5222
B. Wu et al. / Tetrahedron Letters 47 (2006) 5219–5223
OH
COOH
O
OH
HO
HO
H2N
NH
H2N
HN
NH
O
AcHN
HN
HO
HO
O
1) MesNa, PBS, TCEP
2) 10% morpholine
O
O
O
O
O
O
O
O
Fmoc
Fmoc
H
N
H
N
H
H
N
H
H
StBu
N
N
N
N
N
AcHN
N
N
H
O
N
S
N
N
N
O
O
S
3) 0.4 M MeONH2•HCl
H
H
H
H
H
O
O
O
O
O
O
O
O
S
S
OH
O
H
N
H
OH
OH
N
N
HO
HO
HO
HO
HO
HO
S
HO
O
HO
O
O
O
H2N
N
N
O
O
NH
H
H
NH
9
SEt
O
O
O
HO
HO
23
CONH2
AcHN
AcHN
AcHN
AcHN
10
Deprotection
OH
OH
COOH
O
HO
OH
O
HO
O
AcHN
HO
HO
HO
HO
H2N
NH
OH
O
O
O
HO
O
HO
HO
O
AcHN
O
HO
HN
NH
O
O
HO
AcHN
HO
AcHN
OH
O
SH
HO
O
O
O
O
O
O
O
O
O
O
O
HO
HO
H
H
H
N
H
H
H
H
H
O
OH
H2
HS
N
N
N
N
N
N
N
N
N
O
N
H
N
N
N
N
H
N
N
N
N
N
H
O
H
H
H
H
H
H
H
O
O
O
O
O
O
O
O
O
O
CONH2
S
OH
OH
HO
HO
HO
HO
O
O
O
O
SEt
8
24
NH
DmabO
HO
AcHN
AcHN
OH
COOH
O
OH
HO
OH
O
HO
O
AcHN
HO
High Mannose Core
Chitobiose
STn
HO
HO
HO
HO
OH
MesNa, PBS,
TCEP, DMF
O
HO
HO
HO
O
HO
HO
O
HO
O
O
HO
O
O
O
NH
O
NH
O
O
HO
AcHN
HO
HO
AcHN
AcHN
AcHN
AcHN
O
HO
O
O
HO
HO
O
OH
AcNH Ala Glu(ODmab) Asn Ile Thr Thr Gly Cys Ala Asn Arg Ser Gly Phe Cys Ala Thr Ala Ala Pro NH2
7
Scheme 7. Synthesis of 7 through reiterative glycopeptide coupling sequence.
described conditions to provide the complex, structur-
ally homogeneous glycopeptide 7, for the moment in
38% yield.
References and notes
1. (a) Varki, A. Glycobiology 1993, 3, 97–130; (b) Helenius,
A. Mol. Biol. Cell 1994, 2, 253–265; (c) Riederer, M. A.;
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Chem. Rev. 2002, 102, 285–303; (f) Grogan, M. J.; Pratt,
M. R.; Marcaurelle, L. A.; Bertozzi, C. R. Annu. Rev.
Biochem. 2002, 71, 593–634; (g) Nilsson, B. L.; Soellner,
M. B.; Raines, R. T. Annu. Rev. Biophys. Biomol. Struct.
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M.; Dawkins, F.; Perlin, E. J. Natl. Med. Assoc. 1994, 86,
129–135.
In summary, we have demonstrated the synthesis of a
multifunctional glycopeptide through reiterative native
chemical ligation. The compatibility of both N-linked
and O-linked glycans in this process is noteworthy. Its
ability to encompass the biologically critical sialic acid
glycosides is particularly encouraging. In our ongoing
quest to develop methodologies to enable the total syn-
thesis of multiply glycosylated complex glycoproteins of
potential clinical value, this new reiterative coupling
protocol constitutes an important, if early, entry. We
expect that the strategies and protocols of the type
disclosed herein will be extendable in our quest to build
homogeneous complex glycoproteins of value. An
important hurdle to be overcome in this pursuit
required solutions to the problem of noncysteine-based
ligation. Dramatic progress in this regard will be
disclosed soon.
3. (a) Okada, T.; Sato, Y.; Kobayashi, N.; Sumida, K.;
Satomura, S.; Matsuura, S.; Takasaki, M.; Endo, T.
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2004, 126, 736–738.
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Mandal, M.; Danishefsky, S. J. Angew. Chem. Int. Ed.
2004, 43, 2562–2565.
Acknowledgements
This work was supported by the NIH (CA28824 to
S.J.D.). We thank Dr. George Sukenick, Ms. Sylvi Rusli
and Ms. Hui Fang of the Sloan-Kettering Institute’s
NMR core facility for mass spectral and NMR spectro-
scopic analysis (SKI core Grant No.: CA02848). Post-
doctoral fellowship support is gratefully acknowledged
by BW (New York State Department of Health, New
York State Breast Cancer Research and Education
Fund) and JDW (NIH, CA62948).
5. Kornfeld, R.; Kornfeld, S. Annu. Rev. Biochem. 1985, 54,
631–664.
6. (a) Wang, Z. G.; Zhang, X.; Visser, M.; Live, D.; Zatorski,
A.; Iserloh, U.; Lloyd, K. O.; Danishefsky, S. J. Angew.
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Zhang, X.; Live, D.; Danishefsky, S. J. Angew. Chem. Int.
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Dudkin, V. Y.; Zhang, X.; Iserloh, U.; Visser, M.;