COMMUNICATIONS
A second set of condensation reactions was designed using
34 as well as other O-glycosidic units in order to expand the
diversity of the glycoconjugate libraries. The carboxylic acid
36 was obtained by O-glycosylation of ethyl hydroxyacetate
with 35[19] followed by saponification. The corresponding
glycosylation of N-(2-hydroxyethyl)formamide with 35 af-
forded 38. Saponification of 38 provided the amine 37.
Treatment of 38 with triphosgene gave the crystalline
isocyanide 39.
But also the mono- or diglycosyl compounds carrying further
non-carbohydrate residues, reflecting the vast diversity of
organic substituents, are highly important for HTS systems.
As these prototype reactions have disclosed, various carbo-
hydrate units can be assembled under similar conditions,
thereby enabling automatization of the reactions which have
been realized manually until now. It can be predicted that the
biological investigation of these saccharide libraries will be of
considerable interest.
All four model Ugi reactions of these glycosylated building
blocks with nonglycoslated partners provided the monogly-
cosylated amino acid derivatives 27 ± 30 in good yields. Side
reactions were not observed. Individual diasteromers could be
detected with thin-layer chromatography or HPLC, but could
not be resolved by preparative column chromatography. They
were isolated as 1:1 mixtures. Finally, the condensation of 34,
36, 37, and 39 furnished the desired fourfold-glycosylated
amino acid derivate 31.
The above-mentioned aldehyde, acid, and isocyanide build-
ing blocks also reacted smoothly in related Passerini reactions
to give singly to triply glycosylated hydroxyacetic acid
derivatives. According to further preliminary investigations,
analogous reactions using unprotected building blocks pro-
vided the condensation products only in significantly lower
amounts due to competitive reactions leading to acetals or
aminals. O-Acetylated components gave rise to partial
N-acetylation of the amine components. The hydrogenolysis
of various perbenzylated condensation products in the
presence of palladium on charcoal proceeded smoothly and
afforded the completely deblocked glycosylated amino or
hydroxy acid derivatives, for example 40 and 41.[20] All
products gave mass spectra in accordance with their molec-
ular formula.
Experimental Section
Aldehyde (0.05 mmol), amine (0.05 mmol), carboxylic acid (0.05 mmol),
and isocyanide (0.05 mmol) were disolved in ethanol (1 mL) and tetrahy-
drofuran (1 mL) and stirred overnight. The mixture was treated with 1n
hydrochloric acid (0.1 mL), stirred for 30 min, and evaporated. The residue
was taken up in dichloromethane (5 mL), washed with water (2 mL), dried,
evaporated, and purified by column chromatography over silica gel
(hexane/ethyl acetate, 7/1 !3/1).
Received: June 25, 1998 [Z12050IE]
German version: Angew. Chem. 1998, 110, 3634 ± 3637
Keywords: carbohydrates ´ combinatorial chemistry ´ gly-
coconjugates ´ glycomimetics ´ multicomponent reactions
[1] a) M. A. Gallop, R. W. Barrett, W. J. Dower, S. P. A. Fodor, E. M.
Gordon, J. Med. Chem. 1994, 37, 1233 ± 1251; b) G. Jung, A. G. Beck-
Sickinger, Angew. Chem. 1992, 104, 375 ± 391; Angew. Chem. Int. Ed.
Engl. 1992, 31, 367 ± 383.
[2] L. Gold, B. Polisky, O. Uhlenbeck, M. Yarus, Annu. Rev. Biochem.
1995, 64, 763 ± 797.
[3] a) N. K. Terrett, M. Gardner, D. W. Gordon, R. J. Kobylecki, J. Steele,
Tetrahedron 1995, 51, 8135 ± 8173; b) L. A. Thompson, J. A. Ellman,
Chem. Rev. 1996, 96, 555 ± 600.
[4] a) J. C. Paulson, Trends Biochem. Sci. 1989, 14, 272 ± 276; b) K. A.
Karlsson, Trends Pharmacol. Sci. 1991, 12, 265 ± 272; c) A. Varki,
Glycobiology 1993, 3, 97 ± 130; d) J. B. Lowe in Molecular Glycobi-
ology (Eds.: M. Fukuda, O. Hindsgaul), IRL Press, Oxford, 1994,
pp. 163 ± 205; e) R. A. Dwek, Chem. Rev. 1996, 96, 683 ± 720.
[5] a) O. Lockhoff, Methoden Org. Chemie (Houben-Weyl) 4th ed. 1952 ± ,
Vol. E14a/3, pp. 621 ± 1077; b) K. Toshima, K. Tatsuta, Chem. Rev.
1993, 93, 1503 ± 1531; c) F. Barresi, O. Hindsgaul, Mod. Synth. Methods
1995, 7, 283 ± 230; d) H. J. M. Gijsen, L. Qiao, W. Fitz, C.-H. Wong,
Chem. Rev. 1996, 96, 443 ± 473; e) G.-J. Boons, Tetrahedron 1996, 52,
1095 ± 1121.
[6] a) P. Arya, R. N. Ben, Angew. Chem. 1997, 109, 1335 ± 1337; Angew.
Chem. Int. Ed. Engl. 1997, 36, 1280 ± 1282; b) D. Kahne, Curr. Op.
Chem. Biol. 1997, 1, 130 ± 135; c) M. J. Sofia, Mol. Diversity 1998, 3,
75 ± 94.
[7] a) D. Tyrrell, P. James, N. Rao, C. Foxall, S. Abbas, F. Dasgupta, M.
Nashed, A. Hasegawa, M. Kiso, D. Asa, J. Kidd, B. K. Brandley, Proc.
Natl. Acad. Sci. USA 1991, 88, 10372 ± 10376; b) K. Scheffler, B. Ernst,
A. Katapodis, J. L. Magnani, W. T. Wang, R. Weisemann, T. Peters,
Angew. Chem. 1995, 107, 2034 ± 2037; Angew. Chem. Int. Ed. Engl.
1995, 34, 1841 ± 1844.
[8] a) A. Giannis, Angew. Chem. 1994, 106, 188 ± 191; Angew. Chem. Int.
Ed. Engl. 1994, 33, 178 ± 180; b) J. H. Musser, M. B. Anderson, P.
Fügedi, Pharm. News 1996, 3, 11 ± 17; c) H. C. Kolb, B. Ernst, Pure
Appl. Chem. 1997, 69, 1879 ± 1884.
[9] a) I. Ugi, J. Prakt. Chem./Chem.-Ztg. 1997, 339, 499 ± 516; b) A.
Domling, Comb. Chem. High Throughput Screening 1998, 1, 1 ± 22.
[10] a) I. Ugi, Angew. Chem. 1982, 94, 826 ± 835; Angew. Chem. Int. Ed.
Engl. 1982, 21, 810 ± 819; b) G. Gokel, G. Lüdke, I. Ugi in Isonitrile
Chemistry (Ed.: I. Ugi), Academic Press, New York, 1971, pp. 145 ±
199.
These reactions have opened a broad access to libraries of
diverse glycoconjugate libraries. The combination of various
carbohydrate components (with different configurations; C-,
O-, or N-glycosidic bonds; different linkers between sugar
moiety and functional groups; non-anomeric coupling of the
functional groups) carrying aldehyde, acid, amino, and
isocyanide groups should offer a huge variety of different
branched glycoconjugates as tri- or tetrasaccharide mimetics.
3438
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