A stereocontrolled construction of 2-azido-2-deoxy-1,2-trans-β-glycosidic linkages utilizing 2-azido-2-deoxyglycopyranosyl diphenyl phosphates

Article abstract of DOI:10.1016/S0040-4039(03)01557-0

A high-yielding and stereocontrolled construction of 2-azido-2-deoxy-1,2-trans-β-glycosidic linkages has been achieved by exploiting TMSOTf-promoted 1,2-trans-glycosidation of 2-azido-2-deoxyglycopyranosyl diphenyl phosphates with various glycoside alcohols in propionitrile at -78°C. The present method exhibits the highest levels of 1,2-trans-β-selectivity reported to date for this type of glycosidation.

Full text of DOI:10.1016/S0040-4039(03)01557-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6453–6457
A stereocontrolled construction of
2
-azido-2-deoxy-1,2-trans-b-glycosidic linkages utilizing
2
-azido-2-deoxyglycopyranosyl diphenyl phosphates
Toshifumi Tsuda, Seiichi Nakamura and Shunichi Hashimoto*
Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
Received 3 June 2003; revised 21 June 2003; accepted 23 June 2003
Abstract—A high-yielding and stereocontrolled construction of 2-azido-2-deoxy-1,2-trans-b-glycosidic linkages has been achieved
by exploiting TMSOTf-promoted 1,2-trans-glycosidation of 2-azido-2-deoxyglycopyranosyl diphenyl phosphates with various
glycoside alcohols in propionitrile at −78°C. The present method exhibits the highest levels of 1,2-trans-b-selectivity reported to
date for this type of glycosidation.
©
2003 Elsevier Ltd. All rights reserved.
2
-Acetamido-2-deoxy-
D
-glycopyranosides are ubiqui-
An alternative approach to 2-acetamido-2-deoxy-b-
glycopyranosides involves the use of 2-azido-2-
deoxyglycopyranosyl donors. Although the azido group
as a latent amino functionality is incapable of neighbor-
ing group participation, the glycosidation of 2-azido-2-
tous constituents of biologically significant oligosaccha-
rides and glycoconjugates including glycolipids,
glycoproteins, proteoglycans, and peptidoglycan. Most
2
-acetamido-2-deoxy-D-glycopyranosides are present in
4
these molecules in 1,2-trans-b-glycosidic linkages.
deoxyglycosyl trichloroacetimidates in the presence of
5
BF ·OEt2 in CH Cl –hexane
or TMSOTf in
3
2
2
6
In terms of efficiency and practicality, direct glycosida-
tion using 2-acetamido-2-deoxyglycosyl donors should
constitute an ideal procedure for the stereocontrolled
construction of 2-acetamido-2-deoxy-1,2-trans-b-glyco-
acetonitrile has proven to be the method of choice for
a highly stereocontrolled construction of 2-azido-2-
deoxy-b-glycosides. Modest to good levels of b-selectiv-
7
ity were observed with the corresponding S-xanthates,
1
8
9
sidic linkages. In practice, however, reaction of these
isopropenyl carbonate, 2-pyridinecarboxylates, and
10
donors generally leads to the predominant formation of
oxazoline derivatives via neighboring group participa-
tion and subsequent abstraction of an amide proton.
To overcome this problem, a number of different 2-
amino protecting groups with an anchimeric assistance
have been investigated, though this method requires
two additional synthetic steps: deprotection and subse-
quent replacement by an acetyl group. The phthaloyl
phenylthio glycosides.
We have recently developed glycosyl donors incorpo-
rating a variety of phosphorus-containing leaving
groups, the glycosidations of which constitute mild and
efficient methods for the highly stereocontrolled con-
2
,3
struction of 1,2-trans-b- and 1,2-cis-a-glycosidic link-
11,12
ages with or without a participating group at C-2.
A
2
a
group has been most widely used for this purpose,
and results in high yields and virtually complete b-selec-
tivity with most glycosyl acceptors as has been demon-
recent report by Seeberger and co-workers concerning
TMSOTf-promoted glycosidations of 2-azido-2-
13
deoxyglucosyl dibutyl phosphate with modest b-selec-
strated by
a number of syntheses of complex
tivity has prompted us to report our efforts toward the
stereocontrolled construction of 2-azido-2-deoxy-b-gly-
cosides from 2-azido-2-deoxyglycosyl donors carrying
phosphorus-containing leaving groups.
oligosaccharides. However, removal of the phthaloyl
group requires relatively harsh conditions which often
cause partial decomposition of the product.
At the outset of this study, we explored glycosidations
Keywords: 2-azido-2-deoxyglycopyranosyl diphenyl phosphate; b-
selective glycosidation; a-nitrilium ion.
of 2-azido-2-deoxy-3,4,6-tri-O-benzyl-
diphenyl phosphate 1 (a:b=72:28 or 2:98) and tetra-
D
-glucopyranosyl
14
*
Corresponding author. Tel.: +81-11-706-3236; fax: +81-11-706-4981;
16
e-mail: hsmt@pharm.hokudai.ac.jp
methylphosphorodiamidate 2 (a:b=65:35) with 6- or
0
040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01557-0

6
454
T. Tsuda et al. / Tetrahedron Letters 44 (2003) 6453–6457
4
-O-unprotected glycosides 3 or 4 (1.1 equiv. each) as
Next, we selected the phosphate method for ease of
preparation of this type of donor, and explored glycosi-
dations of 2-azido-2-deoxyglycosyl phosphates 1 (a:b=
highly reactive and less reactive acceptor alcohols,
respectively. Some representative results are summa-
rized in Table 1, from which several features have been
noted.
14
14
72:28), 7 (a:b=95:5), and 8 (a:b=95:5) in the
D
-gluco and D-galacto series with a range of suitably
protected glycoside alcohols of different reactivities
(Scheme 1). The examples highlighted in Table 2
deserve some comments. In all cases, TMSOTf-pro-
moted glycosidations in propionitrile at −78°C were
found to offer a facile and high-yielding entry to 1,2-
trans-b-linked disaccharides, in which the a:b ratios
ranged from 9:91 to 1:>99. As touched on above,
Seeberger and co-workers reported that TMSOTf-pro-
moted coupling of 2-azido-2-deoxyglucosyl dibutyl
phosphate with glycoside alcohols 9 or 10 in acetoni-
trile at −40°C produced disaccharides 16 and 17 in
modest yields with a:b ratios of 1:4 and 1:5, respec-
1
1a
As expected from previous work,
moted glycosidations of the diphenyl phosphate 1 with
or 4 in propionitrile at −78°C proceeded smoothly to
TMSOTf-pro-
3
give disaccharides 5 and 6 in high yields with excellent
b-selectivity regardless of the anomeric composition of
the donor (entries 1–4). A solvent survey revealed that
propionitrile was the optimal solvent for this glycosida-
tion, bringing about a beneficial effect on the stereose-
lectivity as well as the reaction rate (entries 1 and 3
versus 5–8). As is consistent with the proposal by
17
6
Schmidt, an exceptionally high order of b-selectivity
13
tively. Clearly, the present method is superior to the
observed with both 3 and 4 may be explained by
dibutyl phosphate method in terms of both product
yield and stereoselectivity (entries 1 and 2). It is also
noteworthy that glucosylation of O-3-unprotected
galactose derivative 11 led to the exclusive formation of
disaccharide 18, which constitutes a building block of
assuming the predominant formation of an intermedi-
ate 2-azido-2-deoxy-a-D-glucosyl-nitrilium ion associ-
18
ated with triflate as a gegenion followed by the back-
side attack of acceptor alcohols on this intermediate.
Not unexpectedly, an increase in the reaction tempera-
ture was accompanied by a significant decrease in
stereoselectivity (entries 1 and 3 versus 9–11). As would
be expected if the reactions proceed via a common
mechanism, TMSOTf-promoted glycosidations of phos-
phorodiamidate 2 under the identical conditions exhib-
ited virtually the same b-selectivities as those with 1
x
gangliosides such as sialyl Lewis (entry 3). As might be
expected from the fact that the fully benzoylated gluco-
syl tetramethylphosphorodiamidate is unaffected at
1
9
temperatures below −5°C by such reaction conditions,
chemoselective glycosidation was uneventfully realized
by using O-6-unprotected glucosyl phosphorodiamidate
12 as a disarmed acceptor (entry 4). It is interesting to
note that 2-azido-2-deoxygalactosyl diphenyl phosphate
7 is even more reactive than the corresponding glucosyl
(
entries 12 and 13), albeit with a slightly lower yield in
the case of 4.
a
b
Table 1. TMSOTf-promoted glycosidation of 2-azido-2-deoxyglucosyl donors 1 and 2
Entry
Donor
ROH
Solvent
Temp. (°C)
Time (h)
Glycoside
Yield (%)d
c
e
a:b
a:b
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
1
2
2
72:28
2:98
72:28
2:98
72:28
72:28
72:28
72:28
72:28
72:28
72:28
65:35
65:35
3
3
4
4
3
3
4
4
3
4
3
3
4
EtCN
EtCN
EtCN
EtCN
CH Cl
−78
−78
−78
−78
−78
−65
−78
−65
−45
−45
−10
−78
−78
1.5
1.5
2
2
4
2
8
8
0.5
0.5
0.1
2.5
3
5
5
6
6
5
5
6
6
5
6
5
5
6
84
85
90
92
88
90
84
81
89
88
92
81
81
1:99
1:99
6:94
7:93
1:99
4:96
10:90
24:76
3:97
13:87
8:92
2:98
7:93
2
2
PhMe
CH Cl
2
2
PhMe
EtCN
EtCN
EtCN
EtCN
EtCN
10
11
12
13
a
b
c
Donor 1/ROH/TMSOTf molar ratio=1.0/1.1/1.5.
Donor 2/ROH/TMSOTf molar ratio=1.0/1.1/1.8.
31
Determined by 109 MHz P NMR using 85% H PO as an external standard.
3
4
d
e
Isolated yield based on the donor used.
The ratio was determined by HPLC (column, Zorbax Sil, 4.6×250 mm; eluent, 17% ethyl acetate in hexane; flow rate 1.0 mL/min).
®

T. Tsuda et al. / Tetrahedron Letters 44 (2003) 6453–6457
6455
In conclusion, we have demonstrated that TMSOTf-
promoted glycosidations of 2-azido-2-deoxyglycopyran-
osyl diphenyl phosphates with a variety of glycoside
alcohols give 1,2-trans-b-linked disaccharides in high
yields. Furthermore, these reactions proceed with the
highest levels of stereoselectivity reported to date for
this type of glycosidation, regardless of the anomeric
configuration of the donor, in which the key to the
success of the present protocol lies in a smooth cou-
pling in propionitrile at −78°C. This method has the
advantages of operational simplicity and practical
value, and thus should be a potent alternative to
21
Schmidt’s trichloroacetimidate procedure.
Acknowledgements
This research was supported in part by a Grant-in-Aid
for Scientific Research on Priority Areas (A) ‘Exploita-
tion of Multi-Element Cyclic Molecules’ from the Min-
istry of Education, Culture, Sports, Science and
Technology, Japan. T.T. is grateful to the JSPS for a
graduate fellowship. We thank Ms. H. Matsumoto, A.
Maeda, S. Oka, and M. Kiuchi of the Center for
Instrumental Analysis, Hokkaido University, for tech-
nical assistance in MS and elemental analysis.
Scheme 1.
References
1
. For reviews, see: (a) Banoub, J.; Boullanger, P.; Lafont,
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1997, 791–802.
donor 1 (entries 5–8), displaying slightly higher b-selec-
tivity than that of 1 (entry 5 versus entry 3 in Table 1).
20
In accordance with a general trend, the 4,6-O-benzyl-
idene protective group in 8 significantly reduced its
reactivity compared with the fully benzylated galactosyl
donor 7, yet had little effect on either product yield or
stereoselectivity (entries 9 and 10).
2. (a) Phthaloyl group: Lemieux, R. U.; Takeda, T.; Chung,
B. Y. ACS Symp. Ser. 1976, 39, 90–115; (b) 2,2,2-
trichloroethoxycarbonyl group: Imoto, M.; Yoshimura,
H.; Shimamoto, T.; Sakaguchi, N.; Kusumoto, S.; Shiba,
a,b
Table 2. Glycosidation of 2-azido-2-deoxyglycosyl diphenyl phosphates 1, 7 and 8
Entry
Donorc
ROH
Time (h)
Glycoside
Yield (%)d
e
a:b
1
2
3
1
1
1
1
7
7
7
7
8
8
9
10
11
12
4
13
14
15
3
2
1.5
2
16
17
18
19
20
21
22
23
24
25
91
79
89
88
93
85
82
86
78
90
9:91
2:98
1:>99
7:93g
4:96
5:95
6:94
8:92
3:97
4:96
f
4
2
5
6
7
8
9
0.5
0.2
0.3
0.5
3
1
0
4
3
a
b
c
The reaction was carried out on 0.1 mmol scale.
Donor/ROH/TMSOTf molar ratio=1.0/1.1/1.5.
The anomeric a:b ratio of the phosphates: 1, 72:28; 7, 95:5; 8, 95:5.
Isolated yield based on the donor used.
The ratio was determined by HPLC (column, Zorbax Sil, 4.6×250 mm; eluent, 17% ethyl acetate in hexane or 14–17% THF in hexane; flow
rate 1.0 mL/min), unless otherwise stated.
d
e
®
f
The reaction was performed with 2.0 equiv. of TMSOTf.
g
1
Determined by 500 MHz H NMR.

6
456
T. Tsuda et al. / Tetrahedron Letters 44 (2003) 6453–6457
T. Bull. Chem. Soc. Jpn. 1987, 60, 2205–2214; (c) allyl-
14. 2-Azido-2-deoxyglycosyl diphenyl phosphates were pre-
pared from the corresponding glycopyranoses according
oxycarbonyl and benzyloxycarbonyl groups: Boullanger,
P.; Jouineau, M.; Bouammali, B.; Lafont, D.; Descotes,
G. Carbohydr. Res. 1990, 202, 151–164; (d)
trichloroacetyl group: Blatter, G.; Beau, J.; Jacquinet, J.
Carbohydr. Res. 1994, 260, 189–202; (e) tetra-
chlorophthaloyl group: Debenham, J. S.; Madsen, R.;
Roberts, C.; Fraser-Reid, B. J. Am. Chem. Soc. 1995,
15a
to the method of Sabesan
[ClP(O)(OPh) , DMAP,
2
CH Cl , 0°C] except the donor 1 of a:b ratio of 2:98
2
2
which was obtained by the reaction of 2-azido-2-deoxy-
3,4,6-tri-O-benzyl-a- -glucopyranosyl trichloroacetimi-
D
5
15b
date (26a) with HOP(O)(OPh) in CH Cl . The crude
2
2
2
diphenyl phosphates 1, 7 and 8 were purified by column
chromatography (silica gel, 2:1–3:1 hexane/AcOEt with
1
17, 3302–3303; (f) dithiasuccinoyl group: Meinjohanns,
E.; Meldal, M.; Paulsen, H.; Bock, K. J. Chem. Soc.,
Perkin Trans. 1 1995, 405–415; (g) N,N-diacetyl group:
Castro-Palomino, J. C.; Schmidt, R. R. Tetrahedron Lett.
2% Et N).
3
15. (a) Sabesan, S.; Neira, S. Carbohydr. Res. 1992, 223,
169–185; (b) Schmidt, R. R.; Stumpp, M. Liebigs Ann.
Chem. 1984, 23, 680–691.
1
995, 36, 6871–6874; (h) 4,5-dichlorophthaloyl group:
Shimizu, H.; Ito, Y.; Matsuzaki, Y.; Iijima, H.; Ogawa,
T. Biosci. Biotechnol. Biochem. 1996, 60, 73–76; (i)
dimethylmaleoyl group: Aly, M. R. E.; Castro-Palomino,
J. C.; Ibrahim, E.-S. I.; El-Ashry, E.-S. H.; Schmidt, R.
R. Eur. J. Org. Chem. 1998, 2305–2316; (j) N,N-dibenzyl
group: Jiao, H.; Hindsgaul, O. Angew. Chem., Int. Ed.
Engl. 1999, 38, 346–348; (k) thiodiglycoloyl group:
Castro-Palomino, J. C.; Schmidt, R. R. Tetrahedron Lett.
16. The donor 2 was prepared from the corresponding
glucopyranose according to the literature procedure
[BuLi, THF, −78°C, then (Me N) P(O)Cl, HMPA,
2
2
−20°C], see: Hashimoto, S.; Yanagiya, Y.; Honda, T.;
Harada, H.; Ikegami, S. Tetrahedron Lett. 1992, 33,
3523–3526.
17. Typical procedure for the glycosidation of 2-azido-2-
deoxyglycopyranosyl diphenyl phosphate (Table 1, entry
3): TMSOTf (1.0 M in CH Cl , 0.15 mL, 0.15 mmol) was
2
000, 41, 629–632.
. For methods involving azaglycosidation of glycals, see:
a) Griffith, D. A.; Danishefsky, S. J. J. Am. Chem. Soc.
990, 112, 5811–5819; (b) Liu, J.; Gin, D. Y. J. Am.
2
2
3
added to a stirred solution of donor 1 (70.8 mg, 0.1
mmol) and acceptor 4 (51.1 mg, 0.11 mmol) in EtCN (1.5
mL) at −78°C under an argon atmosphere. After stirring
at this temperature for 2 h, the reaction was quenched
(
1
Chem. Soc. 2002, 124, 9789–9797.
4
. For reviews, see: (a) Schmidt, R. R. Angew. Chem., Int.
Ed. Engl. 1986, 25, 212–235; (b) Schmidt, R. R.; Kinzy,
W. Adv. Carbohydr. Chem. Biochem. 1994, 50, 21–123; (c)
Schmidt, R. R.; Jung, K.-H. In Carbohydrates in Chem-
istry and Biology, Ernst, B.; Hart, G. W.; Sina y¨ , P. Eds.;
Wiley-VCH: Weinheim, 2000; pp. 5–59.
with Et N (0.1 mL). The mixture was poured into a
3
two-layer mixture of AcOEt (5 mL) and H O (5 mL), and
2
the whole was extracted with AcOEt (15 mL). The
organic layer was successively washed with 10% aqueous
HCl, H O, saturated aqueous NaHCO3 and brine, and
2
dried over anhydrous Na SO . Filtration and evaporation
2
4
5
. Kinzy, W.; Schmidt, R. R. Liebigs Ann. Chem. 1985,
in vacuo followed by flash column chromatography (sil-
ica gel, 5:1 hexane/AcOEt) afforded disaccharide 6 (82.6
mg, 90%, a:b=6:94) as a colorless oil. The a:b ratio was
1
537–1545. High levels of b-selectivity achieved by this
method are mostly limited to the use of a-trichloroace-
timidates. See also Refs. 4a and 4b.
®
determined by HPLC (column, Zorbax Sil, 4.6×250 mm;
6
. Schmidt, R. R.; Behrendt, M.; Toepfer, A. Synlett 1990,
eluent, 17% ethyl acetate in hexane; flow rate 1.0 mL/
min; tR a-disaccharide, 18.0 min; tR b-disaccharide, 25.1
min).
6
94–696. In this paper, it was demonstrated that b-selec-
tivities are practically independent of the anomeric
configuration of the starting trichloroacetimidates.
18. Sakamoto, H.; Nakamura, S.; Tsuda, T.; Hashimoto, S.
Tetrahedron Lett. 2000, 41, 7691–7695.
19. Hashimoto, S.; Sakamoto, H.; Honda, T.; Ikegami, S.
7
8
9
. Marra, A.; Gauffeny, F.; Sina y¨ , P. Tetrahedron 1991, 47,
5
149–5160.
. Marra, A.; Esnault, J.; Veyri e` res, A.; Sina y¨ , P. J. Am.
Chem. Soc. 1992, 114, 6354–6360.
. Furukawa, H.; Koide, K.; Takao, K.; Kobayashi, S.
Tetrahedron Lett. 1997, 38, 5181–5184.
20. (a) Fraser-Reid, B.; Udodong, U. E.; Wu, Z.; Ottosson,
H.; Merritt, J. R.; Rao, C. S.; Roberts, C.; Madsen, R.
Synlett 1992, 927–942; (b) Douglas, N. L.; Ley, S. V.;
L u¨ cking, U.; Warriner, S. L. J. Chem. Soc., Perkin Trans.
1 1998, 51–65; (c) Zhang, Z.; Ollmann, I. R.; Ye, X.-S.;
Wischnat, R.; Baasov, T.; Wong, C.-H. J. Am. Chem.
Soc. 1999, 121, 734–753.
Chem. Pharm. Bull. 1998, 46, 1244–1247.
1
1
0. Cod e´ e, J. D.; Litjens, R. E. J. N.; den Heeten, R.;
Overkleeft, H. S.; van Boom, J. H.; van der Marel, G. A.
Org. Lett. 2003, 5, 1519–1522.
1. (a) Hashimoto, S.; Honda, T.; Ikegami, S. J. Chem. Soc.,
Chem. Commun. 1989, 685–687; (b) Tanaka, H.;
Sakamoto, H.; Sano, A.; Nakamura, S.; Nakajima, M.;
Hashimoto, S. Chem. Commun. 1999, 1259–1260 and
21. For comparison, TMSOTf-promoted glycosidation of 2-
azido-2-deoxy-3,4,6-tri-O-benzyl-
chloroacetimidate (26) with 3 or 4 was investigated
under ‘Schmidt’s standard conditions’ [TMSOTf (0.1
D
-glucopyranosyl
tri-
5
references
cited
therein.
See
also:
http://
6,22
www.glycoforum.gr.jp/science/word/glycotechnology/GT-
A01E.html.
equiv.), MS 4 A
,
, MeCN, −40°C].
The results are
summarized in the table. Glycosidation of 26 with 6-O-
unprotected glycoside 3 was found to give nearly the
same b-selectivities as those obtained by the diphenyl
phosphate method, regardless of the anomeric configura-
tion of the donor (entries 1 and 2). However, coupling of
26 with 4-O-unprotected glycoside 4 resulted in dimin-
ished b-selectivities (entries 3 and 4), in which the use of
a-imidate 26a gave less satisfactory yield (entry 3) due to
1
2. Recently, we have reported the selective construction of
b-mannosidic linkages capitalizing on 4,6-O-benzylidene-
protected
D-mannopyranosyl diethyl phosphite. See:
Tsuda, T.; Sato, S.; Nakamura, S.; Hashimoto, S. Hete-
rocycles 2003, 59, 509–515.
1
3. Plante, O. J.; Palmacci, E. R.; Seeberger, P. H. Org. Lett.
2
000, 2, 3841–3843.

T. Tsuda et al. / Tetrahedron Letters 44 (2003) 6453–6457
6457
the inevitable formation (35%) of trichloroacetamide
22. Greilich, U.; Zimmermann, P.; Jung, K.-H.; Schmidt, R.
23
2
7.
R. Liebigs Ann. Chem. 1993, 859–864.
2
3. For examples of the formation of N-glycosyl trichloroac-
etamides as by-products, see: (a) Sadozai, K. K.;
Nukada, T.; Ito, Y.; Nakahara, Y.; Ogawa, T.; Kobata,
A. Carbohydr. Res. 1986, 157, 101–123; (b) Kinzy, W.;
Schmidt, R. R. Liebigs Ann. Chem. 1987, 407–415; (c)
Nunomura, S.; Ogawa, T. Tetrahedron Lett. 1988, 29,
5
681–5684; (d) Kobayashi, M.; Yamazaki, F.; Ito, Y.;
Ogawa, T. Carbohydr. Res. 1990, 201, 51–67; (e) Lind-
berg, J.; Ohberg, L.; Garegg, P.; Konderson, P. Tetra-
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8