Syntheses of (6S)-6-fluoro- and (6R)-6-hydroxyshikimic acids

Article abstract of DOI:10.1016/S0040-4039(01)01976-1

(6S)-6-Fluoroshikimic acid 2 and (6R)-6-hydroxyshikimic acid 3 have been synthesised via an OsO₄-catalysed dihydroxylation of diene 6, which was derived from (-)-shikimic acid 1.

Full text of DOI:10.1016/S0040-4039(01)01976-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 9069–9071
Syntheses of (6S)-6-fluoro- and (6R)-6-hydroxyshikimic acids
Chuanjun Song,a,b Shende Jianga and Gurdial Singha,*
aDepartment of Chemistry, University of Sunderland, Sunderland SR1 3SD, UK
bDepartment of Applied Chemistry, Tianjin University, Tianjin 300072, PR China
Received 9 July 2001; revised 8 October 2001; accepted 19 October 2001
Abstract—(6S)-6-Fluoroshikimic acid 2 and (6R)-6-hydroxyshikimic acid 3 have been synthesised via an OsO4-catalysed
dihydroxylation of diene 6, which was derived from (−)-shikimic acid 1. © 2001 Elsevier Science Ltd. All rights reserved.
The shikimate pathway is the biosynthetic sequence
that exists in plants, fungi and microorganisms to syn-
Esterification of (−)-shikimic acid9 with methanol using
a catalytic amount of camphorsulphonic acid produced
the crystalline methyl ester, which was protected with
2,2-dimethoxypropane, also in the presence of cam-
phorsulphonic acid, to give the acetonide 410 in 91%
overall yield (Scheme 1). Activation of the hydroxyl
group in acetonide 4 with trifluoromethanesulphonic
anhydride yielded the triflate 5 (98%). Treatment of
triflate 5 with cesium acetate in DMF at room temper-
ature produced the diene 6 in 81% yield.11 After some
experimentation, we found that the elimination of the
triflate group was normally complete within 2 h, pro-
longed reaction time and heating up the reaction mix-
ture invariably led to the diene 6 eliminating further to
give methyl 3-hydroxybenzoate as the sole product.
When a mesylate group was installed rather than the
triflate group, the elimination reaction with cesium
acetate in DMF either did not occur at room tempera-
ture or, when being heated, instead affording methyl
3-hydroxybenzoate. Catalytic dihydroxylation of the
diene 6 with N-methylmorpholine N-oxide and osmium
tetroxide gave the diols 7,12 mp 97−99°C, [h]D −31.3 (c
0.80 in CHCl3), and 8, mp 91−92°C, [h]D +82.7 (c 1.05
in CHCl3), ratio 1:1, in 73% combined yield.
thesise the aromatic amino acids (
tyrosine and
L-phenylalanine, L-
L
-tryptophan) from carbohydrates.1 It has
recently been discovered that the shikimate pathway is
also present in apicomplexan parasites.2 Since the shiki-
mate pathway is absent from mammals,3 enzymes along
this pathway are therefore attractive targets for the
development of antimicrobial agents against bacterial,
fungal and parasitical pathogens. There have been
increasing efforts to design and synthesise analogues of
the shikimate pathway intermediates as potential
enzyme inhibitors.4 Shikimic acid 1 is a key intermedi-
ate in the shikimate pathway, and the synthesis of its
analogues has been a particularly active area of
research.5 Among various analogues of shikimic acid,
(6S)-6-fluoroshikimic acid 2 has been reported to have
antibacterial properties and also to be useful as a
mechanistic probe for studying the enzymology of the
shikimate pathway.6 Both (6S)-6-fluoroshikimic acid 2
and (6R)-6-hydroxyshikimic acid 3 have been previ-
ously synthesised in a lengthy synthesis from quinic
acid5a,b as well as arene cis-dihydrodiols,5c,7 with the
derivatives of (6R)-6-hydroxyshikimic acid 3 being pre-
cursors for the synthesis of (6S)-6-fluoroshikimic acid
2. An enzymatic synthesis of 2 from 3-fluorophospho-
enolpyruvate on a small scale has also been reported.8
However, with the intense interest shown in the shiki-
mate pathway, there still exists an urgent need for the
efficient synthesis of (6S)-6-fluoroshikimic acid 2 to
cater for the mechanistic studies of the shikimate path-
way, and in this communication we report our facile
syntheses of (6S)-6-fluoroshikimic acid 2 and (6R)-6-
hydroxyshikimic acid 3 using shikimic acid as the start-
ing material.
CO2H
CO2H
CO2H
OH
F
HO
OH
HO
OH
HO
OH
OH
OH
OH
(−)-Shikimic acid 1
2
3
Diol
7
was selectively protected with tert-
butyldimethylsilyl triflate to give the monosilyl ether 9
(72%) as colourless crystals, mp 66−67.5°C, [h]D −79.3
(c 0.92 in CHCl3). Treatment of silyl ether 9 with an
excess of N,N-diethylaminosulphur trifluoride (DAST)
* Corresponding author. Tel.: +44 (0) 191 5153094; fax: +44 (0) 191
5153148; e-mail: gurdial.singh@sunderland.ac.uk
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01976-1

9070
C. Song et al. / Tetrahedron Letters 42 (2001) 9069–9071
CO2Me
CO2Me
OH
CO2Me
CO2Me
HO CO2Me
CO2H
HO
iii
v
iv
OSO2CF3
i, ii
+
OH
OH
O
O
O
O
O
HO
OH
O
O
O
O
O
OH
(−)-Shikimic acid 1
4
5
6
7
8
Scheme 1. Reagents and conditions: (i) CSA, MeOH, reflux, 10 h, 96%; (ii) CMe2(OMe)2, CSA, rt, 2 h, 95%; (iii) Tf2O, DMAP,
pyridine, CH2Cl2, −20°C, 40 min, 98%; (iv) CsOAc, DMF, rt, 2 h, 81%; (v) OsO4, NMO, t-BuOH–H2O (10:1), 20°C, 8 h, 38%
for 7, 35% for 8.
CO2Me
OH
CO2Me
OH
CO2Me
F
CO2H
F
i
ii
iii, iv
OH
OTBDMS
OTBDMS
O
O
O
HO
OH
O
O
O
OH
7
9
10
2
Scheme 2. Reagents and conditions: (i) TBDMSOTf (1.05 equiv.), Et3N, CH2Cl2, −20°C, 30 min, 72%; (ii) DAST, CH2Cl2, rt, 4
h, 92%; (iii) LiOH, dioxane–H2O (1:1), rt, 1 h; (iv) TFA–H2O (9:1), rt, 2 h, 81% for two steps.
CO2Me
OH
CO2Me
O
CO2H
CO2H
OH
O
i
ii
iii
O
O
OH
O
O
O
HO
OH
O
O
O
OH
3
7
11
12
Scheme 3. Reagents and conditions: (i) CMe2(OMe)2, CSA, rt, 3 h, 98%; (ii) LiOH, THF–H2O (1:4), rt, 1 h, 98%; (iii) aq. HCl,
MeOH, 30 h, 91%.
at room temperature afforded the fluorinated com-
pound 10 in 92% yield, [h]D +41.1 (c 1.22 in CHCl3)
(Scheme 2). Hydrolysis of the methyl ester group in 10
with lithium hydroxide gave the free acid, which was
further deprotected using aqueous trifluoroacetic acid
to remove both the silyl and isopropylidene groups to
furnish the desired (6S)-6-fluoroshikimic acid 25a,b,8 in
an overall yield of 65%.
Acknowledgements
We thank Dr. Fred Huntley, Professor Bruce Ganem
(Baker Laboratory, Cornell University) for information
with regard to the preparation of diene 6, and the
EPSRC for access to the mass spectrometry service at
the University of Wales, Swansea (Director, Professor
D. E. Games).
Diol 7 could be directly deprotected to give the (6R)-6-
hydroxyshikimic acid 3. Here, for the convenience of
isolating the free acid intermediate, diol 7 was first
converted to the diacetonide 11 (98%), [h]D +41.9 (c
0.86 in CHCl3), which was then hydrolysed with lithium
hydroxide and further deprotected with aqueous hydro-
chloric acid to afford the free acid 3 in 89% overall
yield, [h]D −172.6 (c 0.95 in MeOH) {lit.7b [h]D −169 (c
0.23 in MeOH)} (Scheme 3).
References
1. (a) Bentley, R. Crit. Rev. Biochem. Mol. Biol. 1990, 25,
307–384; (b) Haslam, E. Shikimic Acid, Metabolism and
Metabolites; John Wiley & Sons: Chichester, 1993; (c)
Abell, C. In Enzymology and molecular biology of the
shikimate pathway; Barton, D. H. R.; Nakanishi, K.;
Meth-Cohn, O.; Sankawa, U., Eds. Comprehensive Nat-
ural Products Chemistry; Elsevier: Amsterdam, 1999;
Vol. 1, pp. 573–607.
In conclusion, we have demonstrated a short and
efficient synthesis of (6S)-6-fluoroshikimic acid 2 and
(6R)-6-hydroxyshikimic acid 3. These compounds are
useful tools for biologists to study the enzymes in the
shikimate pathway.
2. (a) Roberts, F.; Roberts, C. W.; Johnson, J. J.; Kyle, D.
E.; Krell, T.; Coggins, J. R.; Coombs, G. H.; Milhous,
W. K.; Tzipori, S.; Ferguson, D. J. P.; Chakrabarti, D.;

C. Song et al. / Tetrahedron Letters 42 (2001) 9069–9071
9071
McLeod, R. Nature 1998, 393, 801–805; (b) Keeling, P.
J.; Palmer, J. D.; Donald, R. G. K.; Roos, D. S.; Waller,
R. F.; McFadden, G. I.; Roberts, C. W.; Finnerty, J.;
Johnson, J. J.; Roberts, F.; Kyle, D. E.; Krell, T.; Cog-
gins, J. R.; Coombs, G. H.; Milhous, W. K.; Tzipori, S.;
Ferguson, D. J. P.; Chakrabarti, D.; McLeod, R. Nature
1999, 397, 219–220.
9. In our laboratory, we have developed an efficient method
for isolating pure shikimic acid from Chinese star anise
(Illicium verum Hook) on a large scale. Shikimic acid has
recently been produced from glucose by fermentation
using recombinant E. coli, see: Draths, K. M.; Knop, D.
R.; Frost, J. W. J. Am. Chem. Soc. 1999, 121, 1603–1604.
10. Chahoua, L.; Baltas, M.; Gorrichon, L.; Tisne`s, P.;
Zedde, C. J. Org. Chem. 1992, 57, 5701–5798.
3. Kishore, G. M.; Shah, D. M. Annu. Rev. Biochem. 1988,
57, 627–663.
11. Huntley, C. F. M.; Wood, H. B.; Ganem, B. Tetrahedron
4. For reviews, see: (a) Campbell, M. M.; Sainsbury, M.;
Searle, P. A. Synthesis 1993, 179–193; (b) Jiang, S.; Singh,
G. Tetrahedron 1998, 54, 4697–4753.
Lett. 2000, 41, 2031–2034.
12. All new compounds reported were characterised (IR, H
1
and 13C NMR, HRMS and/or elemental analyses).
Selected data: Compound 7: wmax (KBr)/cm−1 3436 (OH),
2987, 2940, 2917, 1716 (CꢀO), 1656 (CꢀC), 1434, 1380,
1268, 1205, 1162, 1041; lH (270 MHz, CDCl3) 1.40 (3H,
s, Me), 1.43 (3H, s, Me), 3.55–3.62 (1H, br s, OH), 3.81
(3H, s, CO2Me), 3.93–3.98 (1H, m, CHOH), 4.10–4.14
(1H, br s, OH), 4.45 (1H, t, J 6.6 Hz, CHOR), 4.68 (1H,
br s, CHOH), 4.83 (1H, dd, J 5.9 and 3.3 Hz, CHOR),
6.95 (1H, d, J 3.3 Hz, CHꢀC); lC (67.8 MHz, CDCl3)
25.42 (Me), 27.59 (Me), 52.25 (CO2Me), 65.22, 70.69,
71.91, 75.17 (CHOR), 109.85 (CMe2), 131.30 (CHꢀC),
136.85 (CHꢀC), 166.54 (CꢀO). [m/z HRMS (CI, NH3).
5. (a) Sutherland, J. K.; Watkins, W. J.; Bailey, J. P.;
Chapman, A. K.; Davies, G. M. J. Chem. Soc., Chem.
Commun. 1989, 1386–1387; (b) Sutherland, J. K.; White-
head, R. C.; Davies, G. M. J. Chem. Soc., Chem. Com-
mun. 1993, 464–465; (c) Blacker, A. J.; Booth, R. J.;
Davies, G. M.; Sutherland, J. K. J. Chem. Soc., Perkin
Trans. 1 1995, 2861–2870; (d) Adams, H.; Bailey, N. A.;
Brettle, R.; Cross, R.; Frederickson, M.; Haslam, E.;
MacBeath, F. S.; Davies, G. M. Tetrahedron 1996, 52,
8565–8580; (e) Brettle, R.; Cross, R.; Frederickson, M.;
Haslam, E.; MacBeath, F. S.; Davies, G. M. Tetrahedron
1996, 52, 10547–10556; (f) Jiang, S.; Singh, G.; Boam, D.
J.; Coggins, J. R. Tetrahedron: Asymmetry 1999, 10,
4087–4090 and references cited therein.
6. (a) Davies, G. M.; Barrett-Bee, K. J.; Jude, D. A.; Lehan,
M.; Nichols, W. W.; Pinder, P. E.; Thain, J. L.; Watkins,
W. J.; Wilson, R. G. Antimicrob. Agents Chemother.
1994, 38, 403–406; (b) Ewart, C. D. C.; Jude, D. A.;
Thain, J. L.; Nichols, W. W. Antimicrob. Agents
Chemother. 1995, 39, 87–93; (c) Jude, D. A.; Ewart, C. D.
C.; Thain, J. L.; Davies, G. M.; Nichols, W. W. Biochim.
Biophys. Acta 1996, 1279, 125–129.
+
Found: MNH4 262.1288, C11H20NO6 requires 262.1291]
(found: C, 54.07; H, 6.67. C11H16O6 requires C, 54.09; H,
6.60%). Compound 10: wmax (neat film)/cm−1 2954, 2931,
2857, 1731 (CꢀO), 1664 (CꢀC), 1463, 1371, 1249, 1108,
1072, 840; lH (270 MHz, CDCl3) 0.13 (6H, s, SiMe2),
0.86 (9H, s, CMe3), 1.40 (6H, s, CMe2), 3.84 (3H, s,
CO2Me), 4.24 (1H, t, J 4.6 Hz, CHOR), 4.37–4.45 (1H,
m, CHOR), 4.68–4.74 (1H, m, CHOR), 5.15 (1H, d, JFH
46.2 Hz, CHF), 6.95–7.02 (1H, m, CꢀCHR); lC (67.8
MHz, CDCl3) −5.08 (SiMe2), 17.90 (SiCMe3), 25.54
(CMe3), 26.35 (Me), 27.86 (Me), 52.27 (CO2Me), 68.89
(d, JFC 25.96 Hz, CHOR), 71.15 (d, JFC 2.08 Hz, CHOR),
74.62 (d, JFC 2.08 Hz, CHOR), 84.42 (d, JFC 174.46 Hz,
CHF), 111.08 (CMe2), 127.06 (d, JFC 17.65 Hz, CHꢀC),
7. (a) Carless, H. A.; Dove, Y. Tetrahedron: Asymmetry
1996, 7, 649–652; (b) Tran, C. H.; Crout, D. H. G.;
Errington, W.; Whited, G. M. Tetrahedron: Asymmetry
1996, 7, 691–698.
139.50 (d, JFC 6.23 Hz, CHꢀC), 165.59 (CꢀO) [m/z
HRMS (CI, NH3). Found: MNH4
C17H33FNO5Si requires 378.2112].
+
8. Duggan, P. J.; Parker, E.; Coggins, J.; Abell, C. Bioorg.
378.2109,
Med. Chem. Lett. 1995, 5, 2347–2352.