Efficient synthesis of (-)-methyl 3-epi-shikimate and methyl 3-epi-quinate by one-pot selective protection of trans-1,2-diols

Article abstract of DOI:10.1016/S0040-4039(00)01507-0

trans-1,2-Diol protections of shikimic and quinic acids have been achieved by in situ formation of the protecting group (2,2,3,3-tetramethoxybutane). The synthetic utility of the protected derivatives is demonstrated by the preparation of (-)-methyl 3-epi

Full text of DOI:10.1016/S0040-4039(00)01507-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8759–8762
Efficient synthesis of (−)-methyl 3-epi-shikimate and methyl
3-epi-quinate by one-pot selective protection of
trans-1,2-diols
Nuria Armesto, Miguel Ferrero, Susana Ferna´ndez and Vicente Gotor*
Departamento de Qu´ımica Orga´nica e Inorga´nica, Facultad de Qu´ımica, Universidad de Oviedo, 33071 Oviedo, Spain
Received 20 July 2000; accepted 6 September 2000
Abstract
trans-1,2-Diol protections of shikimic and quinic acids have been achieved by in situ formation of the
protecting group (2,2,3,3-tetramethoxybutane). The synthetic utility of the protected derivatives is
demonstrated by the preparation of (−)-methyl 3-epi-shikimate and methyl 3-epi-quinate through a new
and efficient route from the parent acids. © 2000 Published by Elsevier Science Ltd.
Keywords: one-pot trans-1,2-diol protection; shikimic acid; quinic acid; 3-epi-shikimate; 3-epi-quinate.
1. Introduction
The shikimic acid biosynthetic pathway is utilized by plants, fungi and microorganisms for the
synthesis of the aromatic -a-amino acids phenylalanine, tyrosine and tryptophan, as well as the
L
folate coenzymes and various isoprenoid quinones.1 This metabolite, together with quinic acid,
a substance intimately involved in the shikimic acid route, have received a great deal of attention
as useful chiral building blocks and as optically active synthetic precursors for natural com-
pounds.2 Analogues of shikimate pathway intermediates that inhibit the action of the enzymes
have been highlighted as materials with potential herbicidal, anti-fungal and antibiotic activ-
ity.2c,3 C-3 shikimate and quinate derivatives are important tools in this area, since reactions at
the C-3 hydroxyl group such as oxidation–reduction, phosphorylation or elimination, play an
important role in the biosynthetic pathway.
In the last few years much attention has been focused on to the preparation of various C-3
substituted shikimate derivatives. Thus, synthesis of analogues of (−)-shikimic acid containing
3-amino,4 3-fluoro,5 3-chloro,5b 3-epi4a,5b and 3-phosphate6 functionalities have been reported in
the literature. Some of the published syntheses show limitations due to the difficulty of
* Corresponding author. E-mail: vgs@sauron.quimica.uniovi.es
0040-4039/00/$ - see front matter © 2000 Published by Elsevier Science Ltd.
PII: S0040-4039(00)01507-0

8760
discerning between the three hydroxyl groups in the shikimic acid. In this paper we wish to
report the selective protection of the 1,2-trans vicinal diol7 in shikimic acid and quinic acid, in
one-pot from commercially available starting materials, and avoiding the preparation of the
protecting group.8 The protection of the hydroxyl groups at the C-4 and C-5 positions allows a
direct reaction at C-3, skipping the tedious task of several protection and deprotection steps.
Taking advantage of this, we have synthesized (−)-methyl 3-epi-shikimate and methyl 3-epi-
quinate by an efficient route from the parent acids.
2. Results and discussion
Reaction of shikimic acid 1 with 2.04 equivalents of butane-2,3-dione in methanol at 85°C in
a sealed tube with a catalytic amount of ( )-CSA and 4.89 equivalents of trimethylorthoformate
for 9 h, yields the 1,2-diacetal methyl ester 2 directly from the parent a-diketone (Scheme 1), in
80% isolated yield after flash chromatography. Protection of the cis-diol unit occurred only to
1
a minor extent as shown by H NMR analysis of the crude reaction mixture, in contrast with
a 77:23 ratio (trans:cis-protection) when the reaction was carried out at 65°C. In compound 2,
the junction between the cyclohexene and the cyclic diacetal is trans-diequatorial, as shown by
the coupling constant values of 11 Hz between H-4 and H-5, corresponding to an axial–axial
disposition of both hydrogens (Fig. 1a). Likewise, H-3 has two coupling constants of 4.7 Hz,
which are consistent with the pseudo-equatorial disposition of this hydrogen. Additionally,
Scheme 1. a: (MeCO)2, CH(OMe)3, ( )-CSA, MeOH, 85°C, sealed tube (80%). b: PNBOH, PPh3, DEAD, THF
(quantitative). c: MeONa, MeOH. d: CF3CO2HꢀH2O (95%, two steps)
Figure 1. Conformations of methyl shikimate diacetals from NOESY experiments: (a) trans-1,2-protection; (b)
cis-1,2-protection

8761
NOESY experiments have shown the NOE effects of H-4 and H-5 with the methoxy groups,
which are oriented in the axial position to obtain the maximum anomeric stabilization, whilst
the methyl substituents are placed in the favored equatorial position. Similar studies on the
minor cis-1,2-protected compound are in agreement with a chair conformation with H-4 and
H-5 in an equatorial orientation and H-3 in a pseudo-axial one (Fig. 1b).
To invert the configuration at the C-3 position, Mitsunobu conditions were used. The reaction
takes place in 2 h with total inversion of the configuration, giving quantitatively compound 3.
Deprotection of the p-nitrobenzoate ester with MeONa, and the subsequent removal of the
diacetal moiety with a 19:1 trifluoroacetic acid:water mixture, easily converted 3 in 95% yield
into the corresponding (−)-methyl 3-epi-shikimate. Its spectral data are consistent with the
reported values.5b
To the best of our knowledge, no report exists for the chemical synthesis of methyl
3-epi-quinate 8. Thus, the above efficient methodology was applied to quinic acid 5 (Scheme 2).
In this case, compound 6 was formed as an unique and enantiopure product in the one-pot
selective protection of the trans-1,2-diol. The reaction takes place under reflux in 1 h with 90%
yield after recrystallization. Previous molecular mechanics calculations9 in quinic and shikimic
acids revealed a small energy difference between both possible conformations in shikimic acid
and a large one for quinic acid, which is in agreement with the absence of cis-1,2-protected
derivative in quinic acid and the presence as minor compound in shikimic acid.
Scheme 2. a: (MeCO)2, CH(OMe)3, ( )-CSA, MeOH, reflux (90%). b: PNBOH, PPh3, DIAD, toluene. c: MeONa,
MeOH (50%, two steps). d: PCC, CH2Cl2 (82%). e: NaBH(OAc)3, CH2Cl2, 0°C“rt (80%). f: CF3CO2HꢀH2O
(quantitative)
A Mitsunobu reaction on the free secondary alcohol in compound 6 led to the C-3
p-nitrobenzoate ester together with the corresponding elimination product in a 4.5:1 ratio,
respectively. As a consequence, derivative 7 was obtained with a moderate yield of 50%. An
alternative inversion, using CsF and benzoic acid in DMF on the tosylate derivative, did not
improve the previous results. The inversion was best carried out by oxidation of diol 6 with
PCC, and the subsequent selective reduction of ketone 9 with sodium triacetoxyborohydride.
This afforded almost exclusively diol 7 (diastereomers 7 and 6 were obtained in a 24:1 ratio,

8762
respectively, and 7 was isolated by flash chromatography using CH2Cl2:Et2O 1:1 as eluent).
Removal of the protecting group with aqueous trifluoroacetic acid provided methyl 3-epi-
quinate 8.10
In conclusion, we have introduced the use of 1,2-diacetals in a one-pot procedure for the
regioselective protection of the 4,5-hydroxyl groups of shikimic and quinic acids from commer-
cially available reagents. Thus, esterification of shikimic or quinic acids, preparation of the
protecting group, and diacetal formation were achieved simultaneously. This direct and selective
trans 1,2-vicinal diol protection allowed us to synthesize (−)-methyl 3-epi-shikimate and methyl
3-epi-quinate by short and efficient routes.
Acknowledgements
Financial support from CICYT (Spain; Project BIO98-0770) is gratefully acknowledged. We
also thank the Ministerio de Educacio´n y Cultura (Spain) for postdoctoral fellowships (S.F. and
M.F.).
References
1. (a) Haslam, E. Shikimic Acid: Metabolism and Metabolites; John Wiley and Sons: Chichester, 1993. (b) Campbell,
M. M.; Sainsbury, M.; Searle, P. A. Synthesis 1993, 179–193.
2. (a) For a review of (−)-shikimic acid see: Jiang, S.; Singh, G. Tetrahedron 1998, 54, 4697–4753. (b) For a review
of (−)-quinic acid in natural product synthesis see: Barco, A.; Benetti, S.; De Risi, C.; Marchetti, P.; Pollini, G.
P.; Zanirato, V. Tetrahedron: Asymmetry 1997, 8, 3515–3545. (c) Kim, C. U.; Lew, W.; Williams, M. A.; Liu, H.;
Zhang, L.; Swaminathan, S.; Bischofberger, N.; Chen, M. S.; Mendl, D. B.; Tai, C. Y.; Laver, W. G.; Stevens,
R. C. J. Am. Chem. Soc. 1997, 119, 681–690.
3. Kozlowski, M. C.; Tom, N. J.; Seto, C. T.; Sefler, A. M.; Bartlett, P. A. J. Am. Chem. Soc. 1995, 117, 2128–2140.
4. (a) Alves, C.; Barros, M. T.; Maycock, C. D.; Ventura, M. R. Tetrahedron 1999, 55, 8443–8456. (b) Brettle, R.;
Cross, R.; Frederickson, M.; Haslam, E.; Davies, G. M. Bioorg. Med. Chem. Lett. 1996, 6, 291–294. (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.
5. (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.; Frederickson, M.; Haslam, E.; MacBeath, F. S.; Davies, G.
M. Tetrahedron 1996, 52, 10547–10556.
6. (a) Shih, T.-L.; Wu, S.-H. Tetrahedron Lett. 2000, 41, 2957–2959. (b) Chahoua, L.; Baltas, M.; Gorrichon, L.;
Tisne`s, P.; Zedde, C. J. Org. Chem. 1992, 57, 5798–5801.
7. Protection of trans-vicinal diols have been introduced previously by Ley et al.: (a) Douglas, N. L.; Ley, S. V.;
Osborn, H. M. I.; Owen, D. R.; Priepke, H. W. M.; Warriner, S. L. Synlett 1996, 793–795. (b) Ley, S. V.;
Priepke, H. W. M.; Warriner, S. L. Angew. Chem., Int. Ed. Engl. 1994, 33, 2290–2292. (c) Ley, S. V.; Woods, M.;
Zanotti-Gerosa, A. Synthesis 1992, 52–54.
8. (a) For the protection of methyl quinate with 2,2,3,3-tetramethoxybutane, see: Montchamp, J.-L.; Tian, F.; Hart,
M. E.; Frost, J. W. J. Org. Chem. 1996, 61, 3897–3899. (b) During the preparation of this manuscript a paper
appeared describing the protection of methyl shikimate with 2,2,3,3-tetramethoxybutane that was synthesized in
a separate process from butane-2,3-dione.6a
9. Danieli, B.; De Bellis, P.; Barzaghi, L.; Carrea, G.; Ottolina, G.; Riva, S. Helv. Chim. Acta 1992, 75, 1297–1304.
1
2
10. Compound 8: white hygroscopic solid; H NMR (MeOH-d4, 200.13 MHz): l 1.95 (dd, 2H, H2a+H6a, JHH 12.7,
3JHH 11.6 Hz), 2.21 (m, 2H, H2e+H6e), 3.36 (dd, 1H, H4, JHHꢀ9 Hz), 3.91 (m, 2H, H3+H5), and 3.93 (s, 3H,
3
OMe); 13C NMR (MeOD-d4, 75.5 MHz): l 41.9 (C2+C6), 53.3 (OMe), 70.8 (C3+C5), 75 (C1), 81.7 (C4), and 177
(CꢁO); IR (NaCl): w 3351, 2934, and 1730 cm−1; ESI Positive: 229.1 (M+Na)+.
.