A concise route to (-)-shikimic acid and (-)-5-epi-shikimic acid, and their enantiomers via Barbier reaction and ring-closing metathesis

Article abstract of DOI:10.1016/j.tetlet.2009.09.111

A simple route for the synthesis of naturally occurring (-)-shikimic acid, (-)-5-epi-shikimic acid, and their enantiomers from d-ribose-derived enantiomeric aldehydes 8a and 8b by employing Barbier reaction and ring-closing metathesis as key steps has bee

Full text of DOI:10.1016/j.tetlet.2009.09.111

Tetrahedron Letters 50 (2009) 6951–6954
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Tetrahedron Letters
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A concise route to (ꢀ)-shikimic acid and (ꢀ)-5-epi-shikimic acid, and their
enantiomers via Barbier reaction and ring-closing metathesis
*
Pavan K. Kancharla, Venkata Ramana Doddi, Hariprasad Kokatla, Yashwant D. Vankar
Department of Chemistry, Indian Institute of Technology Kanpur 208 016, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple route for the synthesis of naturally occurring (ꢀ)-shikimic acid, (ꢀ)-5-epi-shikimic acid, and
Received 28 August 2009
Revised 15 September 2009
Accepted 20 September 2009
Available online 2 October 2009
their enantiomers from D-ribose-derived enantiomeric aldehydes 8a and 8b by employing Barbier reac-
tion and ring-closing metathesis as key steps has been developed.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Barbier reaction
Ring-closing metathesis
Carbasugars
Shikimic acid
epi-Shikimic acid
Shikimic acid1 plays a pivotal role as a key intermediate in the
shikimate pathway toward the synthesis of several aromatic amino
acids and a variety of secondary metabolites in plants, fungi, and
microorganisms.2 The absence of this pathway in animals, which
obtain the required aromatic amino acids through diet, makes
the enzymes of this pathway ideal targets for the development of
new antimicrobial agents and nontoxic herbicides. For example,
glyphosate, besides its wide use as a commercial herbicide,3 is an
effective antiparasitic drug, which inhibits 5-enolpyruvyl shikim-
ate 3-phosphate (EPSP) synthase,4 the sixth enzyme of this path-
way. It is also reported to inhibit the in vitro growth of
Toxoplasma gondii, Plasmodium falciparum (malaria), and Cryptospo-
ridium parvum.5 Besides its bio-significance, shikimic acid, which is
a highly functionalized carbocycle, is also an industrially useful6
chiral compound. More recently, it has emerged as an indispens-
able starting material for the synthesis of Tamiflu 1 (Fig. 1).7,8 As
a result, development of efficient syntheses for shikimic acid and
its analogues has been an active area of research with a view to de-
velop selective enzyme inhibitors9 which are of relevance as po-
tential antifungal and antibacterial agents.
4, which was reported to exhibit cytotoxic and cancerostatic activ-
ity with low toxicity. Despite its prospective significance, only a
limited number of synthetic routes are available for (+)- and (ꢀ)-
5-epi-shikimic acid.
By virtue of its importance, it has been the subject of a few re-
views13 and a number of racemic and chiral syntheses for natural
and unnatural shikimic acids are reported in the literature.13b,14
Synthetic approaches using (i) Diels–Alder reaction, (ii) benzene
and its derivatives, (iii) quinic acid, and (iv) carbohydrates as start-
ing materials have been developed.15,16 Similarly, a few reports are
available for the synthesis of both the enantiomers of 5-epi-shiki-
mic acid, the notable among which is the synthesis of (ꢀ)-methyl
3,4-O-isopropylidene-5-epi-shikimate, a key intermediate in their
synthetic approach to avermectins and milbemycins, with an over-
all yield of 51%, from (ꢀ)-quinic acid.18,19
In this context, the realization of different stereoisomers of shiki-
mic acid as chirons for a wide range of target molecules emphasizes
the growing stipulation to develop short synthetic routes toward
these analogues. In continuation of our interest in the synthesis of
carbasugars20 coupled with the aspiration of exploring the synthetic
utility of ring-closing metathesis toward biologically important
molecules,21 herein we report a concise diastereoselective synthesis
of four stereoisomers 6a–d (Fig. 2) of shikimic acid. Our strategy
which emanates from the aldehyde 8a as delineated in the retrosyn-
thetic analysis (Scheme 1) via Barbier reaction with bromomethyl
acrylate, followed by ring-closing metathesis, provides a rapid entry
into the functionalized cylcohexenes (Scheme 2).
In addition, epimers of shikimic acid10 also have attracted great
attention as they form the constituents of several natural products
and compounds of biological importance. Among the three possi-
ble epimers, 5-epi-shikimic acid skeleton has its own identity of
being a part of antitumor class of natural products pericosines 2
and 3, (the absolute structure of 2 (pericosine A) has been deter-
mined only recently)11 and also of the glyoxalase inhibitor COTC12
The aldehyde 8a,17 derived from
D-ribose (Scheme 1), was re-
acted with ethyl bromomethacrylate under Barbier reaction condi-
tions using zinc to give compound 10 as an inseparable mixture of
* Corresponding author. Tel.: +91 512 2597169; fax: +91 512 259 0007.
E-mail address: vankar@iitk.ac.in (Y.D. Vankar).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.111

6952
P. K. Kancharla et al. / Tetrahedron Letters 50 (2009) 6951–6954
Cl
OMe
CO2Et
HO
HO
CO2Me
O
HO
HO
CO2Me
AcHN
NH2. H3PO4
OH
OH
2
3
1
O
OH
OH
O
HO
HO
O
OH
HO
OH
OH
(-)-MK7607
4
5
Figure 1. Structures of some biologically important functionalized cyclohexenes.
OH
OH
OH
OH
HO
HO
HO
HO
HO
HO
HO
HO
CO2H
CO2H
CO2H
CO2H
(+)-5-epi-shikimic acid
6d
(+)-shikimic acid
6c
(-)-5-epi-shikimic acid
6a
(-)-shikimic acid
6b
Figure 2. Structures of four stereosiomers of shikimic acid synthesized.
OH
O
O
CO2Et
PO
PO
HO
HO
O
O
O
O
CO2H
OP1
6
8b
7
8a
65 %
85 %
over two steps
(ref 17)
over two steps
(ref 17)
O
O
OH
O
OH
OH
OMe
HO
HO
HO
O
O
O
O
OH
93 %
69 %
D
-ribose
Scheme 1. Retrosynthesis of Shikimic acid.
two diastereomers in 2:1 ratio. The presence of five olefinic pro-
tons for both the diastereomers in the 1H NMR spectrum (d 6.28–
5.27), in addition to other data, confirms the formation of the prod-
uct. The free hydroxyl group was converted to p-nitrobenzoate es-
ter by treating with p-nitrobenzoyl chloride and pyridine where
the two diastereomers were successfully separated through col-
umn chromatography. Various attempts to cyclize the major dia-
stereomer 11 using 1st and 2nd generation Grubbs’ catalysts
resulted in failure. We, therefore, attempted to cyclize the unpro-
tected diene 10 using 1st generation Grubbs’ catalyst, which also
met with failure even in refluxing toluene. However, ring-closing
metathesis of 1022 proceeded smoothly in the presence of
4 mol % of Grubbs’ 2nd generation catalyst to yield the shikimic
acid skeleton 13 in 80% yield albeit again as an inseparable diaste-
reomeric mixture. The disappearance of the multiplet due to five
olefinic protons in the region d 6.28–5.27 and the appearance of
two new sets of signals at d 6.93 and d 6.80 in its 1H NMR spectrum,
one for each diastereomer, confirmed that the cyclization had oc-
curred. The appearance of each of the olefinic protons of the endo-
cyclic double bond of each isomer as a multiplet indicates strong
allylic coupling with C-6 protons. The diastereomeric mixture
was then subjected to esterification with p-nitrobenzoyl chloride
and triethylamine to obtain the p-nitrobenzoate ester in quantita-
tive yield. Cleavage of the acetonide group using 60% acetic acid
followed by acetylation provided chromatographically separable
mixture of diastereomers 15 and 16.
The chemical shifts of various protons in the 1H NMR spectra of
15 and 16 were assigned using the COSY spectral data. The stereo-
chemistry of the newly generated stereocenter in both the sepa-
rated shikimate derivatives was deduced using the NOE spectral
analysis (Fig. 3). Thus, in an NOE experiment, irradiation of the sig-
nal for H-5 in the major isomer 15 led to the enhancement of H-4

P. K. Kancharla et al. / Tetrahedron Letters 50 (2009) 6951–6954
6953
CO2Et
O
Br
CO2Et
CO2Et
O
Zn, cat. NH4Cl
THF, 81%
O
O
PNBCl
O
9
Pyridine
O
PNBO
CO2Et
OPNB
11
OH
10
8a
12
major seperated
isomer
O
O
3
O
O
4mol% 2nd generation
2
1. 60% AcOH
2. Ac2O, Et3N
PNBCl, Et3N
DCM, 98%
4
10
5
6
1
Grubbs' catalyst
HO
CO2Et
PNBO
OH
CO2Et
91% over two steps
13
14
OAc
HO
AcO
R
1N NaOH
PNBCl: p-nitrobenzoyl
chloride
R
CO2H
1R2
CO2Et
1R2
6a
R1 = OH, R2 = H 61%
R1 = H, R2 = OH 65%
15
16
R
1 = OPNB, R2 = H
6b
R1 = H, R2 = OPNB
Scheme 2. Synthesis of (ꢀ)-5-epi-shikimic acid 6a and (ꢀ)-shikimic acid 6b.
ever, the absolute configurations at C-5 in both 15 and 16 are as
shown in Figure 3 which was further confirmed by converting
them into known (ꢀ)-5-epi-shikimic acid 6a and (ꢀ)-shikimic acid
6b (vide infra), respectively. The global deprotection of both the
shikimate derivatives was carried out in one pot, by treating with
1 N NaOH solution and the products were obtained in their pure
forms24–26 after passing through a short plug of silica gel. Thus,
(ꢀ)-5-epi-shikimic acid was obtained in 19% overall yield whereas
the naturally occurring (ꢀ)-shikimic acid was obtained with an
overall yield of 9% starting from the aldehyde 8a.
AcO
H4
AcO
AcO
H3
H3
H4
8.4%
AcO
X
11.0%
PNBO
CO2Et
H5
PNBO
CO2Et
H5
3.0%
15
16
Figure 3. Diagnostic NOE correlations for the compounds 15 and 16.
Similarly, (+)-5-epi-shikimic acid 6c and (+)-shikimic acid 6d
were also synthesized (Scheme 3) following the same synthetic se-
(11%) and H-3 signals (8.4%) indicating that H-5 is cis to H-3 and
correspondingly revealing the cis relation between the OPNB group
and both the acetoxy groups and thus concluding the major isomer
to be the 5-epi-shikimate derivative. However, irradiation of the
signal for H-5 in the minor isomer 16 also led to a small enhance-
ment23 (3%) of the signal for H-4 and no enhancement in the signal
for H-3. It is clear that the conformations of molecules 15 and 16
are either half chair or slightly distorted23b which allows H-5 and
H-4 to come closer and exhibit small NOE in compound 16. How-
quence starting from the
D-ribose-derived aldehyde 8b. All the
spectral data24,26 of the intermediates as well as the final com-
pounds, except the rotation being opposite, were in absolute match
with their enantiomers.
In summary, we have developed a concise route for the synthe-
sis of (ꢀ)-5-epi-shikimic acid, (+)-5-epi-shikimic acid, and (+)-shi-
kimic acid along with the naturally occurring (ꢀ)-shikimic acid
via Barbier reaction followed by ring-closing metathesis as key
steps. This approach toward the synthesis of functionalized cyclo-
O
O
CO2Et
O
O
Zn, cat. NH4Cl
THF, 81%
4mol% 2nd generation
9
8b
Grubbs' catalyst
75%
HO
CO2Et
OH
17
18
OH
OAc
HO
R
O
AcO
1. 60% AcOH
2. Ac2O, Et3N
O
1N NaOH
PNBCl, Et3N
DCM, 98%
CO2H
1R2
R
CO2Et
1R2
PNBO
CO2Et
91% over
two steps
19
61%
6c R1 = H, R2 = OH
20 R1 = H, R2 = OPNB
21 R1 = OPNB, R2 = H
6d R1 = OH, R2 = H 65%
Scheme 3. Synthesis of (+)-5-epi-shikimic acid 6c and (+)-shikimic acid 6d.

6954
P. K. Kancharla et al. / Tetrahedron Letters 50 (2009) 6951–6954
The mixture was filtered and the precipitate was thoroughly washed with
CHCl3 (4 ꢁ 3 mL). The aqueous layer was separated and treated with 5% HCl to
dissolve the suspended turbid material. The clear solution was extracted with
CHCl3 (3 ꢁ 25 mL). The combined organic layer was washed successively with
10% NaHCO3, water, and finally with brine solution. After removal of the
solvent under reduced pressure a residue was obtained, which was purified by
column chromatography to give compound 10 (709 mg, 81%) as a mixture of
two diastereomers (1:2). Yellow oil, Rf = 0.65 (4:1 hexanes:EtOAc); IR (thin
hexenes, especially to derive different stereoisomers of shikimic
acid, is exemplary and might also be applicable to several other
pseudosugars and biologically important molecules.
Supplementary data
film) 3470, 3084, 2985, 2934, 1714, 1629, 1431, 1214, 1057 cmꢀ1 1H NMR
;
(500 MHz, CDCl3) d 6.28 (d, J = 1.1 Hz, 1H, major), 6.27 (d, J = 1.1 Hz, 1H, minor),
6.07–6.0 (m, 1H, both isomers), 5.73 (s, 1H, major), 5.69 (d, J = 1.1 Hz, 1H,
minor), 5.43 (dd, J = 5.1 Hz, J = 17.1 Hz, 1H, major), 5.30–5.39 (m, 2H, both
isomers), 5.27 (d, J = 10.9 Hz, 1H, major), 4.68 (t, J = 6.8 Hz, 1H, major), 4.61 (t,
J = 7.4 Hz, 1H, minor), 4.19–4.25 (m, 2H, major), 4.05 (dd, J = 4.6 Hz, J = 6.8 Hz,
1H, minor), 4.05 (dd, J = 6.3 Hz, J = 8.6 Hz, 1H, major), 3.79–3.75 (m, 1H, both
isomers), 2.92 (d, J = 4.0 Hz, 1H), 2.84 (dd, J = 2.3 Hz, J = 14.3 Hz, 1H), 2.55–2.44
(m, 2H, both isomers), 1.53 (s, 3H, minor), 1.50 (s, 3H, major), 1.39 (s, 3H,
minor), 1.37 (s, 3H, major), 1.33–1.29 (3H, both isomers); 13C NMR (125 MHz,
CDCl3) d (major): 168.6, 137.1, 134.3, 128.4, 117.9, 108.7, 80.2, 78.8, 68.4, 61.3,
36.8, 27.8, 25.5, 14.2. (minor): 167.3, 136.9, 134.3, 127.8, 119.7, 79.2, 68.4, 60.9,
37.1, 27.3, 25.0, 14.2. Calculated for C19H25NO6Na [M+Na]+: 293.1365, found
293.1361.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.09.111.
References and notes
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a stirred solution of compound 10 (300 mg,
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generation catalyst (4 mol %, 30.5 mg). The mixture was refluxed for 5 h and
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1296, 1238, 1095, 1058 cmꢀ1 1H NMR (500 MHz, CDCl3) d 6.93 (m, 1H, minor),
;
6.79 (m, 1H, major), 4.72–4.76 (m, 1H, both isomers), 4.41 (dd, J = 2.8 Hz,
J = 5.7 Hz, 1H, major), 4.24–4.20 (m, 2H, both isomers), 4.08 (dd, J = 6.2 Hz,
J = 7.1 Hz 1H, minor), 3.98–3.93 (m, 1H, major), 3.89–3.88 (m, 1H, minor), 2.81
(dd, J = 4.5 Hz, J = 17.1 Hz 1H, minor), 2.70 (dd, J = 5.1 Hz, J = 16.6 Hz 1H,
major), 2.53–2.48 (m, 1H, minor), 4.19–4.25 (m, 2H, major), 4.05 (dd, J = 4.6 Hz,
J = 6.8 Hz, 1H minor), 4.05 (dd, J = 6.3 Hz, J = 8.6 Hz, 1H major), 3.79–3.75 (m,
1H, both isomers), 2.92 (d, J = 4.0 Hz, 1H), 2.84 (dd, J = 2.3 Hz, J = 14.3 Hz, 1H),
2.53–2.48 (m, 1H, major), 2.17–2.20 (m, 1H, minor), 1.46 (s, 3H minor), 1.42 (s,
3H, major), 1.41 (s, 3H, major), 1.40 (3H, minor), 1.32–1.30 (m, 3H, both
isomers); 13C NMR (125 MHz, CDCl3) d (major): 166.3, 134.5, 129.5, 110.0,
75.4, 72.9, 66.9, 61.1, 27.8, 27.4, 26.0, 14.2. (minor): 166.1, 133.5, 131.2, 109.8,
78.2, 72.3, 69.1, 61.1, 29.5, 28.1, 25.8, 14.2. Calculated for C19H25NO6Na
[M+Na]+: 265.1052, found 265.1056.
´
10. (a) Armesto, N.; Ferrero, M.; Fernandez, S.; Gotor, V. Tetrahedron Lett. 2000, 41,
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Procedure for the deprotection of acetonide 14.
Compound 14 (250 mg, 0.63 mmol) was dissolved in 1.5 mL of 60% acetic acid
and refluxed for 10 h at 60 °C. The reaction mixture was concentrated under
reduced pressure, diluted with water, and extracted with ethyl acetate
(4 ꢁ 25 mL). The organic layer was dried over Na2SO4 and the filtrate was
concentrated under vacuum to obtain the corresponding diol, which was
subjected to acetylation with excess of triethylamine, Ac2O (1:1, 1 mL) and a
catalytic amount of DMAP at room temperature for 6 h. Removal of solvent
under reduced pressure gave
a residue which was purified by column
16. Mirza, S.; Vasella, A. Helv. Chim. Acta 1984, 67, 1562.
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5075.
chromatography (hexane/EtOAc 9:1) to obtain the mixture of diastereomers
as light yellow oil. (15/16; 68:32 ratio) (253 mg, 91%).
(1S,2R,6S)-4-(Ethoxycarbonyl)-6-(4-nitrobenzoyloxy)-cyclohex-3-ene-1,2-diyl
diacetate (15): Yellow oil, a2D4 ¼ ꢀ100:0 (c 1.10, CH2Cl2). Rf = 0.37 (9:1
hexanes:EtOAc); IR (thin film) 3112, 3055, 2924, 2853, 1749, 1729, 1659,
18. Hanessian, S.; Beaulieu, P.; Dube, D. Tetrahedron Lett. 1986, 27, 5071.
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23. For similar observations see: (a) Liu, S.-L.; Shi, X.-X.; Xu, Y.-L.; Xu, W.; Dong, J.
Tetrahedron: Asymmetry 2009, 20, 78; (b) Bell, R. A.; Osakwe, E. N. C. Chem.
Commun. 1968, 1093.
1234, 1146, 1079 cmꢀ1 1H NMR (500 MHz, CDCl3) d 8.29 (d, J = 8.4 Hz, 2H, Ph),
;
8.16 (d, J = 8.4 Hz, 2H, Ph), 6.83–6.82 (m, 1H, H2), 5.80 (t, J = 4.2 Hz, 1H, H3),
5.57–5.53 (m, 1H, H5), 5.43 (dd, J = 3.8 Hz, J = 8.0 Hz 1H, H4), 4.22 (q, J = 7.2 Hz,
2H, H2’), 3.13 (dd, J = 5.7 Hz, J = 8.3 Hz, 1H, H6), 2.54 (dd, J = 6.4 Hz, J = 8.7 Hz,
1H, H6), 2.10 (s, 3H, OAc), 2.01 (s, 3H, OAc), 1.30 (t, J = 7.2 Hz, 3H, H3’); 13C
NMR (125 MHz, CDCl3) d 169.9, 165.2, 163.6, 150.7, 134.7, 132.0, 131.7, 120.8,
123.6, 68.5, 68.1, 65.8, 61.4, 29.0, 20.7, 20.6, 14.1. Calculated for C19H25NO6Na
[M+Na]+: 458.1063, found 458.1061.
(1S,2R,6R)-4-(Ethoxycarbonyl)-6-(4-nitrobenzoyloxy)- cyclohex-3-ene-1,2-diyl
diacetate (16): Yellow oil, a2D4 ¼ ꢀ26:6 (c 0.45, CH2Cl2). Rf = 0.36 (9:1
hexanes:EtOAc); IR (thin film) 3112, 2924, 2853, 1749, 1727, 1657, 1233,
1120, 1044 cmꢀ1 1H NMR (500 MHz, CDCl3) d 8.30–8.27 (m, 2H, Ph), 8.17–
;
8.14 (m, 2H, Ph), 6.70 (br s, 1H, H2), 5.77 (br s, 1H, H3), 5.66 (br s, 1H, H4),
5.44–5.41 (m, 1H, H5), 4.25 (q, J = 7.2 Hz, 2H, H2’), 2.96(dd, J = 5.8 Hz,
J = 17.8 Hz, 1H, H6), 2.75–2.73 (m, 1H, H6), 2.12(s, 3H, OAc), 2.04 (s, 3H,
OAc), 1.33 (t, J = 7.2 Hz, 3H, H3’); 13C NMR (125 MHz, CDCl3) d 170.2, 169.7,
165.1, 163.6, 150.7, 134.8, 133.5, 130.8, 130.5, 123.5, 69.2, 67.5, 67.2, 61.3,
26.8, 20.7, 20.6, 14.1. Calculated for C19H25NO6Na [M+Na]+: 458.1063, found
458.1068.
24. Adrio, J.; Carretero, J. C.; Ruano, J. L. G.; Cabrejas, L. M. J. Tetrahedron: Asymmetry
1997, 8, 1623.
25. Experimental data of selected compounds.Ethyl 4-((4S,5R)-2,2-dimethyl-5-
vinyl-1,3-dioxolan-4-yl)-4-hydroxy-2-ethylenebutanoate (10): To a cold (10 °C)
and well stirred mixture of 8a (500 g, 3.20 mmol), Zn dust (403 mg, 6.39 mmol)
and bromoester 9 (611 mg, 3.19 mmol) in 10 mL of THF was added a saturated
solution of NH4Cl (1 mL). The mixture was stirred for 4 h at ambient
temperature until the aldehyde was totally consumed (monitored by TLC).
26. Spectral data for these compounds were similar to the ones reported for them
in the literature. See Ref. [24] and Supplementary data for details.