Efficient syntheses-of (-)-shikimate and (-)-quinate 3-phosphate via trans vicinal diol protection with 2,2,3,3-tetramethoxybutane (TMB) of shikimic and quinic acids

Article abstract of DOI:10.1016/S0040-4039(00)00280-X

(-)-Shikimate 3-phosphate and (-)-quinate 3-phosphate can be synthesized by selective protection of their trans diol functionality using 2,2,3,3- tetramethoxybutane (TMB) using D-(-)-shikimic acid and D-(-)-quinic acid as starting materials. This versatile reagent facilitates the synthesis of these important biological targets in fewer steps than previously reported. By the proper choice of protecting group for C-3 hydroxyl in D-(-)-quinic acid, it can be converted to a key intermediate in the synthesis of (-)-shikimate 3- phosphate. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00280-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2957–2959
Efficient syntheses of (−)-shikimate and (−)-quinate 3-phosphate
via trans vicinal diol protection with 2,2,3,3-tetramethoxybutane
(TMB) of shikimic and quinic acids
Tzenge-Lien Shih a,∗ and Shih-Hsiung Wu a,b,∗
aInstitute of Biological Chemistry, Academia Sinica, NanKang 115, Taipei, Taiwan
bInstitute of Biochemical Sciences, National Taiwan University, Taiwan
Received 23 December 1999; accepted 14 February 2000
Abstract
(−)-Shikimate 3-phosphate and (−)-quinate 3-phosphate can be synthesized by selective protection of their
trans diol functionality using 2,2,3,3-tetramethoxybutane (TMB) using D-(−)-shikimic acid and D-(−)-quinic acid
as starting materials. This versatile reagent facilitates the synthesis of these important biological targets in fewer
steps than previously reported. By the proper choice of protecting group for C-3 hydroxyl in D-(−)-quinic acid,
it can be converted to a key intermediate in the synthesis of (−)-shikimate 3-phosphate. © 2000 Elsevier Science
Ltd. All rights reserved.
Keywords: shikimic acid; quinic acid; shikimate 3-phosphate; quinate 3-phosphate; 2,2,3,3-tetramethoxybutane.
The first chemical syntheses of (−)-shikimate 3-phosphate and (−)-quinate 3-phosphate were reported
in 1992.1 Both of these syntheses required protection of the cis vicinal diols at C-3 and C-4 positions,
respectively. This contributed to a long synthetic route.
2,2,3,3-Tetramethoxybutane (TMB) has been used in the protection of vicinal diequatorial diols in a
series of carbocycles and carbohydrates.2 Furthermore, the TMB reagent has been used to convert (−)-
quinic acid into (−)-shikimic acid.3 These results prompted us to propose that the TMB could be used in
the syntheses of both (−)-shikimate 3-phosphate and (−)-quinate 3-phosphate.
Our synthesis of (−)-shikimate-3-phosphate is described in Scheme 1. The trans vicinal diol of 11a,4
was protected with TMB using the known procedure.2 However, we observed that the refluxing time
affected the ratio of 2 and 3 in the product mixture. When the reaction time was 3 h, compounds 2 and 35
were isolated in 75–85% yield in a ratio of 1.5:1. When the reaction was allowed to reflux for 18 h, the
mixture of compounds 2 and 3 was isolated in a ratio of 1:1.25. Prolonged reaction time (up to two days)
provided 3 as the only isolated product in 77% yield. The C-3 position of 3 was phosphorylated6 to afford
47 in 72% yield. The one-step debenzylation and deprotection steps were accomplished simultaneously
∗
Corresponding authors.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00280-X
tetl 16560

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using bromotrimethylsilane in methylene chloride. Saponification and purification provides 5 in 76%
yield.1a Its 1H NMR data is consistent with the reported value.1a
Scheme 1.
The synthesis of (−)-quinate 3-phosphate is outlined in Scheme 2. The C-3 position of compound 62
was phosphorylated using the same procedure as described above, providing 78 in 73% yield. Compound
7 was hydrogenated over Pd/C (in MeOH, rt, overnight)6 followed by acid hydrolysis (80% TFA, rt, 4
h).2,3 The resulting syrup was subjected to a basic workup (1N NaOH) to obtain 8 in 69% (three steps)
after purification. Its 1H NMR data is also consistent with the reported value.1a
Scheme 2.
Some of our effort has focused on the syntheses of intermediates 4 and 109 from 7 and 9, respectively,
using phosphorous oxychloride in pyridine10 (Scheme 3). Compounds 4 and 10 therefore served as
precursors in the synthesis of (−)-shikimate 3-phosphate starting from (−)-quinic acid. In the examples
of dehydration of 7 and 9, we observed that the elimination takes place exclusively opposite to the TMB
protected diol, yielding 4 and 10 in 37 and 76% yields, respectively. The regioselectivity of double bond
formation is consistent with that observed in the synthesis of D-(−)-shikimic acid from D-(−)-quinic
acid.3a However, the isolated yield (37%) for 4 might be due to competing aromatization during the
reaction since the phosphorous group may function as a leaving group. Indeed, a non-polar highly UV-
active spot was observed by TLC which is not readily isolated by column chromatography. Furthermore,
when the C-3 hydroxyl is protected with an acetyl group, the possibility of aromatization was eliminated,
and a higher yield was obtained. The acetyl group of 10 can be further removed to prepare 3.
With this method, (−)-shikimate 3-phosphate and (−)-quinate 3-phosphate were obtained using
the TMB reagent for the protection of trans vicinal diols in methyl-(−)-shikimate or methyl-(−)-
quinate, respectively. This route is more direct than previous routes to these important compounds. The
regioselectivity of double bond formation in the dehydration of 7 and 9 can also be controlled by this
trans diol protection.

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Scheme 3.
Acknowledgements
T.-L. Shih gratefully acknowledges Academia Sinica for a postdoctoral fellowship. We also wish to
thank Dr. C.-C. Lin at Academia Sinica for helpful discussions and Mr. Mark L. Micklatcher at Purdue
University for proofreading this manuscript.
References
1. (a) Chahoua, L.; Baltas, M.; Gorrichon, L.; Tisnès, P.; Zedde, C. J. Org. Chem. 1992, 57, 5798. (b) For racemic synthesis of
3-phosphoshikimate acid, see: Bartlett, P. A.; McQuaid, L. A. J. Am. Chem. Soc. 1984, 106, 7854.
2. (a) Montchamp, J.-L.; Tian, F.; Hart, M. E.; Frost, J. W. J. Org. Chem. 1996, 61, 3897. (b) Douglas, N. L.; Ley, S. V.; Osborn,
H. M. I.; Owen, D. R.; Priepke, H. W. M.; Warriner, S. L. Synlett 1996, 793.
3. (a) Shinada, T.; Yoshida, Y.; Ohfune, Y. Tetrahedron Lett. 1998, 39, 6027. (b) Alves, C.; Teresa Barros, M.; Maycock, C. D.;
Rita Ventura, M. Tetrahedron 1999, 55, 8443. For natural product synthesis by using D-(−)-quinic acid, see review: Barco,
A.; Benetti, S.; Risi, C. D.; Marchetti, P.; Pollini, G.; Zanirato, V. Tetrahedron: Asymmetry 1997, 8, 3515.
4. Shikimic acid, used for the preparation of 3, was purchased from Sigma.
5. The 1H and 13C NMR data are consistent with the reported values in Ref. 3b.
6. Yu, K.-L.; Fraser-Reid, B. Tetrahedron Lett. 1988, 29, 979.
7. Compound 4: pale yellow syrup. 1H NMR (CDCl3, 400 MHz) δ 7.25–7.39 (m, 10H), 6.76 (dd, J=5.5, 2.6 Hz, 1H), 5.13–5.23
(m, 2H), 5.08–5.12 (m, 1H), 5.00–5.06 (m, 2H), 4.10 (dt, J=16.8, 5.9 Hz, 1H), 3.74 (s, 3H), 3.69 (ddd, J=10.9, 4.0, 1.7 Hz,
1H), 3.23 (s, 3H), 3.22 (s, 3H), 2.83 (dd, J=18.0, 6.2 Hz, 1H), 2.25 (ddd, J=18.0, 10.3, 2.8 Hz, 1H), 1.27 (s, 3H), 1.23 (s,
3H). 13C NMR (CDCl3, 100 MHz) δ 166.1, 136.2, 133.3, 132.0, 128.4, 128.3, 128.2, 127.9, 127.7, 99.9, 99.1, 70.9, 70.8,
69.4 (×2), 69.2 (×2), 62.4, 52.2, 48.1, 47.9, 30.3, 17.8, 17.7. LRMS (m/z) 562.9 (M+, 95%), 531.1 (M+−OMe, 100%).
8. Compound 7: white solid. Mp 103–105°C. 1H NMR (CDCl3, 400 MHz) δ 7.25–7.40 (m, 10H), 5.17 (t, J=6.4 Hz, 2H), 5.08
(dd, J=7.6, 4.3 Hz, 2H), 4.92 (dd, J=7.7, 2.9 Hz, 1H), 4.36 (ddd, J=14.8, 10.3, 4.6 Hz, 1H), 3.75 (s, 3H), 3.62 (dt, J=10.3,
2.6 Hz, 1H), 3.31 (brs, 1H), 3.23 (s, 3H), 3.19 (s, 3H), 2.21 (dt, J=15.5, 2.8 Hz, 1H), 1.98–2.12 (m, 2H), 1.93 (t, J=13.0
Hz, 1H), 1.25 (s, 3H), 1.23 (s, 3H). 13C NMR (CDCl3, 100 MHz) δ 175.0, 136.3, 136.0, 128.5, 128.4, 128.3, 128.1, 127.8,
127.7, 100.2, 99.5, 74.7, 74.6, 74.5, 71.6, 69.3, 69.2, 62.2, 48.0, 47.9, 38.8, 37.9, 17.8, 17.6. LRMS (m/z) 580.9 (M+, 75%),
549.1 (M+−OMe, 100%).
9. Compound 10: pale yellow syrup. 1H NMR (CDCl3, 400 MHz) δ 6.80 (dd, J=5.0, 2.3 Hz, 1H), 5.53 (t, J=5.0 Hz, 1H), 4.07
(dtd, J=16.7, 10.5, 6.0 Hz, 1H), 3.74 (s, 3H), 3.69 (dd, J=10.9, 4.4 Hz, 1H), 3.25 (s, 3H), 3.23 (s, 3H), 2.83 (dd, J=17.9 Hz,
6.0 Hz, 1H), 2.26 (dddd, J=17.9, 10.4, 2.8, 0.9 Hz, 1H), 2.07 (s, 3H), 1.28 (s, 3H), 1.25 (s, 3H), 1.23 (brs, 1H). 13C NMR
(CDCl3, 100 MHz) δ 170.4, 166.3, 133.3, 132.2, 99.7, 99.1, 68.8, 66.1, 62.9, 52.2, 48.0, 47.9, 30.0, 20.9, 17.8, 17.6.
10. Ulibarri, G.; Nadler, W.; Skrydstrup, T.; Audrain, H.; Chiaroni, A.; Riche, C.; Grierson, D. S. J. Org. Chem. 1995, 60, 2753.