Efficient Synthesis of O-, S-, N- and C-Glycosides of 2-Amino-2-Deoxy-D- Glucopyranose from Glycosyl Iodides

Article abstract of DOI:10.1055/s-2003-44978

Glycosyl iodides of protected D-glucosamine are generated in situ under mild conditions and coupled with different kinds of nucleophiles, providing the corresponding β-glycosides in good yields.

Full text of DOI:10.1055/s-2003-44978

LETTER
341
Efficient Synthesis of O-, S-, N- and C-Glycosides of 2-Amino-2-Deoxy-D-
Glucopyranose from Glycosyl Iodides
Efficient
S
ynthesis
i
of
O
-,
c
S
-,
N
-
and
o
C
-Glycoside
l
s
as Miquel, Stefano Vignando, Giovanni Russo, Luigi Lay*
Dipartimento di Chimica Organica e Industriale and Centro Interdisciplinare Studi Bio-molecolari e Applicazioni Industriali (CISI),
Università degli Studi di Milano, via Venezian 21, 20133 Milano, Italy
Fax +39(2)50314061; E-mail: luigi.lay@unimi.it
Received 3 October 2003
Dedicated to Prof. R. R. Schmidt.
the protective groups of the monosaccharide precursor in
determining the chemical stability of the corresponding
iodide.14 Only few examples of glycosyl iodides from 2-
amino-2-deoxy sugars have previously been reported.9b,15
In 1976 Lemieux16 employed glycosyl deoxyphthalimido
halides (including iodide) as glycosyl donors in the syn-
thesis of three O-disaccharides. However, the glycosylat-
ing properties of the iodide were not further explored.
The direct synthesis of glycosyl iodides from protected
N-acetylglucosamine resulted unfeasible in our hands; we
therefore employed the dimethylmaleolyl (DMM) as N-
protecting group of acetylated or trimethylsilylated glu-
cosamine derivatives. The treatment of compound 117
with TMSI (1.1 equiv) in CH2Cl2 at room temperature re-
sulted in the complete formation of the corresponding b-
glycosyl iodide 4 in 30 minutes, as deduced by TLC anal-
ysis (Scheme 1). Since compound 4 was not isolable, we
carried out the reaction in a NMR tube in CDCl3 at 25 °C.
After 30 minutes, the spectrum showed the complete
formation of a new product with the anomeric proton as
a doublet at d = 6.56 (J1,2 = 10.1 Hz), thus confirming the
b-configuration.18
Abstract: Glycosyl iodides of protected D-glucosamine are gener-
ated in situ under mild conditions and coupled with different kinds
of nucleophiles, providing the corresponding b-glycosides in good
yields.
Key words: carbohydrates, glycosyl iodides, glycosylations,
stereoselective synthesis
Glycosides of 2-amino-2-deoxy sugars are present in the
most important classes of glycoconjugates and naturally
occurring oligosaccharides.1 In particular, glycosides of
N-acetylglucosamine are widely distributed in living
organisms as building blocks of peptidoglycans and mu-
copolysaccharides. They are also encountered as compo-
nents of human milk, blood group substances and
bacterial lipopolysaccharide antigens, where they consti-
tute part of the epitopes. Due to their great biological rel-
evance, new and reliable methods to synthesize
glycosides of 2-amino sugars are of outstanding impor-
tance.2 Herein, we report an efficient method for the syn-
thesis of O-, S-, N-, and C-glycosides of 2-amino-2-deoxy
sugars from the corresponding in situ generated glycosyl
iodides. Although the use of glycosyl halides in the forma-
tion of glycosidic bonds is largely documented in the lit-
erature,3 glycosyl iodides have not been widely utilized as
glycosyl donors,4 mainly because they are too reactive
and often difficult to handle and isolate.5 Nevertheless,
various methods to obtain glycosyl iodides have been in-
troduced, some employing forcing conditions of rather
limited applicability.6 More reliable protocols include the
generation of anomeric iodides under mild conditions
from glycosyl phosphates,7 phosphites8 and hemiacetals.9
Among them, the preparation of glycosyl iodides with
iodotrimethylsilane (TMSI) from fully protected sugars,
reported in 1980 by Thiem and Meyer, offers various
practical advantages.10 The use of TMSI for the genera-
tion of glycosyl iodides has been extended to different
substrates, such as persilylated11 and 1-O-acetylated ben-
zylated sugars.12 In particular Gervay et al. have exten-
sively employed glycosyl iodides in the synthesis of N-,
C- and O-glycosides and oligosaccharides.13 The exam-
ples mentioned above evidenced the crucial role played by
OR1
OR1
TMSI
(1.1 equiv)
O
O
R1O
R1O
R1O
R1O
OR1
I
NR2
NR2
1 R1 = Ac, R2 = DMM
2 R1 = TMS, R2 = DMM
3 R1 = Ac, R2 = Phth
4 R1 = Ac, R2 = DMM
5 R1 = TMS, R2 = DMM
6 R1 = Ac, R2 = Phth
Nu
Promoter
(when necessary)
OAc
O
AcO
AcO
Nu
NR2
R
2 = DMM or Phth
Scheme 1 Synthesis of glycosides and disaccharides via in situ
formed glycosyl iodides
SYNLETT 2004, No. 2, pp 0341–0343
0
2.
0
2.
2
0
0
4
Advanced online publication: 08.12.2003
DOI: 10.1055/s-2003-44978; Art ID: G26403ST
© Georg Thieme Verlag Stuttgart · New York

342
N. Miquel et al.
LETTER
Tetra-O-trimethylsilylated glucosamine 2, prepared as de- studied. Preliminary explorations with primary and sec-
scribed by Uchiyama and Hindsgaul,11a reacted with ondary amines in the absence of promoter invariably led
TMSI under the same conditions and provided even more to 1,2-elimination and the corresponding glycal 9
rapidly (20 min) the very unstable glycosyl iodide 5. In or- (Figure 1) was obtained in almost quantitative yields.
der to assess the influence of the glucosamine N-protec-
Table 1 Coupling Reactions with Various Nucleophiles of b-Glyc-
tion on the glycosyl iodide formation, we also studied the
osyl Iodides Generated in situ from N-Protected Glucosamine Precur-
reaction with TMSI of the N-phthalimido protected deriv-
sors 1–3
ative 3.19 Compound 3 reacted sluggishly when treated
with TMSI at room temperature, both in CH2Cl2 and in
toluene. However, the complete formation of the b-glyco-
syl iodide 6 took place in 45 minutes in toluene at 80 °C
(Scheme 1). The same reaction was carried out into a
NMR tube (C6D6, 75 °C); after 1 hour, a new single prod-
uct was observed in the spectrum, exhibiting an anomeric
signal at d = 6.90 (J1,2 = 10.0 Hz), which confirmed the b-
configuration.20 Subsequently, we explored the glycosy-
lating properties of the in situ generated glycosyl iodides
4–6.21 First, the glycosylation of simple alkyl alcohols
was examined. As shown in Table 1 (entries 1–4, 10–15),
donors 4–6 afforded the corresponding glycosides in good
to excellent yields. It should be emphasized that no pro-
moter was added to the reaction mixtures and exclusively
b-glycosides were obtained, thus implying an effective
anchimeric assistance from the N-protecting groups.
Moreover, the efficiency of the glycosylation was mostly
unaffected by the nature of the O-protecting groups (com-
pare entries 1–4 with 10–13). As expected, the more
challenging couplings with less reactive glycosyl accep-
tors 7 and 8 (Figure 1) required the addition of silver tri-
fluoromethanesulfonate (AgOTf) as a promoter.
Entry Donor
Nucleophile
(equiv)
Promoter
(equiv)
Yield
(%)a
1
4
4
4
4
4
4
4
4
MeOH (10)
AllOH (10)
i-PrOH (10)
BnOH (10)
7 (1.1)
–
94
92
81
74
81
51
94
80
2
–
3
–
4
–
5
AgOTf (1)
AgOTf (1)
–
6b,c
7
8 (1.1)
PhSH (10)
8
BF3·OEt2 (1)
SiMe3
(1.2)
TMSN3 (2)
9c
4
5
5
5
5
6
6
BF3·OEt2 (1)
80
88
90
79
74
78
74
10
MeOH (10)
AllOH (10)
i-PrOH (10)
BnOH (10)
AllOH (10)
i-PrOH (10)
–
–
–
–
–
–
11
12
13
14
15
HO
BnO
OAc
OBn
O
O
O
AcO
AcO
BnO
BnO
HO
BnO
BnO
NDMM
OMe
OMe
a Isolated total yields based on the donor precursors 1–3.
b Reaction started at 0 °C and performed in the presence of 2,6-di-
t-Bu-4-Me pyridine (1 equiv) as an acid scavenger.
c After iodide formation, the solvent was removed in vacuo and the
residue coevaporated twice with dry toluene to remove TMSOAc,
which can compete as a nucleophile in the following coupling
reaction.
7
8
9
Figure 1 Glycosyl acceptors 7, 8 and glycal 9
The primary acceptor 7 gave the corresponding b-disac-
charide in good yield (entry 5), whereas the sterically hin-
dered, unreactive O-4 unprotected glycoside 8 provided
the b-disaccharide in 51% unoptimized yield (entry 6). In
order to explore in more detail the versatility of these new
intermediates, the reactivity of 4 with nucleophiles other
than alcohols was also investigated (Table 1). When
thiophenol was allowed to react with 4 in the absence of
acidic promoter, the corresponding b-phenyl thioglyco-
side was obtained in 94% yield (entry 7). Allyl trimethyl-
silane, selected as a representative C-nucleophile, reacted
smoothly with intermediate 4 in the presence of BF3·OEt2
as a promoter to afford the b-C-allyl glycoside in 80%
yield (entry 8). This result is particularly remarkable, as it
could open a new and easy access to the challenging syn-
thesis of C-glycosides of 2-amino-2-deoxy sugars, a class
of carbohydrate analogues of great pharmaceutical inter-
est.22 Finally, the possibility of generating N-glycosidic
linkages by reaction with suitable N-nucleophiles was
Eventually, we found that the treatment of 4 with tri-
methylsilyl azide in the presence of BF3·OEt2 afforded the
b-glycosyl azide in 80% yield (entry 9). Glycosyl azides
are important intermediates in the synthesis of N-glyco-
conjugates, which largely occur in many biologically
relevant natural products. In conclusion, we have shown
that b-glycosyl iodides of suitably protected D-glu-
cosamine derivatives can be generated in situ under mild
conditions and stereoselectively coupled with various nu-
cleophiles, giving access to O-, S-, C- and N-glycosides of
2-amino-2-deoxy sugars. Due to the high biological
relevance of carbohydrate structures containing 2-amino
sugars, the promising versatility exhibited by these inter-
mediates is worth to be further explored and extended to
new substrates. These studies are currently in progress in
our laboratory.
Synlett 2004, No. 2, 341–343 © Thieme Stuttgart · New York

LETTER
Efficient Synthesis of O-, S-, N- and C-Glycosides
343
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Acknowledgment
Authors are grateful to the European Community (GlycoTrain
programme, HPRN-CT-2000-00001) for financial support.
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Synlett 2004, No. 2, 341–343 © Thieme Stuttgart · New York