Asymmetric synthesis of (-)-4-epi-shikimic acid

Article abstract of DOI:10.1016/S0040-4039(00)00225-2

The major cycloadduct, arising from the Diels-Alder reaction of maleic anhydride and (1E)-(2',3',4',6'-tetra-O-acetyl-β-D-glucopyranosyloxy)buta- 1,3-diene, is converted into methyl 3-O-(β-D-glucopyranosyl)-4-epi-shikimate and into (-)-4-epi-shikimic acid in overall yields of 20 and 17% (based on the diene). (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00225-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2691–2694
Asymmetric synthesis of (−)-4-epi-shikimic acid
Surachai Pornpakakul, Robin G. Pritchard and Richard J. Stoodley ∗
Department of Chemistry, UMIST, PO Box 88, Manchester, M60 1QD, UK
Received 19 January 2000; accepted 3 February 2000
Abstract
The major cycloadduct, arising from the Diels–Alder reaction of maleic anhydride and (1E)-(20,30,40,60-
tetra-O-acetyl-β-D-glucopyranosyloxy)buta-1,3-diene, is converted into methyl 3-O-(β-D-glucopyranosyl)-4-epi-
shikimate and into (−)-4-epi-shikimic acid in overall yields of 20 and 17% (based on the diene). © 2000 Elsevier
Science Ltd. All rights reserved.
Keywords: asymmetric synthesis; carbohydrates; Diels–Alder reactions; regioselection; shikimic acid and derivatives.
The 4-epi-shikimic acid skeleton 1 is a constituent of numerous natural products, some of which are
endowed with interesting biological properties. For example, it is present in dioxolamycin 2,1 a cytotoxic
agent produced by Streptomyces filamentosus, in cyathiformines B–D 3–5,2 metabolites of Clitocybe
cyathiformis, and in pericosine A 6,3 an antitumour agent obtained from Periconia byssoides.
The first synthesis of 4-epi-shikimic acid (as a racemate) rac-1 was reported in 1967 by Grewe and
Kersten.4 Subsequently, the material was prepared by the groups of Rapoport5 and Berchtold.6 A partial
synthesis of (−)-4-epi-shikimic acid 1 from D-quinic acid was also developed by both groups.5,7 To
date, the only asymmetric synthesis of a 4-epi-shikimic acid derivative is that of Posner and Wettlaufer.8
The key reaction in their 15-step synthesis, which led to methyl 3,4,5-tri-O-acetyl-4-epi-shikimate 10,
involved an inverse-electron-demand asymmetric Diels–Alder reaction between the vinyl ether 7 and
the pyranone 8 to give the cycloadduct 9 (Scheme 1). We now describe an asymmetric synthesis of 4-
epi-shikimic acid 1 and of methyl 3-O-(β-D-glucopyranosyl)-4-epi-shikimate 11, the first glycoside of a
shikimic acid derivative.
∗
Corresponding author. E-mail: richard.stoodley@umist.ac.uk (R. J. Stoodley)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00225-2
tetl 16505

2692
Scheme 1.
It was envisaged that the targets would be accessible from compound 12, the retrosynthesis of which
is outlined in Scheme 2. The key steps would involve: the oxidative decarboxylative elimination of the
acid 13; the regioselective methanolysis of the anhydride 14; and the stereoselective dihydroxylation of
the cyclohexene 15.
Scheme 2.
Earlier, we had shown that N-phenylmaleimide 16 reacted with the diene 18 (in PhH) to give a
mixture of the cycloadducts 19 and 20 (ratio 86:14) (Scheme 3), from which the major cycloadduct
19 was isolated in 59% yield after crystallisation.9 We hoped that the corresponding reaction with maleic
anhydride 17 would provide the cycloadduct 15. In the event, the reaction (in CH2Cl2) afforded a 75:25
mixture of the cycloadducts 15 and 21 (Scheme 3) and several crystallisations were required to provide
compound 15 in a stereopure state. A solvent study revealed that the stereoselectivity of the Diels–Alder
reaction could be improved to 86:14 (using Me2SO). Moreover, subjection of the crude product to
the Upjohn dihydroxylation procedure10 followed by crystallisation gave the required diol 22,11 mp
208–209°C, [α]D +23 (c 0.26, CH2Cl2), in 64% overall yield. Acetylation, under acidic conditions,
provided the anhydride 14,11 mp 172–173°C, [α]D +10 (c 0.42, CH2Cl2), in 84% yield.
Scheme 3. Reagents and conditions: (i) PhH, 20°C, 3 days for 16; Me2SO, 20°C, 18 h for 17; (ii) OsO4 (10 mol%), NMO (100
mol%), Me2CO–H2O (10:1), −10°C, 0.5 h; (iii) crystallisation (from CHCl3); (iv) Ac2O–HClO4 (cat.), 2 h
As shown in Scheme 4, the anhydride 14 underwent a highly regioselective methanolysis under
basic conditions to give largely compound 23. Although this was the less-preferred outcome in the
context of our projected synthesis, it was a simple matter to derive the required methyl ester 13. Thus,
subjection of the anhydride 14 to the action of benzyl alcohol provided compound 2411 (83% yield
after crystallisation), mp 187–188°C, [α]D −13 (c 0.5, CH2Cl2), which was transformed into the methyl
ester 1311 (91% yield after crystallisation), mp 190–192°C (decomp.), [α]D −31 (c 0.5, CH2Cl2), by a

2693
methylation–hydrogenolysis sequence. The acid 13 underwent a Hunsdiecker reaction, using Barton’s
protocol,12,13 to give mainly a 62:38 mixture of the bromides 25 and 26, which was converted into the
4-epi-shikimate 1211 (53% overall yield after chromatography and crystallisation), mp 144°C, [α]D −97
(c 0.33, CH2Cl2), under basic conditions.14 It was possible to isolate the diastereomeric bromides in
pure states after chromatography and crystallisation; compound 2511 (45% yield) showed mp 164°C,
[α]D −31 (c 0.43, CH2Cl2), and compound 2611 (31% yield) showed mp 196–197°C, [α]D −75 (c 0.44,
CH2Cl2).
Scheme 4. Reagents and conditions: (i) MeOH–CH2Cl2 (1:4), Et3N (10 mol%), DMAP (10 mol%), 1 h (for 23); PhCH2OH (100
mol%), Et3N (10 mol%), DMAP (10 mol%), CH2Cl2, 2 h (for 24); (ii) CH2N2, Et2O–CH2Cl2; (iii) H2, 10% Pd–C, CH2Cl2,
4 h; (iv) (COCl)2 (250 mol%), DMF (cat.), CH2Cl2, 1 h; (v) (under Ar) 2-mercaptopyridine N-oxide sodium salt (125 mol%),
BrCCl3, 100°C, 1.5 h, addition of AlBN (cat.) in BrCCl3, 100°C, 2 h; (vi) DBN (100 mol%), CH2Cl2, reflux, 24 h
As the first representative of a shikimic acid-based glycoside, compound 12 was subjected to an X-ray
crystallographic analysis.15 The molecular structure, shown in Fig. 1, not only validated our stereochem-
ical and regiochemical assignments but also established the overall conformational situation. Thus, the
glucose unit adopted the expected chair conformation and the shikimic acid unit the anticipated half-chair
conformation. The values for φ [H(10)–C(10)–O(3)–C(3) torsional angle], ψ [C(10)–(O3)–C(3)–H(3)
torsional angle] and τ [C(10)–O(3)–C(3) angle] were +49.7, +25.9 and 111.6(5)°, in accord with expec-
tations based upon exo-anomeric and torsional effects.16 Under transesterification conditions [dry MeOH,
Amberlite® IRA-420 (OH–), 6 days], the hexaacetate 12 was transformed into the hexaol 11,11,17 (95%
yield after crystallisation), mp 121–123°C (decomp.), [α]D −118 (c 0.28, MeOH).
Fig. 1. Molecular structure of compound 12
Acidic hydrolysis of compound 12 (1 M HCl, reflux, 15 h) gave a mixture of D-glucose and 4-epi-
shikimic acid 1 which was separated by column chromatography (Dowex® 1×8–200 ion-exchange resin).
1
The acid 1, obtained as a syrup (ca. 80% yield), showed the reported H NMR spectral properties5

2694
although its specific rotation, [α]D −53 (c 0.43, H2O), was notably smaller than the literature values
{[α]D −93 (c 0.9, H2O)5 and −80.6 (c 1.03, H2O)7}. However, the derived methyl 3,4,5-tri-O-acetyl-4-
epi-shikimate 10 (prepared from 1 by the action of CH2N2 in MeOH–Et2O and Ac2O–pyridine) displayed
a specific rotation, [α]D −140 (c 0.35, MeOH), that was in excellent agreement with the literature values
{[α]D −137 (c 1.17, MeOH)8 and −140 (c 0.9, MeOH)4}.
The aforecited results are of interest in a number of respects. Thus, the 15→22 transformation shows
that the dihydroxylation reaction, which displays excellent stereoselectivity, can be effected in the
presence of the delicate anhydride ring. The high regioselectivity associated with the alcoholysis of the
anhydride ring of compound 14 is surprising. The success of the Barton–Hunsdiecker reaction and the
subsequent dehydrobromination, in substrates that would be expected to be prone to aromatisation, is also
noteworthy. Finally, as a consequence of the work, the first synthesis of a shikimic acid-based glycoside
and the first asymmetric synthesis of 4-epi-shikimic acid 1 have been accomplished.
Acknowledgements
We thank the Thai government for a scholarship (to S.P.) and the EPSRC for a research grant
(GR/L52246) to assist in the purchase of the 400 MHz 1H NMR spectrometer.
References
1. Zhu, B.; Morioka, M.; Nakamura, H.; Naganawa, H.; Muraska, Y.; Okami, Y.; Umezawa, H. J. Antibiot. 1984, 37, 673–674.
2. Arnone, A.; Cardillo, R.; Nasini, G.; Vajna de Pava, O. Tetrahedron 1993, 49, 7251–7258.
3. Numata, A.; Iritani, M.; Yamada, T.; Minoura, K.; Matsumura, E.; Yamori, T.; Tsuruo, T. Tetrahedron Lett. 1997, 38,
8215–8218.
4. Grewe, R.; Kersten, S. Chem. Ber. 1967, 100, 2546–2553.
5. Snyder, C. D.; Rapoport, H. J. Am. Chem. Soc. 1973, 95, 7821–7828.
6. McGowan, D. A.; Berchtold, G. A. J. Am. Chem. Soc. 1982, 104, 1153–1154.
7. Lesuisse, D.; Berchtold, G. A. J. Org. Chem. 1985, 50, 888–890.
8. Posner, G. H.; Wettlaufer, D. G. J. Am. Chem. Soc. 1986, 108, 7373–7377.
9. Larsen, D. S.; Stoodley, R. J. J. Chem. Soc., Perkin Trans. 1 1989, 1841–1852.
10. VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976, 1973–1976.
11. This compound gave a satisfactory elemental analysis and showed spectral properties in accord with its assigned structure.
12. Barton, D. H. R.; Lacher, B.; Zard, S. Z. Tetrahedron Lett. 1985, 26, 5939–5942.
13. Barton, D. H. R.; Crich, D.; Motherwell, W. B. Tetrahedron 1985, 41, 3901–3924.
14. A small amount (ca. 10%) of methyl 3-(20,30,40,60-tetra-O-acetyl-β-D-glucopyranosyloxy)benzoate,11 mp 100–101°C, [α]D
−35 (c 0.25, CH2Cl2), was also produced in this reaction.
15. Crystal data for compound 12: C26H34O16, M=602.5, orthorhombic, space group P212121, a=17.097(5), b=20.017(3),
c=8.888(2) Å, V=3041.9(12) Å,3 Z=4, Dc=1.316 g cm−3, µ=0.950 mm−1 (Cu–Kα, λ=1.54178 Å), F(000)=1272, T=293(2)
K. Rigaku AFC6S diffractometer, crystal size 0.40×0.35×0.10 mm, θmax 64.98°, 2764 reflections measured, 2761 unique.
Structure solution by direct methods, full-matrix least-squares refinement on F2 using SHELX97-2 with all non-hydrogen
atoms anisotropic and hydrogen atoms constrained in calculated positions. The final cycle converged to R=0.0574 and
wR2=0.1428.
16. Rao, V. S. R.; Qasba, P. K.; Balaji, P. V.; Chandrasekaran, R. Conformation of Carbohydrates; Harwood Academic
Publishers: Amsterdam, 1998.
17. For 11: δH (400 MHz; CD3OD) 2.49 and 2.58 [each 1H, ddt (J 4.5, 18.5 and 1.5 Hz) and ddt (J 4, 18.5 and 2.5 Hz), 6-H2],
3.24 (1H, dd, J 8 and 9 Hz, 20-H), 3.27–3.39 (partly obscured by solvent signals, 40- and 50-H), 3.40 (1H, t, J 9 Hz, 30-H),
3.68 and 3.92 [each 1H, dd (J 6 and 12 Hz) and dd (J 2 and 12 Hz), 60-H2], 3.76 (3H, s, MeO2C), 3.79 (1H, dd, J 2.5 and
7 Hz, 4-H), 4.13 (1H, dt, J 2.5 and 4.5 Hz, 5-H), 4.45–4.51 (1H, m, 3-H), 4.49 (1H, d, J 8 Hz, 10-H) and 6.89–6.93 (1H,
m, 2-H): δC (75 MHz; CD3OD) 32.6 (6-CH2), 52.8 (CH3O), 63.1 (60-CH2), 69.4 (5-CH), 72.0 (40-CH), 73.8 (4-CH), 75.3
(20-CH), 78.4 (30-CH), 78.6 (50-CH), 79.6 (3-CH), 104.5 (10-CH), 130.8 (1-C), 137.3 (2-CH) and 169.1 ( ester CO).