A C 2-symmetric chiral pool-based flexible strategy: Synthesis of (+)- and (-)-shikimic acids, (+)- and (-)-4- epi -shikimic acids, and (+)- and (-)-pinitol

Article abstract of DOI:10.1021/jo402764v

Via combination of a novel acid-promoted rearrangement of acetal functionality with the controlled installation of the epoxide unit to create the pivotal epoxide intermediates in enantiomerically pure form, a simple, concise, flexible, and readily scalable enantiodivergent synthesis of (+)- and (-)-shikimic acids and (+)- and (-)-4-epi-shikimic acids has emerged. This simple strategy not only provides an efficient approach to shikimic acids but also can readily be adopted for the synthesis of (+)- and (-)-pinitols. These concise total syntheses exemplify the use of pivotal allylic epoxide 14 and its enantiomer ent-14. A readily available inexpensive C₂-symmetric l-tartaric acid (7) served as key precursor. In general, the strategy here provides a neat example of the use of a four-carbon chiron and offers a good account of the synthesis of functionalized cyclohexane targets.

Full text of DOI:10.1021/jo402764v

Article
pubs.acs.org/joc
A C2‑Symmetric Chiral Pool-Based Flexible Strategy: Synthesis of (+)-
and (−)-Shikimic Acids, (+)- and (−)-4-epi-Shikimic Acids, and (+)- and
(−)-Pinitol
Bakthavachalam Ananthan, Wan-Chun Chang, Jhe-Sain Lin, Pin-Hui Li, and Tu-Hsin Yan*
Department of Chemistry, National Chung-Hsing University, Taichung 400, Taiwan, Republic of China
S
* Supporting Information
ABSTRACT: Via combination of a novel acid-promoted rearrangement of
acetal functionality with the controlled installation of the epoxide unit to
create the pivotal epoxide intermediates in enantiomerically pure form, a
simple, concise, flexible, and readily scalable enantiodivergent synthesis of
(+)- and (−)-shikimic acids and (+)- and (−)-4-epi-shikimic acids has
emerged. This simple strategy not only provides an efficient approach to
shikimic acids but also can readily be adopted for the synthesis of (+)- and
(−)-pinitols. These concise total syntheses exemplify the use of pivotal
allylic epoxide 14 and its enantiomer ent-14. A readily available inexpensive
C2-symmetric L-tartaric acid (7) served as key precursor. In general, the
strategy here provides a neat example of the use of a four-carbon chiron and
offers a good account of the synthesis of functionalized cyclohexane targets.
C2-symmetric L-tartaric acid (7) to both enantiomers of
shikimic acid, 4-epi-shikimic acid, and pinitol.
INTRODUCTION
■
Biologically and chemically important molecules like (+)- and
(−)-shikimic acid,1−5 (+)- and (−)-4-epi-shikimic acid,6 and
(+)- and (−)-pinitols7−9 have provoked long-term interest in
their total synthesis because of their potential biological
activities. Recently, it has been shown that (−)-shikimic acid
(2) in combination with a cationic amphiphile enhances tumor
protective therapeutic benefits in DC-based DNA vaccination.5a
The biological importance of 4-epi-shikimic acid (3) has also
been described by Kiessling et al.6a Additionally, recent research
has revealed that (+)-pinitol 6 is a potent protector against
breast cancer.9 In light of our continual interest in the total
synthesis of bioactive natural products and their analogues,
focusing on cyclohexane derivatives,10,11 we have been
fascinated by (+)- and (−)-shikimic acid, (+)- and (−)-4-epi-
shikimic acid, and (+)- and (−)-pinitols, because these
molecules also serve as suitable chiral building blocks for the
generation of other biologically important molecules.5,6a,9,12
Shikimic acid, 4-epi-shikimic acid, and pinitol have been
synthesized in racemic forms and as pure enantiomers by
either a chemoenzymatic pathway or a chemical pathway.2,4,6,7
A significant drawback of many of the reported procedures
arises from lengthy protecting group manipulation and
utilization of toxic chemicals.
RESULTS AND DISCUSSION
■
Retrosynthetic Analysis. Scheme 1 outlines, in retro-
synthetic format, the overall plan. We envisioned that the
cyclohexenediol 11 could be formulated by ring-closing
metathesis (RCM) of tartaric acid-derived allylic hydroxyls 9
followed by a novel acid-promoted acetal rearrangement.
Subsequently, the controlled installation of an epoxide unit
leads to the enantiomerically pure pivotal epoxide 14 and its
enantiomer ent-14. The methoxy and carboxyl functional
groups in the cyclohexane ring were contrived at a relatively
later stage of the synthesis to achieve a simple, concise, flexible,
and readily scalable enantiodivergent synthesis.
Synthesis of Allylic Epoxides 14 and ent-14. The
synthesis commenced with the preparation of allylic hydroxyls
9 from cheap L-tartaric acid (7), according to a two-step
procedure (Scheme 2).10,11,13 RCM of allylic hydroxyls 9 was
performed with a second-generation Grubbs catalyst under
diluted reaction conditions to generate the desired cyclo-
hexenol derivative 10 in 92% yield.10,11,14,15 The solvent used in
this step was recycled and reused without yield losses. We next
focused on the conversion of the trans acetonide to more stable
cis acetonide. Toward this end, we examined the reaction with
several acid catalysts, including CSA, TfOH, PTSA, FeCl3,
acetic acid, PPTS, and TFA. Gratifyingly, exposure of the in
situ-generated C2-symmetric trans acetonide 10 to 0.2 mol %
Our goal was to devise an enantiodivergent synthetic strategy
called a “common chiral pool strategy”, in the hope that it could
be amenable to the construction of either a (+)-enantiomer or a
(−)-enantiomer as required from the same chiral compound.
Herein, we report a common chiral pool-based synthetic
strategy that leads from the commercially available and cheap
Received: December 12, 2013
Published: March 11, 2014
© 2014 American Chemical Society
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Scheme 1. Retrosynthetic Analysis
Scheme 3. Enantiospecific Synthesis of Allylic Epoxide ent-
14
addition of acetic anhydride, afforded cyclohexane derivative
ent-14 in good yield. This enantiodivergent sequence offers a
flexible approach to epoxide 14 and its enantiomer ent-14 in 54
and 36% overall yields, respectively, from cheap L-tartaric acid
(7).
Synthesis of (+)-Shikimic Acid. With a facile route to 14
in hand, we turned our attention to construction of
(+)-shikimic acid 1 (Scheme 4). Attempts to perform the
reduction of 12 with superhydride gave an unsatisfactory yield
of 15. On the other hand, addition of LAH to epoxide 14 gave
Scheme 2. Enantiospecific Synthesis of Allylic Epoxide 14
Scheme 4. Synthesis of (+)-Shikimic Acid and (−)-Shikimic
Acid
TFA resulted in the efficient formation of the thermally stable
cis-fused acetonide 11. Other catalysts failed to produce good
yields at various concentrations and temperatures. With
enantiopure cyclohexenediol 11 in hand (92% from compound
9), the key step is the transformation of enediol 11 into allylic
epoxide 14 with retention of configuration. Fortunately,
subsequent treatment of the in situ-generated enediol 11 with
α-acetoxyisobutryl chloride16 led smoothly to the correspond-
ing trans-chlorocyclohexyl acetate 12, which underwent
saponification and intramolecular SN2 nucleophilic attack to
yield allylic epoxide 14. Remarkably, a one-pot conversion of
allylic hydroxyls 9 into allylic epoxide 14 was developed,
delivering the final product in 79% yield.
On the other hand, the preparation of its isomer, ent-14
(Scheme 3), started with the direct conversion of compound 9
to cis-epoxydiol 13. Thus, via the subsequent treatment of 11
with m-CPBA that led to cis-epoxydiol 13, as anticipated,
hydrogen bonding directs the formation of this required
epoxide. Notably, the conversion of 9 to 13 was also performed
in one pot. Treatment of compound 13 with N,N-
dimethylformamide dimethylacetal17 for 16 h, followed by
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exclusively compound 15 in excellent yield. In a similar way,
ent-15 was prepared from ent-14. Epoxidation of cyclohexenol
15 with m-CPBA afforded the desired epoxide 16 in 87% yield.
Regiospecific ring opening of oxirane 16 with a cyanide
nucleophile turned out to be challenging. All attempts to
perform the Lewis acid-promoted epoxide ring opening led to
either extensive decomposition of oxirane 16 or a trace of the
desired epoxide ring opening. Finally, reaction of epoxide 16
with lithium cyanide18 in refluxing THF led to the desired
attack from the less hindered face to give cyanohydrin 17,
which was converted into diacetate 18. The latter was the
precursor of the unsaturated nitrile 19. The direct conversion of
epoxide 16 into nitrile 19 was achieved in 89% yield. Finally,
compound 19 underwent acetate saponification followed by
acid hydrolysis of acetal, yielding (+)-shikimic acid 1, whose
physical properties are identical to those of the reported
compound.2b This efficient asymmetric synthesis requires seven
steps from L-(+)-tartaric acid (7) to give (+)-shikimic acid (1)
in 36% overall yield (Scheme 4).
Scheme 5. Synthesis of (−)-4-epi-Shikimic Acid and (+)-4-
epi-Shikimic Acid
Synthesis of (−)-Shikimic Acid. Having achieved an
efficient synthesis of 1, we turned our focus to the concise
synthesis of (−)-shikimic acid 2 (Scheme 4). We aimed to
devise a simple approach to shikimic acid without cyanide. As a
nucleophilic carboxyl group equivalent, we chose to use
malononitrile as the better alternate for cyanide. Gratifyingly,
the addition of allylic epoxide 14 to a mixture of malononitrile
and sodium ethoxide led to regio- and stereocontrolled
introduction of the malononitrile group by SN2 chemistry to
afford 20. With 20 in hand, the stage was set for the
transformation of malononitrile into carboxylate ester. All
attempts to perform this transformation using various peroxides
such as UHP, m-CPBA, and t-BuOOH led to disappointing
results. On the other hand, addition of 20 to a mixture of
Cs2CO3 and magnesium bis(monoperoxy phthalate)
(MMPA),19 an eco-friendly and highly safe peroxide, gave
reproducibly the desired 21 in 81% yield from 14. Treatment of
21 with m-CPBA yielded epoxide 22 in only ∼60% yield;
nevertheless, the same reaction furnished an 87% yield in the
presence of 10 mol % 2,6-di-tert-butyl-4-methylphenol.
Attention was then focused on the regiospecific reductive
cleavage of epoxide. We anticipated that the neighboring
carboxylate group would facilitate nucleophilic hydride attack at
its adjacent position. Surprisingly, treating 22 with many
reducing agents such as LiBH4, DIBAL, Zn-TMSCl, Zn(BH4)2,
NaBH(t-OBu)3, and NaBH4 led to trace amounts of
elimination product 23 along with starting material 22.
Interestingly, treatment of 22 with NaBH3(CN) yielded 23 as
the sole product. To simplify the synthesis of diol 24, we found
another protocol; thus, treating 22 with DBU (0.11 equiv) and
H2/Pd/C provided the desired product in 94% yield.
Acetylation of compound 24 using Ac2O followed by DBU-
promoted elimination of HOAc and aqueous TFA-mediated
acetonide deprotection2c and ester hydrolysis yielded (−)-shi-
kimic acid2d 2 in 80% yield. This chiral pool-based synthesis
requires nine steps from L-(+)-tartaric acid 7 to give
(−)-shikimic acid 2 in 29% overall yield (Scheme 4).
Exposure of unsaturated carboxylate 27 to reducing reagents
like NaBH4/MeOH, BH3/THF, DIBAL, and Zn(BH4)2 gave an
unsatisfactory yield of 28. Finally, we found that treating
compound 27 with LiBH4 at −55 °C furnished 28 in 81% yield.
Treatment of 28 with aqueous TFA resulted in efficient ester
hydrolysis and acetonide deprotection to give 4-epi-shikimic
acid 3 in 90% yield. Comparison of the spectral properties to
those recorded confirms its identity.6a As before, transformation
of intermediate ent-27 furnished (+)-4-epi-shikimic acid 4 in
two steps. Thus, (−)-4-epi- and (+)-epi-shikimic acids were
available by this flexible strategy from L-tartaric acid 7.
Synthesis of (+)-Pinitol and (−)-Pinitol. The novel
effectiveness of this C2-symmetric chiral pool-based flexible
strategy was next turned to the asymmetric synthesis of (+)-
and (−)-pinitols (Scheme 6). Methanolysis of epoxide 13 with
NaOMe/MeOH followed by the deprotection of acetonide
with TFA resulted in the efficient formation of the desired
Scheme 6. Synthesis of (−)-Pinitol and (+)-Pinitol
Synthesis of (+)-4-epi-Shikimic Acid and (−)-4-epi-
Shikimic Acid. To ensure the effectiveness of our devised
flexible strategy, we intended to generate 4-epi-shikimic acid 3
(Scheme 5). Treatment of 22 with methanesulfonyl chloride
and TEA affords corresponding unsaturated carboxylate 27 in
100% yield. While substrate 27 was treated with reducing
agents, a competition reaction between SN2 and SN2′ arose.
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concentrated. The residue was flash chromatographed with a 1:1
hexane/ethyl acetate mixture to give cis-cyclic diol 11 (2.4 g, 12.9
mmol, 92%): Rf = 0.58 (EtOAc); [α]D25 = +148.9 (c = 2.8, CHCl3); IR
(film) νmax 3419, 3036, 1219, 1042 cm−1; 1H NMR (400 MHz,
CDCl3) δ 5.91−5.90 (m, 2H), 4.64 (d, J = 6, 1H), 4.34 (t, J = 6.4,
1H), 4,29 − 4.28 (m, 1H), 3.95 (dd, J = 6.4, 3.2, 1H), 1.42 (s, 3H),
1.30 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 130.0 (CH), 127.3
(CH), 109.4 (C), 75.7 (CH), 71.8 (CH), 71.0 (CH), 65.9 (CH), 27.8
(CH3), 25.8 (CH3); HRMS (FAB) calcd for C9H15O4 [M + H]+
187.0970, found 187.0965.
(−)-pinitol 5, whose physical properties are identical to those
of the reported compound.7e The entire operations from 9 to 5
were performed in a single vessel to deliver (−)-pinitol in 72%
yield. In the same way, transestrification of acetate 12 with
sodium methoxide at reflux simultaneously effected epoxide
formation and regiospecific opening of an allylic epoxide to give
methoxy alcohol 29 in 96% yield. Dihydroxylation of 29 with
OsO4 followed by addition of TFA provided the desired
(+)-pinitol 6 in 84% yield. By this flexible strategy, inexpensive
L-(+)-tartaric acid 7 can be converted into (+)-pinitol 6 and
(−)-pinitol 5 in 56% (four steps) and 50% (three steps) overall
yields, respectively.
(1R,2R,3S,4S)-1-Chloro-2-acetoxy-3,4-(isopropylidenedioxy)-
cyclohex-5-ene (12). To a solution of allylic hydroxyls 9 (3.0 g, 14
mmol) in CH2Cl2 (1800 mL) at rt was added a solution of the second-
generation Grubbs catalyst (156 mg, 0.18 mmol, 0.013 equiv) in
CH2Cl2 (10 mL). The RM was stirred at reflux for 2 h, and then a
solution of CF3COOH (320 mg, 2.8 mmol) in 4 mL of CH2Cl2 was
added dropwise. The RM was stirred at reflux for an additional 16 h
and then cooled to 0 °C. The RM was treated with 2-acetoxyisobutyryl
chloride (2.76 g, 16.8 mmol). The RM was stirred at rt for 1 h, washed
with saturated aqueous sodium bicarbonate, and extracted with
CH2Cl2 (2 × 100 mL). The combined organic layers were dried
(MgSO4) and concentrated. The residue was flash chromatographed
with a 15:1 hexane/ethyl acetate mixture to give chloro ester 12 (2.9 g,
CONCLUSION
■
In conclusion, less abundant and unnatural pinitols, shikimic
acids, and their analogues were synthesized from highly
abundant L-tartaric acid. In other words, we successfully
synthesized enantiomerically diverse molecules from a single
enantiomer. The flexible technology described above should be
applicable to the preparation of various functionalized cyclo-
hexane natural products, which are required for biological
evaluations and applications. That work is currently ongoing
and will be reported in due course.
25
11.8 mmol, 84%): Rf = 0.6 (3:1 hexane:EtOAc); [α]D = −15.0 (c =
1
2.2, CHCl3); IR (film) νmax 3018, 1754, 1224, 1074 cm−1; H NMR
(400 MHz, CDCl3) δ 5.94 (br, 2H), 5.25 (dd, J = 9.2, 8.8, 1H), 4.62−
4.60 (m, 1H), 4.38 (dt, J = 8.8, 1.2, 1H), 4.12 (dd, J = 9.2, 6.0, 1H),
2.14 (s, 3H), 1.52 (s, 3H), 1.36 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 169.8 (C), 132.2 (CH), 124.7 (CH), 111.2 (C), 75.7 (CH), 74.1
(CH), 72.1 (CH), 56.5 (CH), 27.7 (CH3), 26.2 (CH3), 20.9 (CH3);
HRMS (FAB) calcd for C11H16ClO4 [M + H]+ 247.0737, found
247.0746.
EXPERIMENTAL SECTION
■
General Information. Unless otherwise noted, all nonaqueous
reactions were conducted under an atmosphere of N2 in oven-dried
apparatus. Commercial grade solvents were dried by known methods.
Flash chromatography was performed over silica gel (230−400 mesh).
1H NMR (400 MHz) and 13C NMR (100 MHz) spectra were
(1R,2S,3R,4S,5R,6R)-3,4-(Isopropylidenedioxy)-5,6-epoxycyclo-
hexane-1,2-diol (13). To a solution of allylic hydroxyls 9 (3.0 g, 14
mmol) in CH2Cl2 (1800 mL) at rt was added a solution of the second-
generation Grubbs catalyst (156 mg, 0.18 mmol, 0.013 equiv) in
CH2Cl2 (10 mL). The RM was stirred at reflux for 2 h, and then a
solution of CF3COOH (320 mg, 2.8 mmol) in 4 mL of CH2Cl2 was
added dropwise. The RM was stirred at reflux for an additional 16 h,
allowed to reach rt, and then treated with m-CPBA (4.8 g, 28 mmol).
The RM was stirred at rt for 8 h, cooled to 0 °C, treated with iodine
until a red-yellow color persisted, and then washed with saturated
aqueous sodium bisulfite and aqueous sodium carbonate. The
separated organic layer was dried (MgSO4) and concentrated. The
residue was flash chromatographed with a 1:1 hexane/ethyl acetate
mixture to give cis-epoxydiol 13 (2.1 g, 10.4 mmol, 74%): Rf = 0.7
recorded using the indicated solvent at ambient temperature. Chemical
shifts are reported in parts per million and coupling constants (J)
(H,H) in hertz; spectral splitting patterns have been assigned as singlet
(s), doublet (d), triplet (t), quadruplet (q), broad (br), broad band (br
b), multiplet or more overlapping signals (m), etc. Optical rotations
were measured at 25 °C in the stated solvents. Mass spectra were
obtained using orbitrap apparatus from a high-resolution ESI mass
spectrometer. Mass spectra were obtained using double-focusing
apparatus from a high-resolution EI and FAB mass spectrometer. IR
spectra were recorded as a thin film and expressed in inverse
centimeters. Substrates 8 and 9 were prepared in accordance with our
previous report.10 Reaction mass and room temperature are
abbreviated as RM and rt, respectively.
25
(EtOAc); [α]D = +1.6 (c = 1.9, CHCl3); IR (film) νmax 3247, 2906,
Experimental Procedure and Characterization Data.
(1S,4S,5S,6S)-5,6-(Isopropylidenedioxy)-2-cyclohexene-1,4-diol
(10).14 To a solution of allylic hydroxyls 9 (3.0 g, 14 mmol) in CH2Cl2
(1800 mL) at rt was added a solution of the second-generation Grubbs
catalyst (156 mg, 0.18 mmol, 0.013 equiv) in CH2Cl2 (10 mL). The
RM was stirred at reflux for 2 h, and then the solvent was carefully
distilled (oil bath temperature of 50 °C, and −10 °C as condenser
cooling). The residue was flash chromatographed (1.5:1 hexane:ace-
tone) to give cyclic diol 10 (2.4 g, 12.88 mmol, 92%): Rf = 0.48
1227, 1087, 764 cm−1; 1H NMR (400 MHz, CDCl3) δ 4.57 (d, J = 6.4,
1H), 4.52−4.49 (m, 1H), 4.21 (d, J = 3.6, 1H), 4.03 (m, 1H), 3.52−
3.51 (m, 1H), 3.38−3.37 (m, 1H), 2.84 (br b, 2H), 1.40 (s, 3H), 1.33
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 109.9 (C), 76.9 (CH), 69.7
(CH), 68.4 (CH), 64.2 (CH), 57.7 (CH), 55.9 (CH), 27.3 (CH3),
25.0 (CH3); HRMS (EI) calcd for C9H14O5 202.0841, found
202.0835.
(3aS,5aS,6aS,6bS)-2,2-Dimethyl-3a,5a,6a,6b-tetrahydrooxireno-
[2′,3′:3,4]benzo[1,2-d][1,3]dioxole (14). To a solution of allylic
hydroxyls 9 (3.0 g, 14 mmol) in CH2Cl2 (1800 mL) at rt was
added a solution of the second-generation Grubbs catalyst (156 mg,
0.18 mmol, 0.013 equiv) in CH2Cl2 (10 mL). The RM was stirred at
reflux for 2 h, and then a solution of CF3COOH (320 mg, 2.8 mmol)
in 4 mL of CH2Cl2 was added dropwise. The RM was stirred at reflux
for an additional 16 h and then cooled to 0 °C. The RM was treated
with 2-acetoxyisobutyryl chloride (2.9 g, 11.8 mmol). The RM was
stirred at rt for 1 h, and then solvent was evaporated. Anhydrous
methanol (35 mL) was added to RM and the mixture cooled to 0 °C.
Anhydrous potassium carbonate (2.51 g, 18.2 mmol) was added and
then the mixture stirred at rt for 40 min. RM was poured into an ice/
water mixture (6 mL) and then extracted with CH2Cl2 (10 × 10 mL).
Combined organic extracts were dried (MgSO4) and concentrated.
The residue was subjected to flash chromatography with a 13:1
25
(EtOAc); [α]D = +338.6 (c = 0.7, CHCl3); IR (film) νmax 3349,
1
3037, 2987 cm−1; H NMR (400 MHz, CDCl3) δ 6.01 (dd, J = 3.2,
1.6, 2H), 4.53−4.52 (m, 2H), 3.96 (dd, J = 2.0, 1.2, 2H), 2.30 (br b,
2H), 1.47 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 130.4 (CH), 110.4
(C), 73.4 (CH), 64.6 (CH), 26.8 (CH3); HRMS (FAB) calcd for
C9H15O4 [M + H]+ 187.0970, found 187.0965.
(1S,2S,3S,4S)-3,4-(Isopropylidenedioxy)cyclohex-5-ene-1,2-diol
(11).20 To a solution of allylic hydroxyls 9 (3.0 g, 14 mmol) in CH2Cl2
(1800 mL) at rt was added a solution of the second-generation Grubbs
catalyst (156 mg, 0.18 mmol, 0.013 equiv) in CH2Cl2 (10 mL). The
RM was stirred at reflux for 2 h, and then a solution of CF3COOH
(320 mg, 2.8 mmol) in 4 mL of CH2Cl2 was added dropwise. The RM
was stirred at reflux for an additional 16 h and then cooled to 0 °C.
The RM was quenched with saturated aqueous sodium bicarbonate
(100 mL). The separated organic layer was dried (MgSO4) and
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hexane/ethyl acetate mixture to give allylic epoxide 14 (1.9 g, 11.06
mmol, 79%): Rf = 0.83 (3:1 hexane:EtOAc); [α]D = +22.5 (c = 1.5,
CH2Cl2). For spectral data, see ent-14.
RM was heated to reflux for 5 h and 30 min and then cooled to 0 °C.
The RM was carefully quenched with chilled water (1 mL) and then
filtered through Celite. The ether layer was washed with a 15% NaCl
solution (2 × 5 mL), dried (MgSO4), and concentrated. The residue
proceeded to the next step without purification. The residue was
dissolved in CH2Cl2 (3 mL) at rt, and then m-CPBA (690.3 mg, 4
mmol) was added and the mixture stirred overnight. The RM was
quenched with saturated NaHCO3 (2 mL). The separated organic
layer was dried (MgSO4) and concentrated. The residue was subjected
to flash chromatography with a 3:1 hexane/ethyl acetate mixture to
give 16 (324 mg, 1.74 mmol, 87%): Rf = 0.6 (silica gel, 3:1
hexane:ethyl acetate); IR (film) νmax 3505, 2989, 2932, 1425, 1378,
25
(3aR,5aR,6aR,6bR)-2,2-Dimethyl-3a,5a,6a,6b-tetrahydrooxireno-
[2′,3′:3,4]benzo[1,2-d][1,3]dioxole (ent-14). (1) Epoxy diol 12 (202
mg, 1 mmol) in N,N-dimethylformamide dimethyl acetal (0.8 mL) was
vigorously stirred at rt in an argon atmosphere for 16 h. The excess
acetal was evaporated under reduced pressure and then acetic
anhydride (1 mL) added to the same flask. The RM was vigorously
stirred at 120 °C for 3.5 h and then allowed to cool to rt. RM was
filtered over silica gel, washed with CH2Cl2 (4 mL), and then
concentrated under reduced pressure. The residue was subjected to
flash chromatography with a 13:1 hexane/ethyl acetate mixture to give
ent-allylic epoxide ent-14 (120 mg, 0.71 mmol, 71%): Rf = 0.83 (3:1
1
1228, 1065 cm−1; H NMR (400 MHz, CDCl3) δ 4.57 (d, J = 6.0,
1H), 4.30−4.28 (m, 1H), 3.90 (dt, J = 6.4, 3.6, 1H), 3.39 (dd, J = 2.4,
1.2, 1H), 3.19 (d, J = 3.6, 1H), 2.95 (d, J = 11.2, 1H), 2.27−2.25 (m,
2H), 1.41 (s, 3H), 1.34 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 109.9
(C), 74.5 (CH), 70.4 (CH), 64.6 (CH), 53.2 (CH), 53.0 (CH), 27.6
(CH2), 25.4 (CH3), 25.3 (CH3); HRMS (EI) calcd for C9H14O4
186.0892, found 186.0898.
25
hexane:EtOAc); [α]D = −22.1 (c = 1.5, CH2Cl2). For spectral data,
see the next paragraph.
(2) Epoxy alcohol 16 (186 mg, 1 mmol) in THF (1 mL) was
treated with triethylamine (182 mg, 1.8 mmol) and mesyl chloride
(155 mg, 1.35 mmol) at 0 °C for 5 min and then stirred at rt for 40
min. DBU (274 mg, 1.8 mmol) was added to the RM and stirred at rt
for 2 h. The RM was diluted with CH2Cl2, quenched with an ice/water
mixture, and then extracted with CH2Cl2 (2 × 3 mL). Combined
extracts were dried (MgSO4) and concentrated. The residue was
subjected to flash chromatography with a 13:1 hexane/ethyl acetate
mixture to give ent-allylic epoxide ent-14 (159 mg, 0.71 mmol, 94%):
(3aS,4R,5R,7S,7aR)-4,7-Dihydroxy-2,2-dimethylhexahydrobenzo-
[d][1,3]dioxole-5-carbonitrile (17). To epoxy alcohol 16 (558 mg, 3
mmol) in anhydrous THF (10 mL) was added LiCN (396 mg, 12
mmol), and then the mixture was stirred at reflux for 14 h. The RM
was left to cool, and saturated aqueous potassium carbonate (3 mL)
and ether (10 mL) were added. The separated organic layer was dried
(MgSO4) and concentrated. The residue was subjected to flash
chromatography with a 1:1 hexane/ethyl acetate mixture to give 17
25
Rf = 0.83 (3:1 hexane:EtOAc); [α]D = −22.1 (c = 1.5, CH2Cl2): IR
(film) νmax 3010, 2986, 1379, 1370, 1243, 1167, 1068, 1052, 1000, 826
25
1
cm−1; H NMR (400 MHz, CDCl3) δ 6.00 (ddd, J = 10.0, 4.0, 1.6,
(588 mg, 2.76 mmol, 92%): Rf = 0.2 (1:1 hexane:ethyl acetate); [α]D
= −39.2 (c = 0.73, CHCl3); IR (film) νmax 3419, 2989, 2249, 1383,
1244, 1222 cm−1; 1H NMR (400 MHz, CDCl3) δ 4.25−4.23 (m, 1H),
4.15−4.14 (m, 1H), 4.10−4.07 (m, 1H), 3.85−3.81 (m, 1H), 3.0−2.94
(m, 1H), 2.12−2.09 (m, 2H), 1.5 (s, 3H), 1.35 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 120.3 (CN), 109.9 (C), 78.6 (CH), 76.7 (CH),
72.2 (CH), 65.8 (CH), 30.3 (CH), 28.6 (CH2), 28.0 (CH3), 26.0
(CH3); HRMS (EI) calcd for C10H15NO4 213.1001, found 213.1007.
(3aS,4R,5R,7S,7aR)-5-Cyano-2,2-dimethylhexahydrobenzo[d]-
[1,3]dioxole-4,7-diyl Diacetate (18). To epoxy alcohol 16 (558 mg, 3
mmol) in anhydrous THF (10 mL) was added LiCN (396 mg, 12
mmol), and then the mixture was stirred at reflux for 14 h. The RM
was left to cool. Then TEA (455 mg, 4.5 mmol), DMAP (10 mg), and
Ac2O (408.3 mg, 4 mmol) were sequentially added, and the mixture
was stirred for 15 h at rt. Water (2 mL) and ether (10 mL) were added
to quench the reaction. The separated organic layer was dried
(MgSO4) and concentrated. The residue was subjected to flash
chromatography with a 3:1 hexane/ethyl acetate mixture to give 18
1H), 5.74 (dd, J = 10.0, 1.2, 1H), 4.72 (dt, J = 6.8, 1.2, 1H), 4.40 (dt, J
= 7.2, 1.6, 1H), 3.49 (dd, J = 3.6, 2.4, 1H), 3.28 (dd, J = 3.6, 2.0, 1H),
1.34 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 132.06 (CH), 123.46
(CH), 110.54 (C), 70.81 (CH), 70.74 (CH), 49.20 (CH), 46.50
(CH), 27.79 (CH3), 25.96 (CH3); HRMS (FAB) calcd for C9H13O3
[M + H]+ 169.0865, found 169.0870. Anal. Calcd for C9H12O3: C,
64.27; H, 7.19. Found: C, 64.32; H, 7.10.
(3aR,4S,7aS)-2,2-Dimethyl-3a,4,5,7a-tetrahydrobenzo[d][1,3]-
dioxol-4-ol (15). To a suspension of LAH (139.5 mg, 3.675 mmol) in
anhydrous diethyl ether (5 mL) at 0 °C was added dropwise allylic
epoxide 14 (595 mg, 3.5 mmol) in ether (5 mL). The RM was heated
to reflux for 5 h and 30 min and then cooled to 0 °C. The RM was
carefully quenched with chilled water (1 mL) and then filtered through
Celite. The ether layer was washed with a 15% NaCl solution (2 × 5
mL), dried (MgSO4), and concentrated. The residue was subjected to
flash chromatography with a 3:1 hexane/ethyl acetate mixture to give
15 (583.40 mg, 3.43 mmol, 98%): Rf = 0.2 (silica gel, 3:1
25
25
(802 mg, 2.7 mmol, 90%): Rf = 0.80 (1:1 hexane:ethyl acetate); [α]D
hexane:ethylacetate); [α]D = +143 (c = 1.78, CHCl3). For spectral
= −72.3 (c = 1.72, CHCl3); IR (film) νmax 2988, 2936, 2247, 1748,
1443, 1374 cm−1; 1H NMR (400 MHz, CDCl3) δ 5.4 (dd, J = 6.2, 3.0,
1H), 5.23 (dd, J = 11.2, 7.2, 1H), 4.12−4.04 (m, 2H), 2.90 (td, J =
10.8, 4.8, 1H), 2.20−2.07 (m, 8H), 1.55 (s, 3H), 1.33 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 169.3 (CO), 169.0 (CO), 118.0 (CN),
110.6 (C), 76.4 (CH), 75.3 (CH), 71.2 (CH), 67.0 (CH), 28.6 (CH),
27.7 (CH2), 27.6 (CH3), 26.4 (CH3), 20.9 (CH3), 20.7 (CH3); HRMS
(ESI) calcd for C14H20O6N [M + H]+ 298.1291, found 298.1300.
(3aR,4S,7aS)-6-Cyano-2,2-dimethyl-3a,4,5,7a-tetrahydrobenzo-
[d][1,3]dioxol-4-yl Acetate (19). To epoxy alcohol 16 (558 mg, 3
mmol) in anhydrous THF (10 mL) was added LiCN (396 mg, 12
mmol), and then the mixture was stirred at reflux for 14 h. The RM
was left to cool. Then TEA (455 mg, 4.5 mmol), DMAP (10 mg), and
Ac2O (408.3 mg, 4 mmol) were sequentially added, and the mixture
was stirred for 15 h at rt. Then DBU (1.6 g, 10.5 mmol) was added
and the mixture stirred for 13 h at 45 °C. Water (2 mL) and ether (10
mL) were added to quench the reaction. The separated organic layer
was dried (MgSO4) and concentrated. The residue was subjected to
flash chromatography with a 3:1 hexane/ethyl acetate mixture to give
19 (633 mg, 2.67 mmol, 89%): Rf = 0.22 (hexane:ethyl acetate);
data, see ent-15.
(3aS,4R,7aR)-2,2-Dimethyl-3a,4,7,7a-tetrahydrobenzo[d][1,3]-
dioxol-4-ol (ent-15).21 To a suspension of LAH (139.5 mg, 3.675
mmol) in anhydrous diethyl ether (5 mL) at 0 °C was added dropwise
allylic epoxide ent-14 (595 mg, 3.5 mmol) in ether (5 mL). The RM
was heated to reflux for 5 h and 30 min and then cooled to 0 °C. The
RM was carefully quenched with chilled water (1 mL) and then
filtered through Celite. The ether layer washed with a 15% NaCl
solution (2 × 5 mL), dried (MgSO4), and concentrated. The residue
was subjected to flash chromatography with a 3:1 hexane/ethyl acetate
mixture to give ent-15 (583.40 mg, 3.43 mmol, 98%): Rf = 0.2 (silica
25
gel, 3:1 hexane:ethyl acetate); [α]D = −146 (c = 1.35, CHCl3); IR
(film) νmax 3037, 2986, 1378, 1244, 1217, 1159 cm−1; H NMR (400
1
MHz, CDCl3) δ 5.89−5.82 (m, 2H), 4.60−4.58 (m, 1H), 3.95 (dd, J =
8.4, 6.2, 1H), 3.78−3.75 (m, 1H), 2.45 (d, J = 10.8, 1H), 2.39 (dt, J =
10.0, 5.0, 2H), 2.01 (dddd, J = 10, 4.6, 2.6, 1.4, 1H) 1.47 (s, 3H), 1.37
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 129.3 (CH), 124.3 (CH),
109.2 (C), 79.4 (CH), 72.7 (CH), 69.3 (CH), 30.8 (CH2), 28.4
(CH3), 25.9 (CH3); HRMS (EI) calcd for C9H14O3 170.0943, found
170.0938.
(3aR,4S,5aR,6aR,6bS)-2,2-Dimethylhexahydrooxireno[2′,3′:3,4]-
benzo[1,2-d][1,3]dioxol-4-ol (16). To a suspension of LAH (79.7 mg,
2.1 mmol) in anhydrous diethyl ether (3 mL) at 0 °C was added
dropwise allylic epoxide 14 (338 mg, 2 mmol) in ether (3 mL). The
25
[α]D = +33.5 (c = 1.72, CHCl3); IR (neat) νmax 2989, 2936, 2222,
1747, 1429, 1375 cm−1; 1H NMR (400 MHz, CDCl3) δ 6.55−6.53 (m,
1H), 5.23−5.20 (m, 1H), 4.65−4.63 (m, 1H), 4.22 (t, J = 5.6, 1H),
2.67 (ddt, J = 17.6, 4.2, 1.9, 1H), 2.31 (dd, J = 17.7, 4.9, 1H), 2.06 (s,
2902
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Article
3H), 1.38 (s, 3H), 1.36 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
169.8, 140.6, 117.8, 111.3, 110.5, 72.5, 70.7, 68.0, 28.1, 27.7, 26.0, 20.0;
HRMS (ESI) calcd for C12H16O4N [M + H]+ 238.1079, found
238.1071.
5.9, 1H), 4.45−4.41 (m, 1H), 4.31 (ddd, J = 5.6, 4.0, 1.4, 1H), 3.77
(ddt, J = 3.8, 2.4, 1.4, 1H), 3.71 (s, 3H), 3.32 (d, J = 3.7, 1H), 3.30 (t, J
= 2.8, 1H), 3.14 (d, J = 11.6, 1H), 1.36 (s, 3H), 1.31 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 169.6 (C), 110.4 (C), 74.1 (CH), 70.2
(CH), 66.6 (CH), 53.4 (CH3), 53.1 (CH), 52.0 (CH), 42.5 (CH),
26.6 (CH3), 25.4 (CH3); HRMS (ESI) calcd for C11H17O6 [M + H]+
245.1025, found 245.1017.
(+)-Shikimic acid (1). To the solution of vinyl nitrile (119 mg, 0.5
mmol) in a 1:1 methanol/water mixture (3 mL) was added sodium
hydroxide (2 mmol). The RM was stirred at reflux for 3 h. Then 2 N
HCl was slowly added to neutralize the mixture at rt. The RM was
concentrated and furthur evaporated with absolute ethanol (2 × 4
mL). Anhydrous methanol (4 mL) and Dowex 50 W x-8 resin were
added to the resiude in the same flask. After the mixture had been
stirred for 10 h, the resin was filtered off and concentrated to afford
shikimic acid. A sample was recrystallized from ethanol ether to furnish
(+)-shikimic acid (74 mg, 0.43 mmol, 85%), whose physical properties
are identical to those of the reported compound.2b,d
(3aR,4S,7R,7aS)-Methyl 4,7-Dihydroxy-2,2-dimethyl-3a,4,7,7a-
tetrahydrobenzo[d][1,3]dioxole-5-carboxylate (23). DBU (152 mg,
1.0 mmol) was added to substrate 22 (244 mg, 1 mmol) in methanol
(2 mL) at rt. After the mixture had been stirred for 3 h, water (1 mL)
and CH2Cl2 (2 mL) were added. The separated organic layer was
dried (MgSO4) and concentrated. The residue was subjected to flash
chromatography with a 1:1 hexane/ethyl acetate mixture to give
substrate 23 (234 mg, 0.96 mmol, 96%): Rf = 0.33 (1:1 hexane:ethyl
1
aceate); IR (neat) νmax 3483, 2981, 1720, 1645, 1441, 1374 cm−1; H
2-[(3aR,4S,5S,7aS)-4-Hydroxy-2,2-dimethyl-3a,4,5,7a-tetrahydro-
benzo[d][1,3]dioxol-5-yl]malononitrile (20). Sodium ethoxide (918.7
mg, 13.5 mmol) was added to malanonitrile (905 mg, 13.7 mmol) in
anhydrous ethanol (3 mL) at 0 °C. After the mixture had been stirred
for 5 min, allylic epoxide (504 mg, 3 mmol) in anhydrous ethanol (3
mL) was added and the mixture stirred for 30 min at 0 °C. Chilled
water (2.5 mL) and CH2Cl2 were added to quench the reaction. The
aqueous layer was extracted with CH2Cl2 (2 × 2.5 mL). Combined
organic layers were dried (MgSO4) and concentrated. The residue was
subjected to flash chromatography with a 1:1 hexane/ethyl acetate
mixture to give substrate 20: Rf = 0.58 (1:1 hexane:ethyl acetate);
NMR (400 MHz, CDCl3) δ 7.21 (d, J = 5.2, 1H), 4.72 (s, 1H), 4.56
(dd, J = 6.8, 2.8, 1H), 4.47 (dd, J = 7.2, 2.8, 1H), 4.34 (s, 1H), 3.80 (s,
3H), 3.65 (s, 1H), 3.09 (s, 1H), 1.31 (s, 6H); 13C NMR (150 MHz,
CDCl3) δ 166.3 (C), 142.0 (C), 134.3 (CH), 108.8 (C), 77.8 (CH),
77.3 (CH), 66.7 (CH), 65.6 (CH), 52.3 (CH2), 26.3 (CH3), 24.2
(CH3); HRMS (ESI) calcd for C11H16O6Na [M + Na]+ 267.0845,
found 267.08442.
(3aR,4S,7R,7aS)-Methyl 4,7-Dihydroxy-2,2-dimethylhexahydro-
benzo[d][1,3]dioxole-5-carboxylate (24). To the suspension of
epoxide substrate 22 (976 mg, 4 mmol) and 10% Pd/C (98 mg) in
methanol (8 mL) was added DBU (67 mg, 0.44 mmol). The RM was
kept in a shaker under a hydrogen pressure of 45 psi for 40 h. The RM
was filtered and concentrated. The residue was dissolved in CH2Cl2
and washed with water (3 mL). The organic layer was separated, dried
(MgSO4), and concentrated. The residue was subjected to flash
chromatography with a 1:1 hexane/ethyl acetate mixture to give diol
24 (929 mg, 3.76 mmol, 94%): Rf = 0.30 (1:1 hexane:ethyl acetate); IR
25
[α]D = −10.74 (c = 0.7, CHCl3); IR (neat) νmax 2990, 2920, 2251,
1
2249, 1380, 1216, 1158, 1066 cm−1; H NMR (400 MHz, CDCl3) δ
6.18 (dd, J = 7.0, 3.0, 1H), 5.92 (d, J = 9.6, 1H), 4.68−4.66 (m, 1H),
4.39 (d, J = 3.6, 1H), 4.05 (dd, J = 8.0, 7.0, 1H), 3.59−3.54 (m, 1H),
2.86 (br s, 1H), 2.72 (d, J = 9.2, 1H), 1.5 (s, 3H), 1.4 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 128.9 (CH), 125.9 (CH), 112.1 (C),
110.7 (C), 110.4 (C), 78.5 (CH), 72.4 (CH), 70.3 (CH), 42.5 (CH),
28.0 (CH), 25.6 (CH3), 23.9 (CH3); HRMS (EI) calcd for
C12H14O3N2 234.1004, found 234.1002.
1
(neat) νmax 2944, 1725, 1644, 1446, 1379, 1064 cm−1; H NMR (400
MHz, CDCl3) δ 4.21 (d, J = 3.6, 1H), 4.15−4.12 (m, 2H), 3.92 (dd, J
= 10.0, 7.6, 1H), 3.71 (s, 3H), 3.09 (br b, 1H), 2.77 (td, J = 10.0, 6.2,
1H), 2.20 (s, 1H), 1.98−1.95 (m, 2H), 1.49 (s, 3H), 1.34 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 174.6, 109.4, 79.0, 78.1, 72.5, 66.5, 52.0,
41.7, 30.0, 27.9, 26.0; HRMS (ESI) calcd for C11H19O6 [M + H]+
247.1182, found 247.1173.
(3aR,4S,5R,7aS)-Methyl 4-Hydroxy-2,2-dimethyl-3a,4,5,7a-
tetrahydrobenzo[d][1,3]dioxole-5-carboxylate (21). Sodium ethox-
ide (918.7 mg, 13.5 mmol) was added to malanonitrile (905 mg, 13.7
mmol) in anhydrous ethanol (3 mL) at 0 °C. After the mixture had
been stirred for 5 min, allylic epoxide (504 mg, 3 mmol) in anhydrous
ethanol (3 mL) was added and the mixture stirred for 30 min at 0 °C.
Chilled water (2.5 mL) and CH2Cl2 were added to quench the
reaction. The aqueous layer was extracted with CH2Cl2 (2 × 2.5 mL).
Combined organic layers were dried (MgSO4) and concentrated.
Crude residue 20 was taken in anhydrous methanol (10 mL) at 0 °C.
Cs2CO3 (1.47 g, 4.5 mmol) and magnesium bis(monoperoxy
phthalate) (1.9 g, 3.9 mmol) were added, and the mixture was stirred
for 10 min. The RM was filtered through silica gel and concentrated.
The residue was subjected to flash chromatography with a 1:1 hexane/
ethyl acetate mixture to give substrate 21 (554 mg, 2.43 mmol, 81%):
Rf = 0.45 (1:1 hexane:ethyl acetate); [α]D25 = 15.33 (c = 0.6, CHCl3);
(3aR,4S,7R,7aS)-5-(Methoxycarbonyl)-2,2-dimethylhexahydro-
benzo[d][1,3]dioxole-4,7-diyl Diacetate (25). To diol substrate 24
(864.5 mg, 3.5 mmol) in THF (7 mL) were added triethylamine (885
mg, 8.75 mmol), DMAP (42.75 mg, 0.35 mmol), and acetic anhydride
(786 mg, 7.7 mmol), and the mixture was stirred for 3 h and 40 min.
The RM was quenched with a saturated aqueous solution of sodium
bicarbonate (2 mL). The organic layer was separated, dried (MgSO4),
and concentrated. The residue was subjected to flash chromatography
with a 2:1 hexane/ethyl acetate mixture to give diacetate 25: Rf = 0.62
(1:1 hexane:ethyl acetate); IR (neat) νmax 3478, 2988, 1746, 1441,
1375, 1228, 1051 cm−1; 1H NMR (400 MHz, CDCl3) δ 5.34−5.33 (m,
1H), 5.24 (dd, J = 11.0, 7.0, 1H), 4.11 (d, J = 5.2, 2H), 3.65 (s, 3H),
2.74 (td, J = 11.6, 3.2, 1H), 2.14 (ddd, J = 15.2, 12.1, 3.4, 1H), 2.08 (s,
3H), 2.05 (s, 3H), 1.99 (dt, J = 7.2, 3.2, 1H), 1.54 (s, 3H), 1.33 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 171.8, 169.7, 169.3, 110.1, 75.6,
72.9, 68.1, 65.8, 52.2, 41.0, 27.62, 27.58, 26.4, 20.99, 20.86; HRMS
(ESI) calcd for C15H22O8 330.1315, found 330.1311.
(3aR,7R,7aS)-Methyl 7-Acetoxy-2,2-dimethyl-3a,6,7,7a-
tetrahydrobenzo[d][1,3]dioxole-5-carboxylate (26).22−24 To diol
substrate 24 (864.5 mg, 3.5 mmol) in THF (7 mL) were added
triethylamine (885 mg, 8.75 mmol), DMAP (42.75 mg, 0.35 mmol),
and acetic anhydride (786 mg, 7.7 mmol), and the mixture was stirred
for 3 h and 40 min. Then DBU (959 mg, 6.3 mmol) was added and
the mixture stirred for 10 h. The RM was quenched with a saturated
aqueous solution of sodium bicarbonate (2 mL). The organic layer was
separated, dried (MgSO4), and concentrated. The residue was
subjected to flash chromatography with a 3:1 hexane/ethyl acetate
mixture to give vinyl ester 26: Rf = 0.68 (2:1 hexane:ethyl acetate);
[α]D25 = −59 (c = 0.4, CDCl3); IR (neat) νmax 1724, 1657, 1438, 1373,
1237, 1038 cm−1; 1H NMR (400 MHz, CDCl3) δ 6.88 (dt, J = 3.4, 1.7,
1
IR (neat) νmax 3461, 2987, 2931, 1736, 1638, 1255, 1211 cm−1; H
NMR (400 MHz, CDCl3) δ 5.97 (dt, J = 10, 3.0, 1H), 5.88 (d, J = 10,
1H), 4.62−4.61 (m, 1H), 4.11−4.04 (m, 1H), 3.93 (t, J = 9.0, 1H),
3.77 (s, 3H), 3.10 (d, J = 9.2, 1H), 3.01 (br s, 1H), 1.51 (s, 3H), 1.38
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 172.5 (C), 127.4 (CH),
125.7 (CH), 110.0 (C), 78.1 (CH), 72.2 (CH), 70.4 (CH), 52.5
(CH), 48.0 (CH3), 28.1 (CH3), 25.7 (CH3); HRMS (ESI) calcd for
C11H16O5 228.0998, found 228.0993.
(3aR,4S,5S,5aR,6aR,6bS)-Methyl 4-Hydroxy-2,2-dimethylhexa-
hydrooxireno[2′,3′:3,4]benzo[1,2-d][1,3]dioxole-5-carboxylate (22).
To methyl ester 21 (342 mg, 1.5 mmol) in dichloroethane (5 mL)
were added m-CPBA (518 mg, 3 mmol) and butylated hydroxytoluene
(33 mg, 0.15 mmol). The RM was refluxed for 14 h and then
quenched with sodium bicarbonate. The separated organic layer was
dried (MgSO4) and concentrated. The residue was subjected to flash
chromatography with a 4:1 hexane/ethyl acetate mixture to give
substrate 22 (320 mg, 1.31 mmol, 87%): Rf = 0.83 (1:1 hexane:ethyl
acetate); [α]D25 = −36.13 (c = 6.3, CHCl3); IR (neat) νmax 2989, 2940,
1
1732, 1440, 1380 cm−1; H NMR (400 MHz, CDCl3) δ 4.59 (d, J =
2903
dx.doi.org/10.1021/jo402764v | J. Org. Chem. 2014, 79, 2898−2905

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Article
1H), 5.13 (td, J = 6.6, 4.8, 1H), 4.72−4.69 (m, 1H), 4.20 (t, J = 6.4,
1H), 3.75 (s, 3H), 2.76 (dd, J = 17.6, 4.8, 1H), 2.32 (ddt, J = 17.9, 6.7,
1.6, 1H), 2.04 (s, 3H), 1.38 (s, 3H), 1.36 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 170.2, 166.4, 134.2, 129.5, 110.0, 74.0, 71.9, 70.0,
52.1, 27.8, 26.5, 26.0, 21.1; HRMS (ESI) calcd for C13H18O6Na [M +
Na]+ 293.1001, found 293.0996.
(−)-Shikimic Acid (2). To diol substrate 24 (247 mg, 1 mmol) in
THF (3 mL) were added triethylamine (253 mg, 2.5 mmol), DMAP
(12 mg, 0.1 mmol), and acetic anhydride (225 mg, 2.2 mmol), and the
mixture was stirred for 3 h and 40 min. Then DBU (274 mg, 1.8
mmol) was added and the mixture stirred for 10 h. A saturated
aqueous solution of sodium bicarbonate (2 mL) and CH2Cl2 (4 mL)
were added. The organic layer was separated, dried (MgSO4), and
concentrated. Aqueous trifluoroacetic acid [3 mL, 70% (v/v)] was
added to the residue and the mixture stirred for 12 h at rt. The RM
was concentrated with absolute ethanol to afford (−)-shikimic acid 2.
A sample was recystallized from ethanol ether to furnish (−)-shikimic
acid (140 mg, 0.8 mmol, 80%), whose physical properties are identical
to those of the reported compound.2d
allowed to reach rt, and then treated with m-CPBA (0.48 g, 2.8 mmol).
The RM was stirred at rt for 8 h, and then the solvent was evaporated.
Methanol (15 mL) and sodium methoxide (9.3 mmol) were added to
the residue in the same flask and stirred at reflux for 24 h. The RM was
left to cool to rt. Trifluoroacetic acid (2 mL) was added to the same
flask and the mixture stirred for 1 day and then concentrated. The
residue was subjected to flash chromatography with a 1:4 methanol/
dichloromethane mixture to give (−)-pinitol (5) (195 mg, 1 mmol,
72%) as a white solid, whose physical properties are identical to those
of the reported compound.7e
(3aR,4S,5R,7aS)-5-Methoxy-2,2-dimethyl-3a,4,5,7a-tetrahydro-
benzo[d][1,3]dioxol-4-ol (29). To a solution of chloro ester 13 (0.3 g,
1.2 mmol) in methanol (5 mL) at rt was added sodium methoxide
(0.33 g, 6 mmol). The RM was stirred at reflux for 24 h. Then water (3
mL) and CH2Cl2 (10 mL) were added. The aqueous layer was
extracted with CH2Cl2 (2 × 15 mL). The combined organic layers
were dried (MgSO4) and concentrated. The residue was flash
chromatographed with a 5:1 hexane/ethyl acetate mixture to give
methoxycyclohexenol 29 (0.23 g, 1.15 mmol, 96%): Rf = 0.34 (1:1
hexane:EtOAc); [α]D25 = +22.9 (c = 1.4, CHCl3); IR (film) νmax 3454,
3041, 1059 cm−1; 1H NMR (400 MHz, CDCl3) δ 5.94−5.85 (m, 2H),
4.62 (dd, J = 6.8, 3.2, 1H), 4.10 (dd, J = 8.8, 6.8, 1H), 3.67−3.59 (m,
2H), 3.47 (s, 3H), 1.50 (s, 3H), 1.38 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 130.9 (CH), 124.0 (CH), 110.5 (C), 79.7 (CH), 77.6
(CH), 73.3 (CH), 72.4 (CH), 57.2 (CH3), 28.1 (CH3), 25.7 (CH3);
HRMS (FAB) calcd for C10H17O4 [M + H]+ 201.1127, found
201.1123.
(3aR,5aR,6aR,6bR)-Methyl 2,2-Dimethyl-3a,5a,6a,6b-tetrahydro-
oxireno[2′,3′:3,4]benzo[1,2-d][1,3]dioxole-5-carboxylate (27). To
substrate 22 (244 mg, 1 mmol) in CH2Cl2 (4 mL) at 0 °C were
added triethylamine (455 mg, 4.5 mmol) and methanesulfonyl
chloride (171.84 mg, 1.5 mmol). The RM was stirred at rt for 5 h
and 30 min and then quenched with a saturated aqueous solution of
sodium carbonate (4 mL). The separated organic layer was dried
(MgSO4) and concentrated. The residue was subjected to flash
chromatography with a 3:1 hexane/ethyl acetate mixture to give 27
(+)-Pinitol (6). To a mixture of methoxycyclohexenol 29 (0.1 g, 0.5
mmol) and NMO (0.18 g, 1.5 mmol) in a 1:1 acetone/water mixture
(2 mL) was added 0.3 mL of a 0.1 M OsO4 solution in THF, and the
mixture was stirred at rt for 24 h, treated with CF3COOH (0.37 mL, 5
mmol), and stirred for an additional 24 h. After concentration, the
residue was flash chromatographed with a 1:4 MeOH/CH2Cl2 mixture
to give (+)-pinitol 6 (80 mg, 84%), whose physical properties are
identical to those of the reported compound.7e
25
(226 mg, 1 mmol, 100%): Rf = 0.78 (2:1 hexane:ethyl acetate); [α]D
= −42.286 (c = 0.7, CHCl3); IR (neat) νmax 2992, 2945, 2359, 1724,
1
1654, 1445, 1378, 1097 cm−1; H NMR (400 MHz, CDCl3) δ 6.81
(dd, J = 2.0, 1.2, 1H), 4.78 (ddd, J = 7.0, 1.6, 0.8, 1H), 4.55 (dd, J =
6.8, 2.4, 1H), 3.97 (ddd, J = 3.7, 1.6, 0.6, 1H), 3.81 (s, 3H), 3.65−3.63
(m, 1H), 1.39 (s, 3H), 1.34 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
165.4, 140.0, 127.4, 111.0, 71.2, 70.4, 52.3, 49.3, 46.1, 27.8, 25.8;
HRMS (EI) calcd for C11H14O5 226.0841, found 226.0845.
(3aR,7R,7aS)-Methyl 7-Hydroxy-2,2-dimethyl-3a,4,7,7a-
tetrahydrobenzo[d][1,3]dioxole-5-carboxylate (28).25 To substrate
27 (226 mg, 1 mmol) in methanol (4 mL) at −55 °C was added
LiBH4 (39.2 mg, 1.8 mmol). The reaction temperature was slowly
increased to 0 °C over 1 h and then the mixture stirred for 20 h at 0
°C. Then water (2 mL) and CH2Cl2 (4 mL) were added. The
separated organic layer was dried (MgSO4) and concentrated. The
residue was subjected to flash chromatography with a 2:1 hexane/ethyl
acetate mixture to give 28 (185 mg, 0.81 mmol, 81%): Rf = 0.35 (2:1
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H and 13C NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: thyan@mail.nchu.edu.tw.
Notes
25
hexane:ethyl acetate); [α]D = −65.8 (c = 0.43, CHCl3); IR (neat)
1
νmax 3438, 2989, 1716, 1648, 1439, 1378 cm−1; H NMR (400 MHz,
CDCl3) δ 6.93 (s, 1H), 4.36 (q, J = 6.5, 1H), 4.31−4.23 (m, 1H), 3.99
(t, J = 6.7, 1H), 3.74 (s, 3H), 3.13 (dd, J = 16.5, 6.9, 1H), 2.30−2.18
(m, 1H), 1.45 (s, 3H), 1.34 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
166.0, 140.8, 129.0, 109.3, 80.3, 71.8, 71.2, 52.0, 28.0, 27.3, 25.0;
HRMS (ESI) calcd for C11H17O4 [M + H]+ 229.1127, found 229.1123.
(−)-4-epi-Shikimic Acid (3).6a To substrate 28 (115 mg, 0.5 mmol)
was added aqueous trifluoroacetic acid [2.5 mL, 60% (v/v)], and the
mixture was stirred for 12 h. The RM was concentrated with absolute
ethanol and recrystallized with an ethanol/ether mixture to give 4-epi-
shikimic acid (78 mg, 0.45 mmol, 90%), whose physical properties are
identical to those of the reported compound. Anal. Calcd for C7H10O5:
C, 48.28; H, 5.79. Found: C, 48.19; H, 5.89.6d
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Science Council of the Republic of
China for generous financial support. B.A. thanks MOFA for
the Taiwan Scholarship programme.
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■
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