J. Am. Chem. Soc. 1999, 121, 5089-5090
5089
Bending Trisaccharides by a Chelation-Induced Ring
Flip of a Hinge-Like Monosaccharide Unit
Hideya Yuasa* and Hironobu Hashimoto*
Department of Life Science
Faculty of Bioscience and Biotechnology
Tokyo Institute of Technology
Nagatsuta, Midori-ku
Yokohama 226-8501, Japan
ReceiVed NoVember 25, 1998
Chelation-induced conformational change of polypeptides is a
useful strategy in de novo protein design,1 which ultimately aims
at the construction of artificial proteins with tailor-made structures
and functionalities. Employing this strategy with oligosaccharides
may lead to the development of novel sugar-based architectures.
Although the addition of metal ions to solutions of some natural
polysaccharides causes coil-helix transitions2,3 and some monosac-
charides undergo shifts in the ring conformation equilibrium by
the addition of metal ions,2,4 the extent to which metal ions
influence these conformational properties is usually small, and
no extraordinary conformations are created.
Figure 1. Structures of hinge sugar 1 and the hinged trisaccharides 2
and 3. Upon chelation of a metal ion (Hg2+ or Zn2+), a ring flip of the
hinge unit is induced to give the turn structure shown in the upper right.
In the frame is the global minimum of the turn structure of 2-Zn2+
,
In this study, we created a novel turn structure of the
preliminarily calculated by molecular dynamics simulation (MM2 force
field, 300 K); all hydrogen atoms are omitted for clarity.
4
trisaccharides 2 and 3 by a hinge-like C1-to-1C4 ring flip of the
2,4-diamino-2,4-dideoxy-â-D-xylopyranoside unit (Figure 1). This
ring flip was enabled by the flexible ring structure5 and the strong
chelating ability of diamino groups in the 1,3-diaxial orientation.6
Conformational behavior of the methyl glycoside 1 and that of
the hinge unit on addition of metal ions were investigated by 1H
NMR.
Scheme 1a
The methyl glycoside 1 was synthesized in five steps from the
known compound 47 (Scheme 1). The methods for synthesizing
2,4-diazido-2,4-dideoxy derivatives of glucopyranoside8 and
R-xylopyranoside9 were employed for the synthesis of the key
intermediate 7. Birch reduction of 7 gave the compound 1. The
trisaccharides 2 and 3 were designed to mimic the trisaccharide
sequence (Galâ1-3GlcNAcâ1-2ManR)10 of complex N-linked
glycans, in which the central sugar, GlcNAc, is replaced with
the hinge unit. Introduction of the mannose units at the reducing
end of 1 was accomplished by conversion of 7 into the
1-O-trichloroacetimidate 10 and then conversion of 10 by the
Schmidt method11 to give disaccharides 11 and 12. Galactose
residues were incorporated into 11 and 12 by the trichloroace-
(1) (a) Kohn, W. D.; Kay, C. M.; Sykes, B. D.; Hodges, R. S. J. Am. Chem.
Soc. 1998, 120, 1124-1132. (b) Schneider, J. P.; Kelly, J. W. J. Am. Chem.
Soc. 1995, 117, 2533-2546. (c) Kohn, W. D.; Hodges, R. S. Trends
Biotechnol. 1998, 16, 379-389. (d) Schneider, J. P.; Kelly, J. W. Chem. ReV.
1995, 95, 2169-2187.
a (a) MsCl, pyr; then 88% AcOH, 80%. (b) NaOMe. (c) MsCl, pyr,
90% in 2 steps. (d) NaN3, Bu4NBr, toluene-H2O (1:1), 140 °C, 7, 51%;
8, 21%. (e) Ac2O, H2SO4, 89%. (f) H2NNH2‚AcOH, DMF, 50 °C. (g)
Cl3CCN, Cs2CO3, ClCH2CH2Cl, 58% in 2 steps. (h) Na, liq. NH3, 88%.
(i) M-OH, TMSOTf, CH3CN, -40 °C; then NaOMe. 11, 63%; 12, 53%
(R-isomer: 23%). (j) G-OC(dNH)CCl3, BF3‚OEt2, MS4A, CH2Cl2, -78
°C f rt. 13, 71%; 14, 86%. (k) NaOMe; then H2S, pyr-H2O (1:1); then
Na, liq. NH3, -78 °C. 2, 50%; 3, 63%.
(2) Whitfield, D. M.; Stojkovski, S.; Sarkar, B. Coord. Chem. ReV. 1993,
122, 171-225.
(3) Wittgren, B.; Borgstro¨m, J.; Piculell, L.; Wahlund, K.-G. Biopolymers
1998, 45, 85-96.
(4) (a) Angyal, S. J. AdV. Carbohydr. Chem. Biochem. 1989, 47, 1-43.
(b) Whitfield, D. M.; Sarkar, B. J. Inorg. Biochem. 1991, 41, 157-170. (c)
Symons, M. C. R.; Benbow, J. A.; Pelmore H. J. Chem. Soc., Faraday Trans.
1 1984, 80, 1999-2016.
timidate method to give trisaccharides 13 and 14, which were
subjected to deprotection and reduction of the azido groups to
give the desired trisaccharides 2 and 3.
(5) See, for example: Kim, J. M.; Roy, R. J. Carbohydr. Chem. 1997, 16,
1281-1292.
(6) Hausherr-Primo, L.; Hegetschweiler, K.; Ru¨egger, H.; Odier, L.;
Hancock, R. D.; Schmalle, H. W.; Gramlich, V. J. Chem. Soc., Dalton Trans.
1994, 1689-1701.
The 1H NMR spectrum of 1 showed the J-values characteristic
of the 4C1 chair conformation (Figure 2a), and these did not change
within the temperature range 298-353 K. Addition of diamagnetic
metal ions, Hg(OAc)2 and Zn(OAc)2, caused a line-broadening
at 298 K (Figure 2b). This line-broadening can be explained by
the relatively slow exchange process between different structures
when there are more than two structures, because acceleration of
the process by increasing the temperature up to 348 K resulted
(7) Helm, R. F.; Ralph, J.; Anderson, L. J. Org. Chem. 1991, 56, 7015-
7021.
(8) Paulsen, H.; Koebernick, H.; Stenzel, W.; Ko¨ll, P. Tetrahedron Lett.
1975, 1493-1494.
(9) Janairo, G.; Malik, A.; Voelter, W. Liebigs Ann. Chem. 1985, 653-
655.
(10) Gal, GlcNAc, and Man denote galactose, N-acetyl-glucosamine, and
mannose, respectively.
(11) Schmidt, R. R.; Behrendt, M.; Toepfer, A. Synlett 1990, 694-696.
10.1021/ja984062p CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/15/1999