Expedient synthesis of triazole-linked glycosyl amino acids and peptides

Article abstract of DOI:10.1021/ol048841o

(Chemical Equation Presented) An expedient, high-yielding synthesis of two types of triazole-linked glycopeptides is described. These novel and stable glycopeptide mimics were prepared via Cu(I)-catalyzed [3 + 2] cycloaddition of either azide-functionaliz

Full text of DOI:10.1021/ol048841o

ORGANIC
LETTERS
2
004
Vol. 6, No. 18
123-3126
Expedient Synthesis of Triazole-Linked
Glycosyl Amino Acids and Peptides
3
†
†
†
Brian H. M. Kuijpers, Stan Groothuys, A. (Bram) R. Keereweer,
‡
§
†
Peter J. L. M. Quaedflieg, Richard H. Blaauw, Floris L. van Delft, and
,
†
Floris P. J. T. Rutjes*
Department of Organic Chemistry, NSRIM, UniVersity of Nijmegen, ToernooiVeld 1,
6525 ED Nijmegen, The Netherlands, DSM Research, Life SciencessAdVanced
Synthesis, Catalysis and DeVelopment, P.O. Box 18, 6160 MD Geleen, The
Netherlands, and Chiralix B.V., ToernooiVeld 100, 6525 EC Nijmegen, The Netherlands
rutjes@sci.kun.nl
Received June 18, 2004
ABSTRACT
An expedient, high-yielding synthesis of two types of triazole-linked glycopeptides is described. These novel and stable glycopeptide mimics
were prepared via Cu(I)-catalyzed [3 + 2] cycloaddition of either azide-functionalized glycosides and acetylenic amino acids or acetylenic
glycosides and azide-containing amino acids.
1
Glycopeptides constitute a class of natural compounds,
involved in a number of important biological functions. By
far the most commonly encountered members of this family
these syntheses, however, are rather complex and often
feature low overall yields. Our research efforts aim at an
efficient, high-yielding synthesis of triazole-linked glyco-
peptides such as 1 and 2 (Scheme 1), via a mild, Cu-catalyzed
4
2
are N- and O-linked glycopeptides. Synthesis of such
glycopeptides is complicated by the sensitivity of the
glycosidic linkage between the (oligo)saccharide and the
peptide toward chemical and enzymatic hydrolysis. Synthesis
of (unnatural) amino acids, with the amino acid side chain
connected to the sugar unit via an isosteric linkage, may lead
to chemically and metabolically more stable analogues with
Scheme 1. Retrosynthesis
3
potential biological activity (e.g., inhibitory activity toward
glycosidases) or provide means to elucidate biochemical
pathways.
Approaches to obtain stable glycopeptide analogues often
involve the synthesis of C-linked glycopeptides. Most of
†
University of Nijmegen.
DSM Research.
Chiralix B.V.
‡
§
(
1) Glycopeptides and Related Compounds: Synthesis, Analysis and
Applications; Large, D. G., Warren, C. D., Eds.; Marcel Dekker: New York,
997.
2) (a) Kunz, H. Angew. Chem., Int. Ed. 1987, 26, 294. (b) Spiro, R. G.
Glycobiology 2002, 12, 43R. (c) Seitz, O. ChemBioChem 2000, 1, 214.
3) (a)Wu, T. C.; Goekjian, P. G.; Kishi, Y. J. Org. Chem. 1987, 52,
procedure for the [3 + 2] cycloaddition between organic
1
azides and acetylenes (“click reactions”). As recently inde-
(
5
6
pendently reported by the groups of Meldal and Sharpless,
(
this reaction generally results in the corresponding 1,4-
disubstituted 1,2,3-triazoles in high yields. Application of
4
819. (b) Haneda, T.; Goekjian, P. G.; Kim, S. H.; Kishi, Y. J. Org. Chem.
992, 57, 490.
1
1
0.1021/ol048841o CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/31/2004

this reaction to either azidoglycosides 3 and acetylenic amino
acids 4 or acetylenic glycosides 5 and azide-containing amino
acids 6 would then result in the triazole-linked glycopeptides
Table 1. Variation of the Carbohydrate Moiety
1
and 2, respectively, which constitute a novel compound
7
class. Besides the aim of constructing stable glycopeptide
mimics, the resulting substituted triazoles may display
relevant biological activity against various targets.
8
To probe the viability of our approach, various glycosides
containing an anomeric azide functionality were prepared
and reacted with (R)-N-Boc-propargylglycine methyl ester
9
(
7, Table 1). The coupling was initially studied using
10
azidoglucoside (8) and azidogalactoside (9) in combination
with different Cu(I) species (e.g., CuI, CuCl, and CuCN)
and different bases (e.g., Et
were obtained using modified Sharpless conditions, involv-
ing 0.2 equiv of Cu(OAc) and 0.4 equiv of sodium ascorbate
in a 1:1 (v/v) mixture of H O and tert-BuOH. This eventually
provided the targeted glycoamino acids 15 and 16 in 98 and
3
N and DIPEA). Optimal results
6
2
2
88% yields (entries 1 and 2).
Under the same conditions, the benzylated glycosyl azide
1
011 reacted smoothly to give the corresponding adduct 17
with retention of the anomeric configuration (entry 3).
Likewise, the glucosamine- and galactosamine-derived
azides 11 and 12,12 respectively, reacted in an efficient
manner with the acetylenic amino acid 7 to give the
(4) For entries into C-glyco amino acid synthesis, see for example: (a)
Taylor, C. M. Tetrahedron 1998, 54, 11317. (b) Du, Y.; Lindhardt, R. J.
Tetrahedron 1998, 54, 9913. (c) Dondoni, A.; Marra, A. Chem. ReV. 2000,
100, 4395. (d) Vincent, S. P.; Schleyer, A.; Wong, C.-H. J. Org. Chem.
2000, 65, 4440. (e) Xu, X.; Fakha, G.; Sinou, D. Tetrahedron 2002, 58,
7539. (f) Lane, J. W.; Halcomb, R. L. J. Org. Chem. 2003, 68, 1348 (g)
Turner, J. J.; Leeuwenburgh, M. A.; Van der Marel, G. A.; Van Boom, J.
H. Tetrahedron 2001, 42, 8713. (h) Dondoni, A.; Mariotti, G.; Marra, A.;
Massi, A. Synthesis 2001, 14, 2129. (i) Westermann, B.; Walter, A.; Fl o¨ rke,
U.; Altenbach, H.-J. Org. Lett. 2001, 3, 1375. (j) McGarvey, G. J.; Benedum,
T. E.; Schmidtmann, F. W. Org. Lett. 2002, 4, 3591. (k) Dondoni, A.;
Giovannini, P. P.; Marra, A. J. Chem. Soc., Perkin Trans. 1 2002, 2380. (l)
Nolen, E. G.; Kurish, A. J.; Wong, K. A.; Orlando, M. D. Tetrahedron
Lett. 2003, 44, 2449. (m) Palomo, C.; Oiarbide, M.; Landa, A.; Concepci o´ n
Gonz a´ lez-Rego, M.; Garc ´ı a, J. M.; Gonz a´ les, A.; Odriozola, J. M.; Mart ´ı n-
Pastor, M.; Linden, A. J. Am. Chem. Soc. 2002, 124, 8637.
(
5) Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67,
057.
6) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.
Angew. Chem. Int. Ed. 2002, 41, 2596.
7) For earlier reports on [3 + 2] cycloadditions of azidoglycosides and
acetylenes, see: (a) Br o¨ der, W.; Kunz, H. Carbohydr. Res. 1993, 249, 221.
3
(
(
(
(
b) Al-Masoudi, N. A.; Al-Soud, Y. A. Tetrahedron Lett. 2002, 43, 4021.
c) Marco-Contelles, J.; Jim e´ nez, C. A. Tetrahedron 1999, 55, 10511 (d)
a
Reagents and conditions: 1 equiv of azidoglycoside, 1 equiv of amino
acid derivative, 0.2 equiv of Cu(OAc)2, 0.4 equiv of sodium ascorbate, H2O/
Peto, C.; Batta, G.; Gyorgydeak, Z.; Sztaricskai, F. Carbohydr. Chem. 1996,
5, 465 and references therein
8) For examples of biologically active triazoles, see: (a) Alvarez, R.;
tert-BuOH 1:1 (v/v), rt, 16 h. b Yield of isolated product.
1
(
Velazquez, S.; San, F.; Aquaro, S.; De, C.; Perno, C. F.; Karlsson, A.;
Balzarini, J.; Camarasa, M. J. J. Med. Chem. 1994, 37, 4185. (b) Velazquez,
S.; Alvarez, R.; Perez, C.; Gago, F.; De, C.; Balzarini, J.; Camarasa, M. J.
AntiVir. Chem. Chemother. 1998, 9, 481. (c) Genin, M. J.; Allwine, D. A.;
Anderson, D. J.; Barbachyn, M. R.; Emmert, D. E.; Garmon, S. A.; Graber,
D. R.; Grega, K. C.; Hester, J. B.; Hutchinson, D. K.; Morris, J.; Reischer,
R. J.; Ford, C. W.; Zurenko, G. E.; Hamel, J. C.; Schaadt, R. D.; Stapert,
D.; Yagi, B. H. J. Med. Chem. 2000, 43, 953.
corresponding products 18 and 19 in good yields (entries 4
and 5). The benzoyl-protected glucosamine 13 surprisingly
gave a somewhat lower yield of the glycosylamino acid 20
13
(
entry 6). Finally, the 2-azido functionalized glucose deriva-
1
4
tive 14 gave the desired coupling product in 77% yield
(entry 7). Clearly, there were no notable differences in
(9) Enantiopure propargylglycine is commercially available but in our
hands was prepared via an enzymatic resolution process: (a) Wolf, L. B.;
Sonke, T.; Tjen, K. C. M. F.; Kaptein, B.; Broxterman, Q. B.; Schoemaker,
H. E.; Rutjes, F. P. J. T. AdV. Synth. Catal. 2001, 343, 662. (b) Sonke, T.;
Kaptein, B.; Boesten, W. H. J.; Broxterman, Q. B.; Kamphuis, J.; Formaggio,
F.; Toniolo, C.; Rutjes, F. P. J. T.; Schoemaker, H. E. In StereoselectiVe
Biocatalysis; Patel, R. N., Ed.; Marcel Dekker: New York, 2000; p 23.
(12) Prepared via tetra-O-acetyl-R-D-pyranosyl chloride from the corre-
sponding glucosamine and galactosamine (ref 13) and subsequent treatment
with NaN3: Lehnhoff, S.; Goebel, M.; Karl, R. M.; Kloesel, R.; Ugi, I.
Angew. Chem., Int. Ed. 1995, 34, 1104.
(13) Prepared by reaction of the benzoylated thioglycoside with ICl and
Me3SiN3, respectively.
(14) Prepared from the corresponding glucosamine via azido transfer,
followed by acetylation: Alper, P. B.; Hung, S.; Wong, C.-H. Tetrahedron
Lett. 1996, 37, 6029.
(
10) Shiozaki, M.; Arai, M.; Macindoe, W. M.; Mochizuki, T.; Kurakata,
S.; Maeda, H.; Nishijima, M. Chem. Lett. 1996, 9, 735
11) Prepared from 2,3,4,6-tetra-O-benzylglucose by treatment with DBU
and DPPA: Mizuno, M.; Shioiri, T. Chem. Commun. 1997, 2165.
(
3124
Org. Lett., Vol. 6, No. 18, 2004

reactivity between the several monosaccharides or between
the R- and â-isomers. Preliminary experiments to determine
the stability of the triazole linkage in compound 15 revealed
that this moiety is stable under a variety of acidic and basic
Table 3. Cycloaddition Reactions Involving a Dipeptide
1
5
conditions.
Table 2 shows the application of different acetylenic amino
acids containing a variety of amino protecting groups in the
Table 2. Variation of the Amino Acid Moiety
a
Reagents and conditions: 1 equiv of azidoglycoside 8, 1 equiv of
dipeptide, 0.2 equiv of Cu(OAc)2, 0.4 equiv of sodium ascorbate, H2O/
tert-BuOH 1:1 (v/v), rt, 16 h. b Yield of isolated product.
products 30 and 31 in good yields. Similarly, R-methyl-
substituted propargylglycine 26 (entry 5) afforded the gly-
coamino acid 32 in 85% yield.
In addition, subjection of the acetylenic aminonitrile 2717
gave the desired adduct 33 in 60% yield.
Tables 3 and 4 show that the scope of the click reactions
can be extended to dipeptides and disaccharides, respectively.
Table 4. Cycloaddition Reactions Involving a Disaccharide
a
Reagents and conditions: 1 equiv of azidoglycoside, 1 equiv of amino
acid derivative, 0.2 equiv of Cu(OAc)2, 0.4 equiv of sodium ascorbate, H2O/
b
tert-BuOH 1:1 (v/v), rt, 16 h. Yield of isolated product.
a
Reagents and conditions: 1 equiv of azidoglycoside 38, 1 equiv of
amino acid, 0.2 equiv of Cu(OAc)2, 0.4 equiv of sodium ascorbate, H2O/
cycloaddition with azidoglycoside 8. From Table 1, the
compatibility of the Boc group with these reaction conditions
was already clear; entries 1 and 2 of Table 2 now show that
Fmoc and Ts are also well-suited for this reaction. Increasing
the length of the side chain of the amino acid16 (entries 3
and 4) showed no significant change in reactivity, providing
tert-BuOH 1:1 (v/v), rt, 16 h. b Yield of isolated product.
18
For example, the two protected dipeptides 34 and 35 were
successfully coupled to glycosyl azide 8, affording the
glycopeptides 36 and 37 in 51 and 92% yields, respectively.
(
15) Triazole linkage appeared to be stable using, for example: 2.5 M
HCl in EtOAc, 2 h, rt; 1 M aqueous HCl, >5 days, rt; 1 M HCl in MeOH,
h, reflux; K2CO3 in MeOH, 4 h, rt; 1.25 M aqueous NaOH, 24 h, reflux.
16) van Esseveldt, B. C. J.; van Delft, F. L.; de Gelder, R.; Rutjes, F.
(17) Prepared from Boc-protected (S)-propargylglycine amide via de-
hydration: Cossu, S.; Giacomelli, G.; Conti, S.; Falorni, M. Tetrahedron
1994, 50, 5083.
(18) Dipeptides 34 and 35 were synthesized using a standard coupling
reaction involving PyBOP.
6
(
P. J. T. Org. Lett. 2003, 5, 1717.
Org. Lett., Vol. 6, No. 18, 2004
3125

19
Inversely, the disaccharide azide 38 was coupled to amino
acid 7 and dipeptide 34 in satisfactory yields (Table 4).
Considering the fact that disaccharides and dipeptides couple
very well under these conditions, we anticipate that also
larger and more complex oligosaccharides and oligopeptides
can be successfully ligated in this way.
Scheme 2. Cycloaddition between an R-Acetylenic Glycoside
and Azide-Containing Amino Acids
Since all examples so far comprise the combination of
azidoglycosides with acetylenic amino acids, we were
intrigued whether ligation of constituents with inverted
functionality, with the triazole-N1 position bound to the
amino acid, would also be feasible. To this end, acetylenic
glycosides and azide-containing amino acid derivatives were
prepared: the R- and â-acetylenic glucose derivatives 41 and
a
Reagents and conditions: 1 equiv of acetylenic glycoside 46,
1
2
equiv of azide, 0.2 equiv of Cu(OAc) , 0.4 equiv of sodium
ascorbate, H O/tert-BuOH 1:1 (v/v), rt, 16 h. Yield of isolated
20
b
46, respectively, from 2,3,4,6-tetra-O-benzyl-D-glucose, and
2
the required amino acid azides (42a-c and 43) from the
corresponding amines via azido transfer using TfN .
3
product.
2
1
Evidently, these “reversed” triazole-linked glycopeptides
were also readily obtained via the Cu-catalyzed [3 + 2]
cycloaddition. Both the R- and â-glycopeptide products were
formed uneventfully in yields ranging from 60 to 84% (Table
may explain the slightly lower yields. Furthermore, there is
again virtually no change in reactivity upon elongation of
the amino acid side chain as can be inferred from Table 5,
entries 1-3, and Scheme 2.
In conclusion, we have developed a straightforward,
versatile, and high-yielding method for the synthesis of a
novel class of glycopeptides. Both R- and â-triazole-linked
glycopeptides can be efficiently prepared using a variety of
suitably functionalized (oligo)saccharides and (oligo)peptides.
Currently, we aim at further expanding the scope of this
application and more specifically at the synthesis of triazole-
containing mimics of biologically active glycopeptides.
5
and Scheme 2). In general, amino acid derivatives
Table 5. Cycloaddition between a â-Acetylenic Glycoside and
Azide-Containing Amino Acids
Acknowledgment. S. A. M. W. van den Broek, B. C. J.
van Esseveldt, B. Verheijen, and M. IJsselstijn are kindly
acknowledged for the preparation of several compounds.
Senter (Ministry of Economic Affairs, The Netherlands) is
gratefully acknowledged for providing financial support.
glycopeptidea
yield (%)b
entry
amino acid
n
R
1
2
3
4
42a
42b
42c
43
1
2
3
1
H
h
H
Me
44a
44b
44c
45
70%
73%
71%
84%
Supporting Information Available: Experimental pro-
cedures and spectroscopic data of the triazole-linked glyco-
peptides. This material is available free of charge via the
Internet at http://pubs.acs.org.
a
Reagents and conditions: 1 equiv of acetylenic glycoside 41, 1 equiv
of azide, 0.2 equiv of Cu(OAc)2, 0.4 equiv of sodium ascorbate, H2O/tert-
BuOH 1:1 (v/v), rt, 16 h. Yield of isolated product.
b
OL048841O
containing a free carboxylic acid appeared to be somewhat
harder to purify than their methyl ester counterparts, which
(
20) Dondoni, A.; Mariotti, G.; Marra, A. J. Org. Chem. 2002, 67, 4475.
(21) (a) Rosenberg, S. H.; Spina, K. P.; Woods, K. W.; Polakowski, J.;
Martin, D. L.; Yao, Z. L.; Stein, H. H.; Cohen, J.; Barlow, J. L.; Egan, D.
A.; Tricarico, K. A.; Baker, W. R.; Kleinert, H. D. J. Med. Chem. 1993,
36, 449. (b) Lundquist, J. T.; Pelletier, J. C. Org. Lett. 2001, 3, 781.
(
19) Hepta-O-acetyl-â-lactosyl azide (38) was prepared from lactose by
8
peracetylation followed by treatment with SnCl4 and Me3SiN3.
3126
Org. Lett., Vol. 6, No. 18, 2004