Approaches to the synthesis of 3-fluoroshikimic acids

Article abstract of DOI:10.1016/j.tetlet.2004.06.092

a- a- a- Exploitation of the dual dehydrating and fluorodeoxygenating properties of the dialkylaminosulfurtrifluorides has allowed access to the C3-fluorinated analogues of (a')-shikimic acid.

Full text of DOI:10.1016/j.tetlet.2004.06.092

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Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 6249–6253
Approaches to the synthesis of 3-fluoroshikimic acids
Lovely Begum,a Michael G. B. Drew,a Jane L. Humphreys,b David J. Lowes,b
Pamela R. Russi,b Helen L. Whitbyb and Roger C. Whiteheadb,
*
aDepartment of Chemistry, The University of Reading, Whiteknights, Reading RG6 6AD, UK
bDepartment of Chemistry, The University of Manchester, Oxford Road, Manchester M13 9PL, UK
Received 28 May 2004; revised 16 June 2004; accepted 22 June 2004
Abstract—Exploitation of the dual dehydrating and fluorodeoxygenating properties of the dialkylaminosulfurtrifluorides has
allowed access to the C3-fluorinated analogues of (ꢀ)-shikimic acid.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
Over recent years, there has been much interest in the
efficient preparation of analogues of (ꢀ)-shikimic acid
(1), which have been targeted as likely inhibitors of en-
zymes on the shikimic acid pathway and which are of
Figure 1.
relevance as potential antifungal, antibacterial and anti-
parasitic agents. A principal goal of our present research
is the synthesis of analogues of (ꢀ)-shikimic acid (1),
which either inhibit shikimate kinase, or alternatively
undergo intracellular phosphorylation by the kinase
and thereby act as prodrugs for inhibitors of enzymes
further downstream on the pathway (e.g., EPSP syn-
thase or chorismate synthase (Scheme 1)).1a,b
isomer 5, a compound, which was previously reported
by Haslam and collaborators as a very minor product
isolated during the synthesis of the diastereoisomeric
compound 6.2a,b Compound 5 was of interest to us with
regard to its potential antimicrobial properties, and also
as a likely competitive inhibitor of shikimate kinase,
which might assist in the crystallographic location of
the shikimate binding site. We report herein, novel syn-
thetic approaches to compounds 5 and 6 and a modifica-
tion of the literature synthesis of the difluorinated
analogue 7.3
As part of a research program concerned with the syn-
thesis and biological evaluation of fluorinated analogues
of polyoxygenated enzyme substrates, we became inter-
ested in the 3-deoxy-3-fluorinated analogues (5, 6 and 7)
of (ꢀ)-shikimic acid (Fig. 1). Our principal goal was the
development of a short synthesis of the (3R)-3-fluoro-
Scheme 1.
*
Corresponding author. Tel.: +44-161-275-7856; fax: +44-161-275-4939; e-mail: roger.whitehead@man.ac.uk
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.06.092

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L. Begum et al. / Tetrahedron Letters 45 (2004) 6249–6253
2. Results and discussion
reported herein has been carried out on both series of
compounds, the superior yield of preparation of the
butane diacetal (BDA) protected compound 12b makes
this our protecting group of choice. Oxidation of the
free secondary hydroxyl in 12b was accomplished
cleanly using the Ley–Griffith reagent (tetrapropylam-
monium perruthenate):7 use of this reagent avoided
any erosion in yield due to competitive elimination proc-
esses, which have been reported to occur during oxida-
tion of 12b under Swern conditions.3,8 Directed
reduction of the ketone 13b was then accomplished in
good yield using sodium triacetoxyborohydride to give
the protected 3-epi-quinate 14b.9a,b With 14b in hand,
we were in position to investigate the tandem dehydra-
tion–fluorodeoxygenation sequence. Thus, addition of
a dichloromethane solution of 14b to an ice-cooled solu-
tion of diethylaminosulfurtrifluoride (DAST, 2.2equiv)
in dichloromethane resulted in the formation of a prin-
ciple fluorine-containing compound, which was isolated,
after chromatography, in 27% yield (Scheme 4). NMR
analysis of this material indicated it to be the desired
(3R)-3-fluoro isomer 15b.10,11
Over recent years we, and others, have carried out exten-
sive investigations into the application of aminosulfur-
trifluorides as versatile reagents for the fluorode-
oxygenation of organic substrates. Of particular rele-
vance to our current research are the literature reports,
which describe regioselective reactions with substrates
possessing several unprotected hydroxyl groups.4a,b
A
less extensively exploited property of aminosulfurtrifluo-
rides is their ability to mediate mild and efficient dehy-
dration reactions on tertiary substrates.5 A pertinent
example from this laboratory is the dehydration of com-
pound 8, which occurred at ambient temperature and
with a pleasing level of regiocontrol (Scheme 2).
In designing a synthesis of compound 5, it was our
intention to marry the fluorodeoxygenating and dehy-
drating properties of the aminosulfurtrifluorides. With
this aim in mind, we envisaged the diacetal protected
3-epi-quinates 14a,b to be key intermediates (Scheme
3). We reasoned that these compounds may undergo
double activation in the presence of an excess of amino-
sulfurtrifluoride, followed by tandem regioselective
dehydration and fluorodeoxygenation at C3 to give the
desired (3R)-3-fluoro-shikimates.
The tertiary fluoride 16b, in which the stereochemistry at
both C1 and C3 had been inverted, was also isolated
from this reaction in 20% yield.12 An inseparable mix-
ture (ꢁ1:1) of (3S)-3-fluoro compound 17b and the allyl-
ic fluoride 18b was obtained in 21% combined yield. A
similar product distribution was obtained when the reac-
tion was carried out with [bis-(2-methoxyethyl)]-amino-
The diacetal protected methyl quinates 12a,b were pre-
pared from (ꢀ)-quinic acid (11) using standard proce-
dures (Scheme 3).6 Although much of the chemistry
Scheme 2.
Scheme 3. Reagents and conditions: (i) CH3OH, Amberliteꢁ IR 120(H), D, 8h; (ii) 1,1,2,2-tetramethoxycyclohexane, (CH3O)3CH, camphorsulfonic
acid, CH3OH, D, 12h, 73% yield of 12a over two steps; (iii) butan-2,3-dione, (CH3O)3CH, camphorsulfonic acid, CH3OH, D, 12h, 98% yield of 12b
˚
over one step; (iv) tetrapropylammoniumperruthenate, N-methylmorpholine-N-oxide, 4A molecular sieves, CH2Cl2, rt, 5h, 88% yield for 13a, 93%
yield for 13b; (v) NaBH(OAc)3, THF, 0ꢂC to rt, 74% for 14a, 82% for 14b.
Scheme 4.

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L. Begum et al. / Tetrahedron Letters 45 (2004) 6249–6253
6251
give the (3S)-3-fluoro isomer 17b. Mitsunobu inversion
of 2017 followed by methanolysis of the resulting benzo-
ate ester gave (3S)-allylic alcohol 21,8,18,19 which under-
went fluorodeoxygenation to give the (3R)-3-fluoro
isomer 15b as the major product (19% overall yield from
12b). This last reaction was less efficient than the corre-
sponding transformation of 20, with significant quanti-
ties of the (3S)-3-fluoro isomer 17b and tertiary allylic
fluoride 18b also being generated. This finding is pre-
sumed to be a consequence of the pseudo-equatorial ori-
entation of the C3 substituent in 21, which may retard
direct SN2 displacement by fluoride.
Figure 2.
In order to complete the syntheses of all C3-fluorinated
analogues of shikimic acid, we have again exploited the
dual dehydrating and fluorodeoxygenating properties of
the aminosulfurtrifluorides in a modification of the liter-
ature synthesis of the difluorinated analogue 7.3 Thus,
treatment of hydroxyketone 13b with 5equiv of Deoxo-
sulfurtrifluoride (DeoxoFluorꢁ).13 Confirmation of the
stereochemical assignment of the tertiary fluoride 16b
was accomplished by X-ray crystallographic analysis
of the corresponding cyclohexanediacetal (CDA) pro-
tected material 16a (Fig. 2).14,15
Fluorꢁ in dichloromethane for a prolonged reaction
13
Disappointingly, similar reaction of diacetal protected
quinate 12b was less efficient and resulted in generation
of a mixture of compounds from which (3S)-3-fluoro
isomer 17b was isolated in 17% yield (Scheme 5).16
time resulted in dehydration, to give enone 22, and
sequential fluorodeoxygenation to give the gem-difluo-
ride 23. The product from the reaction was invariably
contaminated with trace amounts of an inseparable
impurity believed to be a mixture of the diastereoiso-
meric vinyl fluorides 24, which may arise from allylic
rearrangement during the fluorodeoxygenation step [dF
(376.3MHz; CDCl3) (major impurity) ꢀ109.9 (1F, m)
and ꢀ131.2 (1F, m)]. It is noteworthy that, in our hands,
all attempts to prepare 23, either from ketone 13b or
from enone 22, have resulted in generation of this insep-
arable impurity: the level of contamination varying in an
unpredictable fashion with the nature of the reaction
conditions20 (Scheme 7).
Alternative syntheses of 15b and 17b have also been
developed, which involve additional protection and de-
protection steps and are consequently lengthier than
the routes described above (Scheme 6).
Thus, monosilylation of 12b followed by regioselective
dehydration, according to the procedure recently re-
ported by ourselves,1a,5 furnished protected methyl shik-
imate 19 in excellent yield. Deblocking of the C3 oxygen
substituent proceeded cleanly to give the allylic alcohol
20, which underwent smooth fluorodeoxygenation to
Two-step deprotection of the three fluorinated com-
pounds 15b, 17b and 23 furnished the target compounds
5, 6 and 7, which were each purified by reverse phase
HPLC.21 In the case of deprotection of 23, the unwanted
contaminant derived from 24 was removed by chroma-
tography after the initial saponification step (Scheme 8).
In summary, we have successfully prepared all three C3-
fluorinated analogues of (ꢀ)-shikimic acid (5, 6 and 7)
from commercially available (ꢀ)-quinic acid (11). The
Scheme 5.
Scheme 6. Reagents and conditions: (i) tert-butyldimethylsilyl trifluoromethanesulfonate, Et3N, CH2Cl2, 0ꢂC, 2h, 97%; (ii) Ph2S[OC(CF3)2Ph]2,
CH2Cl2, rt, 24h, 84%; (iii) TBAF, THF, 0ꢂC to rt, 3h, 91%; (iv) Et2NSF3, CH2Cl2, 0ꢂC to rt, 17h, 72% for 17b, 41% for 15b; (v) Ph3P,
diisopropylazodicarboxylate, C6H5CO2H, THF, rt, 4h, 90%; (vi) K2CO3, CH3OH, rt, 3h, 71%.

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L. Begum et al. / Tetrahedron Letters 45 (2004) 6249–6253
Scheme 7.
5. See for examples: Box, J. M.; Harwood, L. M.; Humph-
reys, J. L.; Morris, G. A.; Redon, P. M.; Whitehead, R. C.
Synlett 2002, 358–360.
6. For a review see; Ley, S. V.; Baeschlin, D. K.; Dixon, D.
J.; Foster, A. C.; Owen, D. R.; Ince, S. J.; Priepke, H. W.
M.; Reynolds, D. J. Chem. Rev. 2001, 101, 53–80.
7. Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D.
J. Chem. Soc., Chem. Commun. 1987, 1625–1627.
8. Alves, C.; Barros, M. T.; Maycock, C. D.; Ventura, M. R.
Tetrahedron 1999, 55, 8443–8456.
Scheme 8. Reagents and conditions: (i) LiOH, H2O, CH3OH, rt; (ii)
TFA–H2O (6:1), rt, 78% for 5, 54% for 6, 63% for 7.
9. (a) Saksena, A. K.; Mangiaracina, P. Tetrahedron Lett.
´
1983, 24, 273–276; (b) Armesto, N.; Ferrero, M.; Fernan-
dez, S.; Gotor, V. Tetrahedron Lett. 2000, 41, 8759–8762.
10. Typical experimental procedure for tandem dehydration/
fluorodeoxygenation. A solution of the diol (0.36mmol) in
CH2Cl2 (1mL) was added dropwise, under an atmosphere
of nitrogen, to an ice-cooled solution of dialkylaminosul-
furtrifluoride (0.8mmol) in CH2Cl2 (1mL). Once addition
was complete, the ice bath was removed and the reaction
mixture was stirred at room temperature for 5h. The
reaction mixture was diluted with CH2Cl2 (10mL) and
then quenched by the careful addition of a saturated
aqueous solution of sodium bicarbonate (10mL). The
organic phase was collected and the aqueous phase was
most expedient syntheses of 5, 6 and 7 utilised the dual
dehydrating and fluorodeoxygenating properties of the
aminosulfurtrifluorides and were accomplished in six,
four and five steps, respectively. In the case of (3S)-3-
fluoroshikimic acid (6) a lengthier seven step synthesis
was found to be higher yielding overall but this was
not the case for the isomeric compound 5.
extracted with
a further three portions of CH2Cl2
Acknowledgements
(3·10mL). The combined organic extracts were dried
(MgSO4) and concentrated in vacuo. Purification by flash
column chromatography (SiO2; EtOAc–petroleum ether
(40–60), 1:10) provided the fluorinated products.
We acknowledge, with thanks, the EPSRC for funding
(L.B., J.L.H, D.J.L and H.L.W.) and we wish to
acknowledge the EPSRC National Mass Spectrometry
Service Centre in Swansea for the provision of high res-
olution mass measurements. We thank the EPSRC and
the University of Reading for funds for the Image Plate
system. We are particularly grateful to Rehana Sung for
assistance with HPLC purification of compound 5, 6
and 7 and Dr. Julian Box for his contribution to initial
investigations into the synthesis of compound 6.
11. Spectroscopic data for compound 15b. Mp 107–109ꢂC;
22
½aꢂD +14.4 (c 10.5, CH2Cl2); mmax (film)/cmꢀ1 2992 m,
2952 m, 2916 m and 2834 m (C–H), 1725 s (C@O), 1650 w
(C@C); dH (400MHz; CDCl3) 1.33 and 1.40 (2·3H, 2·s,
2·butyl CH3), 2.35 (1H, dddd, J 18.1, 15.0, 10.2, 2.7 Hz,
C(6)Hb), 2.93 (1H, dtd, J 18.1, 6.2, 0.9 Hz, C(6)Ha), 3.29
and 3.30 (2·3H, 2·s, 2·acetal OCH3), 3.70 (1H, ddd, J
24.5, 11.1, 3.6 Hz, C(4)H), 3.79 (3H, s, CO2 CH3), 4.15
(1H, ꢁtd, J 10.7, 6.2 Hz, C(5)H), 5.10 (1H, ddd, J 50.1,
5.2, 3.6 Hz, C(3)HF), 6.90 (1H, ddd, J 5.2, 2.7, 2.2 Hz,
C(2)H); dC (75.4MHz; CDCl3) 17.98 and 18.08 (2·butyl
CH3), 30.67 (d, J 3.1 Hz, C(6)H2), 48.30 and 48.40
(2·acetal OCH3), 52.63 (CO2 CH3), 62.72 (C(5)H), 69.95
(d, J 17.0 Hz, C(4)H), 84.17 (d, J 175.5, C(3)HF), 99.48
and 100.38 (2·acetal C), 130.96 (d, J 13.5 Hz, C(2)H),
135.20 (d, J 9.8 Hz, C(1)), 166.38 (C@O); dF (376.3MHz;
CDCl3) ꢀ180.2 (ddddd, J 50.1, 24.5, 15.0, 6.2, 2.2 Hz,
C(3)HF); m/z (CI/NH3) 322 (MNHþ4 , 12%), 290 (82), 273
(88), 270 (30), 258 (30), 241 (30), 85 (100); (found
322.1669: C14H25FNO6 (MNHþ4 ) requires 322.1666).
12. A definitive mechanistic explanation for the formation of
16b is not possible, however it is plausible that the reaction
may procceed via an oxetane intermediate, which under-
goes nucleophilic ring opening at C1.
References and notes
1. (a) Begum, L.; Box, J. M.; Drew, M. G. B.; Harwood, L.
M.; Humphreys, J. L.; Lowes, D. J.; Morris, G. A.;
Redon, P. M.; Walker, F. M.; Whitehead, R. C. Tetra-
hedron 2003, 59, 4827–4841; (b) Humphreys, J. L.; Lowes,
D. J.; Wesson, K. A.; Whitehead, R. C. Tetrahedron Lett.
2004, 45, 3429–3432.
2. (a) Brettle, R.; Cross, R.; Frederickson, M.; Haslam, E.;
MacBeath, F. S.; Davies, G. M. Bioorg. Med. Chem. Lett.
1996, 6, 1275–1278; (b) Brettle, R.; Cross, R.; Frederick-
son, M.; Haslam, E.; MacBeath, F. S.; Davies, G. M.
Tetrahedron 1996, 52, 10547–10556.
3. Jiang, S.; Singh, G.; Boam, D. J.; Coggins, J. R.
Tetrahedron: Asymmetry 1999, 10, 4087–4090.
13. Lal, G. S.; Pez, G. P.; Pesaresi, R. J.; Prozonic, F. M.;
Cheng, H. J. Org. Chem. 1999, 64, 7048–7054.
4. See for examples; (a) Card, P. J.; Reddy, G. S. J. Org.
Chem. 1983, 48, 4734–4743; (b) Weigert, F. J.; Shenvi, A.
J. Fluorine Chem. 1994, 66, 19–21.
14. Crystallographic data (excluding structure factors) for
structure 16a have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publica-