Dehydration of quinate derivatives: Synthesis of a difluoromethylene homologue of shikimic acid

Article abstract of DOI:10.1055/s-2002-19772

An optimised procedure for the conversion of a quinate to shikimate structure has been developed using Martin's Sulfurane {Ph₂S[OC(CF₃)₂Ph]₂}. This protocol has been exploited in the synthesis of a novel difluor

Full text of DOI:10.1055/s-2002-19772

3
58
LETTER
Dehydration of Quinate Derivatives: Synthesis of a Difluoromethylene
Homologue of Shikimic Acid
a
a
b
b
b
D
J
ehydrati
u
on of
Q
uinat
l
e
Deriv
i
atives an M. Box, Laurence M. Harwood, Jane L. Humphreys, Gareth A. Morris, Perrine M. Redon,
b
Roger C. Whitehead*
a
Department of Chemistry, The University of Reading, Whiteknights, Reading, Berkshire, RG6 6AD, UK
b
Department of Chemistry, The University of Manchester, Oxford Road, Manchester, M13 9PL, UK
Fax +44(161)2754939; E-mail: roger.whitehead@man.ac.uk
Received 14 November 2001
pared from (–)-quinic acid 5 in 73% and 79% yields re-
Abstract: An optimised procedure for the conversion of a quinate
to shikimate structure has been developed using Martin's Sulfurane
spectively (Scheme 1).9
,10
Selective silylation of the
remaining secondary hydroxyl of both compounds pro-
ceeded smoothly to give tert-butyldimethylsilyl ethers 8
and 9 in 79% and 97% yields respectively.11 Although
many of the reactions described herein have been carried
out on both series of bis-acetal protected compounds, the
higher overall yield of preparation of 9 has made the bu-
tane diacetal our protecting group of preference. The en-
suing discussion therefore focuses on the BDA series of
compounds.
{
Ph S[OC(CF ) Ph] }. This protocol has been exploited in the syn-
2 3 2 2
thesis of a novel difluoromethylene homologue of shikimic acid.
Key words: acetals, antibiotics, fluorine, Reformatsky reaction
Shikimic acid 1 (Figure) is a key intermediate on the bio-
synthetic pathway in bacteria, plants and fungi leading
from D-glucose to the essential aromatic amino acids
(
Phe, Tyr, Trp) as well as a number of other important me-
1
tabolites including folic acid. Over recent years, much
synthetic effort has been expended on the preparation of a
range of fluorinated analogues of shikimic acid which in-
HO COOH
HO COOCH3
HO COOCH3
i), ii)
or
iii)
iv)
2
3,4
5
clude 2-fluoro, 3 - and 3 -fluoro, 3,3-difluoro, 3 ,5 -
TBSO
O
HO
OH
OH
HO
O
OCH3
6
7,8
OCH3
difluoro and 6 - and 6 -fluoro compounds. These
compounds, by virtue of their structural similarity to the
natural product, have been targeted as likely inhibitors of
a number of enzymes on the shikimate pathway and are of
biological interest as potential antifungal, antibacterial
and antiparasitic agents.
O
O
R
R
H3CO
H3CO
R
R
5
(CH2)4
6
7
R =
R = CH3
(CH2)4
8
9
R =
R = CH3
Scheme 1 Reagents; i) CH OH, Amberlite® IR 120(H),
ii)
1,1,2,2-tetramethoxycyclohexane, (CH O) CH, camphorsulfonic
3
3
3
acid, CH OH, , 73% over 2 steps iii) butan-2,3-dione, (CH O) CH,
3
3
3
In this letter, we report the synthesis of the difluorometh-
ylene homologue 2 (Figure) of shikimic acid and the cor-
responding homologue 3 of (–)-quinic acid. These
compounds were selected as possible prodrugs for the in-
tracellular generation of the difluoromethylene homo-
logue 4 of 5-enolpyruvylshikimic acid-3-phosphate.
Compound 4 was targeted as a likely competitive inhibitor
of chorismate synthase, the enzyme which catalyses the
seventh step of the shikimic acid pathway.
camphorsulfonic acid, CH OH, , 79% iv) tert-butyldimethylsilyl
3
trifluoromethanesulfonate, Et N, CH Cl , 0 °C, 79% for 8, 97% for 9.
3
2
2
In anticipation of the key dehydration step necessary for
the preparation of 2, we decided to carry out an examina-
tion of the quinate to shikimate transformation. Previous
literature reports indicated that the dehydration of quinic
acid derivatives proceeded with varying levels of regiose-
lectivity. In general, these reactions were found to proceed
via preferential loss of a C2 hydrogen to give the shiki-
mate isomer as the major product, rather than the 4-epi-
shikimate isomer arising from loss of a C6 hydrogen.12
We therefore investigated the behaviour of 9 under a vari-
ety of dehydration conditions (Scheme 2). The ratio of
isomeric alkenes arising from these reactions was as-
COOH
CF2COOH
HO CF2COOH
CF2COOH
HO
OH HO
OH
HO
OH
P O
O
COOH
OH
OH
OH
OH
1
2
3
4
1
Figure
sessed by examination of the H NMR spectra of the crude
product mixtures and comparison of the integrals for the
vinyl hydrogens of the two isomers 10 and 11 (Table).
BDA) derivatives (6 and 7) of methyl quinate were pre- Martin’s Sulfurane (MS)13,14 proved to be the optimum re-
The cyclohexane diacetal (CDA) and butane diacetal
(
agent for generation of the desired regioisomer and, ac-
cordingly, treatment of 9 with an excess of MS in CH Cl2
2
Synlett 2002, No. 2, 01 02 2002. Article Identifier:
437-2096,E;2002,0,02,0358,0360,ftx,en;G33401ST.pdf.
Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214
at room temperature gave 11 in 83% yield after purifica-
1
©
tion by chromatography and crystallisation.1 The struc-
6,17

LETTER
Dehydration of Quinate Derivatives
359
COOCH3
with diethylaminosulfur trifluoride (DAST) gave 15 con-
taminated with about 10% of the undesired regioisomer.
Pleasingly, treatment of 14 with an excess of Martin's Sul-
furane in CH Cl cleanly gave 15 which was assigned a
‘shikimate’ regiochemistry by comparison of NMR data
with those of compound 11. It proved impossible to sepa-
rate 15 from minor amounts of aromatic contaminants
arising from decomposition of the sulfurane, but 2-step
deprotection of 15 followed by purification by reverse
phase HPLC gave the target compound 2 in pure form
(Scheme 3).21 A similar two-step deprotection sequence
of 14 provided the corresponding difluoromethylene ho-
mologue 3 of (–)-quinic acid.
TBSO
O
HO COOCH3
OCH3
O
H3CO
2
2
1
4
2
3
6
5
- H
2
O
10
TBSO
O
+
OCH3
O
COOCH3
H3CO
COOCH3
9
TBSO
O
OCH3
TFA,
O,
rt
O
H3CO
HO
OH
H
2
OH
1
1
12
Scheme 2
O
HO
CF2CO2Et
CF2CO2Et
Table (DAST = Diethylaminosulfur Trifluoride)
i), ii)
iii)
iv)
9
Dehydration Conditions
Product Ratio
10:11)
TBSO
O
TBSO
O
OCH3
TBSO
O
OCH3
(
OCH3
O
O
O
H3CO
H3CO
13,14
H3CO
Martin's Sulfurane, CH Cl , r.t.
~1:30
1:15
1:8
13
2
2
14
15
vii), viii)
v), vi)
POCl , pyridine,
3
15
Burgess Reagent, CH CN,
HO
CF2CO2H
CF2CO2H
3
DAST, CH Cl , 0 °C to r.t.
1:4
2
2
HO
OH
HO
OH
OH
OH
(
CF SO ) O, pyridine, CH Cl
2
1:1.1
3
2 2
2
3
2
Scheme 3 Reagents: i) NaBH , CH OH, 0 °C to r.t. ii) NaIO , H O,
4
3
4
2
CH OH, r.t., pH 7.3, 86% over two steps iii) CF BrCO Et, Zn, THF,
3
2
2
ture of 11 was initially assigned by analysis of vicinal
,
63% iv) Martin's Sulfurane, CH Cl , r.t. v) LiOH, H O, CH OH,
2 2 2 3
proton-proton coupling constants and was confirmed by 50% over two steps vi) TFA:H O (7:1), 0 °C, 75% vii) LiOH, H O,
2
2
the finding that deprotection with aqueous trifluoroacetic CH
acid (TFA) gave methyl shikimate 12 with spectroscopic
data identical to those reported in the literature.18 Al-
though there is no obvious explanation for the variable re-
gioselectivities of these dehydrations, the greater stability
of the trans-decalin system present in 11 compared with
that in 10 may be an influencing factor if the transition
state for the reaction has significant ‘product character’.
OH viii) TFA:H O (7:1), 0 °C, 68% over two steps.
3
2
In summary, an optimised procedure for the conversion of
quinate to shikimate derivatives has been developed using
Martin’s Sulfurane dehydrating agent. This protocol has
been exploited in the synthesis of a novel difluoromethyl-
ene homologue of shikimic acid.
With conditions now optimised for the regioselective de-
hydration of 9, we embarked on the synthesis of the diflu-
oromethylene homologue of shikimic acid 2. Reduction of
the ester function of 9 using an excess of sodium borohy-
dride in methanol followed by oxidative cleavage of the
Acknowledgement
We acknowledge with thanks the University of Reading for provi-
ding a studentship (J. M. B), the EPSRC for funding (J. L. H) and
AstraZeneca for kindly supplying Martin’s Sulfurane dehydrating
agent. We are also very grateful to Rehana Sung for assistance with
the purification of compounds 2 and 3.
resulting diol with NaIO gave ketone 13 in 86% yield.
4
Subsequent treatment of 13 with the zinc reagent derived
from ethyl bromodifluoroacetate in THF under reflux,19
gave a single adduct 14. Extensive NMR analysis of a
References
sample of 14 in C D , including the use of heteronuclear
6
6
(1) Haslam, E. In Shikimic Acid, Metabolites and Metabolism;
Wiley: New York, 1993.
(2) Rich, R. H.; Bartlett, P. A. J. Org. Chem. 1996, 61, 3916.
1
9
1
20
NOE measurements ( F– H), allowed confirmation of
the structure of 14 as that expected from ‘equatorial’ ap-
proach of the organozinc reagent on ketone 13. Com-
pound 14 therefore possessed the same stereochemistry as
(
3) Brettle, R.; Cross, R.; Frederickson, M.; Haslam, E.;
MacBeath, F. S.; Davies, G. M. Bioorg. Med. Chem. Lett.
1996, 6, 1275.
(
–)-quinic acid and was expected to exhibit similar dehy-
dration behaviour to the protected quinic acid derivative
. Interestingly, treatment of 14 with either POCl in pyri-
(
4) Brettle, R.; Cross, R.; Frederickson, M.; Haslam, E.;
MacBeath, F. S. Tetrahedron 1996, 52, 10547.
(5) Jiang, S.; Singh, G.; Boam, D. J.; Coggins, J. R.
Tetrahedron: Asymmetry 1999, 10, 4087.
9
3
dine or Burgess reagent in CH CN at elevated tempera-
3
ture, induced no detectable reaction whereas, treatment
(6) Weigert, F. J.; Shenvi, A. J. Fluorine Chem. 1994, 66, 19.
Synlett 2002, No. 2, 358–360 ISSN 0936-5214 © Thieme Stuttgart · New York

3
60
J. M. Box et al.
LETTER
(
7) Sutherland, J. K.; Watkins, W. J.; Bailey, J. P.; Chapman, A.
[1 H, dd, J = 10.9, 3.9 Hz, C(4)H], 3.75 (3 H, s, CO CH ),
2
3
K.; Davies, G. M. J. Chem. Soc., Chem. Commun. 1989,
4.11 [1 H, ddd, J = 10.9, 10.4 Hz, 6.0 Hz, C(5)H], 4.31 [1 H,
dd, J = 5.5, 3.9 Hz, C(3)H], 6.77 [1 H, dd, J = 5.5, 2.6 Hz,
C(2)H]; (75.4 MHz; CDCl ) –4.89 and –4.76 [(CH ) Si],
1386.
(
(
8) Bowles, S.; Campbell, M. M.; Sainsbury, M.; Davies, G. M.
Tetrahedron Lett. 1989, 30, 3711.
C
3
3 2
17.60 and 17.76 (2 butyl CH ), 18.27 [(CH ) CSi], 25.68
3
3 3
9) 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.
[(CH ) CSi], 30.34 [C(6)H ], 47.53 and 47.68 (2 acetal
3 3 2
OCH ), 51.87 (CO CH ), 62.29 [C(5)H], 65.89 [C(3)H],
3
2
3
70.75 [C(4)H], 98.64 and 99.41 (2 acetal C), 129.67
(
(
(
10) Montchamp, J. L.; Tian, F.; Hart, M. E.; Frost, J. W. J. Org.
Chem. 1996, 61, 3897.
11) Shinada, T.; Yoshida, Y.; Ohfune, Y. Tetrahedron Lett.
[C(1)], 136.64 [C(2)H], 166.97 (CO CH ); m/z (CI/NH )
2
3
3
+
434 (MNH , 25%), 402(95), 385(80), 285(45), 270(85),
4
85(100); (Found: 434.2584. C H NO Si requires
2
0
40
7
1998, 39, 6027.
434.2574).
12) See: Jiang, S.; Singh, G. Tetrahedron 1998, 54, 4697; and
references cited therein.
13) Arhart, R. J.; Martin, J. C. J. Am. Chem. Soc. 1972, 94, 5003.
14) Martin, J. C.; Arhart, R. J.; Franz, J. A.; Perozzi, E. F.;
Kaplan, L. J. Org. Synth. 1988, 163.
(17) Dehydration of a substrate similar to 9 using POCl has
3
recently been reported: Shih, T.-L.; Wu, S.-H. Tetrahedron
Lett. 2000, 41, 2957.
(18) Chahoua, L.; Baltas, M.; Gorrichon, L.; Tisnès, P.; Zedde, C.
J. Org. Chem. 1992, 57, 5798.
(
(
(
(
15) Burgess, E. M.; Penton, H. R. Jr.; Taylor, E. A. J. Org.
Chem. 1973, 38, 26.
(19) Hallinan, E. A.; Fried, J. Tetrahedron Lett. 1984, 25, 2301.
1
19
(20) Heteronuclear H– F NOE's were measured by cross-peak
integration of pulsed field gradient heteronuclear NOESY
(HOESY) spectra measured using a Varian INOVA 400
spectrometer. No special equipment was used; fluorine
pulses were applied directly to a single-tuned proton coil.
Clear heteronuclear NOE's were observed between fluorine
and protons 2 , 6 , 2 and 6 in descending order of strength..
(21) Data for compound 2: Viscous oil; (300 MHz; D O) 1.96
16) Procedure for the Preparation of Compound 11: A solution
of Martin’s Sulfurane (4.83 g, 7.18 mmol) in CH Cl (25 mL)
2
2
was added dropwise to a solution of silylated quinate 9 (2.08
g, 4.79 mmol) in CH Cl (35 mL) under an atmosphere of N
2
2
2
at r.t. The resulting pale yellow solution was stirred for 24 h
when the residual solvent was removed in vacuo to yield the
crude product as an orange solid. Purification by flash
column chromatography (5% EtOAc in cyclohexane)
H
2
[1 H, dd, J = 17.7, 7.0 Hz, one of C(6)H ], 2.46 [1 H, dd, J =
2
followed by recrystallisation from MeOH–H O furnished
17.7, 5.4 Hz, one of C(6)H ], 3.56 [1 H, dd, J = 8.9, 4.5 Hz,
2
2
the target compound 11 as a colourless solid (1.66 g, 83%);
C(4)H], 3.85 [1 H, ddd, J = 8.9, 7.0, 5.4 Hz, C(5)H], 4.19–
2
2
mp 74–75 °C; [ ]D –16.4 (c 1.0 in CH Cl ); (Found: C,
4.25 [1 H, m, C(3)H], 6.01 [1 H, br, s, C(2)H]. (75.4 MHz;
2
2
C
5
7.7; H, 8.7. C H O Si requires C, 57.7; H 8.7%); IR (film,
D O) 28.99 [C(6)H ], 65.26, 65.97 and 71.16 [C(3)H, C(4)H
2
0
36
7
2
2
–
1
cm ): 1724 (C=O), 1649 (C=C). (400 MHz; CDCl ) 0.10
and C(5)H], 113.90 (t, J = 251 Hz, CF CO H), 127.38 [t, J =
H
3
2 2
and 0.12 [2 3 H, s, (CH ) Si], 0.89 [9 H, s, (CH ) C], 1.28
8 Hz, C(2)H], 131.25 [t, J = 24.1 Hz, C(1)], 167.73 (br,
C=O); (282.4 MHz; D O) –105.26 (1 F, d, J = 245 Hz), –
3
2
3 3
and 1.29 (2 3 H, s, 2 butyl CH ), 2.21 [1 H, ddd, J = 17.6,
3
F
2
1
0.4, 2.6 Hz, C(6)H ], 2.80 [1 H, dd, J = 17.6, 6.0 Hz,
105.59 (1 F, d, J = 245 Hz). m/z (negative ion electrospray)
223 [(M–H) ].
–
C(6)H ], 3.23 and 3.24 (2 3 H, s, 2 acetal OCH ), 3.48
3
Synlett 2002, No. 2, 358–360 ISSN 0936-5214 © Thieme Stuttgart · New York