Novel and efficient syntheses of (-)-methyl 4-epi-shikimate and 4,5-epoxy-quinic and -shikimic acid derivatives as key precursors to prepare new analogues

Article abstract of DOI:10.1021/jo0606249

We have developed simple methods that provide a rapid entry into the synthesis of a series of quinate and shikimate analogues, including (-)-methyl 4-epi-shikimate and the 4,5-epoxy analogues of the parent acids. Epoxy derivatives of quinic and shikimic a

Full text of DOI:10.1021/jo0606249

CHART 1
Novel and Efficient Syntheses of (-)-Methyl
4-epi-Shikimate and 4,5-Epoxy-Quinic and
-Shikimic Acid Derivatives as Key Precursors to
Prepare New Analogues
Laura Sa´nchez-Abella, Susana Ferna´ndez, Nuria Armesto,
Miguel Ferrero, and Vicente Gotor*
Departamento de Qu´ımica Orga´nica e Inorga´nica and Instituto
UniVersitario de Biotecnolog´ıa de Asturias, UniVersidad de
OViedo, 33006-OViedo (Asturias), Spain
CHART 2
VGS@fq.unioVi.es
ReceiVed March 21, 2006
We have developed simple methods that provide a rapid entry
into the synthesis of a series of quinate and shikimate
analogues, including (-)-methyl 4-epi-shikimate and the 4,5-
epoxy analogues of the parent acids. Epoxy derivatives of
quinic and shikimic acids were converted into methyl scyllo-
quinate and (+)-methyl 3-epi-shikimate, respectively, by
processes involving a regio- and stereoselective epoxide ring
opening. The strategies described take place through short,
high-yield reaction sequences.
In addition, quinic and shikimic acid epimers are important
derivatives. Improved syntheses of 3-epi-9 and 5-epi-10 analogues
of both acids have been reported. However, only a limited
number of syntheses of the 4-epi isomer have been reported in
the literature, although the 4-epi-shikimic acid skeleton is a
constituent of several natural products such as dioxolamycin
(7),11 cythiaformines B, C, and D (8, 9, and 10, respectively),12
and pericosine A (11;13 Chart 2). There are two published
asymmetric syntheses of 4-epi-shikimic acid derivatives based
on a Diels-Ader reaction. In 1986, Posner and Wettlaufer
The shikimate pathway is the biosynthetic sequence that links
the metabolism of carbohydrates to the biosynthesis of aromatic
amino acids, folate coenzymes, and various isoprenoid quino-
nes.1 Additionally, all the intermediates can also be considered
branch point compounds that may serve as substrates for other
metabolic pathways. This route is exclusively present in plants,
fungi, and microorganisms.2 The complete absence in mammals
makes shikimate-pathway enzymes potential targets for nontoxic
herbicides, antimicrobial agents, and antifungal agents.3 Another
relevant fact is the evidence of this pathway in apicomplexa
parasites (malaria, pneumonia, tuberculosis), opening a new field
in the design of new antiparasite compounds.4
The syntheses of quinic and shikimic acids (1 and 2,
respectively, Chart 1) as well as their analogues, have been an
active area of research with a view to the study of enzymatic
mechanisms and to the design and synthesis of inhibitors.5 Potent
and selective inhibitors of influenza neuraminidase, such as
oseltamivir (3) and GS-4071 (4),6 the glyoxalase I inhibitor
COCT (5),7 or the potent R-glycosidase inhibitor valiolamine
(6),8 are some key examples of such analogues (Chart 2).
(4) (a) Coombs, G. H.; Muller, S. Int. J. Parasitol. 2002, 32, 497-508.
(b) Roberts, C. W.; Roberts, F.; Lyons, R. E.; Kirisits, M. J.; Mui, E. J.;
Finnerty, J.; Johnson, J. J.; Ferguson, D. J. P.; Coggins, J. R.; Krell, T.;
Coombs, G. H.; Milhous, W. K.; Kyle, D. E.; Tzipori, S.; Barnwell, J.;
Dame, J. B.; Carlton, J.; McLeod. J. Infect. Dis. 2002, 185, S25-S36. (c)
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.; Mcleod, R. Nature 1998, 393, 801-805.
(5) (a) Jiang, S.; Singh, G.; Boam, D. J.; Coggins, J. R. Tetrahedron:
Asymmetry 1999, 10, 4087-4090. (b) Brettle, R.; Cross, R.; Frederickson,
M.; Haslam, E.; MacBeath, F. S.; Davies, G. M. Tetrahedron 1996, 52,
10547-10556. (c) Adams, H.; Bailey, N. A.; Brettle, R.; Cross, R.;
Frederickson, M.; Haslam, E.; MacBeath, F. S.; Davies, G. M. Tetrahedron
1996, 52, 8565-8580.
(6) Abrecht, S.; Harrington, P.; Iding, H.; Karpf, M.; Trussardi, R.; Wirz,
B.; Zutter, U. Chimia 2004, 58, 621-629.
(7) Kamiya, D.; Uchiata, Y.; Ichikawa, E.; Kato, K.; Umezawa, K.
Bioorg. Med. Chem. Lett. 2005, 15, 1111-1114.
(8) (a) Ogawa, S.; Ohoshi, Y.; Asada, M.; Tomoda, A.; Takahashi, A.;
Ooki, Y.; Mori, M.; Itoh, M.; Korenaga, T. Org. Biomol. Chem. 2004, 2,
884-889. (b) Carballido, M.; Castedo, L.; Gonza´lez-Bello, C. Eur. J. Org.
Chem. 2004, 3663-3668.
(1) (a) Abell, C. Enzymology and Molecular Biology of the Shikimate
Pathway. In ComprehensiVe Natural Products Chemistry; Barton, D. H.
R., Nakanishi, K., Meth-Cohn, O., Sankawa, U., Eds.; Elsevier: Amsterdam,
1999; Vol. 1, pp 573-607. (b) Haslam, E. Shikimic Acid Metabolism and
Metabolites; Wiley: New York, 1993. (c) Weiss, U.; Edwards, J. M. The
Biosynthesis of Aromatic Compounds; Wiley-Interscience: New York, 1987;
pp 260-270.
(2) Kishore, G. M.; Shah, D. M. Annu. ReV. Biochem. 1988, 57, 627-
663.
(3) Jiang, S.; Singh, G. Tetrahedron 1998, 54, 4697-4753.
(9) Armesto, N.; Ferrero, M.; Ferna´ndez, S.; Gotor, V. Tetrahedron Lett.
2000, 41, 8759-8762 and references therein.
(10) Ferna´ndez, S.; D´ıaz, M.; Ferrero, M.; Gotor, V. Tetrahedron Lett.
1997, 38, 5225-5228 and references therein.
10.1021/jo0606249 CCC: $33.50 © 2006 American Chemical Society
Published on Web 05/26/2006
5396
J. Org. Chem. 2006, 71, 5396-5399

SCHEME 1a
reported the synthesis of methyl 3,4,5-tri-O-acetyl-4-epi-shiki-
mate through a 15-step procedure,14 and more recently, Stoodley
and co-workers have described the synthesis of 4-epi-shikimic
acid in eight steps and 17% overall yield.15 Additionally, syn-
theses of (-)-4-epi-shikimic acid from natural quinic acid have
also been developed by Rapoport and Snyder16 and Berchtold
and Lesuisse17 in 12 and 17% estimated yields, respectively.
Similarly, two syntheses of 4-epi-quinic acid analogues have
been described. Snyder and Rapoport16 have reported the
synthesis of (-)-methyl 4-epi-quinate via HF epimerization of
1,3,4,5-tetraacetylquinate in 10% yield. In another report, Frank
and Miethchen18 have shown the conversion of (-)-methyl
quinate into its 4-epi derivative 12, which contains a carbamoyl
function in 3-position and trichloroethylidene acetal group in
4,5-position, in addition to a spiro byproduct 13 (10%). This
convenient acetalation reaction is accompanied by inversion of
the configuration at the middle chiral carbon atom of the triol
unit. Despite the short, simple procedure, in our experience,
this reaction sequence leads to a tedious workup and chromato-
graphic steps.
a
Reagents and conditions: (a) Na2SO4, H2SO4, acetone, reflux, 24 h,
85%; (b) NaOMe, MeOH, 0 °C to room temperature, 5 h, 82%; (c) PCC,
CH2Cl2, rt, 8 h, 80%; (d) 1.3 equiv POCl3, Py, 0 °C to room temperature,
8 h, 85%; (e) CF3CO2H-H2O (1:1), 0 °C, 45 min, 90%; (f) NaBH(OAc)3,
CH2Cl2, rt, 2 h, 70%; (g) PCC, Py, CH2Cl2, 4 Å molecular sieves, rt, 24 h,
45%.
In this context, both 4-epi-shikimic and 4-epi-quinic acids
can be regarded as important chirons that should have manifold
uses as starting materials in the chemical synthesis of a wide
range of target molecules. Our interest in the chemistry of quinic
and shikimic acid derivatives prompted us to report here our
own studies on a more efficient synthesis of methyl 4-epi-
shikimate and on approaches to the preparation of methyl 4-epi-
quinate.
SCHEME 2a
Starting with relatively inexpensive, commercially available
quinic acid (1), Scheme 1 illustrates the synthetic pathway
toward the (-)-methyl 4-epi-shikimate (19).
The acid-catalyzed reaction of 1 with acetone, according to
Stoodley and co-workers,19 led to isopropylidene acetal 14 in
high yield. In the presence of sodium methoxide in methanol,
ring-opening of the lactone was performed to give diol 15. The
secondary alcohol in 15 was oxidized into the corresponding
ketone 16, which was followed by dehydration of the tertiary
alcohol with POCl3 in pyridine, giving the enone 17 in high
yield. The formation of 17 from 15 via an oxidation followed
by a â-elimination has been reported by Shing and Tang20 as a
high yielding process; however, in our hands, we were only
able to obtain a yield of 45% for this process. As a result, we
utilized a two-step procedure to obtain 17. Then hydrolysis of
the acetal group in 17 with aqueous trifluoroacetic acid gave
keto diol 18. Selective reduction of the carbonyl group in 18
was accomplished with NaBH(OAc)3, giving exclusively the
allylic alcohol 19 in good yield. It is noteworthy that the
synthesis of (-)-methyl 4-epi-shikimate (19) from (-)-quinic
a Reagents and conditions: (a) p-TsOH, toluene, reflux, 24 h, 100%;
(b) TBDMSCl, DMAP, imidazole, DMF, 0 °C, 2 h and then rt, 3 h, 70%;
(c) Dess-Martin, CH2Cl2, rt, overnight, 100%; (d) TBAF, AcOH, THF, rt,
2 h; (e) reduction: see Table 1.
acid was achieved in six steps with an overall yield of 30%
using cheap and commercially available starting material. As a
result of the latter and of the simplicity of all the reactions
involved in this synthesis, the scale-up of the process has been
carried out easily up to 10 g.
Having established a route for the preparation of (-)-methyl
4-epi-shikimate, we embarked on the synthesis of (-)-methyl
4-epi-quinate (20, Scheme 2).
It was envisaged that (-)-methyl 4-epi-quinate (20) would
be accessible from lactone 21; the retrosynthesis from quinic
acid (1) is outlined in the upper part of Scheme 2. To have
access to keto lactone 21, the first step involves the double
protection of quinic acid (1) in the toluene-p-sulfonic acid
catalyzed reaction, to quantitatively yield lactone 22. The
selective protection of the C-3 hydroxyl group of 22 was
achieved in 70% yield using tert-butyldimethylsilyl chloride
(11) Zhu, B.; Morioka, M.; Nakamura, H.; Naganawa, H.; Muraska, Y.;
Okami, Y.; Umezawa, H. J. Antibiot. 1984, 37, 673-674.
(12) (a) Meier, R.-M.; Ganem, B. Tetrahedron 1994, 50, 2715-2720.
(b) Arnome, A.; Cardillo, R.; Nasini, G.; Vajna de Pava, O. Tetrahedron
1993, 49, 7251-7258.
(13) (a) Usami, Y.; Ueda, Y. Chem. Lett. 2005, 34, 1062-1063. (b)
Numata, A.; Iritani, M.; Yamada, T.; Minoura, K.; Matsumura, E.; Yamori,
T.; Tsuruo, T. Tetrahedron Lett. 1997, 38, 8215-8218.
(14) Posner, G. H.; Wettlaufer, D. G. J. Am. Chem. Soc. 1986, 108,
7373-7377.
(15) Pornpakakul, S.; Pritchard, R. G.; Stoodley, R. J. Tetrahedron Lett.
2000, 41, 2691-2694.
(16) Snyder, C. D.; Rapoport, H. J. Am. Chem. Soc. 1973, 95, 7821-
7828.
(17) Lesuisse, D.; Berchtold, G. A. J. Org. Chem. 1985, 50, 888-890.
(18) Frank, M.; Miethchen, R. Carbohydr. Res. 1998, 313, 49-53.
(19) Elliott, J. D.; Hetmansky, M.; Stoodley, R. J.; Palfreyman, M. N.
J. Chem. Soc., Perkin Trans. 1 1981, 1782-1789.
(20) Shing, T. K. M.; Tang, Y. Tetrahedron 1991, 47, 4571-4578.
J. Org. Chem, Vol. 71, No. 14, 2006 5397

TABLE 1. Reaction Conditions for the Reduction of Ketone 24
SCHEME 4
reduction
agent
entry
equiv
T (°C)
t (h)
ratioa 23:25
1
2
3
4
NaBH(OAc)3
LiAlH(t-BuO)3
L-selectride
K-selectride
1
2
2
1.1
1.1
25
0
-70
-70
24
24
16
16
100:0
100:0
75:25
80:20
a Calculated by H NMR.
SCHEME 3a
CHART 3
The formation of these compounds can be explained by the
mechanism shown in Scheme 4, which involves initial removal
of the TBDMS groups from 27 by means of fluoride ions present
in the reagent CsF, followed by displacement of the mesyl group
with the oxyanion located at the 5-position. The subsequent
opening of the epoxide intermediate 30 with the benzoate anion
afforded 28 as the major compound and 29a, which can undergo
a migration of the benzoate group from O-4 to O-3, giving rise
to 29b.
To confirm the mechanism, the reaction was carried out in
the absence of benzoic acid. As expected, epoxide 30 was
obtained, although under these conditions, 30 was isolated in
low yield.
The proposed epoxy alcohol (+)-30 is not reported in the
literature. However, we have found that its diastereomer 31
(Chart 3) is a useful key intermediate in the synthesis of
neuraminidase enzyme inhibitors.23 On the other hand, the
corresponding shikimate epoxide (-)-3224 is a versatile chiral
building block for the synthesis of chorismate-type analogues.
Other isomers of this derivative, such as (+)-32,24b (-)-33,24b,25
and (+)-33,24b,26 have also proven to be important precursors
of biologically active compounds, because they contain several
stereocenters and a high diversity of functionality. Given the
importance of these derivatives, we have explored the synthesis
of epoxides (+)-30 and (-)-32 through a strategy that allows
easy access to these synthons.
a Reagents and conditions: (a) MeOH, HCl, 60 °C, 6 h, 100%; (b)
TBDMSCl, Et3N, DMF, 0 °C, 2 h and then 0 °C to room temperature, 16
h, 75%; (c) MsCl, Py, rt, 8 h, 85%; (d) PhCO2H, CsF, DMF, 90 °C, 24 h,
55% of 28 and 30% of 29.
(TBDMSCl). Then, the secondary alcohol in 23 was oxidized
by reaction with Dess-Martin reagent in methylene chloride
at room temperature to give ketone 24. The next step was the
deprotection of the silyl group in 24 to get 21. The reaction
was carried out in the presence of TBAF-AcOH-THF, which
gave a mixture of unidentified products. Several other standard
desilylation methods also failed. At this point, we decided to
use the crude mixture from the oxidation step to reduce the
ketone directly. The reaction conditions are given in Table 1.
The synthesis of the key intermediate, 4-epi-diol 25, was first
tried using NaBH(OAc)3 at room temperature. In these condi-
tions, we isolated exclusively diol 23 after 24 h (entry 1, Table
1). A similar result was obtained when the reaction was
performed with LiAlH(t-BuO)3, a milder reducing agent, at 0
°C (entry 2, Table 1). Entries 3 and 4 of Table 1 show the results
when the reduction of the keto compound 24 was carried out
with L- and K-selectride, which provided diastereoisomers 23
and 25 in ratios 75:25 and 80:20, respectively. However, the
moderate ratio toward compound 25 in these processes prompted
us to search for a more efficient route. A Mitsunobu21 reaction
(p-NO2-C6H4CO2H, Ph3P, DEAD, toluene or THF) of the free
secondary alcohol in compound 23 did not give positive results,
and a complex mixture of compounds was obtained.
The analogue (+)-30 was prepared from mesylate 27,
according to Scheme 5. Desilylation of 27 with HCl in MeOH
(21) Mitsunobu, O. Synthesis 1981, 1-28.
An alternative approach is an inversion of the disilyl-protected
derivative of methyl quinate 26 (Scheme 3). When the latter
was treated under Mitsunobu conditions (p-NO2-C6H4CO2H,
Ph3P, DEAD, toluene or THF), the reaction led to the recovery
of the starting material. Thus, the conversion of diol 26 (prepared
from quinic acid in two steps: esterification followed by
hydroxyl protection22) to the inverted hydroxyl derivative at C-4
would be best achieved by activation of the hydroxyl group as
mesylate (compound 27), followed by a reaction with benzoic
acid-cesium fluoride in DMF at 90 °C. Surprisingly, this
approach provides the benzoate derivatives 28 and 29 (the latter
as an inseparable mixture of products) in isolated yields of 55
and 30%, respectively.
(22) Perlman, K. L.; Swenson, R. E.; Paaren, H. E.; Schnoes, H. K.;
DeLuca, H. F. Tetrahedron Lett. 1991, 32, 7663-7666.
(23) Maring, C. J.; Giranda, V. L.; Kempf, D. J.; Stoll, V. S.; Sun, M.;
Zhao, C.; Gu, Y. G.; Hanessian, S.; Stewart, K. D.; Wang, G. T.; Wang, J.;
Madigan, D. L. Patent WO 01/28981, April 26, 2001.
(24) (a) Wood, H. B.; Ganem, B. J. Am. Chem. Soc. 1990, 112, 8907-
8909. (b) Pawlak, J. L.; Berchtold, G. A. J. Org. Chem. 1987, 52, 1765-
1771.
(25) (a) Kim, C. U.; Lew, W.; Williams, M. A.; Liu, H.; Zhang, L.;
Swaminathan, S.; Bischofberger, N.; Chen, M. S.; Mendel, D. B.; Tai, C.
Y.; Laver, W. G.; Stevens, R. C. J. Am. Chem. Soc. 1997, 119, 681-690.
(b) McGowan, D. A.; Berchtold, G. A. J. Org. Chem. 1981, 46, 2381-
2383.
(26) Rigby, J. H.; Maharoof, U. S. M.; Mateo, M. E. J. Am. Chem. Soc.
2000, 122, 6624-6628.
5398 J. Org. Chem., Vol. 71, No. 14, 2006

SCHEME 5a
yield. It is noteworthy that only one synthesis is reported in the
literature for this isomer.28 This takes place with lower yield
(22%) and in nine steps using tedious chromatographic columns
to separate the mixture of isomers obtained in various reactions.
In summary, we have shown that the synthesis of (-)-methyl
4-epi-shikimate from quinic acid has been efficiently achieved
in six steps with a 30% overall yield. The approach detailed
here is a significant improvement over previously reported
protocols, thus providing easy access to this chiron for other
synthetic applications. Additionally, we have prepared the 4,5-
epoxy derivatives of quinic and shikimic acids and have
highlighted the synthetic utility of these metabolites by describ-
ing an efficient synthesis of methyl scyllo-quinate and (+)-
methyl 3-epi-shikimate.
a Reagents and conditions: (a) HCl concd, MeOH, rt, 4 h, 95%; (b)
K2CO3, MeOH, 0 °C, 5 h, 77%; (c) CF3CO2H, H2O, rt, 36 h, 100%.
SCHEME 6a
Experimental Section
(-)-Methyl 4-epi-Shikimate (19). NaBH(OAc)3 (1.14 g, 5.38
mmol) was added to a solution of 18 (500 mg, 2.69 mmol) in 34
mL of anhydrous CH2Cl2. After stirring for 2 h at room temperature,
the reaction was quenched with solid NaHCO3 and filtered, and
the filtrate was then extracted with water. The aqueous layer was
concentrated, and the crude residue was purified by flash chroma-
tography using silica gel 60 Å (32-63 µm) at pH 7 (gradient eluent
15-50% MeOH/EtOAc) to give 19 as a white hygroscopic solid
in 70% yield.
(+)-Methyl (1S,3R,4S,5R)-4,5-Epoxy-1,3-dihydroxycyclohex-
ane-1-carboxylate (30). To a solution of 34 (80 mg, 0.28 mmol)
in anhydrous MeOH (4.6 mL) at 0 °C was added K2CO3 (39 mg,
0.28 mmol). The reaction was stirred for 5 h at 0 °C, and then the
solvent was evaporated. The residue was poured into water and
extracted with CHCl3. Subsequent purification by flash chroma-
tography, using silica gel 60 Å (32-63 µm) at pH 7 and with EtOAc
as eluent, afforded 30 as a white solid in 83% yield.
(-)-Methyl (3R,4S,5R)-4,5-Epoxy-3-hydroxy-1-cyclohexene-
1-carboxylate (32).23a To a stirred solution of 39 (115 mg, 0.46
mmol) in anhydrous toluene (2.3 mL) at 0 °C was added dropwise
DBU (0.103 mL, 0.69 mmol). After stirring the mixture at room
temperature overnight, the solvent was evaporated. The crude
material was purified by flash chromatography, using silica gel 60
Å (32-63 µm) at pH 7 and with Et2O/hexane as eluent, to afford
(-)-32 as a white solid in 80% yield.
a Reagents and conditions: (a) HCl concd, MeOH, 60 °C, 6 h, 100%;
(b) TBDMSCl, Et3N, DMAP, DMF, rt, 1 h, 75%; (c) MsCl, Py, 0 °C to rt,
2 h, 84%; (d) HCl concd, MeOH, rt, 3 h, 96%; (e) DBU, toluene, rt,
overnight, 78%; (f) CF3CO2H-H2O (1:1), rt, 36 h, 100%.
furnished the triol 34. The latter was converted to epoxide (+)-
30 by treatment with potassium carbonate in MeOH at 0 °C for
5 h. Alternatively, (+)-30 can be obtained with NaOMe in
MeOH or DBU in THF. However, these procedures proved to
be inefficient because longer reaction times are required and
lower yields are achieved. Thus, quinic acid was transformed
into epoxide (+)-30 in five steps with an overall yield of 47%.
We next investigated various reaction conditions for nucleo-
philic ring opening of the epoxide. The opening was efficiently
accomplished both regio- and stereoselectively with aqueous
trifluoroacetic acid, with methyl scyllo-quinate (35) being
isolated exclusively in quantitative yield. This attractive route
allows, for the first time, an efficient synthesis of the scyllo-
derivative of quinic acid, which could have manifold uses as a
chiron starting material in the synthesis of a wide range of target
molecules. Previously, this isomer was isolated, along with other
derivatives, by random isomerization of quinic acid.27
The corresponding methyl shikimate epoxide (-)-32 was
prepared from shikimic acid in a similar manner, as outlined in
Scheme 6. Commercial shikimic acid (2) was transformed into
methyl shikimate 36 by refluxing with HCl in MeOH, and the
latter was selectively protected at OH-3 and OH-5 with
TBDMSCl to afford 37 in 75% yield. Treatment of 37 with
mesyl chloride gave the mesylate 38, which was silyl depro-
tected in HCl/MeOH. To prepare epoxide (-)-32 bases such
as NaOMe, DBU, or K2CO3 were employed. Best results were
achieved with DBU in toluene, resulting in the formation of
the epoxide 32 in 47% overall yield and in five steps from
shikimic acid.
Methyl scyllo-Quinate (35). To a stirred solution of 30 (71 mg,
0.38 mmol) in water (2 mL) was added trifluoroacetic acid (0.006
mL, 0.075 mmol). The reaction was stirred at room temperature
for 36 h. Two additional portions of trifluroacetic acid (0.006 mL)
were added after 12 and 24 h. The mixture was extracted with CH2-
Cl2, and the aqueous fraction was concentrated to afford 35 as a
colorless oil in quantitative yield.
(+)-Methyl 3-epi-Shikimate (40).27 A similar procedure to that
described for 35 afforded 40 as a white solid in quantitative yield.
Acknowledgment. Financial support of this work by the
Spanish Ministerio de Educacio´n y Ciencia (MEC; Project CTQ-
2004-04185) is gratefully acknowledged. S.F. thanks MEC for
a personal grant (Ramo´n y Cajal Project). L.S. thanks MEC for
a predoctoral fellowship. We thank Robin Walker for the
English language revision of the final manuscript.
Supporting Information Available: Complete experimental
procedures, 1H and 13C NMR spectral data, and some two-
dimensional NMR experiments are shown in addition to mp, IR,
optical rotation, microanalysis, and MS data. The level of purity is
Selective opening of the epoxide under identical conditions
to those mentioned above for the quinate derivative, gives rise
exclusively to (+)-methyl 3-epi-shikimate (40) in quantitative
1
indicated by the inclusion of copies of H and 13C NMR spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(27) Gorin, P. A. J. Can. J. Chem. 1963, 41, 2417-2423.
(28) Banwell, M. G.; Edwards, A. J.; Essers, M.; Jolliffe, K. A. J. Org.
Chem. 2003, 68, 6839-6841.
JO0606249
J. Org. Chem, Vol. 71, No. 14, 2006 5399