A practical method for preparation of β-glycosides of N-acetylglucosamine

Article abstract of DOI:10.1016/j.tetlet.2004.04.127

A mild and efficient method for preparation of GlcNAc derivatives by reaction of glycosyl acceptors with glycosyl oxazolines has been developed. The key feature is use of Yb(OTf)₃ as promoter, requiring moderate reaction times and equivalence s

Full text of DOI:10.1016/j.tetlet.2004.04.127

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4891–4894
A practical method for preparation of b-glycosides of
N-acetylglucosamine
Curtis F. Crasto and Graham B. Jones*
Bio-organic and Medicinal Chemistry Laboratories, Department of Chemistry and Chemical Biology, Northeastern University,
360 Huntington Ave., Boston, MA 02115 USA
Received 13 April 2004; revised 20 April 2004; accepted 21 April 2004
Available online 8 May 2004
Abstract—A mild and efficient method for preparation of GlcNAc derivatives by reaction of glycosyl acceptors with glycosyl
oxazolines has been developed. The key feature is use of Yb(OTf)3 as promoter, requiring moderate reaction times and equivalence
stoichiometry. We anticipate application in the preparation of a wide range of derivatives of this biologically important class of
building blocks.
Ó 2004 Elsevier Ltd. All rights reserved.
The 2-acetamido-2-deoxy-
D
-glucose moiety (GlcNAc) is
tives, and sought to develop a mild and efficient coup-
ling strategy.
found in a wide variety of biologically significant
structures, including glycoproteins and lipids.1 Accord-
ingly, methodology for the efficient preparation of
GlcNAc derivatives remains an important component of
contemporary carbohydrate chemistry.2 A seemingly
attractive route involves reaction of O,N-acetyl pro-
tected glucosamines with donor nucleophiles, which
(proceeding via an oxazolinium intermediate) gives
mixtures of desired conjugate and varying amounts of
oxazoline (e.g., 1).3 Means to minimize formation of
oxazoline byproduct have been investigated but typi-
cally require substitution of the N-acetyl group for other
moieties, limiting the usefulness of the process given the
biological significance of GlcNAc derivatives.4 As the
oxazolines themselves are readily prepared from corres-
ponding glucosamine hydrochlorides (Ac2O, Py then
TMSOTf) a more reliable route involves direct coupling
of oxazoline with desired donor group in the presence of
activators.5 However, typical conditions often require
elevated temperatures and unfavorable stoichiometries,
the latter compounding purification of product by con-
ventional means. Due to an interest in the preparation
of glycosylated enediyne metabolites for screening as
sequence specific DNA binders, we required an effective
and reliable route for preparation of GlcNAc deriva-
Stimulated by reports of metal halide mediated glyco-
sylation procedures, 6 we were further guided by reports
from the Danishefsky laboratories on the activating
effects of lanthanide triflates for manipulating carbohy-
drate anomers.7 Our reasoning was that lanthanide
chelation to the oxazoline would result in anchimeric
activation to suitable alkanol acceptor species. After
consideration of various combinations of lanthanide
halides and acid catalysts, economic analysis pointed to
use of Yb(OTf)3.8 Using 1 with cyclohexanol and benzyl
alcohol as test substrates, a variety of conditions were
probed. In the absence of catalyst no coupled products
were formed even after several days whereas with
5 mol % Yb(OTf)3 products 2 were generated within
hours. The importance of TfOH in the cycle is high-
lighted when Et3N is added, ceasing conversion. Though
>90% conversion is typically achieved within 24 h using
1 equiv of catalyst, in practise using 30 mol % gave
comparable results (Scheme 1). Application to a panel of
alicyclic, aromatic, and heterocyclic acceptors was
effective (Chart 1) and the process was amenable to large
scale (ꢀ5 g) application, workup merely requiring fil-
tration through a silica gel plug and solvent removal.
The process is also compatible with other acetylated
aminosugars. As shown in Scheme 2, coupling of a
protected galactose with glucosamine derived 1 pro-
duces 7, whereas coupling with galactosamine derived 8
(Ac2O, Py then TMSOTf) gives coupled derivative 9 in
Keywords: Glycosylation; Enediyne; Aminoglucose; Lanthanide.
* Corresponding author. Tel.: +1-617-373-8619; fax: +1-617-373-8795;
e-mail: gr.jones@neu.edu
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.04.127

4892
C. F. Crasto, G. B. Jones / Tetrahedron Letters 45 (2004) 4891–4894
OAc
O
OAc
O
Yb(OTf)3 (30 mol equiv.)
CH2Cl2, reflux, 24 h
OR
O
AcO
AcO
AcO
AcO
ROH
+
N
HN
O
1
2
Scheme 1. Yb catalyzed preparation of b-glycosides.
OH
OAc
O
O
AcO
AcO
(75%)
(77%)
H
AcN
3
4
OH
OAc
O
AcO
AcO
O
Ac
H
N
O
OTMS
N
NH
OAc
O
O
N
AcO
AcO
(80%)
N
OTMS
5
Ac
H
N
O
O
OAc
O
O
AcO
AcO
(77%)
O
O
O
6
Ac
NH
HO
naphthyl
O
Chart 1. Yb catalyzed coupling of oxazolines with alcohol substrates.
OAc
Ac
1
O
O
O
O
OH
O
O
AcO
AcO
Yb(OTf)3
CH2Cl2
O
NH
O
O
O
O
O
7
(89%)
(83%)
+
OAc
AcO
AcO
O
O
O
Ac
O
OAc
O
AcNH
Yb(OTf)3
CH2Cl2
O
AcO
O
O
N
O
O
8
9
Scheme 2. Divergent routes to gal-glu and gal-gal derivatives.
good yield.5 Analysis of the likely mechanism of the
process suggests a cycle as depicted in Scheme 3, where
trifluoromethanesulfonic acid is cycled and is consistent
with observed effects of lanthanide loading, scavenging
of byproducts, induction period, and stoichiometry on
rate. Consistent with this pathway, it was evident that
at elevated temperatures and stoichiometries, partial
de-acetylation of product could be achieved on workup.
As the liberation of a Bronsted acid might be useful for
subsequent in situ product transformations, we sought
to demonstrate the application of the method to prep-
aration of library precursors where in situ unmasking of
the O-acetyl groups is desirable.
We have been particularly interested in preparation of
libraries of conjugates composed of biologically active
molecules coupled to post-activated enediynes.9;10 By
screening these chemically stable hybrids against bio-
logical targets in affinity driven assays, candidates can
then be identified for the study of the chemically reactive
enediyne parent with the biological target. This had led
to the discovery of enediyne–estrogens capable of
binding to and degrading human estrogen receptor.11
Given that the DNA binding of the enediyne antitumor
antibiotic calicheamicin has been linked to its pendant
aminosugar moiety,12 methodology for the production
and bioassay of aminosugar–enediyne hybrids is of

C. F. Crasto, G. B. Jones / Tetrahedron Letters 45 (2004) 4891–4894
4893
OAc
O
OTf-
OAc
O
AcO
AcO
AcO
AcO
+
O
N
O
N
TfO
Yb
TfO
ion-pair
ROH
Yb(OTf)3
TfOH
OAc
O
OAc
O
AcO
AcO
OR
O
AcO
AcO
OR
HN
N
O
TfO
Yb
TfO
Me
Me
TfOH
Scheme 3. Proposed mechanism for Yb catalyzed coupling.
OAc
O
OH
1
Ph
O
O
AcO
AcO
1 eq. Yb(OTf)3
HN
1,2-dichloroethane,
60%
Ph
10
11
1. 1 eq. Yb(OTf)3
ClCH2CH2Cl
2. H2O
OH
O
OAc
O
Ph
O
Ph
HO
HO
O
AcO
AcO
O
HN
O
HN
40%
12
13
Scheme 4. Preparation and in situ cycloaromatization of enediyne–glu hybrid.
potential significance. Accordingly, we wished to deter-
mine if the present coupling methodology could be used
to prepare such an agent, and then perform controlled
cycloaromatization. Enediyne 10, available from Pd
coupling methodology,13 was subjected to coupling with
1 using 1:1 stoichiometry (Scheme 4). To achieve effi-
cient coupling it was ultimately required to utilize a
higher boiling solvent, and under these conditions,
substantial quantities of the post-cyclized products
derived from conjugate 11 were recovered. Following
prolonged reaction (40 h) it was possible to isolate
coupled, cycloaromatized and deacetylated product 13,
presumably formed via capture of diyl radical 12 and
subsequent trifluoromethanesulfonic acid mediated
deprotection. Especially intriguing is the mechanism of
the cycloaromatization process, as attempts to deacetyl-
ate 11 in situ always resulted in cycloaromatization.
Given the propensity for Yb to form alkyne complexes14
and precedent for metal assisted Bergman cycloaromati-
zations,15 it is likely that this transformation can be
optimized yet further.16 Additionally, with a glycosy-
lated post-Bergman substrate in hand, we are now in a
position to study binding characteristics and design then
produce libraries of such analogs.
In summary, a facile method for preparation of GlcNAc
derivatives has been developed. Reagent acceptor stoi-
chiometry and mild conditions are attractive features,
and we anticipate application in the preparation of a
range of derivatives of this biologically important class
of building blocks.
Acknowledgements
Work in these laboratories was supported by grants
from the National Institutes of Health, Petroleum Re-
search Fund (Administered by the American Chemical
Society), Elsa U. Pardee Foundation, Department of

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C. F. Crasto, G. B. Jones / Tetrahedron Letters 45 (2004) 4891–4894
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