Scheme 1. Synthesis of Indoxylic Acid Allyl Ester (1)
Figure 1. Monitoring glycosidase activity employing indoxyl
glycosides.
Apparently this compares favorably with a yield of 15%
for the above-mentioned indoxyl glucopyranoside. One
potential problem in this approach seems to be the high
temperature required (160 °C) for decarboxylation. Fur-
thermore, the glycoside would need to be deprotected
before decarboxylation. Both these steps are known to
cause side reactions and decomposition, especially for
sensitive structures such as di-, tri,- and oligosaccharides
for which these conditions are not suitable. We here report
a novel efficient synthetic route for the preparation of
indoxyl glycosides, which was tested for monosaccharides
as well as for more complex and sensitive sugar structures.
First glycosylation of the sugar donor with indoxylic
acid allyl ester was carried out by phase transfer catalysis
(PTC). The use of indoxylic acid allyl ester instead of
indoxyl reduced the side reactions to a minimum and made
selective cleavage of the allyl ester6 possible. Subsequent
mildsilvermediated decarboxylation (90ꢀ100 °C) gavethe
protected X-glycosides in good overall yields (X: common
abbreviation for 5-bromo-4-chloro-indoxyl). A modifica-
tion of the recently published decarboxylation method
could be favorably used in this step.7 Instead of NMP
or DMF, acetic anhydride as solvent with potassium
carbonate in combination with silver acetate turned out
tobe the best conditionsforhighyields, aswellasmoderate
bromine in acetic acid to give intermediate 3 in 70%
yield.10 5-Bromo-6-chloro-anthranilic acid (7, 88%) was
obtained after deprotection with aqueous sodium hydrox-
ide solution.11 Treatment with triphosgene/pyridine in
MeCN12 gave the isatoic anhydride (8, 88%) which was
easily N-alkylated13 using sodium hydride and allyl bro-
moacetate (9, 93%). Opening of the anhydride with allyl
alcohol and a catalytic amount of sodium hydride gave
3-bromo-2-chloro-N-(methoxycarbonylallyl)-anthranilic
acid allyl ester (10) in 80% yield.
Scheme 2. Synthesis of Fucose Indoxyl Glycoside (X-Fuc, 14)
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temperatures (80ꢀ100 °C). Deacetylation under Zemplen
conditions8 and, if required ester hydrolysis, gave the un-
protected compounds in good yields.
The indoxylic acid allyl ester 1 was prepared in seven
steps in an overall yield of 33% (Scheme 1). 4-Bromo-3-
chloro-2-methylaniline (2) was first acetylated (3, 97%)
and then oxidized with KMnO4 (4, 70%).9 An alterna-
tive was to start from cheap 3-chloro-2-methylaniline (5),
N-acetylate to obtain 6 (88%) and then treat this with
(6) Kunz, H.; Waldmann, H. Angew. Chem., Int. Ed. 1984, 23, 71–71.
(7) Gooßen, L. J.; Linder, C.; Rodrıguez, N.; Lange, P. P.; Fromm,
A. Chem. Commun. 2009, 7173–7175.
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(8) Zemplen, G. Ber. Dtsch. Chem. Ges. 1926, 59B, 1254–1266.
(9) Jin, Y.; Li, H.; Lin, L.; Tan, J.; Ding, J.; Luoc, X.; Longa, Y.
(11) Rogister, F.; Laeckmann, D.; Plasman, P. O.; Van Eylen, F.;
Bioorg. Med. Chem. 2005, 13, 5613–5622.
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Ghyoot, M.; Maggetto, C.; Liegeois, J. F.; Geczy, J.; Herchuelz, A.;
Delarge, J.; Masereel, B. Eur. J. Med. Chem. 2001, 36, 597–614.
(12) Huang, J. M.; Chen, H.; Chen, R. Y. Synth. Commun. 2002, 14,
2215–2225.
(10) Li, J. J.; Sutton, J. C.; Nirschl, A.; Zou, Y.; Wang, H.; Sun, C.; Pi,
Z.; Johnson, R.; Krystek, S. R.; Seethala, R.; Golla, R.; Sleph, P. G.;
Beehler, B. C.; Grover, G. J.; Fura, A.; Vyas, V. P.; Li, C. Y.; Gougoutas,
J. Z.; Galella, M. A.; Zahler, R.; Ostrowski, J.; Hamann, L. G. J. Med.
Chem. 2007, 50, 3015–3025.
(13) Malamas, M. S.; Millen, J. J. Med. Chem. 1991, 34, 1492–1503.
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