A convenient method for the synthesis of dehydroquinic acid

Article abstract of DOI:10.1081/SCC-120015805

A convenient synthesis of dehydroquinic acid and its corresponding methyl ester are described. Protection of the trans diol of quinic acid, followed by PCC oxidation, gave fully protected dehydroquinic acid. This gave methyl dehydroquinate on mild acid ca

Full text of DOI:10.1081/SCC-120015805

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A Convenient Method for the Synthesis of
Dehydroquinic Acid
Christine Le Sann a , Chris Abell b & Andrew D. Abell a
a Department of Chemistry , University of Canterbury , Christchurch, New Zealand
b University Chemical Laboratory , Cambridge, UK
Published online: 16 Aug 2006.
To cite this article: Christine Le Sann , Chris Abell & Andrew D. Abell (2003) A Convenient Method for the Synthesis of
Dehydroquinic Acid, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 33:4, 527-533, DOI: 10.1081/SCC-120015805
To link to this article: http://dx.doi.org/10.1081/SCC-120015805
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 4, pp. 527–533, 2003
A Convenient Method for the Synthesis of
Dehydroquinic Acid
2
1
Christine Le Sann,1, Chris Abell, and Andrew D. Abell
*
1Department of Chemistry, University of Canterbury,
Christchurch, New Zealand
2University Chemical Laboratory,
Cambridge, UK
ABSTRACT
A convenient synthesis of dehydroquinic acid and its corresponding
methyl ester are described. Protection of the trans diol of quinic acid,
followed by PCC oxidation, gave fully protected dehydroquinic acid.
This gave methyl dehydroquinate on mild acid catalyzed hydrolysis.
Ester hydrolysis then gave potassium dehydroquinate which was
treated with amberlite to afford dehydroquinic acid.
Key Words: Shikimate pathway; Dehydroquinic acid; Synthesis;
Selective protection.
*Correspondence: Christine Le Sann, Department of Chemistry, University of
Canterbury, Private Bag 4800, Christchurch, Canterbury, New Zealand; Fax:
+00 64(0)3 364 2110; E-mail: chem237@its.canterbury.ac.nz.
527
DOI: 10.1081/SCC-120015805
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
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528
Le Sann, Abell, and Abell
Chorismic acid, a key intermediate to aromatic metabolites such as
folate, ubiquinone and the aromatic amino acids is biosynthesized by
a sequence of reactions collectively known as the shikimate pathway.[1]
A key step in this pathway involves dehydration of dehydroquinic acid 6
to give dehydroshikimic acid in a process that has recently been shown to
be catalyzed by either Type I or II dehydroquinases.[1] Inhibitors of these
enzymes are now actively being sought to provide leads for the develop-
ment of new herbicides and antimicrobial agents.[2,3] Therefore,
a convenientsynhteitc source of dehydroquinic acid
6, and its corre-
sponding methyl ester 4, is required for use in enzyme inhibition
assays[3] and to provide convenient starting materials for the preparation
of new inhibitors.[4]
A good deal of effort has gone into trying to develop a convenient
method for the preparation of these deceptively simple molecules.
Literature methods for the synthesis of dehydroquinic acid, notably oxi-
dation of quinic acid 1 using a platinum–oxygen system[5,6] or nitric
acid,[7,8] are difficult to reproduce, invariably require tedious purification,
and afford the desired acid in variable yield. Here, we report a convenient
and reproducible synthesis of dehydroquinic acid 6, and its methyl ester 4,
which is amenable to multigram scale. In this method, the acid 6 is
prepared from the methyl ester 4 by simple hydrolysis followed by mild
acidification. By contrast, the literature preparation of 4 involves a
problematic esterification of 6,[9] which is itself difficult to prepare.
The initial step in the synthesis involved a one-pot protection of the
vicinal trans diol and acid groups of quinic acid 1 to give 2, which was
purified by treatment with decolorizing charcoal and recrystalization. We
found that optimum yields of 2 were obtained after vigorous reflux with
trimethylorthoformate, butanedione and methanol in the presence of
camphorsulfonic acid catalyst for 18 h. This contrasts with the literature
method of Gotor et al.[10] who reported a reaction time of 1 h. The
masked quinic acid 2 was then oxidized using a four-fold excess of pyr-
idinium chlorochromate (PCC) to furnish the protected form of dehy-
droquinic acid 3 in 88% after treatment with decolorizing charcoal and
recrystalization.[10] Subsequent cleavage of the acetal protecting group
with trifluoroacetic acid[11] proceeded smoothly to afford the methyl
dehydroquinate 4[9] that was purified by column chromatography on
deactivated silica gel.[12] Hydrolysis of the methyl ester 4, with aqueous
KOH, furnished the potassium dehydroquinate 5 as an off-white solid
that did not require further purification. The deprotection and hydrolysis
steps were carefully monitored by thin layer chromatography, because
prolonged exposure of the dehydroquinates 4 and 5 to strongly acidic or
basic conditions readily led to the elimination of the hydroxyl group at C-1

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Synthesis of Dehydroquinic Acid
529
Scheme 1.
to form dehydroshikimate, which is susceptible to aromatization. The
potassium salt 5 was finally stirred over amberlite[3] to give dehydroquinic
acid 6 (hygroscopic solid) in excellentyield (Sch. 1). The acid hence
obtained gave satisfactory analytical data and all spectroscopic data
was consistent with the proposed structure where reported in the litera-
ture.[6] The optical rotation was equivalent to that reported by Grewe
and Jeschke at a similar concentration and in the same solvent.[7]
In conclusion, we reporta convenientand reproducible meht od for
the preparation of dehydroquinic acid 6 and its corresponding methyl
ester 4. The preparation of 4 is conveniently carried out on gram scales
(see experimental), however, 6 is particularly hygroscopic and is best
prepared from a stock pile of 4 as required.
EXPERIMENTAL
1
General: H-NMR spectra were obtained using a 300 MHz Varian
Unity 300 NMR spectrometer. 13C-NMR spectra were recorded at a
frequency of 75 MHz. 1H–13C-NMR Correlation experiments were
carried out on an Inova 500 spectrometer at 500 MHz. Chemical shifts
(ꢀ) are given in partper million (ppm). Mass spectra were recorded on a
Kratos MS80RFA instrument for electron impact (EI) and fast atom
bombardment (FAB) techniques, or a micromass LCT spectrometer for
the time-of-flight (TOF) method. Infrared spectra were obtained on a

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530
Le Sann, Abell, and Abell
Shimadzu Hyper FT-IR instrument. Optical rotations were measured
using a Perkin 341 spectrometer. Melting points were taken on an
Electrothermal apparatus and are uncorrected.
Methyl (1S,3R,4R,5R)-1,3-dihydroxy-4,5-[(2S,3S )-2,3-
dimethoxybutan-2,3-dioxy)]cyclohexan-1-carboxylate 2
2,3-Butanedione(4.65 mL,53 mmol),trimethylorthoformate(13.9 mL,
127 mmol) and D-camphorsulfonic acid (302 mg, 1.3 mmol) were added to
a suspension of quinic acid 1 (5 g, 26 mmol) in methanol (40 mL). The
mixture was heated to vigorous reflux for 18 h, then left to cool to room
temperature and treated with sodium bicarbonate (200 mg, 2 mmol). The
solvent was removed under reduced pressure to give a paste that was
dissolved in ethyl acetate. Activated charcoal was added and the mixture
was heated to reflux for 2 h, then left to cool to room temperature. The
mixture was filtered over a thick pad of silica gel which was further washed
using ethyl acetate–methanol (9:1), and the resulting colorless filtrate was
evaporated in vacuo to give a white solid. The crude ester 2 was recrysta-
lized from ethyl acetate to furnish the protected quinic acid 2 as white shiny
20
crystals (6.3 g, 76%). M.p. 139–140ꢀC [Lit.[11] m.p. 138–140ꢀC], ½ꢁŠ
D
20
D
þ121.9 (c 1.08, CH2Cl2) [Lit.[11] ½ꢁŠ þ116.3 (c 1.06, CH2Cl2); ꢀH
(CDCl3) 1.30 (3H, s, CH3), 1.34 (3H, s, CH3), 1.92 (1H, dd, J 12.5, 12.5,
6-HH), 2.03 (1H, dd, J 14.5, 14.5, 2-HH), 2.10 (1H, ddd, J 12.5, 4.5, 3, 6-
HH ), 2.18 (1H, ddd, J 14.5, 3, 3, 2-HH), 3.18 (1H, d, J 3, OH), 3.26 (3H, s,
CHCH3), 3.27 (3H, s, CHCH3), 3.60 (1H, dd, J 10, 3, 4-H), 4.20 (1H, m, 3-
H), 4.31 (1H, ddd, J 12.5, 10, 4.5, 5-H); ꢀC 17.5 (CH3), 17.6 (CH3), 37.3 (C-
2), 38.5 (C-6), 47.8 (2 ꢁ COCH3), 52.8 (CO2CH3), 62.3 (C-5), 69.0 (C-5),
76.2 (C-4), 75.7 (C-1), 99.6 (COCH3), 100.2 (COCH3), 174.2 (CO2CH3);
m/z (EI) Found 289.1287 (C13H21O7 requires 289.3016); 289 (M-OMe,
5%), 193 (10), 178 (25), 154 (30), 94 (52), 70 (100), 57 (81).
Methyl (1R,4S,5R)-1-hydroxy-4,5-[(2S,3S )-2,3-
dimethoxybutan-2,3-dioxy)]-3-oxo-cyclohexan-1-carboxylate 3
The protected quinic acid 2 (5.7 g, 19.7 mmol) was added to a suspen-
sion of pyridinium chlorochromate (22 g) in dichloromethane (100 mL)
over molecular sieves (4 A). The reaction mixture was stirred at room
temperature for 15 h. It was then filtered over a pad of silica gel which
was washed with ethyl acetate–methanol (9:1). The resulting brown
filtrate was treated with decolorizing charcoal and then heated to reflux

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Synthesis of Dehydroquinic Acid
531
for 1 h. After cooling to room temperature, the mixture was filtered over
a thick pad of silica gel which was washed using ethyl acetate–methanol
(9:1). The filtrate was concentrated under reduced pressure to afford
a pale yellow solid that was recrystallized from ethyl acetate to give
the protected dehydroquinic acid 3 as white crystals (4.64 g, 81%).
M.p. 212–214ꢀC [Lit [.11] m.p. 212–214ꢀC]; ½ꢁŠ þ105.1 (c 1.05, CHCl3)
20
D
20
D
[Lit.[11] ½ꢁŠ þ82.7 (c 1.05, CHCl3)]; ꢂmax/cmꢂ1(KBr) 3485, 2947, 1749,
1732, 1442, 1078; ꢀH (CDCl3) 1.30 (3H, s, CH3), 1.34 (3H, s, CH3), 2.10
(1H, J 13, 13, 6-HH), 2.34 (1H, dd, J 13, 13, 6-HH ), 2.51 (1H, dd, J 14,
4, 2-HH), 2.87 (1H, d, J 14, 2-HH ), 3.21 (3H, s, OCH3), 3.24 (3H,
s, OCH3), 3.26 (1H, brs, OH), 3.82 (3H, s, CO2CH3), 4.23 (1H, ddd,
J 10, 4, 4, 5-H), 4.40 (1-H, dd, J 10, 4-H); ꢀC 17.6 (CH3), 17.7 (CH3),
37.9 (C-6), 48.1 (OCH3), 48.4 (OCH3), 49.1 (C-2), 53.7 (CO2CH3), 67.1
(C-5), 74.1 (C-1), 77.2 (C-4), 99.7 (COCH3), 100.6 (COCH3), 174.2
(CO2CH3), 199.7 (C-3); m/z (EI) Found 287.1131 (C13H19O7 requires
287.2858); 287 (10%, M-OMe), 152 (25), 111 (100), 75 (60).
Methyl 3-Dehydroquinate 4
The protected dehydroquinic acid 3 (2 g, 6.28 mmol) was treated with
a mixture of trifluoroacetic acid and water (95:5, 30 mL), and stirred at
0ꢀC for 15 min. The resulting yellow mixture was concentrated in vacuo
to afford the methyl ester of dehydroquinic acid 4 as a yellow oil. The
crude product was purified by column chromatography on deactivated
silica gel obtained by rinsing the column of silica gel with 2% triethyla-
mine in the eluent, then rinsing the column with pure eluent. Elution with
1.2% methanol in ethyl acetate afforded methyl dehydroquinate 4 as a
20
very sticky colorless oil (1.06 g, 83%). ½ꢁŠ ꢂ34.8 (c 1.50, MeOH);
D
ꢂ
max/cmꢂ1 3388, 3141, 2958, 1732, 1436, 1041; ꢀH (acetone-d6) 2.32
(1H, dd, J 13.5, 10.5, 6-HH), 2.36 (1H, ddd, J 13.5, 6, 2.5, 6-HH ), 2.64
(1H, dd, J 14, 2.5, 2-HH), 3.19 (1H, dd, J 14, 1, 2-HH ), 3.86 (3H, s,
CH3), 4.05 (1H, ddd, J 10.5, 9.5, 6, 5-H), 4.27 (1H, dd, J 9.5, 1, 4-H); ꢀC
(acetone-d6) 40.5 (C-6), 47.6 (C-2), 52.3 (CO2CH3), 72.1 (C-5), 74.3 (C-1),
81.7 (C-4), 173.9 (CO2CH3), 205.6 (C-3); m/z (TOF) 189 (100%,
M-OMe), 171 (90), 153 (26).
Potassium 3-Dehydroquinate 5
A solution of the methyl dehydroquinate 4 (400 mg, 1.96 mmol) in
water (2 mL) was added with a solution of potassium hydroxide (109 mg,

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532
Le Sann, Abell, and Abell
1.96 mmol) in water (1 mL). The reaction mixture was stirred at room
temperature for 10 min. It was then concentrated under reduced pressure,
dried under high vacuum for 4 h to give potassium dehydroquinate 5 as
an off-white solid that gave satisfactory analytical data and was hence
20
D
used crude in the next step (429 mg, 96%). M.p. 170–172ꢀC; ½ꢁŠ ꢂ47.6
(c 1.49, H2O); Anal. calcd. for C7H9O6K C, 36.83; H, 3.94. Found C,
36.72, H, 3.94; ꢂmax/cmꢂ1 (Nujol) 3176, 1708, 1045; ꢀH (D2O) 2.12 (1H,
ddd, J 13.5, 5.5, 3, 6-H H); 2.19 (1H, dd, J 13.5, 11, 6-HH ), 2.38 (1H, dd,
J 14, 3, 2-H H), 2.99 (1H, d, J 14, 2-HH ), 3.81 (1H, ddd, J 11, 10, 5.5,
5-H), 4.22 (1H, d, J 10, 4-H); ꢀC (D2O) 40.4 (C-6), 48.5 (C-2), 72.1 (C-5),
75.4 (C-1), 80.7 (C-4), 179.6 (CO2K), 209.5 (C-3); m/z (TOF) Found
189.0401 (C7H9O6 requires 189.0399); 189 (75%, M ꢂ Kþ), 171 (100).
3-Dehydroquinic Acid 6
Potassium dehydroquinate 5 (170 mg, 0.74 mmol) was dissolved in
water (2 mL), amberlite IR-120 (H) (100 mg) was added, and the mixture
was stirred for 5 min. The ion-exchange resin was filtered off, the resulting
filtrate was evaporated in vacuo, and then dried under high vacuum for
5 h to give dehydroquinic acid 6 quantitatively as a very hygroscopic
20
D
20
D
white solid (140 mg). ½ꢁŠ ꢂ42.6 (c 0.35, MeOH) [Lit.[7] ½ꢁŠ ꢂ43.2 ꢃ 4
(c 0.35, MeOH)]; ꢂmax/cmꢂ1 (KBr) 3294, 2933, 2621, 1724, 1091; ꢀH
(D2O) 2.20 (1H, m, 6-H2), 2.46 (1H, brd, J 14, 2-H H), 3.02 (1H, d, J
14, 2-HH ), 3.79 (1H, brdd, J 9.5, 9.5, 5-H), 4.18 (1H, d, J 9.5, 4-H); ꢀC
(D2O) 39.5 (C-6), 47.5 (C-2), 71.3 (C-5), 74.0 (C-1), 80.6 (C-4), 176.5
(CO2H), 208.1 (C-3).
ACKNOWLEDGMENTS
This research was gratefully supported by a Royal Society of
New Zealand Marsden Fund (CLS). Mary A. Gower and Kelly A. Smith
are acknowledged for technical assistance.
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Synthesis of Dehydroquinic Acid
533
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Received in Japan December 25, 2001

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