield; (+)-4-epi-ent-SA ent-3 was synthesized
from (À )-SA 1 via 7 steps in 42% overall yield; (À )-5-epi-SA 4
was synthesized from (À )-SA 1 via 6 steps in 56% overall yield;
and (+)-5-epi-ent-SA ent-4 was synthesized from (À )-SA 1 via 12
steps in 29% overall yield. The stereochemistry of all the above
seven stereoisomers of (À )-SA 1 were further studied by two
dimensional (2D) 1H NMR technique.
Introduction
(À )-Shikimic acid [(À )-SA 1, in Figure 1] is a fascinating natural
product featured with a structural motif of chiral polyhydroxyl-
substituted cyclohexene. It has captured worldwide attentions
in the recent decades[1] due to many uses in pharmaceutical
industry. (À )-SA 1 could be obtained by means of extraction
from plants,[2] fermentation based on microbial engineering[1f,h,3]
and chemical syntheses.[1a,4] So far (À )-SA 1 has been found in a
lot of plant species,[5] and it is noted to be extremely high
abundant (up to 17% on dry basis[5h]) in Chinese star anise (the
fruit of Illicium verum Hook. f.). Chinese star anise is a popular
flavoring material for foods in China, it can be readily and
annually planted in many areas, therefore, (À )-SA 1 can be
manufactured in a large quantity by extraction from the
Chinese star anise using new rapid and high-yielding extraction
methods.[2b,6] (À )-SA 1 is very useful material for syntheses of
drugs and pharmaceutically valuable natural products. For
examples, it has been extensively used in the syntheses of
oseltamivir phosphate (Tamiflu),[7] valiolamine,[8] valienamine,[8a,9]
NOV,[10] NOEV,[10] pericosines (A, B, D and E),[11] zeylenones,[12]
(À )-MK7607,[13] previtamin D3,[14] quercitols,[15] and (À )-quinic
acid.[16] (À )-SA 1 and its derivatives might also be very
important in drug discovery, since they have shown a wide
range of physiological activities[17] such as antiviral, anti-
bacterial, anti-fungi, anti-osteoclastogenesis, anti-platelet, anti-
Figure 1. The structures of all stereoisomers of (À )-SA 1.
thrombogenic, anti-inflammatory, anti-oxidant, and anti-tumor
activities.
As a molecule with three stereogenic centers, it should have
totally eight stereoisomers as depicted in Figure 1. They are (À )-
SA 1, (+)-ent-SA ent-1, (À )-3-epi-SA 2, (+)-3-epi-ent-SA ent-2,
(À )-4-epi-SA 3, (+)-4-epi-ent-SA ent-3, (À )-5-epi-SA 4 and (+)-5-
epi-ent-SA ent-4, respectively. Although (À )-SA 1 itself has been
extensively studied in synthetic chemistry and physiological
chemistry, only few physiological or synthetic studies of the
other stereoisomers have been reported. (À )-4-epi-SA 3 has
been used as building block for the syntheses of
glycomimetics[18] and sialytransferase inhibitors;[19] (À )-3-epi-SA
2, (À )-4-epi-SA 3 and (À )-5-epi-SA 4 have also been used as
building blocks in the syntheses of vitamin D3 analogues.[20] (À )-
SA 1 and all of its stereoisomers might constitute a versatile
chiral pool for the syntheses of diverse polyhydroxy-cyclo-
hexenoid (or polyhydroxy-cyclohexanoid) bioactive natural
products and their analogues. However, all the seven stereo-
isomers of (À )-SA 1 can scarcely be obtained from natural
resources, so it is very important to develop convenient and
[a] Y.-G. He, Y.-K. Huang, Z.-L. Xu, W.-J. Xie, Y.-Q. Luo, F.-L. Li, X.-L. Zhu,
Prof. Dr. X.-X. Shi
Engineering Research Center of Pharmaceutical Process Chemistry of the
Ministry of Education,
School of Pharmacy, East China University of Science and Technology,
130 Mei-Long Road, Shanghai 200237, P. R. China
E-mail: xxshi@ecust.edu.cn
http://orcid.org/0000-0002-2751-5122
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.202100653
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practical methods to synthesize all of these stereoisomers. In
bis-silylated ethyl shikimate 6. (+)-ent-SA ent-1 can be prepared
via ring-opening of epoxide 12, which can be obtained from
compound 13 via the successive substitution at C-3 and
intramolecular regioselective cyclization, compound 13 can be
prepared from the key intermediate 7. (À )-5-epi-SA 4 can be
prepared via reduction of compound 14, which can be obtained
via oxidation of the key common compound 7.
order to facilitate the studies on bioactivities and synthetic
applications of all stereoisomers of (À )-SA 1, we have
performed and herein would like to report the stereodivergent
syntheses of all the seven stereoisomers of (À )-SA 1 starting
from the commercially available and inexpensive (À )-SA 1.
According to the above retrosynthetic analysis, our syn-
thetic routes for all the seven stereoisomers of (À )-SA 1 are
depicted in Schemes 2–6. These novel syntheses are discussed
as below:
Results and Discussion
Our retrosynthetic analysis of all the seven stereoisomers of (À )-
SA 1 was outlined in Scheme 1, which showed that all the
target molecules can be synthesized starting from (À )-SA 1 via
several common intermediates such as compounds 5, 6 and 7,
which can be efficiently prepared from (À )-SA 1 by the known
methods.[7e,8b] As the diagram depicted, (À )-3-epi-SA 2 can be
prepared via ring-opening of the key epoxide 5. (+)-4-epi-ent-
SA ent-3 can be prepared via ring-opening of epoxide ent-8,
which can also be prepared from epoxide 5 by Mitsunobu
reaction. Both of (+)-5-epi-ent-SA ent-4 and (À )-4-epi-SA 3 can
be prepared from a common epoxide 8, which can be derived
from intermediate 9; compound 9 can also be prepared from
the key epoxide 5. (+)-3-epi-ent-SA ent-2 can be prepared via
ring-opening of epoxide 10, which can be obtained from
intermediate 11, the compound 11 can be prepared from the
Synthesis of (À )-3-epi-SA 2from (À )-SA 1
(À )-3-epi-SA 2 is a naturally occurring compound in some
plants[21] and was first isolated from Sequoiadendron giganteum
by Pluovier et al. in 1959.[21a] Frederickson et al. reported the first
synthesis of (À )-3-epi-SA 2.[22] Sugai et al. also reported a
synthesis of (À )-3-epi-SA 2 via Diels-Alder reaction and enzyme-
catalyzed resolution.[23] Herein, we disclose a short and more
efficient synthesis of (À )-3-epi-SA 2 starting from (À )-SA 1. Our
synthetic route was depicted in Scheme 2. Firstly, epoxide 5 can
be easily prepared from (À )-SA 1 in 84% yield via 3 steps by a
known method.[8b] Epoxide 5 then underwent highly regio-
Scheme 1. Retrosynthetic analysis of all stereoisomers of (À )-SA 1.
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Scheme 2. Syntheses of (À )-3-epi-SA 2 and (+)-4-epi-ent-SA ent-3 from (À )-SA 1.
Scheme 3. Syntheses of (À )-4-epi-SA 3 and (+)-5-epi-ent-SA ent-4 from (À )-SA 1.
selective ring-opening at more reactive allylic C-3 position at
water was both used as a nucleophile and the environment-
°
95 C to afford compound 15 in 89% yield. In the ring-opening,
friendly solvent. Subsequently, compound 15 was first treated
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Scheme 4. Synthesis of (À )-5-epi-SA 4 from (À )-SA 1.
Scheme 5. Synthesis of (+)-ent-SA ent-1 from (À )-SA 1.
Scheme 6. Synthesis of (+)-3-epi-SA ent-2 from (À )-SA 1.
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°
with 2.0 equiv. of NaOH in methanol at 40 C, and then treated
described in Scheme 2 for synthesis of (+)-4-epi-ent-SA ent-3
from epoxide ent-8.
with diluted aq. HCl, the (À )-3-epi-SA 2 could be thus obtained
in 88% yield.
Synthesis of (+)-5-epi-ent-SA ent-4from (À )-SA 1
Synthesis of (+)-4-epi-ent-SA ent-3from (À )-SA 1
Only one synthesis of (+)-5-epi-ent-SA ent-4 via asymmetric
Diels-Alder reaction was reported by Carretero et al. in 1997.[27]
Our novel synthetic route was depicted in Scheme 3. As can be
seen from Scheme 3, epoxide 8 was treated with 2.0 equiv. of
Only one synthesis of (+)-4-epi-ent-SA ent-3 from L-tartaric acid
has been reported by Yan et al. in 2014.[24] Herein we disclose a
new synthesis of (+)-4-epi-ent-SA ent-3 from (À )-SA 1 according
to the route depicted in Scheme 2. As can be seen from
Scheme 2, epoxide 5 was treated with 1.5 equiv. of benzoic acid
(BzOH), 1.5 equiv. of triphenylphosphine (PPh3) and 1.5 equiv. of
diethyl azodicarboxylate (DEAD) in CH2Cl2 at room temperature.
The Mitsunobu reaction occurred to give epoxide ent-8 in 65%
yield, during this SN2 substitution, the (R) configuration at C-5
was inversed to (S) configuration. Then epoxide ent-8 then
underwent highly regio-selective ring-opening at more reactive
°
hydrobromic acid (HBr, w/w 40%) in ethyl acetate at 0 C,
exclusive regiospecific ring-opening at allylic C-3 position by
bromide anion occurred to produce compound 21 in 97% yield.
Compound 21 was then exposed to 1.3 equiv. of acetic
anhydride (Ac2O), 1.5 equiv. of Et3N and 0.1 equiv. of DMAP in
°
CH2Cl2 at 0 C to afford compound 22 in 95% yield. Next, when
compound 22 was treated with 8.0 equiv. of acetic acid (AcOH)
and 2.0 equiv. of potassium acetate (AcOK) in isopropyl alcohol
(i-PrOH) under refluxing, inseparable mixture of two isomers 23
and 24 formed via Woodward-Prevost reaction.[28] 1H NMR
analysis revealed that ratio of compounds 23 and 24 was
approximate 1:1. Then the mixture of compounds 23 and 24
were exposed to 3.0 equiv. of anhydrous K2CO3 in ethanol at
room temperature to furnish the desired (+)-ethyl 5-epi-ent-
shikimate 25 in 85% yield over two steps (from compound 22).
Finally, compound 25 was first treated with 2.0 equiv. of NaOH
°
allylic C-3 position at 95 C in a mixed solvent of H2O and 1,4-
dioxane (v:v=2:3) to afford compound 16 in 90% yield.
Subsequently, compound 16 was exposed to 1.5 equiv. of
anhydrous K2CO3 in absolute ethanol at room temperature,
debenzylation occurred smoothly to furnish compound 17 in
95% yield. Finally, compound 17 was first treated with
°
2.0 equiv. of NaOH in methanol at 40 C, and then treated with
diluted aq. HCl, (+)-4-epi-SA ent-3 could be thus obtained in
89% yield.
°
in methanol at 40 C, and then treated with diluted aq. HCl,
(+)-5-epi-ent-SA ent-4 could be thus obtained in 87% yield.
Synthesis of (À )-4-epi-SA 3from (À )-SA 1
Synthesis of (À )-5-epi-SA 4from (À )-SA 1
Rapoport et al. reported the first synthesis of (À )-4-epi-SA 3
from (À )-quinic acid in 1973.[25] Berchtold et al. also reported a
synthesis of (À )-4-epi-SA 3 from (À )-quinic acid in 1985.[26] Later,
Yan et al. reported a synthesis of (À )-4-epi-SA 3 from L-tartaric
acid in 2014.[24] Our novel and efficient synthesis of (À )-4-epi-SA
3 starting from (À )-SA 1 was depicted in Scheme 3. As can be
seen from Scheme 3, epoxide 5 was treated with 1.5 equiv. of
benzyl chloride, 2.0 equiv. of Et3N and 0.1 equiv. of 4-N,N-
The first synthesis of (À )-5-epi-SA 4 from D-ribose was reported
by Wightman et al. in 1994.[29] Then Vankar et al. also reported a
synthesis of (À )-5-epi-SA 4 from D-ribose in 2009.[30] Gotor et al.
also reported a synthetic route to methyl ester of (À )-5-epi-SA 4
from (À )-quinic acid.[31] Our novel synthetic route was depicted
in Scheme 4. As can be seen from Scheme 4, to protect the cis-
vicinal diols, compound 7 was prepared from (À )-SA 1 in 92%
yield over two steps by a known method.[7e] Compound 7 was
treated with 1.3 equiv. of trichloroisocyanuric acid (TCCA) and
0.05 equiv. of 2,2,6,6-tetramethyl-piperidine N-oxide (TEMPO) in
CH2Cl2 at room temperature to afford a ketone 14 in 85% yield.
Then compound 14 was exposed to 1.2 equiv. of sodium
borohydride (NaBH4) in a mixed solvent of EtOAc and H2O (v/
°
dimethylaminopyridine (DMAP) in CH2Cl2 at 0 C to room
temperature to afford 18 in 90% yield. Compound 18 was
exposed to 5.0 equiv. of AcOH and 0.5 equiv. of trifluoroacetic
acid (TFA) in CH2Cl2 under refluxing to furnish compound 19 in
80% yield. In this reaction, the acetoxy anion regio-selectively
attacked the allylic C-3 position, and the (R) configuration at C-3
was inversed to (S) configuration during the reaction. The
compound 19 was treated with 1.2 equiv. of methanesulfonyl
chloride (MsCl), 1.5 equiv. of Et3N and 0.1 equiv. of DMAP in
°
v=7:1) at 0 C to room temperature to furnish compound 26 in
93% yield with >98% de. During the reduction of ketone 14,
the high steric hindrance of the isopropylidene moiety forced
the borohydride anion to attack the carbonyl group via upward
side, and thus the desired (S) configuration of secondary alcohol
at C-5 formed. Subsequently, compound 26 was treated with
5 equiv. of conc. HCl in a mixed solvent of tetrahydrofuran
(THF) and water (v/v=10:1) at room temperature to produce
compound ent-25 in 90% yield. Finally, compound ent-25 was
°
CH2Cl2 at 0 C to give compound 9 in 95% yield. Then
compound 9 was exposed to 2.0 equiv. of p-toluenesulfonic
acid (p-TsOH) in ethanol under refluxing, the selective deacety-
lation occurred smoothly to afford compound 20 in 90% yield.
Next, compound 20 was treated with 2.0 equiv. of NaH (w/w
60%) in CH2Cl2 at room temperature, an intramolecular SN2
substitution occurred to give pivotal epoxide ent-8 in 80%
yield. Finally, (À )-4-epi-SA 3 was prepared from epoxide 8 in
76% yield over 3 steps according to the same procedures as
°
first treated with 2.0 equiv. of NaOH in methanol at 40 C, and
then treated with diluted aq. HCl to afford (À )-5-epi-SA 4 in
86% yield.
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Synthesis of (+)-ent-SA ent-1from (À )-SA 1
CH2Cl2 at room temperature to furnish compound 31 in 85%
yield. Compound 31 was exposed to 4.8 equiv. of conc. HCl in
ethanol at room temperature to afford diol 11 in 96% yield.
Subsequently, compound 11 was treated with 1.5 equiv. of
anhydrous K2CO3 in absolute ethanol at room temperature to
afford epoxide 10 in 92% yield. Epoxide 10 was treated with
The synthesis of (+)-ent-SA ent-1 via asymmetric Diels-Alder
reaction was achieved by Evans et al. and Carretero et al. in
1997.[27,32] Then Vankar et al.[30] and Yan et al.[24] revealed the
syntheses of (+)-ent-SA ent-1 from D-ribose and L-tartaric,
respectively. Our novel synthetic route for the synthesis of
(+)-ent-SA ent-1 was depicted in Scheme 5. As can be seen
from Scheme 5, the common intermediate 7 was treated with
1.2 equiv. of Ac2O, 1.5 equiv. of Et3N and 0.1 equiv. of DMAP in
°
0.05 equiv. of AcOH in water at 90 C to provide ent-15 in 90%
yield. In the epoxide-opening, water attacked the less hindered
C-5 position with high regio-selectivity to afford the desired
trans-vicinal hydroxyls. Finally, compound ent-15 was first
°
°
CH2Cl2 at 0 C to afford acetylated product 27 in 92% yield.
treated with 2.0 equiv. of NaOH in methanol at 40 C, and then
treated with diluted aq. HCl, the (+)-3-epi-ent-SA ent-2 was thus
obtained in 88% yield.
Then compound 27 was exposed to 5 equiv. of conc. HCl in a
mixed solvent of tetrahydrofuran and water (v/v=15:1) at
room temperature to provide the cis-vicinal diol 28 in 90%
yield. Subsequently, compound 28 was treated with 3.0 equiv.
of MsCl, 4.0 equiv. of Et3N and 0.2 equiv. of DMAP to give
bismesylate 13 in 89% yield. Next, according to our known
method,[33] compound 13 was treated with 6.0 equiv. of acetic
acid (AcOH) and 1.5 equiv. of diisopropylethylamine (DIPEA) in
EtOAc under refluxing to produce compound 29 in 86% yield.
In this reaction, the much more reactive methanesulfoxyl (OMs)
leaving group at allylic C-3 position was replaced by acetoxy
anion to give the product 29 with high regioselectivity.
Compound 29 was first treated with a catalytic amount of conc.
H2SO4 (20 mol%) in ethanol under refluxing to give intermediate
I-3, which was then directly treated with 1.2 equiv. of potassium
carbonate (K2CO3) at room temperature to afford epoxide 12 in
Two dimensional (2D) 1H NMR study on the stereochemistry
of all the seven stereoisomers of (À )-SA 1
Although stereochemical structures of all the above seven
stereoisomers (i.e., ent-1, 2, ent-2, 3, ent-3, 4 and ent-4)
obtained from (À )-SA 1 via above synthetic routes (Schemes 2–
6) are quite certain, the stereochemistry of these stereoisomers
of (À )-SA 1 were further studied by 1H-1H COSY and 1H-1H
NOESY spectra. Discussions are detailed in the “Supporting
Information”.
70% yield over 2 steps. It is worth noting that two epoxides Conclusion
(i.e. an epoxide between C-3 and C-4 as well as another
epoxide between C-4 and C-5) might be formed, but the latter
is much more favorable due to less repulsion between epoxy
and π electrons of the double bond.[34] Epoxide 12 could
spontaneously crystallize out from the generated mixture as
white acicular crystals. Subsequently, epoxide 12 underwent
In conclusion, we revealed the novel syntheses of all the seven
stereoisomers (i.e., ent-1, 2, ent-2, 3, ent-3, 4 and ent-4) of (À )-
SA 1 starting from the naturally abundant (À )-SA1 itself.
(+)-ent-SA ent-1 was synthesized from (À )-SA 1 via 9 steps in
31% overall yield; (À )-3-epi-SA 2 was synthesized from (À )-SA 1
via 5 steps in 66% overall yield; (+)-3-epi-ent-SA ent-2 was
synthesized from (À )-SA 1 via 7 steps in 43% overall yield; (À )-
4-epi-SA 3 was synthesized from (À )-SA 1 via 11 steps in 32%
overall yield; (+)-4-epi-ent-SA ent-3 was synthesized from (À )-SA
1 via 7 steps in 42% overall yield; (À )-5-epi-SA 4 was
synthesized from (À )-SA 1 via 6 steps in 56% overall yield;
(+)-5-epi-ent-SA ent-4 was synthesized from (À )-SA 1 via 12
steps in 29% overall yield.
°
epoxide-opening in water at 90 C to afford compound 30 in
87% yield using 5 mol% of AcOH as the catalyst. Finally,
compound 30 was first treated with 2.0 equiv. of NaOH in
°
methanol at 40 C, and then treated with diluted aq. HCl, the
desired (+)-ent-SA ent-1 could be thus obtained in 86% yield.
Synthesis of (+)-3-epi-ent-SA ent-2from (À )-SA 1
In comparison to the literature syntheses of the target
molecules, our novel stereodivergent syntheses might be more
efficient, benign and economical. In addition, all the target
molecules and the synthetic intermediates (i.e., compounds 5–
30) as shown in the Schemes 2–6 are useful chiral compounds,
they would constitute a versatile chiral pool for the syntheses of
diverse stereodivergent polyhydroxy-cyclohexenoid (or-cyclo-
hexanoid) natural products and their analogues, which have
various bioactivities and might be very important in medicinal
chemistry and pharmaceutical industry.
The shikimate pathway was present in many plants and
microorganisms,[37] and (À )-SA 1 is an important metabolite in
shikimate pathway. With all the seven stereoisomers of (À )-SA 1
in hands, it worth exploring how these seven compounds react
with the enzymes in the shikimate pathway in future.
Kiessling et al. revealed a synthesis of (+)-3-epi-ent-SA ent-2
from D-arabinose in 2011.[18] Banwell et al. reported a synthesis
of methyl ester of ent-2 from (À )-quinic acid in 2003.[35] Gotor
et al. also reported a synthesis of methyl ester of ent-2 from (À )-
quinic acid in 2006.[36] Our novel synthetic route for the
synthesis of (+)-3-epi-ent-SA ent-2 was depicted in Scheme 6.
As can be seen from the Scheme 6, ethyl shikimate ent-30 was
treated with 2.5 equiv. of tert-butyldimethylsilyl chloride (TBSCl),
3.0 equiv. of Et3N and 0.2 equiv. of DMAP in dimethylformide
(DMF) at room temperature to give compound 6 in 75% yield.
In this reaction, two less hindered hydroxyls at C-3 and C-5
positions of compound ent-30 were selectively protected by
two TBS groups. Compound 6 was then treated with 2.0 equiv.
of MsCl and 5.0 equiv. of pyridine and 0.2 equiv. of DMAP in
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another H-6). 13C NMR (100 MHz, D2O) δ [ppm]=169.68 (C=O),
Experimental Section
139.16 (C-2), 128.15 (C-1), 76.18, 71.47, 68.60, 31.76. HRMS (ESI)
calcd. for C7H9O5: 173.0450. Found: 173.0449. IR (KBr film) 3472,
3326, 3147, 2921, 2876, 1680, 1650, 1430, 1415, 1281, 1257, 1075,
General Method. Optical rotation was tested by a Rudolph Autopol
1
I S2 polarimeter. H NMR and 13C NMR spectra were acquired on a
1067, 985 cmÀ 1
.
Bruker AM-400 instrument; chemical shifts are given on the δ scale
as parts per million (ppm) with tetramethylsilane (TMS) as the
internal standard (zero point), positive values represent downfield
from TMS, and negative values represent upfield from TMS. 2D
NMR spectra were acquired on a Bruker Avance-III-500 instrument.
Infrared (IR) spectra were recorded with a Nicolet Magna IR-550
instrument. Mass spectra were performed with an HP1100 LC-MS
spectrometer. Melting points were determined on a Mel-TEMP II
apparatus. Column chromatography was performed on silica gel
(200–300 mesh, Qingdao Ocean Chemical Corp.), unless otherwise
indicated. All chemicals were analytically pure. (À )-Shikimic acid 1
can be purchased from many chinese venders such as Guangxi
Fenghui Biotechnology Co. Ltd., Xi-an Kono Chemical Co. Ltd.,
Shaanxi Sinote Biotechnology Co. Ltd., and Jia-xing Eisen Chemical
Co. Ltd. Compounds 5 and 7 were prepared according to the
known procedures.[8b,7e]
Synthesis of (+)-4-epi-ent-SA ent-3
Ethyl (3R,4S,5S)-5-benzoyloxy-3,4-epoxy-cyclohex-1-ene-1-carb
-oxylate ent-8. Compound 5 (15.04 g, 81.65 mmol), benzoic acid
(14.96 g, 122.5 mmol) and triphenylphosphine (32.13 g,
122.5 mmol) were dissolved in dichloromethane (300 mL), and then
diethyl azodicarboxylate (21.32 g, 122.4 mmol) was slowly added at
room temperature over 10 min. The mixture was stirred for 5 h.
After the reaction was complete (checked by TLC, EtOAc/hexane=
1:6), dichloromethane was removed by vacuum distillation and
then ethyl acetate (100 mL) and hexane (50 mL) were added. The
suspension was filtrated by Buchner funne and the filtrate was
concentrated by vacuum distillation to give pale yellow oil, which
was purified by chromatography (eluent: EtOAc/hexane=1:8) to
afford compound ent-8 (15.29 g, 53.07 mmol) as a colorless oil in
25
1
°
65% yield. ½a�D = +49.0 (c 1.11, CHCl3). H NMR (400 MHz, CDCl3)
δ [ppm]=8.15–8.08 (d, J=8.2 Hz, 2H, two ortho-H in Bz), 7.59 (t, J=
7.6 Hz, 1H, para-H in Bz), 7.50–7.41 (dd, J1 =8.2 Hz, J2 =7.6 Hz, 2H,
two meta-H in Bz), 7.08 (dd, J1 =4.0 Hz, J2 =3.3 Hz, 1H, H-2), 5.50–
5.43 (m, 1H, H-5), 4.21 (q, J=7.1 Hz, 2H, OCH2CH3), 3.81 (dd, J1 =
4.4 Hz, J2 =2.0 Hz, 1H, H-3), 3.57 (dd, J1 =4.4 Hz, J2 =4.3 Hz, 1H, H-4),
3.09–2.99 (m, 1H, H-6), 2.46–2.34 (m, 1H, another H-6), 1.29 (t, J=
7.1 Hz, 3H, OCH2CH3). 13C NMR (CDCl3, 100 Hz) δ [ppm]=166.10
(C=O), 165.22 (C=O), 133.41 (sp2À C), 133.36 (sp2À C), 132.65 (sp2À C),
129.84 (two sp2À C), 129.66 (sp2À C), 128.45 (two sp2À C), 70.53, 61.19,
56.21, 48.55, 25.88, 14.20. HRMS (ESI) calcd. for [C16H16O5Na]+:
311.0895, found: 311.0887. IR (neat) 3064, 2980, 2936, 2906, 1718,
1601, 1584, 1451, 1375, 1321, 1257, 1202, 1177, 1110, 1073, 1051,
Synthesis of (À )-3-epi-SA 2
Ethyl (3S,4S,5R)-3,4,5-trihydroxy-cyclohex-1-ene-1-carboxylate 15.
Epoxide 5 (8.002 g, 43.44 mmol) was put into a round-bottom flask,
and water (150 mL) was then added. The mixture was heated to
°
95 C, and was stirred with a magnetic stirrer bar for 2 h. After the
reaction was complete (checked by TLC, EtOAc/hexane=1:2), the
mixture was cooled to room temperature and water was removed
by vacuum distillation to afford pale yellow crude, which was
purified by flash chromatography (eluent: EtOAc/hexane=1:4–9:1)
to afford pure compound 15 (7.817 g, 38.66 mmol) as white solid in
89% yield. M.p. 112–114 C. ½a�2D5 =À 16.4 (c 0.52, MeOH). H NMR
1
°
(400 MHz, DMSO-d6) δ [ppm]=6.52 (dd, J1 =2.3 Hz, J2 =2.5 Hz, 1H,
H-2), 4.11 (q, J=7.2 Hz, 2H, OCH2CH3), 4.01–3.94 (m, 1H, H-3), 3.52–
3.41 (m, 1H, H-5), 3.19 (dd, J1 =9.7 Hz, J2 =7.6 Hz, 1H, H-4), 2.61–
2.51 (m, 1H, H-6), 2.07–1.87 (m, 1H, another H-6), 1.19 (t, J=7.2 Hz,
3H, OCH2CH3). 13C NMR (100 MHz, DMSO-d6) δ [ppm]=165.73
(COOEt), 140.54 (C-2), 127.02 (C-1), 76.61, 71.23, 68.47, 60.20, 32.54,
14.03. HRMS (ESI) calcd. for [C9H14O5Na]+: 225.0739; found:
225.0736. IR (KBr film) 3424 (br.), 2994, 2916, 1715, 1646, 1275,
1026, 990, 965, 924, 893, 881, 854, 833, 740, 713 cmÀ 1
.
Ethyl (3S,4R,5S)-5-benzoyloxy-3,4-dihydroxy-cyclohex-1-ene-1-
carboxylate 16. Compound ent-8 (10.02 g, 34.78 mmol) was
dissolved in a mixed solvent of water (60 mL) and 1,4-dioxane
°
(90 mL) at room temperature and the mixture was stirred at 90 C
for 4 h. After the reaction was complete, the mixture was cooled to
room temperature. Ethyl acetate (150 mL) was added, and the
mixture was further stirred for 5 min., two phases were separated
and the aqueous solution was extracted twice with ethyl acetate
(80 mL×2). The organic ectracts were combined and dried over
anhydrous MgSO4. Organic solvents were removed by vacuum
distillation to give pale yellow oil, which was purified by flash
chromatography (eluent: EtOAc/hexane=1:2) to afford compound
1254, 1074, 974, 890, 863, 738 cmÀ 1
.
(À )-3-epi-SA 2. Compound 15 (4.002 g, 19.80 mmol) and methanol
(80 mL) were added into a round-bottom flask with a magnetic
stirrer bar, and then NaOH (1.584 g, 39.60 mmol) was added at
°
room temperature. The mixture was heated to 40 C and then
stirred for approximate 10 h. After the reaction was complete
(checked by TLC, eluent: EtOAc), methanol was removed by vacuum
distillation. The residue was dissolved in water (20 mL), and a dilute
aqueous solution of HCl (1 N) was added to adjust pH=4.1–4.4.
After water was removed by vacuum distillation, ethanol (50 mL)
and activated carbon (1.00 g) were added. The mixture was stirred
at room temperature for 10 h. The suspension was filtered by a
Buchner funnel and rinsed twice with ethanol (2×10 mL). Filtrate
was concentrated by vacuum distillation to afford crude product as
a colorless oil. A column (2×20 cm) of Amberlite IR 120 resin (Na+
form, particle size: 0.600–0.800 mm) was first washed successively
with an aqueous solution of HCl (1 mol/L) and water prior to use,
and then the crude product was purified by chromatography on
the resin column (eluent: pure water) to afford (À )-3-epi-shikimic
16 (9.600 g, 31.34 mmol) as white crystals in 90% yield. M.p. 98–
25
99 C. ½a�D = +70.6 (c 1.03, CHCl3). 1H NMR (400 MHz, CDCl3) δ
[ppm]=7.95 (d, J=7.0 Hz, 2H, two ortho-H in Bz), 7.52 (t, J=7.4 Hz,
1H, para-H in Bz), 7.38 (dd, J1 =7.4 Hz, J2 =7.0 Hz, 2H, two meta-H in
Bz), 6.93–6.89 (m, 1H, H-2), 5.58–5.50 (m, 1H, H-5), 4.63–4.54 (m, 1H,
H-3), 4.16 (q, J=7.1 Hz, 2H, OCH2CH3), 3.94–3.78 (m, 3H, H-4 and
two OH), 2.78–2.59 (m, 2H, two H-6), 1.27 (t, J=7.1 Hz, 3H,
OCH2CH3). 13C NMR (100 MHz, CDCl3) δ [ppm]=166.54 (C=O),
166.29 (C=O), 138.23 (sp2À C), 133.32 (sp2À C), 129.72 (two sp2À C),
129.70 (sp2À C), 128.42 (two sp2À C), 127.93 (sp2À C), 72.81, 71.86,
69.29, 61.10, 29.82, 14.14. HRMS (ESI) calcd. for [C16H18O6Na]+:
329.1001; found: 329.1008.
°
°
Ethyl (3S,4S,5S)-3,4,5-trihydroxy-cyclohex-1-ene-1-carboxylate 17.
Compound 16 (8.004 g, 26.13 mmol) was dissolved in absolute
ethanol (150 mL) and powdered anhydrous K2CO3 (5.418 g,
39.20 mmol) was added. The mixture was stirred at room temper-
ature for 24 h. After the reaction was complete (checked by TLC,
EtOAc/hexane=1:1), the suspension was filtered by a Buchner
acid 2 (3.034 g, 17.42 mmol) as white solid in 88% yield. M.p. 188–
25
190 C. ½a�D ¼< MÀ > 30:1 ðc 1:20; H2OÞ flit:22b ½a�2D5 =À 31.0 (c
°
1
0.1, H2O)}. H NMR (400 MHz, D2O) δ [ppm]=6.55 (dd, J1 =2.7 Hz,
J2 =2.4 Hz,1H, H-2), 4.18–4.10 (m, 1H, H-3), 3.65 (ddd, J1 =10.2 Hz,
J2 =6.0 Hz, J3 =4.2 Hz, 1H, H-5), 3.35 (dd, J1 =10.2 Hz, J2 =8.1 Hz, 1H,
H-4), 2.65 (dd, J1 =17.2 Hz, J2 =6.0 Hz, 1H, H-6), 2.14–2.01 (m, 1H,
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funnel and rinsed twice with ethanol (2×10 mL). Filtrate was
concentrated by vacuum distillation to give pale yellow oil, which
(28.20 g, 97.81 mmol) as a colorless oil in 90% yied. ½a�2D5 = +253.2
(c 1.16, CHCl3). 1H NMR (400 MHz, CDCl3) δ [ppm]=7.96 (d, J=
7.7 Hz, 2H, two ortho-H in Bz), 7.54 (t, J=7.4 Hz, 1H, para-H in Bz),
7.40 (dd, J1 =7.7 Hz, J2 =7.4 Hz, 2H, two meta-H in Bz), 7.19 (dd, J1 =
3.6 Hz, J2 =3.4 Hz, 1H, H-2), 5.90–5.84 (m, 1H, H-5), 4.21 (q, J=
7.1 Hz, 2H, OCH2CH3), 3.79–3.72 (m, 1H, H-3), 3.54 (dd, J1 =3.9 Hz,
J2 =3.6 Hz, 1H, H-4), 2.96 (dd, J1 =18.1 Hz, J2 =2.0 Hz, 1H, H-6), 2.45
(dd, J1 =18.1 Hz, J2 =5.2 Hz, 1H, another H-6), 1.28 (t, J=7.1 Hz, 3H,
OCH2CH3). 13C NMR (100 MHz, CDCl3) δ [ppm]=165.77 (C=O),
165.67 (C=O), 133.30 (sp2À C), 132.83 (sp2À C), 131.30 (sp2À C), 129.74
(two sp2À C), 129.65 (sp2À C), 128.40 (two sp2À C), 66.24, 61.05, 54.02,
46.61, 26.47, 14.17. HRMS (ESI) calcd. for [C16H16O5Na]+: 311.0895;
found: 311.0894. IR (neat) 2939, 2841, 1715, 1451, 1382, 1340, 1258,
was purified by flash chromatography (eluent: EtOAc) to afford oily
25
°
compound 17 (5.019 g, 24.82 mmol) in 95% yield. ½a�D = +74.0 (c
1
1.62, MeOH). H NMR (400 MHz, DMSO-d6 with addition of D2O) δ
[ppm]=6.63–6.57 (m, 1H, H-2), 5.19 (d, J=5.6 Hz, 0.24H, OH,
partially exchanged with D2O), 4.78 (d, J=4.6 Hz, 0.24H, OH,
partially exchanged with D2O), 4.73 (d, J=4.4 Hz, 0.24H, OH,
partially exchanged with D2O), 4.11 (q, J=7.1 Hz, 2H, OCH2CH3),
4.09–4.02 (m, 1H, H-3), 3.85–3.77 (m, 1H, H-5), 3.47–3.41 (dd, J1 =
5.6 Hz, J2 =2.3 Hz, 1H, H-4), 2.41–2.29 (m, 1H, H-6), 2.28–2.17 (m, 1H,
another H-6), 1.20 (t, J=7.1 Hz, 3H, OCH2CH3). 13C NMR (100 MHz,
DMSO-d6) δ [ppm]=166.69 (CO2Et), 139.13 (C-2), 128.58 (C-1), 73.59,
69.11, 67.05, 60.60, 31.02, 14.57. HRMS (ESI) calcd. for [C9H14O5Na]+:
225.0739; found: 225.0733.
1240, 1094, 1024, 925, 810, 764, 711 cmÀ 1
.
Ethyl (3S,4S,5R)-5-benzoyloxy-3-acetoxy-4-hydroxy-cyclohex-1-
(+)-4-epi-ent-SA ent-3. Compound 17 (3.810 g, 18.84 mmol) and
methanol (80 mL) were added into a round-bottom flask with a
magnetic stirrer bar, and then NaOH (1.508 g, 37.70 mmol) was
ene-1-carboxylate 19. Compound 18 (15.04 g, 52.17 mmol), acetic
acid (15.67 g, 260.9 mmol) and trifluoroacetic acid (2.974 g,
26.09 mmol) were dissolved in dichloromethane (300 mL) in a
round-bottom flask with a magnetic stirrer bar. The mixture was
stirred at reflux for 30 h. After the reaction was complete (checked
by TLC, EtOAc/hexane=1:2), the mixture was cooled to room
temperature and water (200 mL) was added. Powder potassium
carbonate (25.00 g) was slowly added to neutralize the solution,
which then transformed to a separatory funnel. Two phases were
separated, and aqueous solution was twice extracted by dichloro-
methane (150 mL×2). Organic extracts were combined and dried
over MgSO4. The solution was then concentrated by vacuum
distillation to give the crude product as a pale yellow oil, which was
purified by flash chromatography (eluent: EtOAc/hexane=1:4) to
afford compound 19 (14.55 g, 41.77 mmol) as a colorless oil in 80%
yield. ½a�2D5 =À 5.6 (c 1.98, CHCl3). 1H NMR (400 MHz, CDCl3) δ
[ppm]=8.04 (d, J=7.9 Hz, 2H, two ortho-H in Bz), 7.56 (t, J=7.2 Hz,
1H, para-H in Bz), 7.43 (dd, J1 =7.9 Hz, J2 =7.2 Hz, 2H, two meta-H
in Bz), 6.72–6.67 (m, 1H, H-2), 5.54 (dd, J1 =3.0 Hz, J2 =2.9 Hz, 1H, H-
3), 5.32 (m, 1H, H-5), 4.21 (q, J=7.1 Hz, 2H, OCH2CH3), 4.09 (dd, J1 =
7.4 Hz, J2 =4.8 Hz, 1H, H-4), 3.12–2.95 (m, 2H, H-6 and OH), 2.50 (dd,
J1 =17.8 Hz, J2 =8.8 Hz, 1H, another H-6), 2.10 (s, 3H, CH3 in Ac), 1.29
(t, J=7.1 Hz, 3H, OCH2CH3). 13C NMR (100 MHz, CDCl3) δ [ppm]=
170.92 (C=O), 166.23 (C=O), 165.40 (C=O), 133.98 (sp2À C), 133.37
(sp2À C), 130.07 (sp2À C), 129.79 (two sp2À C), 129.65 (sp2À C), 128.44
(two sp2À C), 73.62, 71.62, 71.40, 61.28, 29.18, 20.97, 14.18. HRMS
(ESI) calcd. for [C18H20O7Na]+: 371.1107; found: 371.1113. IR (neat)
3481, 2982, 2936, 1718, 1450, 1372, 1315, 1233, 1178, 1114, 1098,
°
added at room temperature. The mixture was heated to 40 C and
then stirred for approximate 10 h. After the reaction was complete
(checked by TLC, eluent: EtOAc), methanol was removed by vacuum
distillation. The residue was dissolved in water (20 mL), and a dilute
aqueous solution of HCl (1 N) was added to adjust pH=4.1–4.4.
After water was removed by vacuum distillation, ethanol (50 mL)
and activated carbon (1.00 g) were added. The mixture was stirred
at room temperature for 10 h. The suspension was filtered by a
Buchner funnel and filter cake was rinsed twice with ethanol (2×
10 mL). Filtrate was concentrated by vacuum distillation to afford
crude product as a colorless oil. A column (2×20 cm) of Amberlite
IR 120 resin (Na+ form, particle size: 0.600–0.800 mm) was first
washed successively with an aqueous solution of HCl (1 mol/L) and
water prior to use, and then the crude product was purified by
chromatography on the resin column (eluent: pure water) to afford
(+)-4-epi-SA ent-3 (2.918 g, 16.76 mmol) as white crystals in 89%
25
22
°
yield. M.p. 110–112 C. ½a�D ¼ þ79:8 ðc 0:64; H2OÞ flit:26 ½a�D
=
1
À 80.6 (c 1.03, H2O) for 3}. H NMR (400 MHz, D2O) δ [ppm]=6.77–
6.72 (m, 1H, H-2), 4.37–4.30 (m, 1H, H-3), 4.10 (ddd, J1 =3.2 Hz, J2 =
4.4 Hz, J3 =2.4 Hz, 1H, H-5), 3.68 (dd, J1 =7.2 Hz, J2 =2.4 Hz, 1H, H-4),
2.62–2.52 (m, 1H, H-6), 2.44–2.35 (dd, J1 =18.4 Hz, J2 =4.4 Hz, 1H,
another H-6). 13C NMR (100 MHz, D2O) δ [ppm]=170.12 (C=O),
137.94 (C-2), 128.65 (C-1), 72.98, 68.53, 67.79, 30.46. IR (KBr film)
3378, 3279, 2957, 2920, 2895, 1601, 1695, 1418, 1371, 1329, 1305,
1271, 1242, 1206, 1126, 1089, 1073, 1036, 1016, 951, 922, 901, 837,
763, 733 cmÀ 1
.
1069, 1028, 959, 929, 894, 865, 806, 738, 714 cmÀ 1
.
Ethyl (3S,4S,5R)-5-benzoyloxy-3-acetoxy-4-methanesulfonyloxy-
cyclohex-1-ene-1-carboxylate 9. Compound 19 (15.00 g,
43.06 mmol), triethylamine (6.536 g, 64.59 mmol) and 4-dimeth-
ylamino-pyridine (526.5 mg, 4.306 mmol) were dissolved in di-
chloromethane (300 mL) in a round-bottom flask. The solution was
Synthesis of (À )-4-epi-SA 3
Ethyl (3R,4S,5R)-5-benzoyloxy-3,4-epoxy-cyclohex-1-ene-1-carb
-oxylate 18. Epoxide
5 (20.03 g, 108.7 mmol), triethylamine
(22.04 g, 217.8 mmol) and 4-dimethylamino-pyridine (1.328 g,
10.87 mmol) were dissolved in dichloromethane (200 mL) in a
round-bottom flask, which was equipped with a magnetic stirrer
°
cooled to 0 C by an ice bath, and then methanesulfonyl chloride
(6.130 g, 53.50 mmol) was added dropwise over 10 min. The
°
mixture was further stirred at 0 C for 2 h. After the reaction was
°
bar. The solution was cooled to 0 C by an ice bath and then
complete (checked by TLC, EtOAc/hexane=1:2), an aqueous
solution of HCl (150 mL, 1 N) was added, mixture was further stirred
for 5 min. Two phases were separated by a separatory funnel, and
the organic layer was successively washed with an aqueous
solution of K2CO3 (100 mL, 5% w/w) and water (50 mL). After
organic layer was dried over anhydrous MgSO4, the solution was
concentrated by vacuum distillation to give an off-white crude,
which was triturated in a mixed solution of ethyl acetate and
hexane (EtOAc/hexane=1:4). The mixture was filtered by suction
and rinsed twice by the above mixed solvent to afford compound 9
(17.45 g, 40.92 mmol) as white crystals in 95% yield. M.p. 128–
benzoyl chloride (22.93 g, 163.1 mmol) was added dropwise over
15 min. 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, EtOAc/hexane=1:4), an aqueous
solution of potassium carbonate (200 mL, 10% w/w) was added
and the mixture was further stirred for 3 h. Then two phases were
separated by a separatory funnel and the organic layer was
successively washed with an aqueous solution of HCl (150 mL, 2 N)
and water (50 mL). After organic layer was dried over anhydrous
MgSO4, the solution was concentrated by vacuum distillation to
afford a pale yellow oil, which was purified by flash chromatog-
raphy (eluent: EtOAc/hexane=1:8) to afford compound 18
129 C. ½a�2D5 =À 46.8 (c 4.52, CHCl3). 1H NMR (400 MHz, CDCl3) δ
°
[ppm]=8.10 (d, J=7.8 Hz, 2H, two ortho-H in Bz), 7.60 (t, J=7.4 Hz,
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1H, para-H in Bz), 7.46 (dd, J1 =7.8 Hz, J2 =7.4 Hz, 2H, two meta-H in
H-2), 5.52–5.42 (m, 1H, H-5), 4.22 (q, J=7.1 Hz, 2H, OCH2CH3), 3.82
(d, J=3.7 Hz, 1H, H-3), 3.58 (dd, J1 =6.4 Hz, J2 =3.7 Hz, 1H, H-4), 3.05
(dd, J1 =16.4 Hz, J2 =6.6 Hz, 1H, H-6), 2.45–2.35 (m, 1H, another H-
6), 1.30 (t, J=7.1 Hz, 3H, OCH2CH3). 13C NMR (100 MHz, CDCl3) δ
[ppm]=166.15 (C=O), 165.25 (C=O), 133.47 (sp2À C), 133.38 (sp2À C),
132.64 (sp2À C), 129.87 (two sp2À C), 129.68 (sp2À C), 128.47 (two
sp2À C), 70.53, 61.21, 56.22, 48.57, 25.89, 14.20. HRMS (ESI) calcd. for
[C16H16O5Na]+: 311.0895; found: 311.0901. IR (neat) 3063, 3031,
2981, 2931, 2870, 1718, 1450, 1374, 1320, 1257, 1201, 1177, 1110,
Bz), 6.72–6.67 (m, 1H, H-2), 5.82–5.75 (m, 1H, H-3), 5.53–5.43 (m, 1H,
H-5), 5.13 (dd, J1 =9.6 Hz, J1 =7.6 Hz, 1H, H-4), 4.22 (q, J=7.1 Hz, 2H,
OCH2CH3), 3.20 (dd, J1 =17.9 Hz, J2 =6.0 Hz, 1H, H-6), 2.93 (s, 3H, CH3
in Ms), 2.62–2.52 (m, 1H, another H-6), 2.12 (s, 3H, CH3 in Ac), 1.29 (t,
J=7.1 Hz, 3H, OCH2CH3). 13C NMR (100 MHz, CDCl3) δ [ppm]=
170.06 (C=O), 165.36 (C=O), 164.76 (C=O), 133.63 (sp2À C), 133.19
(sp2À C), 130.02 (sp2À C), 129.89 (two sp2À C), 129.11 (sp2À C), 128.59
(two sp2À C), 78.15, 70.46, 68.27, 61.47, 38.78, 29.68, 20.82, 14.15.
HRMS (ESI) calcd. for [C19H22O9SNa]+: 449.0882; found: 449.0872. IR
(KBr film) 3088, 3057, 2938, 2939, 2921, 2850, 1750, 1346, 1271,
1072, 1025, 924, 739, 713 cmÀ 1
.
(À )-4-epi-SA 3. It was prepared from compound 8 in 76% yield (3
1218, 1166, 1112, 1034, 1009, 969, 923, 756, 734 cmÀ 1
.
steps) through the same sequence as that for the preparation of
Ethyl (3S,4R,5R)-5-benzoyloxy-3-hydroxy-4-methanesulfonyl-oxy-
(+)-4-epi-SA ent-3 from compound ent-8. Characterization data:
25
cyclohex-1-ene-1-carboxylate 20. Compound (20.03 g,
9
M.p. 110–112 C. ½a�D ¼ À 79:7 ðc 0:65; H2OÞ flit:26 ½a�2D2 =À 80.6
°
1
46.97 mmol), p-toluenesulfonic acid (17.87 g, 93.94 mmol) and
absolute ethanol (300 mL) were added into a round-bottom flask.
Then the mixture was heated to reflux, and was further stirred
under refluxing for 7 h. After the reaction was complete (checked
by TLC, EtOAc/hexane=1:2), the solution was cooled to room
temperature, and concentrated to dryness by vacuum distillation.
Ethyl acetate (350 mL) and water (150 mL) were added into the
flask, powdered K2CO3 (8.002 g) was added slowly to neutralize the
(c 1.03, H2O)}. H NMR (400 MHz, D2O) δ [ppm]=6.76–6.71 (m, 1H,
H-2), 4.37–4.27 (m, 1H, H-3), 4.10 (ddd, J1 =3.2 Hz, J2 =4.4 Hz, J3 =
2.5 Hz, 1H, H-5), 3.66 (dd, J1 =7.2 Hz, J2 =2.5 Hz, 1H, H-4), 2.61–2.51
(m, 1H, H-6), 2.46–2.32 (m, J1 =18.3 Hz, J2 =4.4 Hz, 1H, another H-6).
13C NMR (101 MHz, D2O) δ [ppm]=170.07 (C=O), 137.97 (C-2),
128.62 (C-1), 72.98, 68.52, 67.79, 30.45. HRMS (ESI) calcd. for
[C7H9O5]: 173.0450; found: 173.0449.
°
solution. The mixture was warmed up to 50~60 C, and further
Synthesis of (+)-5-epi-ent-SA ent-4
stirred for 15 min., and two phases were then separated under the
warm temperature. The aqueous solution was twice extracted with
ethyl acetate (150 mL×2). The organic extracts were combined and
dried over anhydrous MgSO4. After filtration under the warm
temperature, the solution was concentrated by vacuum distillation
to give an off-white solid product, which was triturated in a mixed
solution of ethyl acetated and hexane (eluent: EtOAc/hexane=1:2).
The mixture was filtered by suction and rinsed twice by the above
mixed solvent to afford compound 20 (16.60 g, 43.18 mmol, 92%)
Ethyl
(3R,4R,5R)-3-bromo-5-benzoyloxy-4-hydroxy-cyclohex-1-
ene-1-carboxylate 21. Compound 8 (15.04 g, 52.17 mmol) was
dissolved in ethyl acetate (300 mL). After the solution was cooled to
°
0 C by an ice bath, hydrobromic acid (21.10 g, 104.3 mmol, 40% w/
w) was added dropwise over 10 min. After the reaction was
complete (checked by TLC, EtOAc/hexane=1:2), an aqueous
solution of K2CO3 (200 mL, 5% w/w) was added to quench the
reaction. Two phases were separated and the aqueous solution was
twice extracted with ethyl acetate (150 mL×2). Organic extracts
were combined and dried over anhydrous MgSO4, and then the
solution was concentrated by vacuum distillation to give a pale
yellow oily crude product, which was purified by flash chromatog-
raphy (eluent: EtOAc/hexane=1:4) to afford compound 21
(18.68 g, 50.59 mmol) as a colorless oil in 97% yield. ½a�2D5 =À 122.8
as a white crystals in 92% yield. M.p. 159–161 C. ½a�2D5 =À 101.8 (c
°
1
1.20, CHCl3). H NMR (400 MHz, CDCl3) δ [ppm]=8.08 (d, J=7.9 Hz,
2H, ortho-H in Bz), 7.58 (t, J=7.4 Hz, 1H, para-H in Bz), 7.46 (dd, J1 =
7.9 Hz, J2 =7.4 Hz, 2H, two meta-H in Bz), 6.82–6.78 (m,1H, H-2),
5.46–5.36 (m, 1H, H-5), 5.00–4.91 (m, 1H, H-4), 4.71–4.62 (m, 1H, H-
3), 4.21 (q, J=7.0 Hz, 2H, OCH2CH3), 3.19 (dd, J1 =17.7 Hz, J2 =
6.3 Hz, 1H, H-6), 3.02 (s, 3H, CH3 in Ms), 2.89 (s, 1H, OH), 2.51 (dd, J1
=17.7 Hz, J2 =9.8 Hz, 1H, another H-6), 1.28 (t, J=7.1 Hz, 3H,
OCH2CH3). 13C NMR (100 MHz, CDCl3) δ [ppm]=165.61 (C=O),
165.07 (C=O), 136.53 (sp2À C), 133.63 (sp2À C), 129.87 (two sp2À C),
129.20 (sp2À C), 128.65 (two sp2À C), 128.46 (sp2À C), 82.85, 70.32,
68.35, 61.39, 38.68, 30.20, 14.17. HRMS (ESI) calcd. for
[C17H20O8SNa]+: 407.0777; found: 407.0774. IR (KBr film) 3429, 3021,
2998, 2954, 1701, 1450, 1421, 1356, 1313, 1285, 1257, 1167, 1118,
1
(c 0.68, CHCl3). H NMR (400 MHz, CDCl3) δ [ppm]=8.02 (d, 2H, J=
8.4 Hz, two ortho-H in Bz), 7.58 (t, 1H, J=8.4 Hz, para-H in Bz), 7.44
(dd, J1 =8.4 Hz, J2 =7.4 Hz, 2H, two meta-H in Bz), 7.05–6.99 (m, 1H,
H-2), 5.71–5.60 (m, 1H, H-5), 4.86–4.75 (m, 2H, H-3 and OH), 4.33
(dd, J1 =5.7 Hz, J2 =2.2 Hz, 1H, H-4), 4.22 (q, J=7.2 Hz, 2H,
OCH2CH3), 3.00–2.88 (m, 1H, H-6), 2.88–2.76 (m, 1H, another H-6),
1.30 (t, J=7.2 Hz, 3H, OCH2CH3). 13C NMR (100 MHz, CDCl3) δ
[ppm]=165.98 (C=O), 165.51 (C=O), 135.18 (sp2À C), 133.46 (sp2À C),
129.75 (two sp2À C), 129.58 (sp2À C), 129.34 (sp2À C), 128.51 (two
sp2À C), 72.53, 69.71, 61.33, 47.55, 27.68, 14.19. HRMS (ESI) calcd. for
[C16H17O5BrNa]+: 391.0157; found: 391.0160. IR (neat) 3470, 3065,
2980, 2937, 1717, 1601, 1584, 1451, 1368, 1314, 1270, 1177, 1113,
1098, 1069, 1027, 963, 947, 905, 875, 844, 805, 787, 771, 751,
1095, 980, 896, 863, 852, 784, 751 cmÀ 1
.
Ethyl (3S,4R,5R)-5-benzoyloxy-3,4-epoxy-cyclohex-1-ene-1-car-
boxylate 8. Compound 20 (10.02 g, 26.07 mmol) was dissolved in
dichloromethane (300 mL), and the resoluting solution was cooled
to 0 C by an ice bath. Sodium hydride (2.086 g, 52.14 mmol, 60%
°
713 cmÀ 1
.
w/w) was slowly added in portions over 1 h. When addition was
finished, the mixture was warmed to room temperature, and was
further stirred for 6 h. After the reaction was complete (checked by
TLC, EtOAc/hexane=1:4), the reaction solution was quenched by
slow addition of water (50 mL). Two phases were separated, and
aqueous solution was twice washed with dichloromethane (50 mL×
2). Organic extracts were combined and dried over anhydrous
MgSO4. The solution was concentrated by vacuum distillation to
afford crude product as a bright yellow oil, which was purified by
flash chromatography (eluent: EtOAc/hexane=1:8) to give com-
pound 8 (6.014 g, 20.86 mmol, 80%) as a colorless oil. ½a�2D5 =À 48.3
(c 2.69, CHCl3). 1H NMR (400 MHz, CDCl3) δ [ppm]=8.11 (d, J=
8.0 Hz, 2H, ortho-H in Bz), 7.59 (t, J=7.3 Hz, 1H, para-H in Bz), 7.48
(dd, J1 =8.0 Hz, J2 =7.3 Hz, 2H, two meta-H in Bz), 7.12–7.08 (m, 1H,
Ethyl
(3R,4R,5R)-4-acetoxy-3-bromo-5-benzoyloxy-cyclohex-1-
ene-1-carboxylate 22. Compound 21 (12.01 g, 32.53 mmol), acetic
anhydrate (4.320 g, 42.32 mmol) and DMAP (397.4 mg, 3.253 mmol)
were dissolved in dichloromethane (200 mL). After the solution was
°
cooled to 0 C by an ice bath, triethylamine (4.938 g, 48.80 mmol)
was dropwise added over 10 min., the mixture was further stirred
°
for 2 h at 0 C. After the reaction was complete (checked by TLC,
EtOAc/hexane=1:4), an aqueous solution of HCl (100 mL, 1 N) was
added to quench the reaction. Two phases were separated, and the
organic layer was successively washed with an aqueous solution of
K2CO3 (50 mL, 5% w/w) and water (50 mL). The organic solution
was dried over anhydrous MgSO4 and then concentrated by
vacuum distillation to give crude product as a pale yellow oil, which
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was purified by flash chromatography (eluent: EtOAc/hexane=1:6)
to afford compound 22 (12.70 g, 30.88 mmol) as an off-white solid
product as a colorless oil. A column (2×20 cm) of Amberlite IR 120
resin (Na+ form, particle size: 0.600–0.800 mm) was first washed
successively with an aqueous solution of HCl (1 mol/L) and water
prior to use, and then the crude product was purified by
chromatography on the resin column (eluent: pure water) to afford
(+)-5-epi-ent-SA ent-4 (2.925 g, 16.80 mmol) as white crystals in
1
in 95% yield. M.p. 84–86 C. ½a�2D5 =À 162.4 (c 0.92, CHCl3). H NMR
°
(400 MHz, CDCl3) δ [ppm]=7.98 (d, J=8.4 Hz, 2H, two ortho-H in
Bz), 7.57 (t, J=7.4 Hz, 1H, para-H in Bz), 7.45 (dd, J1 =8.4 Hz, J2 =
7.4 Hz, 2H, two meta-H in Bz), 7.05–6.99 (m, 1H, H-2), 5.77–5.69 (m,
1H, H-5), 5.47 (dd, J1 =5.5 Hz, J2 =2.3 Hz, 1H, H-4), 4.86–4.78 (m, 1H,
H-3), 4.24 (q, J=7.1 Hz, 2H, OCH2CH3), 3.07–2.95 (m, 1H, H-6), 2.85–
2.74 (m, 1H, another H-6), 2.11 (s, 3H, CH3 in Ac), 1.31 (t, J=7.1 Hz,
3H, OCH2CH3). 13C NMR (100 MHz, CDCl3) δ [ppm]=169.91 (C=O),
165.47 (C=O), 165.32 (C=O), 134.70 (sp2À C), 133.40 (sp2À C), 129.72
(sp2À C), 129.70 (two sp2À C), 129.56 (sp2À C), 128.50 (two sp2À C),
72.86, 67.23, 61.39, 42.90, 27.69, 20.84, 14.20. HRMS (ESI) calcd. for
[C18H19O6BrNa]+: 433.0263; found: 433.0258. IR (KBr film) 3072, 2994,
2974, 2898, 1746, 1719, 1602, 1583, 1493, 1448, 1373, 1343, 1301,
1317, 1281, 1249, 1222, 1201, 1135, 1121, 1101, 1084, 1069, 1042,
87% yield. M.p. 108–110 C. ½a�2D5 = +63.2 (c 0.59, H2O). 1H NMR
°
(400 MHz, D2O) δ [ppm]=6.68 (d, J=3.6 Hz, 1H, H-2), 4.52–4.43 (m,
1H, H-3), 4.04 (dd, J1 =3.6 Hz, J2 =2.8 Hz, 1H, H-4), 3.97 (ddd, J1 =
4.0 Hz, J2 =6.2 Hz, J3 =2.8 Hz, 1H, H-5), 2.58 (dd, J1 =17.4 Hz, J2 =
6.2 Hz, 1H, H-6), 2.33–2.19 (m, 1H, another H-6). 13C NMR (100 MHz,
D2O) δ [ppm]=169.87 (C=O), 138.95 (C-2), 128.74 (C-1), 70.55,
68.13, 67.36, 27.56. IR (KBr film) 3377, 2963, 2922, 2905, 1697, 1442,
1415, 1377, 1347, 1299, 1274, 1251, 1236, 1152, 1107, 1089, 1059,
1042, 1025, 976, 923, 881, 787, 716 cmÀ 1
.
1015, 969, 938, 908, 889, 862, 767, 748, 717 cmÀ 1
.
Synthesis of (À )-5-epi-SA 4
Ethyl (3S,4R,5R)-3,4,5-trihydroxy-cyclohex-1-ene-1-carboxylate 25.
Compound 22 (14.03 g, 34.12 mmol) and acetic acid (16.39 g,
273.0 mmol) were dissolved in isopropanol (200 mL). Powdered
anhydrous potassium acetate (6.697 g, 68.24 mmol) was added, and
the mixture was heated to reflux, and was then stirred under
refluxing for 30 h. After the reaction was complete (checked by TLC,
EtOAc/hexane=1:2), isopropanol was removed by vacuum distil-
lation. Then ethyl acetate (350 mL) and an aqueous solution of
K2CO3 (250 mL, 15% w/w) were added. After the mixture was
vigorously stirred for 30 min., two phases were separated and the
aqueous solution was twice extracted with ethyl acetate (150 mL×
2). Organic extracts were combined and dried over anhydrous
MgSO4. The solution was concentrated by vacuum distillation to
give a pale yellow oil, which was purified by flash chromatography
(eluent: EtOAc/hexane=1:4) to afford a mixture of compounds 23
and 24. It was then dissolved in absolute ethanol (250 mL) in a
round-bottom flask. Then powdered anhydrous K2CO3 (14.14 g,
102.4 mmol) was added into the flask, and the mixture was then
stirred at room temperature for 7 h. After the reaction was
complete, the suspension was filtered by a Buchner funnel, and the
filter cake was washed twice with ethanol (50 mL×2). The filtrates
were combined and concentrated by vacuum distillation to give a
pale yellow oil, which was purified by flash chromatography
(eluent: EtOAc) to afford compound 25 (5.860 g, 28.98 mmol) as
Ethyl
(3R,4R)-3,4-isopropylidenedioxy-5-oxo-cyclohex-1-ene-1-
carboxylate 14. Compound 7 (12.03 g, 49.66 mmol) was dissolved
in dichloromethane (240 mL), and then trichloroisocyanuric acid
(15.00 g, 64.56 mmol) and 2,2,6,6-tetramethyl-1-piperidine N-oxide
(388.0 mg, 2.483 mmol) were added. The mixture was stirred at
room temperature for 4 h. After the reaction was complete
(checked by TLC, EtOAc/hexane=1:3), dichloromethane was
removed by vacuum distillation. Then ethyl acetate (250 mL) and
water (150 mL) were added and further stirred for 0.5 h. The
suspension was filtrated by a Buchner funnel, and the filter cake
was twice rinsed with ethyl acetate (20 mL×2). Two phases were
separated and the aqueous solution was twice extracted with ethyl
acetate (100 mL×2). The organic extracts were combined and dried
over anhydrous MgSO4. The solution was concentrated by vaccum
distillation to give a bright yellow oil, which was purified by flash
chromatography (eluent: EtOAc/hexane=1:6) to afford compound
14 (10.15 g, 42.25 mmol) as a pale yellow oil in 85% yield. ½a�D
25
=
1
À 20.6 (c 1.34, CHCl3). H NMR (400 MHz, CDCl3) δ [ppm]=7.00–6.96
(m, 1H, H-2), 5.10–5.02 (m, 1H, H-3), 4.50 (d, J=6.2 Hz, 1H, H-4), 4.26
(q, J=7.1 Hz, 2H, OCH2CH3), 3.42 (d, J=19.7 Hz, 1H, H-6), 3.24 (d, J=
19.7 Hz, 1H, another H-6), 1.47 (s, 3H, CH3 in isopropylidene), 1.42 (s,
3H, another CH3 in isopropylidene), 1.32 (t, J=7.1 Hz, 3H, OCH2CH3).
13C NMR (100 MHz, CDCl3) δ [ppm]=203.41 (C-5), 165.07 (C=O),
133.17 (sp2À C), 130.13 (sp2À C), 111.54, 77.63, 75.96, 61.58, 37.05,
27.45, 26.08, 14.18. HRMS (ESI) calcd. for [C12H16O5Na]+: 263.0895;
found: 263.0891. IR (neat) 3067, 2986, 2937, 2908, 1719, 1456, 1374,
white crystals in 85% yield. M.p. 134–135 C. ½a�2D5 = +55.1 (c 0.55,
°
MeOH). 1H NMR (400 MHz, DMSO-d6) δ [ppm]=6.52–6.46 (m, 1H, H-
2), 4.23–4.15 (m, 1H, H-3), 4.09 (q, J=7.1 Hz, 2H, OCH2CH3), 3.80–
3.73 (m, 1H, H-4), 3.68–3.60 (m, 1H, H-5), 2.36–2.25 (dd, J1 =16.8 Hz,
J2 =5.8 Hz, 1H, H-6), 2.18–2.06 (m, 1H, another H-6), 1.17 (t, J=
7.1 Hz, 3H, OCH2CH3). 13C NMR (100 MHz, DMSO-d6) δ [ppm]=
166.27 (CO2Et), 139.79 (C-2), 127.91 (C-1), 70.30, 67.85, 67.14, 60.50,
28.29, 13.90. HRMS (ESI) calcd. for [C9H14O5Na]+: 225.0739; found:
225.0730. IR (KBr film) 3371, 3204, 2987, 2959, 2931, 2848, 1714,
1478, 1434, 1411, 1376, 1247, 1155, 1085, 1062, 1033, 950, 923, 896,
1249, 1160, 1082, 1019, 978, 926, 911, 853, 785, 741 cmÀ 1
.
Ethyl (3R,4S,5S)-3,4-isopropylidenedioxy-5-hydroxy-cyclohex-1-
ene-1-carboxylate 26. Compound 14 (10.05 g, 41.83 mmol) was
dissolved in ethyl acetate (175 mL) in a round-bottom flask, which
°
was cooled to 0 C by an ice bath. Then sodium borohydride
(1.900 g, 50.22 mmol) was dissolved in water (25 mL), and then was
added dropwise into the flask over 10 min. Then the ice bath was
removed and the solution was stirred at room temperature for 2 h.
After the reaction was complete (checked by TLC, EtOAc/hexane=
1:2), ethyl acetate (50 mL) and water (150 mL) were added. The
solution was further stirred at room temperature for 0.5 h. Two
phases were separated and the aqueous layer was twice extracted
with ethyl acetate (100 mL×2). The organic extracts were combined
and then dried over anhydrous MgSO4. The solution was concen-
trated by vacuum distillation to give a colorless oil, which was
purified by flash chromatography (eluent: EtOAc/hexane=1:2) to
afford compound 26 (9.420 g, 38.88 mmol) as a colorless oil in 93%
yield. ½a�2D5 = +35.2 (c 1.37, CHCl3). 1H NMR (400 MHz, CDCl3) δ
[ppm]=6.78–6.69 (m, 1H, H-2), 4.74–4.64 (m, 1H, H-3), 4.38 (dd, J1 =
5.8 Hz, J2 =2.6 Hz, 1H, H-4), 4.17 (q, J=7.1 Hz, 2H, OCH2CH3), 3.95–
3.85 (m, 1H, H-5), 2.76–2.54 (m, 2H, H-6 and OH), 2.50–2.38 (m, 1H,
878, 861, 801, 735 cmÀ 1
.
(+)-5-epi-ent-SA ent-4. Compound 25 (3.902 g, 19.30 mmol) and
methanol (80 mL) were added into a round-bottom flask with a
magnetic stirrer bar, and then NaOH (1.545 g, 38.63 mmol) was
°
added at room temperature. The mixture was heated to 40 C and
then stirred for approximate 10 h. After the reaction was complete
(checked by TLC, eluent: EtOAc), methanol was removed by vacuum
distillation. The residue was dissolved in water (20 mL), and a dilute
aqueous HCl (1 N) was added to adjust pH=4.1–4.4. After water
was removed by vacuum distillation, ethanol (50 mL) and activated
carbon (1.0 g) were added. The mixture was stirred at room
temperature for 10 h. The suspension was filtered by a Buchner
funnel and filter cake was rinsed twice with ethanol (2×10 mL).
Filtrate was concentrated by vacuum distillation to afford crude
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another H-6), 1.36 (s, 3H, CH3 in isopropylidene), 1.34 (s, 3H, another
Synthesis of (+)-ent-SA ent-1
CH3 in isopropylidene), 1.26 (t, J=7.1 Hz, 3H, OCH2CH3). 13C NMR
(100 MHz, CDCl3) δ [ppm]=166.31 (C=O), 134.52 (sp2À C), 129.47
(sp2À C), 109.98 (ketal C in isopropylidene), 75.54, 73.03, 66.96, 61.00,
27.61, 27.43, 26.05, 14.13. HRMS (ESI) calcd. for [C12H18O5K]+:
281.0791; found: 281.0791. IR (neat) 3462, 2985, 2934, 2911, 1713,
1445, 1376, 1297, 1239, 1163, 1141, 1095, 1059, 1032, 978, 950, 904,
Ethyl
(3R,4S,5R)-5-acetoxy-3,4-isopropylidenedioxy-cyclohex-1-
ene-1-carboxylate 27. Compound 7 (15.04 g, 62.08 mmol), triethyl-
amine (9.420 g, 93.09 mmol) and DMAP (760.0 mg, 6.221 mmol)
were dissolved in dichloromethane (300 mL). The solution was
°
cooled to 0 C by an ice bath and then acetic anhydrate (7.610 g,
74.54 mmol) was added dropwise over 10 min. The solution was
859, 833, 786, 741, 724 cmÀ 1
.
°
further stirred at 0 C for 0.5 h. After the reaction was complete
Ethyl
(3R,4S,5S)-3,4,5-trihydroxy-cyclohex-1-ene-1-carboxylate
(checked by TLC, EtOAc/hexane=1:2), an aqueous solution of
K2CO3 (200 mL, 10% w/w) was added to quench the reaction. Two
phases were separated and aqueous solution was extracted with
dichloromethane (150 mL) again. The organic extracts were
combined and was washed with water (150 mL). Then the solution
was dried over anhydrous MgSO4 and then concentrated by
vacuum distillation to give crude product as a colorless oil. The
crude was purified by flash chromatography (eluent: EtOAc/
hexane=1:6) to afford compound 27 (16.24 g, 57.12 mmol, 92%)
ent-25. Compound 26 (8.001 g, 33.02 mmol) was dissolved in
tetrahydrofuran (150 mL) in a round-bottom flask. Concentrated
HCl aqueous solution (14 mL, 167.0 mmol, 36.5% w/w) was diluted
with water (10 mL) and then added dropwise at room temperature
over 5 min. The solution was further stirred for 8 h. After the
reaction was complete (checked by TLC, EtOAc/hexane=1:1), THF
was removed by vacuum distillation. The residue was dissolved in
ethyl acetate (250 mL). Then powdered K2CO3 (11.45 g, 82.84 mmol)
was added slowly to neutralize the solution. After the suspension
was vigorously stirred for 2 h, the mixture was filtrated by a
Buchner funnel and filter cake was twice rinsed with ethyl acetate
(20 mL×2). Then the filtrate was concentrated by vacuum distil-
as a white solid in 92% yield. ½a�2D5 =À 60.7 (c 1.35, CHCl3). H NMR
1
(400 MHz, CDCl3) δ [ppm]=6.91–6.85 (m, 1H, H-2), 5.16–5.07 (m,
1H, H-5), 4.71 (dd, J1 =5.8 Hz, J2 =3.8 Hz, 1H, H-3), 4.24–4.14 (m, 3H,
H-4 and OCH2CH3), 2.76 (dd, J1 =17.7 Hz, J2 =4.5 Hz, 1H, H-6), 2.35–
2.25 (m, 1H, another H-6), 2.05 (s, 3H, CH3 in Ac), 1.39 (s, 3H, CH3 in
isopropylidene), 1.36 (s, 3H, another CH3 in isopropylidene), 1.27 (t,
J=7.1 Hz, 3H, OCH2CH3). 13C NMR (100 MHz, CDCl3) δ [ppm]=
170.16 (C=O), 165.83 (C=O), 133.79 (sp2À C), 129.88 (sp2À C), 109.92
(ketal C in isopropylidene), 74.11, 71.90, 69.96, 61.03, 27.77, 26.52,
25.93, 21.08, 14.12. HRMS (ESI) calcd. for [C14H20O6Na]+: 307.1158;
found: 307.1161. IR (neat) 2985, 2936, 1748, 1718, 1446, 1372, 1287,
lation to give
a colorless oil, which was purified by flash
chromatography (eluent: EtOAc) to afford compound ent-25
°
(6.010 g, 29.72 mmol) as white solid in 90% yield. M.p. 135–136 C.
½a�2D5 =À 54.2 (c 0.97, MeOH). 1H NMR (400 MHz, DMSO-d6) δ
[ppm]=6.54–6.47 (m, 1H, H-2), 4.87 (d, J=7.5 Hz, 1H, OH), 4.76 (d,
J=5.7 Hz, 1H, OH), 4.59 (d, J=3.7 Hz, 1H, OH), 4.23–4.15 (m, 1H, H-
3), 4.12 (q, J=7.1 Hz, 2H, OCH2CH3), 3.79–3.73 (m, 1H, H-5), 3.63 (dd,
J1 =10.0 Hz, J2 =5.9 Hz, 1H, H-4), 2.31 (dd, J1 =16.8 Hz, J2 =5.8 Hz,
1H, H-6), 2.22–2.11 (m, 1H, another H-6), 1.22 (t, J=7.1 Hz, 3H,
OCH2CH3). 13C NMR (101 MHz, DMSO-d6) δ [ppm]=165.89 (CO2Et),
140.30 (C-2), 127.82 (C-1), 70.72, 68.13, 67.45, 60.03, 28.79, 14.08.
HRMS (ESI) calcd. for [C9H14O5Na]+: 225.0739; found: 225.0730. IR
(KBr film) 3346, 3176, 2982, 2958, 2919, 2849, 1713, 1441, 1377,
1324, 1248, 1233, 1176, 1156, 1084, 1063, 1030, 949, 917, 896, 879,
1237, 1166, 1106, 1060, 1038, 940, 863, 753, 728 cmÀ 1
.
Ethyl (3R,4R,5R)-5-acetoxy-3,4-dihydroxy-cyclohex-1-ene-1-carb
-oxylate 28. Compound 27 (15.01 g, 52.79 mmol) was dissolved in
tetrahydrofuran (300 mL) in a round-bottom flask at room temper-
ature. Concentrated aqueous solution of hydrochloric acid (22 mL,
36.5% w/w, 262.9 mmol) was diluted with water (20 mL), which
was then added dropwise into the flask over 10 min. The solution
was further stirred at room temperature for 8 h. After the reaction
was complete (checked by TLC, EtOAc), powdered K2CO3 (18.17 g,
131.5 mmol) was added slowly to quench the reaction. After the
mixture was vigorously stirred for 1 h, tetrahydrofuran was removed
by vacuum distillation, ethyl acetate (300 mL) was added into the
flask. The suspension was filtrated by a Buchner funnel and filter
cake was twice rinsed with ethyl acetate (30 mL×2). The filtrate
was dried over anhydrous MgSO4 and concentrated by vacuum
distillation to give a colorless oil, which was purified by flash
chromatography (eluent: EtOAc/hexane=1:1) to afford compound
799, 735 cmÀ 1
.
(À )-5-epi-SA 4. Compound ent-25 (3.501 g, 17.31 mmol) and
methanol (70 mL) were added into a round-bottom flask with a
magnetic stirrer bar, and then NaOH (1.386 g, 34.65 mmol) was
°
added at room temperature. The mixture was heated to 40 C and
further stirred for approximate 10 h. After the reaction was
complete(checked by TLC, eluent: EtOAc), methanol was removed
by vacuum distillation. The residue was dissolved in water (20 mL),
and a dilute aqueous solution of HCl (1 N) was added to adjust
pH=4.1–4.4. After water was removed by vacuum distillation,
ethanol (50 mL) and activated carbon (1.0 g) were added. The
mixture was stirred at room temperature for 10 h. The suspension
was filtered by a Buchner funnel and filter cake was rinsed twice
with ethanol (2×10 mL). Filtrate was concentrated by vacuum
distillation to afford crude product as a colorless oil. A column (2×
20 cm) of Amberlite IR 120 resin (Na+ form, particle size: 0.600–
0.800 mm) was first washed successively with an aqueous solution
of HCl (1 mol/L) and water prior to use, and then the crude product
was purified by chromatography on the resin column (eluent: pure
water) to afford (À )-5-epi-SA 4 (2.580 g, 14.81 mmol) as white
°
°
28 (11.60 g, 47.49 mmol) as white solid in 90% yield. M.p. 92–94 C.
1
½a�2D5 =À 140.1 (c 0.78, CHCl3). H NMR (400 MHz, CDCl3) δ [ppm]=
6.88–6.79 (m, 1H, H-2), 5.23–5.11 (m, 1H, H-5), 4.40 (m, 1H, H-3),
4.18 (q, J=7.1 Hz, 2H, OCH2CH3), 3.93–3.78 (dd, J1 =5.8 Hz, J2 =
4.8 Hz,1H, H-4), 3.52–3.20 (m, 2H, two OH), 2.84 (dd, J1 =18.4 Hz,
J2 =5.0 Hz, 1H, H-6), 2.36–2.24 (m, 1H, another H-6), 2.06 (s, 3H, CH3
in Ac), 1.27 (t, J=7.1 Hz, 3H, OCH2CH3). 13C NMR (101 MHz, CDCl3) δ
[ppm]=171.16 (C=O), 166.17 (C=O), 136.30 (sp2À C), 129.76 (sp2À C),
69.93, 69.32, 66.07, 61.10, 28.21, 21.18, 14.15. HRMS (ESI) calcd. for
[C11H16O6Na]+: 267.0845; found: 267.0841. IR (KBr film) 3281, 2984,
2938, 1718, 1477, 1434, 1373, 1316, 1279, 1235, 1099, 1055, 1037,
crystals
in
86%
yield.
M.p.
108–109 C.
½a�D ¼ À 63:5 ðc 1:04; H2OÞ: flit:29 ½a�2D0 =À 57.6 (c 0.8, MeOH)}. 1H
NMR (400 MHz, D2O) δ [ppm]=6.66 (d, J=3.6 Hz, 1H, H-2), 4.48–
4.41 (m, 1H, H-3), 4.02 (dd, J1 =3.6 Hz, J2 =2.8 Hz, 1H, H-4), 3.97
(ddd, J1 =4.0 Hz, J2 =6.2 Hz, J3 =2.8 Hz, 1H, H-5), 2.56 (dd, J1 =
17.4 Hz, J2 =6.2 Hz, 1H, H-6), 2.30–2.18 (m, 1H, another H-6). 13C
NMR (100 MHz, D2O) δ [ppm]=169.81 (C=O), 138.97 (C-2), 128.70
(C-1), 70.53, 68.11, 67.35, 27.54. HRMS (ESI) calcd. for [C7H9O5]:
173.0450; found: 173.0449.
25
931, 830, 796, 752, 684 cmÀ 1
.
Ethyl (3R,4S,5R)-5-acetoxy-3,4-bis(methanesulfonyloxy)-cyclo-
hex-1-ene-1-carboxylate 13. Compound 28 (10.02 g, 41.03 mmol),
triethylamine (16.53 g, 163.4 mmol) and DMAP (1.000 g,
8.206 mmol) were dissolved in dichloromethane (200 mL). The
°
solution was cooled to 0 C by an ice bath and then methanesulfon-
yl chloride (14.07 g, 122.8 mmol) was added dropwise over 30 min.
°
Then the solution was further stirred at 0 C for 2 h. After the
reaction was complete (checked by TLC, EtOAc/hexane=1:1), an
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aqueous solution of HCl (160 mL, 1 N) was added to quench the
(eluent: EtOAc/hexane=1:2) to afford a colorless oil, which
crystalized spontaneously after standing for several hours to give
reaction. Two phases were separated and the organic layer was
washed with an aqueous solution of K2CO3 (100 mL, 5% w/w). The
organic solution was dried over anhydrous MgSO4 and concen-
trated by vacuum distillation to give crude oily product. The crude
product was purified by flash chromatography (eluent: EtOAc/
hexane=1:2) to afford compound 13 (14.60 g, 36.46 mmol) as a
colorless oil in 89% yield. ½a�2D5 =À 126.5 (c 2.21, CHCl3). 1H NMR
(400 MHz, CDCl3) δ [ppm]=6.82–6.73 (m, 1H, H-2), 5.50–5.44 (m,
1H, H-3), 5.38–5.29 (m, 1H, H-5), 4.93 (dd, J1 =8.8 Hz, J2 =3.9 Hz, 1H,
H-4), 4.20 (q, J=7.1 Hz, 2H, OCH2CH3), 3.13 (s, 3H, SO2CH3), 3.11 (s,
3H, SO2CH3), 3.02 (dd, J1 =19.0 Hz, J2 =5.7 Hz, 1H, H-6), 2.49–2.34
(dd, J1 =19.0 Hz, J2 =6.8 Hz, 1H, another H-6), 2.07 (s, 3H, CH3 in Ac),
1.27 (t, J=7.1 Hz, 3H, OCH2CH3). 13C NMR (101 MHz, CDCl3) δ
[ppm]=169.50 (C=O), 164.64 (C=O), 133.36 (sp2À C), 130.04 (sp2À C),
74.83, 72.70, 66.21, 61.61, 38.84, 38.66, 28.97, 20.91, 14.10. HRMS
(ESI) calcd. for [C13H20O10S2 Na]+: 423.0396; found: 423.0392. IR
(neat) 3029, 2982, 2941, 2878, 2737, 2663, 2529, 2346, 2312, 2108,
1749, 1717, 1467, 1416, 1361, 1254, 1231, 1177, 1139, 1103, 1076,
compound 12 (2.830 g, 15.36 mmol) as white crystals in 70% yield.
M.p. 84–86 C. ½a�2D5 = +46.4 (c 1.28, CHCl3). 1H NMR (400 MHz,
°
CDCl3) δ [ppm]=6.71–6.62 (m, 1H, H-2), 4.58–4.47 (m, 1H, H-3), 4.16
(q, J=7.1 Hz, 2H, OCH2CH3), 3.53–3.47 (m, 2H, H-4 and OH), 3.02–
2.93 (m, 1H, H-5), 2.92 (d, J=10.3 Hz, 1H, H-6), 2.48–2.37 (m, 1H,
another H-6), 1.25 (t, J=7.1 Hz, 3H, OCH2CH3). 13C NMR (100 MHz,
CDCl3) δ [ppm]=166.15 (C=O), 135.82 (sp2À C), 126.61 (sp2À C),
65.45, 60.94, 54.66, 52.14, 24.23, 14.15. HRMS (ESI) calcd. for
[C9H12O4Na]+: 207.0633; found: 207.0634. IR (KBr film) 3284, 2993,
2983, 2960, 2926, 1712, 1656, 1476, 1422, 1386, 1367, 1298, 1258,
1204, 1115, 1087, 1027, 983, 927, 900, 872, 850, 745, 694 cmÀ 1
Ethyl (3S,4R,5S)-3,4,5-trihydroxy-cyclohex-1-ene-1-carboxylate 30.
Compound 12 (6.000 g, 32.58 mmol) was dissoved in water
(120 mL), and then AcOH (96.5 mg, 1.608 mmol) added. The
°
solution was heated to 90 C and further stirred for 2 h. After the
reaction was complete (checked by TLC, EtOAc/hexane=1:1), the
solution was cooled to room temperature. Water was removed by
vacuum distillation to give crude product as a white solid. The
crude product was triturated with a mixed solvent of ethyl acetate
and hexane (EtOAc/hexane=1:3, v/v). The mixture was filtered by
suction and rinsed twice with the above mixed solvent to afford
compound 30 (5.731 g, 28.34 mmol) as white crystals in 87% yield.
1047, 973, 905, 852, 769, 749 cmÀ 1
.
Ethyl (3S,4S,5R)-3,5-diacetoxy-4-methanesulfonyloxy-cyclohex-1-
ene-1-carboxylate 29. Compound 13 (13.20 g, 32.97 mmol) was
dissolved in ethyl acetate (70 mL) in a round-bottom flask. AcOH
(11.91 g, 198.3 mmol) was dissolved ethyl acetate (60 mL) in
another flask, which was cooled to 0 C by an ice bath, and then
M.p. 74–76 C. ½a�2D5 = +128.6 (c 0.50, MeOH). 1H NMR (400 MHz,
°
°
N,N-diisopropyl-ethylamine (6.381 g, 49.37 mmol) was added drop-
wise. The resulting solution of AcOH/DIPEA (4:1) was then added
to the above solution of compound 13. The reaction solution was
heated to reflux and further stirred for 2 h. After the reaction was
complete (checked by TLC, EtOAc/hexane=1:2), the solution was
cooled to room temperature. Ethyl acetate (100 mL) and an
aqueous solution of K2CO3 (200 mL, 15% w/w) were added and the
solution was stirred for 5 min. Two phases were separated and
aqueous solution was twice extracted with ethyl acetate (100 mL×
2). The organic extracts were combined and dried over anhydrous
MgSO4. The solution was concentrated by vacuum distillation to
give crude oily product, which was purified by flash chromatog-
raphy (eluent: EtOAc/hexane=1:4) to afford compound 29
(10.34 g, 28.38 mmol) as a colorless oil in 86% yield. ½a�2D5 = +29.8
DMSO-d6) δ [ppm]=6.61 (dd, J1 =3.6 Hz, J2 =1.6 Hz, 1H, H-2), 4.88–
4.80 (m, 2H, two OH), 4.64 (d, J=4.3 Hz, 1H, OH), 4.26–4.18 (m, 1H,
H-3), 4.11 (q, J=7.1 Hz, 1H, OCH2CH3), 3.91–3.81 (m, 1H, H-5), 3.57
(dd, J1 =10.1 Hz, J2 =4.4 Hz,1H, H-4), 2.48–2.37 (m, 1H, H-6), 2.11–
2.00 (m, 1H, another H-6), 1.21 (t, J=7.1 Hz, 3H, OCH2CH3). 13C NMR
(101 MHz, DMSO-d6) δ [ppm]=166.20 (C=O), 139.52 (sp2À C), 127.53
(sp2À C), 70.01, 66.76, 65.38, 59.98, 29.58, 14.11. HRMS (ESI) calcd. for
[C9H14O5Na]+: 225.0739; found: 225.0731. IR (KBr film) 3376, 2987,
2942, 2905, 2680, 2474, 1721, 1449, 1423, 1390, 1370, 1318, 1252,
1184, 1095, 1071, 1056, 1039, 998, 931, 845, 767, 747 cmÀ 1
.
(+)-ent-SA ent-1. Compound 30 (3.800 g, 18.80 mmol) and meth-
anol (75 mL) were added into a round-bottom flask with a magnetic
stirrer bar, and then NaOH (1.505 g, 38.63 mmol) was added at
°
room temperature. The mixture was heated to 40 C and then
1
(c 0.93, CHCl3). H NMR (400 MHz, CDCl3) δ [ppm]=6.63–6.58 (m,
stirred for approximate 10 h. After the reaction was complete
(checked by TLC, eluent: EtOAc), methanol was removed by vacuum
distillation. The residue was dissolved in water (20 mL), and a dilute
aqueous solution of HCl (1 N) was added to adjust pH=4.1–4.4.
After water was removed by vacuum distillation, ethanol (50 mL)
and activated carbon (1.0 g) were added. The mixture was stirred at
room temperature for 10 h. The suspension was filtered by a
Buchner funnel and filter cake was rinsed twice with ethanol (2×
10 mL). Filtrate was concentrated by vacuum distillation to afford
crude product as a colorless oil. A column (2×20 cm) of Amberlite
IR 120 resin (Na+ form, particle size: 0.600–0.800 mm) was first
washed successively with an aqueous solution of HCl (1 mol/L) and
water prior to use, and then the crude product was purified by
chromatography on the resin column (eluent: pure water) to afford
1H, H-2), 5.73–5.66 (m, 1H, H-5), 5.24–5.16 (m, 1H, H-3), 4.91 (dd,
J1 =10.3 Hz, J2 =7.7 Hz, 1H, H-4), 4.20 (q, J=7.1 Hz, 2H, OCH2CH3),
3.09–2.98 (m, 4H, H-6 and SO2CH3), 2.47–2.35 (m, 1H, another H-6),
2.12 (s, 3H, CH3 in Ac), 2.10 (s, 3H, CH3 in another Ac), 1.27 (t, J=
7.1 Hz, 3H, OCH2CH3). 13C NMR (100 MHz, CDCl3) δ [ppm]=169.96
(C=O), 169.87 (C=O), 164.68 (C=O), 133.19 (sp2À C), 130.01 (sp2À C),
78.86, 70.74, 67.61, 61.46, 38.83, 29.71, 20.93, 20.84, 14.14. HRMS
(ESI) calcd. for [C14H20O9SNa]+: 387.0726; found: 387.0719. IR (neat)
3022, 2984, 2941, 2875, 2724, 2663, 2523, 2409, 2347, 2309, 2105,
1749, 1718, 1442, 1358, 1303, 1223, 1177, 1118, 1078, 1047, 1026,
967, 933, 892, 841, 781, 749 cmÀ 1
.
Ethyl (3S,4S,5R)-4,5-epoxy-3-hydroxy-cyclohex-1-ene-1-carboxy
-late 12. Compound 29 (8.001 g, 21.96 mmol) and concentrated
sulfuric acid (440.5 mg, 4.401 mmol, 98% w/w) were dissolved in
absolute ethanol (160 mL) at room temperature. Then the solution
was heated to reflux and further stirred for 12 h. After the
compound 29 disappeared (checked by TLC, EtOAc/hexane=1:2),
the solution was cooled to room temperature. Then powdered
anhydrous K2CO3 (3.641 g, 26.35 mmol) was added. The mixture
(+)-ent-SA ent-1 (2.846 g, 16.34 mmol) as white crystals in 87%
[38]
°
°
yield. M.p. 183–185 C (lit.
m.p. 183–184 C for compound 1).
½a�D ¼ þ179:7 ðc 0:50; H2OÞ: flit:½38� ½a�2D0 =À 179.5 (c 0.8, H2O)
for compound 1}.1H NMR (400 MHz, D2O) δ [ppm]=6.77 (d, J=
3.6 Hz, 1H, H-2), 4.42–4.36 (m, 1H, H-3), 3.97 (ddd, 1H, J1 =5.4 Hz,
J2 =4.8 Hz, J3 =6.3 Hz, H-5), 3.71 (dd, J1 =8.2 Hz, J2 =4.8 Hz, 1H, H-
4), 2.67 (dd, J1 =16.5 Hz, J2 =5.4 Hz, 1H, H-6), 2.22–2.08 (m, 1H,
another H-6). 13C NMR (100 MHz, D2O) δ [ppm]=169.97 (C=O),
137.22 (sp2À C), 129.61 (sp2À C), 71.00, 66.48, 65.69, 30.29. HRMS (ESI)
calcd. for [C7H9O5]: 173.0450; found: 173.0451. IR (KBr film) 3482,
3386, 3223, 2904, 2882, 2662, 2522, 1682, 1453, 1387, 1351, 1293,
25
°
was heated to 50 C and further stirred for 18 h. After the
intermediate disappeared (checked by TLC, EtOAc/hexane=1:1),
the suspension was filtrated by a Buchner funnel and the filter cake
was twice rinsed with ethanol (10 mL×2). The filtrate was
concentrated by vacuum distillation to give crude product as a pale
yellow oil. The crude product was purified by flash chromatography
1275, 1239, 1131, 1113, 1092, 1070, 1018, 930, 862, 751, 742 cmÀ 1
.
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Synthesis of (+)-3-epi-ent-SA ent-2
TBS), 0.09 (s, 3H, SiCH3 in TBS). 13C NMR (100 MHz, CDCl3) δ
[ppm]=166.17 (C=O), 136.89 (sp2À C), 128.86 (sp2À C), 80.30,
66.68, 66.10, 60.89, 38.50, 30.79, 25.89, 25.85 (three CH3 in t-Bu),
25.68 (three CH3 in t-Bu), 18.33, 17.90, 14.21, À 4.74 (SiCH3 in
TBS), À 4.78 (SiCH3 in TBS), À 4.81 (SiCH3 in TBS), À 4.92 (SiCH3 in
TBS). IR (neat) 2954, 2931, 2896, 2858, 1718, 1470, 1364, 1250,
1178, 1123, 1101, 1084, 1056, 1003, 964, 918, 840, 779 cmÀ 1.
Ethyl (3R,4S,5R)-3,5-dihydroxy-4-methanesulfonyloxy-cy-
clohex-1-ene-1-carboxylate 11. Compound 31 (15.01 g,
29.53 mmol) was dissolved in absolute ethanol (100 mL), and
Ethyl (3R,4S,5R)-3,5-bis(tert-butyldimethylsilyloxy)-4-hydroxy-
cyclohex-1-ene-1-carboxylate 6. Compound ent-30 (20.05 g,
99.15 mmol), triethylamine (30.10 g, 297.5 mmol) and DMAP
(2.423 g, 19.83 mmol) were dissolved in fresh DMF (100 mL),
and then tert-butyldimethylsilyl chloride (37.35 g, 247.9 mmol)
was added slowly. The mixture was further stirred at room
temperature for 6 h. After the reaction was complete (checked
by TLC, EtOAc/hexane=1:8), hexane (250 mL) and water
(150 mL) were added into the flask. After the solution was
stirred for about 5 min, two phases were separated. The
aqueous solution was extracted again with hexane (150 mL).
The organic extracts were combined and then washed with
water (150 mL). After dried over anhydrous MgSO4, the organic
solution was concentrated by vacuum distillation to give a
colorless oil, which was purified by flash chromatography
(eluent: EtOAc/hexane=1:15) to afford compound 6 (32.04 g,
74.38 mmol) as a colorless oil in 75% yield. ½a�2D5 =À 65.3 (c 1.30,
°
then the solution was cooled to 0 C by an ice bath.
Concentrated aqueous solution of hydrochloric acid (12 mL,
143.4 mmol, 36.5% w/w) was diluted with absolute ethanol
(50 mL) and then was added dropwise into the flask over 5 min.
Then the ice bath was removed and the solution was further
stirred at room temperature for 10 h. Atfer the reaction was
complete (checked by TLC, EtOAc/hexane=1:15), ethanol was
removed by vacuum distillation. Then ethyl acetate (200 mL)
and water (150 mL) were added, and the mixtuer was stirred for
a few minutes. Two phases were separated and the aqueous
solution was twice extracted with ethyl acetate (150 mL×2).
The organic extracts were combined and dried over anhydrous
MgSO4. The solution was concentrated by vacuum distillation to
give a colorless oil, which was purified by flash chromatography
(eluent: EtOAc/hexane=1:1) to afford compound 11 (7.950 g,
1
CHCl3). H NMR (400 MHz, CDCl3) δ [ppm]=6.62–6.58 (m, 1H, H-
2), 4.55–4.46 (m, 1H, H-3), 4.24–4.12 (m, 3H, H-5 and OCH2CH3),
3.72–3.64 (dd, J1 =6.8 Hz, J2 =5.2 Hz, 1H, H-4), 2.65–2.54 (m, 1H,
H-6), 2.25–2.16 (m, 1H, another H-6), 1.28 (t, J=7.1 Hz, 3H,
OCH2CH3), 0.91 (s, 9H, t-C4H9 in TBS), 0.84 (s, 9H, t-C4H9 in
another TBS), 0.13 (s, 3H, SiCH3 in TBS), 0.12 (s, 3H, SiCH3 in TBS),
0.06 (s, 3H, SiCH3 in TBS), 0.05 (s, 3H, SiCH3 in TBS). 13C NMR
(100 MHz, CDCl3) δ [ppm]=166.82 (C=O), 137.04 (sp2À C), 128.82
(sp2À C), 70.69, 68.27, 67.61, 60.70, 29.64, 25.85 (three CH3 in t-
Bu), 25.74 (three CH3 in t-Bu), 18.20, 18.00, 14.27, À 4.55 (SiCH3 in
TBS), À 4.74 (SiCH3 in TBS), À 4.84 (SiCH3 in TBS), À 4.90 (SiCH3 in
TBS). HRMS (ESI) calcd. for [C21H42O5Si2Na]+: 453.2469; found:
453.2462. IR (neat) 3419, 2955, 2931, 2890, 2851, 1718, 1469,
1253, 1094, 1047, 960, 907, 838, 809 cmÀ 1.
°
28.36 mmol) as off-white crystals in 96% yield. M.p. 85–87 C.
½a�2D5 =À 112.2 (c 0.63, CHCl3). 1H NMR (400 MHz, CDCl3) δ
[ppm]=6.80–6.72 (m, 1H, H-2), 4.67–4.61 (m, 1H, H-4), 4.58 (dd,
J1 =8.3 Hz, J2 =3.9 Hz, 1H, H-3), 4.29–4.20 (m, 1H, H-5), 4.16 (q,
J=7.1 Hz, 2H, OCH2CH3), 3.13 (s, 3H, CH3 in Ms), 2.82 (dd, J1 =
18.4 Hz, J2 =5.3 Hz, 1H, H-6), 2.37–2.23 (m, 1H, another H-6),
1.25 (t, J=7.1 Hz, 3H, OCH2CH3). 13C NMR (100 MHz, CDCl3) δ
[ppm]=166.27 (C=O), 135.20 (sp2À C), 130.41 (sp2À C), 82.06,
65.08, 64.51, 61.30, 38.21, 31.24, 14.05. IR (KBr film) 3471, 3049,
3028, 2978, 2959, 2921, 1702, 1345, 1329, 1273, 1254, 1174,
1106, 1066, 1042, 983, 969, 914, 866 cmÀ 1.
Ethyl
(3R,4S,5R)-3,5-bis(tert-butyldimethylsilyloxy)-4-
methane-sulfonyloxy-cyclohex-1-ene-1-carboxylate 31. Com-
pound 6 (20.00 g, 46.43 mmol), pyridine (18.36 g, 232.2 mmol)
and DMAP (2.837 g, 23.22 mmol) were dissolved in fresh
Ethyl
(3R,4S,5R)-4,5-epoxy-3-hydroxy-cyclohex-1-ene-1-
°
dichloromethane (300 mL). After the solution was cooled to 0 C
carboxy -late 10. Compound 11 (10.03 g, 35.78 mmol), anhy-
drous powdered K2CO3 (7.418 g, 53.67 mmol) and absolute
ethanol (200 mL) were added into a round-bottom flask, the
mixture was stirred at room temperature for 15 h. After the
reaction was complete (checked by TLC, EtOAc/hexane=1:1),
the suspension was filtrated by a Buchner funnel and the filter
cake was rinsed with ethyl acetate (20 mL×2). The filtrate was
concentrated by vacuum distillation to give crude oily product,
which was purified by flash chromatography (eluent: EtOAc/
hexane=1:2) to afford compound 10 (6.067 g, 32.94 mmol) as
a colorless oil in 92% yield. ½a�2D5 =À 30.4 (c 0.71, CHCl3). 1H NMR
(400 MHz, CDCl3) δ [ppm]=6.76–6.68 (m, 1H, H-2), 4.61–4.52 (m,
1H, H-3), 4.14 (q, J=7.2 Hz, 2H, OCH2CH3), 3.38 (dd, J1 =3.9 Hz,
J2 =2.8 Hz, 1H, H-4), 3.31 (d, J=7.2 Hz, 1H, OH), 3.24–3.20 (m,
1H, H-5), 2.91–2.82 (m, 1H, H-6), 2.64–2.53 (m, 1H, another H-6),
1.24 (t, J=7.2 Hz, 3H, OCH2CH3). 13C NMR (100 MHz, CDCl3) δ
[ppm]=166.71 (C=O), 133.78 (sp2À C), 126.78 (sp2À C), 62.78,
61.11, 52.84, 50.71, 24.23, 14.07. IR (neat) 3428, 2986, 2934,
2906, 1715, 1447, 1421, 1368, 1304, 1254, 1094, 1081, 1031, 946,
802, 775 cmÀ 1.
by an ice bath, methanesulfonyl chloride (10.6 g, 93.0 mmol)
was added dropwise over 30 min. Then the ice bath was
removed and the solution was further stirred at room temper-
ature for 6 h. After the reaction was complete (checked by TLC,
EtOAc/hexane=1:15), an aqueous solution of HCl (200 mL, 2 N)
was added to quench the reaction. Two phases were separated
and the organic layer was washed with an aqueous solution of
K2CO3 (200 mL, 5% w/w). The organic solution was dried over
anhydrous MgSO4 and then concentrated by vacuum distillation
to give a colorless oil, which was purified by flash chromatog-
raphy (eluent: EtOAc/hexane=1:15) to afford compound 31
25
(17.55 g, 34.49 mmol) as a colerless oil in 85% yield. ½a�D
=
1
À 69.2 (c 1.51, CHCl3). H NMR (400 MHz, CDCl3) δ [ppm]=6.70–
6.64 (m, 1H, H-2), 4.80–4.71 (m, 1H, H-3), 4.62–4.53 (m, 1H, H-5),
4.31 (dd, J1 =10.2 Hz, J2 =4.0 Hz 1H, H-4), 4.20 (q, J=7.1 Hz, 2H,
OCH2CH3), 3.05 (s, 3H, CH3 in Ms), 2.77–2.64 (m, 1H, H-6), 2.35–
2.24 (m, 1H, another H-6), 1.29 (t, J=7.1 Hz, 3H, OCH2CH3), 0.92
(s, 9H, t-C4H9 in TBS), 0.86 (s, 9H, t-C4H9 in another TBS), 0.15 (s,
3H, SiCH3 in TBS), 0.14 (s, 3H, SiCH3 in TBS), 0.10 (s, 3H, SiCH3 in
Eur. J. Org. Chem. 2021, 1–16
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13
© 2021 Wiley-VCH GmbH
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Full Papers
doi.org/10.1002/ejoc.202100653
Ethyl (3R,4R,5S)-3,4,5-trihydroxy-cyclohex-1-ene-1-carbox- Conflict of Interest
ylate ent-15. Compound 10 (6.004 g, 32.60 mmol ) and AcOH
(96.9 mg, 1.630 mmol) were dissolved in water (100 mL). The
The authors declare no conflict of interest.
°
mixture was stirred at 90 C for 2 h. After the reaction was
complete (checked by TLC, EtOAc/hexane=1:2), water was
removed by vacuum distillation to give crude product as a
white solid. The crude product was triturated with a mixed
solvent of ethyl acetate and hexane (EtOAc/hexane=1:2). The
mixture was filtered by suction and rinsed twice by the above
Keywords: Chiral pool
Stereodivergent synthesis · Stereoisomers
·
Cyclitol
·
Shikimic acid
·
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mixed solvent to afford compound ent-15 (5.940 g, 29.38 mmol)
1
in 90% yield. M.p. 110–112 C. ½a�2D5 = +16.9 (c 1.50, MeOH). H
°
NMR (400 MHz, DMSO-d6) δ [ppm]=6.53 (dd, J1 =2.4 Hz, J2 =
2.6 Hz, 1H, H-2), 5.17 (d, J=6.1 Hz, 1H, OH), 4.98 (d, J=4.2 Hz,
1H, OH), 4.85 (d, J=4.5 Hz, 1H, OH), 4.11 (q, J=7.1 Hz, 2H,
OCH2CH3), 4.02–3.93 (m, 1H, H-3), 3.52–3.41 (m, 1H, H-5), 3.20
(dd, J1 =9.6 Hz, J2 =7.6 Hz, 1H, H-4), 2.61–2.52 (m, 1H, H-6),
2.06–1.94 (m, 1H, another H-6), 1.21 (t, J=7.1 Hz, 3H, OCH2CH3).
13C NMR (100 MHz, DMSO-d6) δ [ppm]=165.75 (C=O), 140.58
(sp2À C), 127.02 (sp2À C), 76.62, 71.23, 68.46, 60.21, 32.56, 14.05.
HRMS (ESI) calcd. for [C9H14O5Na]+: 225.0739; found: 225.0729.
(+)-3-epi-ent-SA ent-2. Compound ent-15 (3.950 g,
19.53 mmol) and methanol (80 mL) were added into a round-
bottom flask with a magnetic stirrer bar, and then NaOH
(1.564 g, 39.10 mmol) was added at room temperature. The
°
mixture was heated to 40 C and then stirred for approximate
10 h. After the reaction was complete (checked by TLC, eluent:
EtOAc), methanol was removed by vacuum distillation. The
residue was dissolved in water (20 mL), and a dilute aqueous
solution of HCl (1 N) was added to adjust pH=4.1–4.4. After
water was removed by vacuum distillation, ethanol (50 mL) and
activated carbon (1.00 g) were added. The mixture was stirred
at room temperature for 10 h. The suspension was filtered by a
Buchner funnel and rinsed twice with ethanol (2×10 mL).
Filtrate was concentrated by vacuum distillation to afford crude
product as a colorless oil. A column (2×20 cm) of Amberlite IR
120 resin (Na+ form, particle size: 0.600–0.800 mm) was first
washed successively with an aqueous solution of HCl (1 mol/L)
and water prior to use, and then the crude product was purified
by chromatography on the resin column (eluent: pure water) to
afford (+)-3-epi-SA ent-2 (2.995 g, 17.20 mmol) as white solid in
1
88% yield. M.p. 187–189 C. ½a�2D5 = +30.0 (c 1.05, H2O). H NMR
°
(400 MHz, D2O) δ [ppm]=6.57 (dd, J1 =2.6 Hz, J2 =2.4 Hz, 1H, H-
2), 4.20–4.12 (m, 1H, H-3), 3.66 (ddd, J1 =10.2 Hz, J2 =6.0 Hz, J3 =
4.2 Hz, 1H, 1H, H-5), 3.38 (dd, J1 =10.2 Hz, J2 =8.1 Hz, 1H, H-4),
2.67 (dd, J1 =17.3 Hz, J2 =6.0 Hz, 1H, H-6), 2.16–2.03 (m, 1H,
another H-6). 13C NMR (100 MHz, D2O) δ [ppm]=169.77 (C=O),
139.11 (C-2), 128.20 (C-1), 76.20, 71.49, 68.62, 31.78.
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Acknowledgements
We are grateful to the National Natural Science Foundation of
China (No. 20972048) for the financial support of this work.
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Manuscript received: May 29, 2021
Revised manuscript received: June 26, 2021
Accepted manuscript online: June 28, 2021
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© 2021 Wiley-VCH GmbH
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These are not the final page numbers!

FULL PAPERS
(À )-Shikimic acid [(À )-SA 1] is a
naturally-abundant product from
Chinese star anise. All of the seven
stereoisomers [i.e. (+)-ent-SA ent-1,
(À )-3-epi-SA 2, (+)-3-epi-ent-SA ent-2,
(À )-4-epi-SA 3, (+)-4-epi-ent-SA ent-3,
(À )-5-epi-SA 4 and (+)-5-epi-ent-SA
ent-4] have been systematically syn-
thesized from (À )-SA 1.
Y.-G. He, Y.-K. Huang, Z.-L. Xu, W.-J.
Xie, Y.-Q. Luo, F.-L. Li, X.-L. Zhu,
Prof. Dr. X.-X. Shi*
1 – 16
Stereodivergent Syntheses of All
Stereoisomers of (À )-Shikimic Acid:
Development of a Chiral Pool for
the Diverse Polyhydroxy-cyclohexe-
noid (or -cyclohexanoid) Bioactive
Molecules