COMMUNICATIONS
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From Glycals to Glycopeptides: A Convergent
and Stereoselective Total Synthesis of a High
Mannose N-Linked Glycopeptide**
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Samuel J. Danishefsky*
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Given the elaborate machinery required for the biosyn-
thesis of glycoproteins in cells, it seems likely that such
systems perform significant biological functions.[
1, 2]
Indeed,
1
3
1
997, 36, 6571; e) D. B. Hall, R. E. Holmlin, J. K. Barton, Nature 1996,
82, 731; f) R. E. Holmlin, P. J. Dandliker, J. K. Barton, Angew. Chem.
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protein glycosylation has been implicated in mediating
[3]
[4]
protein folding, in protecting against proteolysis, in
[5]
[6]
cellular differentiation, and in cell ± cell communication.
Hall, S. O. Kelley, J. K. Barton, Biochemistry 1998, 37, 15933.
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Major breakthroughs in the detection, purification, sequenc-
ing, and spectroscopic analysis of glycans have enabled a
growing appreciation of the role of glycobiology in vital life
[
[7]
[8±10]
processes. Chemical synthesis
can play an important role
[
10] A. A. Voityuk, J. Jortner, M. Bixon, N. Rösch, Chem. Phys. Lett. 2000,
24, 430.
in our understanding of glycobiology by providing access to
well-selected, homogeneous, but realistically complex, probe
structures for elucidating the relationship of glycoarchitecture
3
[
11] For studies involving similar X -DNA duplexes, see: a) K. Fukui, K.
Tanaka, M. Fujitsuka, A. Watanabe, O. Ito, J. Photochem. Photobiol.
B 1999, 50, 18; b) K. Fukui, K. Tanaka, Angew. Chem. 1998, 110, 167;
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AcidsRes . 1996, 24, 3962.
[11, 12]
and function.
Broadly speaking, glycoproteins are of two major types. In
one motif, the terminal galNAc hexose of the saccharide
domain is joined to the polypeptide through an a-O-glycosidic
[
12] S. Hess, M. Götz, W. B. Davis, M. E. Michel-Beyerle, unpublished
results. When intercalated in the DNA duplexes presented in this
[13]
paper, X displays a rapid excited-state relaxation (on the 50 ps time
linkage to the hydroxyl group of a serine (or threonine).
scale) which leads to energy loss. When a charge-shift reaction can
compete with this relaxation, the forward-transfer rate has been
shown to be (nearly) free of activation barriers and is faster than the
back-transfer rate, which is deep in the Marcus-inverted region of the
The target systems which prompted the research described
herein are N-linked glycoproteins, wherein the two domains
are joined through a b-N linkage of an asparagine group to a
.
[14]
log (rate) versus energy plot. In this case, the intermediate X is seen in
glcNAc unit at the reducing end of the oligosaccharide.
absorption. Conversely, when charge transfer cannot compete with
relaxation, there is excited-state energy loss and the activation energy
of the forward transfer increases. This leads to kinetics where the rate
of charge recombination is faster than that of the forward charge-shift
Specifically, we focused on a target where the consensus
core high mannose pentamer sequence (see below) would be
joined to the peptide domain through a carboxyl group of an
Asp side chain (1, Scheme 3). Our goals in reaching 1 by
chemical synthesis included a concise and efficient assembly
.
reaction and, thus, the X intermediate is not detectable.
[
[
[
13] The laser system used to obtain the data reported here has been
described in detail previously (M. Volk, G. Aumeier, T. Häberle, A.
[15]
of the required oligosaccharide. Clearly, global deprotec-
Ogrodnik, M. E. Michel-Beyerle, Biochim. Biophys. Acta 1992, 1102,
tion of diversely protected functionalities would eventually be
required. To this set of specifications we added another,
namely, that the fashioning of the asparagine linkage be
conducted in a maximally convergent sense with high stereo-
control by joining a fully mature high mannose saccharide to a
fully mature peptide. In this way we hoped to pave the way for
À4
2
53) and is arranged for ultrahigh sensitivity probing, DOD > 10
.
14] In the inverted region, electron-transfer reactions usually display
small activation energies due to vibronic coupling. See, for instance:
a) R. A. Marcus, N. Sutin, Biochem. Biophys. Acta 1985, 811, 265;
b) M. Bixon, J. Jortner, Adv. Chem. Phys. 1999, 106, 35.
15] Structural characterization of the duplexes using 2D-NMR techniques
is currently underway in collaboration with C. Griesinger, University
of Frankfurt.
[
[
[
[
16] A. A. Voityuk, N. Rösch, M. Bixon, J. Jortner, J. Phys. Chem. B 2000,
in press.
[
*] Prof. S. J. Danishefsky, Dr. Z.-G. Wang, X. Zhang
Laboratory for Bioorganic Chemistry
Sloan-Kettering Institute for Cancer Research
17] E. Meggers, D. Kusch, M. Spichty, U. Willie, B. Giese, Angew. Chem.
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ski, Nature 2000, 406, 51.
19] M. Bixon, B. Giese, S. Wessely, T. Langenbacher, M. E. Michel-
Beyerle, J. Jortner, Proc. Natl. Acad. Sci. USA 1999, 96, 11713.
1
275 York Avenue, New York, N.Y. 10021 (USA)
Fax : (1)212-772-8691
E-mail: s-danishefsky@ski.mskcc.org
Dr. D. Live
Deptartment of Biochemistry
Molecular Biol. and Biophysics University of Minnesota Minneapolis,
MN 55455 (USA)
Prof. S. J. Danishefsky
Department of Chemistry
Columbia University, Havemeyer Hall
New York, N.Y. 10027(USA)
E-mail: dshefsky@chem.columbia.edu
[
**] This work was supported by the National Institutes of Health (Grant
Numbers AI16943/CA28824). We thank Dr. George Sukenick of the
MSKCC NMR Core Facility for NMR and mass spectral analyses
(
NIH Grant Number: CA08748).
3652
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