N-glycosyl amides: Removal of the anomeric protecting group and conversion into glycosyl donors

Article abstract of DOI:10.1002/anie.200351351

Reactivity upon demand: Because of their stability towards acids, bases, and many oxidizing and reducing agents, N-glycosyl amides 1 (see scheme) can be used as anomerically protected carbohydrates. The amide function can be cleaved under mild conditions

Full text of DOI:10.1002/anie.200351351

Communications
Anomeric Protecting Groups
N-Glycosyl Amides: Removal of the Anomeric
Protecting Group and Conversion into Glycosyl
Donors**
Norbert Pleuss and Horst Kunz*
Dedicated to Professor Helmut Schwarz
on the occasion of his 60th birthday
Scheme 1. General reaction scheme for the synthesis of glycosides
from N-glycosyl amides. PG=protecting group.
During the past years important functions of the carbohy-
drates in glycoconjugates have been discovered in bio-
[
1,2]
logical recognition phenomena.
Recently developed
methods for the synthesis of glycosides and saccharides
used as model substances have been crucial to the
considerable progress made in this area. Besides modern
[
3]
versions of the Koenigs–Knorr reaction, the trichloro-
[
4]
acetimidate method and the activation of thioglycosides
[
6]
with soft thiophilic activators have become increasingly
important. Glycosyl donors such as thioglycosides, 4-
[
7]
[8]
pentenylglycosides, and to some extent also glycals
have the advantage of being stable enough to serve as
anomerically protected compounds as long as they are not
exposed to electrophiles. They also are not stable under the
conditions of hydrogenolysis, for example, during the
removal of benzyl protecting groups.
Scheme 2. Conversion of N-glycosyl acetamide 5 into orthoester 7 and
transition-metal-catalyzed rearrangement of orthoester 7 into glycoside 8.
N-Glycosyl amides are stable under acidic as well as
under basic conditions and also insensitive towards oxidation
and hydrogenation. Because of their resistance to cleavage,
N-glycosyl amides have not been considered as protecting
groups for the anomeric center. In contrast, the inertness of
temperature that it releases acetonitrile with formation of
the glycosyl cation to furnish the acyloxonium ion or the a-
glycosyl bromide (analogous to 3), which in the absence of
alcohols can be isolated and identified by NMR spectroscopy.
When a base and allyl alcohol are added, orthoester 7 is
obtained.
4
the N -glycosylasparagine structure, which is based on the
stability of N-glycoproteins, has been used for many years in
biochemical analyses for differentiation against O-glycopro-
teins.
The unexpected reactivity of imidoyl bromide 2 was
utilized to develop a new method for the synthesis of
glycosides. First amide 1 was treated with the Appel reagent.
[
9]
[
12]
We describe here a mild method not only for the cleavage
of N-glycosyl amides as anomeric protecting groups but also
for their activation as glycosyl donors in glycoside synthesis. It
consists of a retro-Ritter reaction, which is initiated by the
Then, instead of the tertiary amine, silver triflate was used
with the alcohol to yield glycoside 4. The electronic features
of the amide substituent have a significant effect on the
efficiency of this glycoside synthesis, as is shown by the yields
of stereoselective glycosylation reactions of N-galactosyl
amides 5 and 9 with alcohols and amines (Scheme 3,
Table 1). N-Galactosyl amides 5 and 9 were prepared
almost quantitatively from 2,3,4,6-tetra-O-pivaloyl-b-d-galacto-
[
10]
treatment of glycosyl amide 1 with the Appel reagent
triphenylphosphane/tetrabromomethane (Scheme 1). The
reaction was discovered when N-(2,3,4,6-tetra-O-pivaloyl-b-
d-galactopyranosyl)acetamide (5) was to be converted into
O-allyl-imidoester 6 (Scheme 2). Surprisingly, allyl orthoester
[
13]
pyranosylamine and the corresponding acid chlorides in the
presence of triethylamine in dichloromethane. Under basic
conditions the electron-rich anomeric amide 9 is much more
stable than 5, but under acidic conditions they are compara-
7
was isolated instead. Orthoester 7 undergoes rearrangement
when treated with copper or scandium triflate catalysts to give
allyl glycoside 8. Apparently the imidoyl bromide intermedi-
ate (analogous to 2, Scheme 1) is so unstable at room
[
*] Prof. Dr. H. Kunz, Dipl.-Chem. N. Pleuss
Institut für Organische Chemie
Universität Mainz
Duesbergweg 10–14, 55128 Mainz (Germany)
Fax: (+49)6131-392-4786
E-mail: hokunz@uni-mainz.de
[
**] This work was supported by the Deutsche Forschungsgemeinschaft
Scheme 3. Glycosylation reactions with N-glycosyl acetamide 5 and
N-glycosyl anisamide 9.
and the Fonds der Chemischen Industrie.
3
174
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/anie.200351351
Angew. Chem. Int. Ed. 2003, 42, 3174 – 3176

Angewandte
Chemie
Table 1: Synthesis of O- and N-glycosides 10 from N-glycosyl amides 5
and 9.
R’-XH
Product Yield [%] from 5 Yield [%] from 9
1
1
0a
0b
27
38
81
60
1
1
0c
0d
24
11
69
83
1
0e
–
66
NH3
10 f
0g
25
45
79[13]
74
1
ble. Thus, electronic effects do not affect the capacity of N-
glycosyl amides as protecting groups.
Scheme 4. Reactions of tetra-O-acetyl-protected glycosyl bromide 12.
The results in Table 1 show that the glycosides 10 are
obtained in moderate yields from acetamide 5 but in good
yields from anisoyl amide 9, which has higher electron density
at the oxygen atom of the carbonyl group. Furthermore, acid-
labile structures in the glycosyl acceptor (10b) are not
affected, and even steroid alcohols like 10e can be glycosyl-
ated. The examples 10 f and 10 g show that N-glycosides are
also accessible by this method. It should be noted that
pivaloyl-protected glycosyl donors, which block the formation
the amide carbonyl oxygen atom. The N-glycosyl trifluoro-
acetamide analogous to 5 cannot be transformed into a
glycosyl donor by this procedure. This example shows that the
described glycosylation method employing an amide as the
anomeric function and a nitrile as the leaving group is
formally an inversion of Schmidt's trichloroacetimidate
method, in which a nitrile is introduced for anomeric
activation and an amide serves as the leaving group.
In summary glycosylation reactions with N-glycosyl
amides exhibit a number of advantages. The N-glycosyl
amides are very stable compounds that can be activated at
room temperature under mild and neutral conditions. Labile
functional groups in the glycosyl acceptors are not affected,
and a variety of alcohols and amines can be glycosylated with
high yields.
[
4]
[
14]
of orthoesters by steric hindrance,
reactive. For this reason they are often used in the synthesis
are generally less
[
15,16]
of complex oligosaccharides,
especially since the O-
acetyl-protected glycosyl bromides undergo undesired side
reactions in the presence of silver triflate, resulting mainly the
formation of orthoesters and products of their further
[
14]
conversion.
This method for activating N-glycosyl amides can be
applied to O-acetyl-protected compounds like N-(tetra-O-
acetyl-b-d-galactopyranosyl)anisoyl amide (11, Scheme 4).
The tetra-O-galactosyl bromide 12, which is formed almost
quantitatively by treatment with the Appel reagent, reacts
with di-O-isopropylidene galactopyranose and silver triflate
to give galactoside 13 and the corresponding orthoester 14.
During workup orthoester 14 is hydrolyzed to give the
anomerically deprotected compound 15. The total yield of
this anomeric activation is high, although glycoside 13 is
obtained only in moderate yields due to the side reactions of
Experimental Section
General procedure for glycosylation reactions with N-glycosyl amide
9
: To a solution of 9 (200 mg, 0.31 mmol) and PPh3 (162 mg,
0.62 mmol) in anhydrous CH CN (15 mL) under an argon atmos-
3
phere was added a solution of CBr
CH CN (5 mL) at room temperature. The reaction mixture was
(306 mg, 0.92 mmol) in dry
4
3
stirred for 4 h, then a solution of the glycosyl acceptor (1.5–3 equiv)
and AgOTf (158 mg, 0.62 mmol) in anhydrous CH CN (5 mL) was
3
added. The mixture was stirred for 18 h, AgBr was filtered off,
anhydrous CH Cl (100 mL) was added, and the solution was washed
2
2
[
14]
acetyl-protected glycosyl bromides mentioned above. With
water as the nucleophile, compound 15 can be prepared
almost quantitatively and used for activation, for example as
with saturated aqueous NaCl (3 ” 30 mL). The organic layer was dried
over MgSO , the solvent removed in vacuo, and the resulting residue
4
purified by chromatography on silica gel (cyclohexane/EtOAc 3:1 to
5:1) to afford O- and N-glycosides.
[
4]
trichloroacetimidate. When the glycosyl bromide is reacted
with an amine, N-b-galactosylpiperidine 16 can be isolated in
good yield since orthocarboxylic acid derivatives of amines
are more acid-labile than orthoesters.
Received: March 7, 2003 [Z51351]
A major requirement for the activation of N-glycosyl
amides with the Appel reagent is sufficient electron density at
Keywords: Appel reagent · glycosides · glycosyl amides ·
protecting groups · retro-Ritter reaction
.
Angew. Chem. Int. Ed. 2003, 42, 3174 – 3176
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ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3175

Communications
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176
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Angew. Chem. Int. Ed. 2003, 42, 3174 – 3176