Selective synthesis of anomeric α-glycosyl acetamides via intramolecular Staudinger ligation of the α-azides

Article abstract of DOI:10.1016/j.tetlet.2003.12.159

α-Glycosyl azides can be transformed into the corresponding α-glycosyl acetamides with complete retention of configuration via reduction-acylation (Staudinger ligation) reactions using specifically functionalized phosphines. The α-acetamides of per-O-benz

Full text of DOI:10.1016/j.tetlet.2003.12.159

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 2231–2234
Selective synthesis of anomeric a-glycosyl acetamides via
intramolecular Staudinger ligation of the a-azidesq
Aldo Bianchi and Anna Bernardi*
Dipartimento di Chimica Organica e Industriale, Universitꢀa degli Studi di Milano, via Venezian 21, 20133 Milano, Italy
Received 5 November 2003; revised 10 December 2003; accepted 19 December 2003
Abstract—a-Glycosyl azides can be transformed into the corresponding a-glycosyl acetamides with complete retention of config-
uration via reduction–acylation (Staudinger ligation) reactions using specifically functionalized phosphines. The a-acetamides of
per-O-benzylated-fucose, per-O-benzylated-glucose and per-O-benzylated-galactose were selectively synthesized by this process.
Ó 2004 Elsevier Ltd. All rights reserved.
The synthesis of glycosyl amides is receiving increasing
attention because of the importance of glycopeptides
and glycoproteins in many biological processes. In the
course of our studies towards the design of glycomi-
metics we needed to evaluate whether a-fucosyl amides
could be used as building blocks to allow an easycon-
nection of the carbohydrate fragment to non-sugar
scaffolds. However, the a-amino glycopyranoses such as
1 required to form the corresponding amides are not
configurationallystable and immediatelyequilibrate to
the b-anomer (Scheme 1).
amides avoiding intermediate formation of the free
amines.1–6 However, in most cases, and in particular for
fucosyl derivatives (see below), anomerization remains a
significant problem.4
In this paper we show that the Staudinger ligation of
a-glycosyl azides7;8 with specificallyfunctionalized
phosphines is an effective method for synthesizing a-
fucosyl acetamides from a-fucosyl azide 4 and applies
equallywell to the synthesis of other a-glycosyl aceta-
mides. In the process, we also introduce a new and
effective method for the stereoselective synthesis of 4.
Various schemes have been proposed to circumvent this
process, which compromises the stereochemical integrity
of the product amides, and to synthesize a-glycosyl
a-Glycosyl azides are generally synthesized via SN2
azide displacement of anomeric halides9;10 or bytreating
Scheme 1. a ! b isomerization of anomeric amines precludes their use for the stereoselective synthesis of a-glycosyl amides.
Keywords: Carbohydrates; Glycosyl amides; Ligation reactions; Stereoselective synthesis.
q Supplementarydata associated with this article can be found, in the online version, at doi: 10.1016/j.tetlet.2003.12.159
* Corresponding author. Tel.: +39-02-50314092; fax: +39-02-50314072; e-mail: anna.bernardi@unimi.it
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.12.159

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A. Bianchi, A. Bernardi / Tetrahedron Letters 45 (2004) 2231–2234
Scheme 2. Stereoselective synthesis of the a-fucosyl azide 4. Reagents and conditions: (a) TMSI, CH2Cl2, 0 °C, 1 h; (b) Bu4NI, NaN3, CH2Cl2,
room temperature, 24 h (64% overall yield from 2); (c) reduction–acetylation of 4 (see tables).
monosaccharides acylated at position 1 and bearing a
non-participating group in position 2 with trimethylsilyl
azide.9 In the case of fucose, treatment of the acetate 2
with trimethylsilyl azide gave a 55:45 mixture of the
desired a-anomer 4 and of the corresponding b-azide.
The starting a-fucosyl azide 4 was synthesized with good
intermediate a-amine 1 (R ¼ Bn) could be trapped and
the fucosyl acetamide (Scheme 2) was formed in an
80:20 a/b ratio (Table 1, entry2). In contrast, using
THF in the presence of excess AcCl led to a 40:60 a/b
mixture in modest yield (Table 1, entry 3).
yields and total stereocontrol using glycosyl iodide
Reductive acylation of azides with thioacids has recently
been suggested for the conversion of glycosyl azides into
amides with no epimerization.6 However, treatment of 4
with excess AcSH in the presence of 2,6-lutidine gave a
1:1 mixture of anomers 5a and 6 in poor yield (Table 1,
entry4).
11;12
chemistry(Scheme 2).
Thus, starting from the ace-
tate 2, the a-iodide 3 was formed byreaction with
TMSI. Treatment of 3 with an excess of NaN3 in
CH2Cl2 in the presence of Bu4NI gave 4 in 64% overall
yield and in a one-pot sequence, which does not require
purification of the intermediate iodide. In the presence
of Bu4NI some b-iodide is presumablyformed from 3. It
has been shown12 that this more reactive anomer is
selectivelydisplaced in S N2 reactions byweak nucleo-
One-pot reduction–acylation of a-anomeric azides using
phosphines as the reducing agent (the Staudinger reac-
tion13) in the presence of acylating reagents has been
used to prevent anomerization with some success.2;4
Under these conditions an intermediate iminophosphor-
ane is initiallyformed (Scheme 3). This species is also
subject to anomeric isomerization, but it can be trapped
byaclyating agents to give a configurationallysta-
ble acylamino phosphonium salt. This in turn, upon
quenching, yields the corresponding amide. Thus,
starting from an a-azide, the anomeric ratio of the final
amide product depends on the relative ratio of the imino-
phosphorane anomeric equilibration (k1 in Scheme 3)
and of its acylation (k2).14 In practice, the group of
philes, such as alcohols. The low solubilityof NaN in
3
CH2Cl2 dampens its reactivityand allows selective for-
mation of the a-azide, presumablybyselective dis-
placement of the more reactive b-anomer of 3. Soluble
azide salts (i.e., Bu4NN3) are too reactive to display
11
a-selectivityin this reaction.
As expected, catalytic hydrogenation of 4, followed by
acetylation of the intermediate amine, gave the b-fucosyl
acetamide 6 (Scheme 2) in quantitative yield and with
complete stereocontrol (Table 1, entry1). Running the
catalytic hydrogenation in Ac2O as the solvent, the
€
ꢁ
Gyorgydeak has reported that a ! b epimerization can
onlybe avoided byusing verypotent acylating agents,
such as trifluoroacetic anhydride,4 and the range of
a-glycosyl amides that are readily available through this
procedure appears to be rather limited. Indeed, reaction
of 4 with Me3P followed bythe in situ addition of tri-
fluoroacetic anhydride afforded only the a-amide 5b
(Table 1, entry5), whereas addition of acetic anhydride
afforded exclusivelythe b-amide 6 (Table 1, entry6).
Similar results were obtained using other acetylating
agents. Under these conditions, the most a-selective
acetylating agent appeared to be pentafluorophenol
acetate (PFPOAc), which afforded a 20:80 a/b ratio of
anomers (Table 1, entry7).
Table 1. Reduction–acetylation of 4 under various reaction conditions
EntryReaction conditions
a/b
5:6 ratioa
Total Y
(%)
1
(a) H2/Pd in MeOH
0:100
98
(b) Ac2O, Et3N, CH2Cl2
H2/Pd, Ac2O, AcONab
H2/Pd, THF, AcCl, AcONab
AcSH, CHCl3, 2,6-lutidinec
2
3
4
5
80:20
40:60
50:50
100:0
80
50
23
76e
d
(a) Me3P in CH2Cl2
(b) (CF3CO)2O, Et3Nf
d
6
7
(a) Me3P in CH2Cl2
(b) Ac2O, Et3N, DMAPf
0:100
20:80
94
67
Recently, so-called ÔStaudinger ligationÕ reactions have
been introduced to couple peptides to azido groups.7;8
These reactions use specificallyfunctionalized phos-
phines to trap the Staudinger aza-ylide intermediates in
an intramolecular fashion, resulting in the direct for-
mation of an amide link. Fast, intramolecular acylation
of the anomeric nitrogen should prevent epimerization
of the anomeric carbon, therefore we examined the
reaction of 4 with two of the reported8 phosphine
reagents 715 and 8.16
d
(a) Me3P in CH2Cl2
(b) PFPOAcg
a Determined by 1H NMR of the crude products.
b 3 h at room temperature.
c 3 days at room temperature.
d 30 min at room temperature.
e Reaction product is 5b.
f 3 h, )78 °C.
g 3 h, 0 °C.

A. Bianchi, A. Bernardi / Tetrahedron Letters 45 (2004) 2231–2234
2233
Scheme 3. The mechanism of the Staudinger reduction–acylation of azides.
The 2-diphenylphosphino-N-acetylimidazole 7 reacts
veryslowlywith
ligation can be obtained at 70 °C. Both yields and a/b-
selectivitydisplayed a marked solvent effect, going from
10:90 a/b and 70% yield in THF (Table 2, entry 1) to
50:50 a/b and 68% yield in CCl4 (Table 2, entry3).
temperature was reduced to 40 °C following the disap-
pearance of the azide spot from the TLC plate, the
process became more selective, and the a/b ratio was
improved to synthetically useful levels (Table 2, entry 7).
4 at room temperature, but clean
This reaction can be extended to other glycosyl azides.
For instance the a-glucosyl azide 99 and the a-galactosyl
azide 109 (Scheme 4) were both reduced with complete
a-selectivitybytreatment with 8 at 70 °C in CCl4 for
24 h.17
Better results were obtained using phosphine 8, which
displayed a-selectivityin all the solvents examined
(Table 2, entries 4–7). Running the reactions at 70 °C
overnight in CCl4 (entry6) the acetamide was formed in
77% yield and in an 80:20 a/b ratio. In toluene (entry5),
a 75% yield and 85:15 a/b anomer ratio were obtained.
TLC inspection of the reaction course showed that at
70 °C in both solvents, consumption of the azide 4 was
complete in 3 h. At this stage an intermediate was
formed, which is slowlyconverted to 5a. When the
In conclusion, we have described here the first general
methodologyfor reductive aceltaytion (Staudinger
ligation) of a-glycosyl azides that proceeds with reten-
tion of configuration at the anomeric carbon. The
reagent employed, the functionalized phosphine 8,16 can
be easilysynthesized and handled, and can be stored
Table 2. Reduction–acetylation of 4 with functionalized phosphines 7
and 8
EntryReagent Solvent
T (°C) t (h)
a/b
ratioa
Yield
(%)
1
2
3
4
5
6
7
7
7
7
8
8
8
8
THF
70
70
70
70
70
2
6
10:90
30:70
50:50
75:25
85:15
80:20
94:6
70
25
68
50
75
77
84
Toluene
CCl4
THF
18
18
18
18
Toluene
CCl4
CCl4
70
b
b
Scheme 4. Reduction–acetylation of a-glucosyl and a-galactosyl azides
9 and 10. Reagents and conditions: (a) 1.2 equiv of 8, 24 h at 70 °C in
CCl4.
a Determined by 1H NMR of the crude products.
b 3 h at 70 °C, followed by24 h at 40 °C.

2234
A. Bianchi, A. Bernardi / Tetrahedron Letters 45 (2004) 2231–2234
6. Shangguan, N.; Katukojvala, S.; Greenberg, R.; Williams,
L. J. J. Am. Chem. Soc. 2003, 125, 7754–7755.
7. Nillson, B. L.; Kiessling, L. K.; Raines, R. T. Org. Lett.
2000, 2, 1939–1941.
8. Saxon, E.; Armstrong, J. I.; Bertozzi, C. R. Org. Lett.
2000, 2, 2141–2143.
under Ar as a 1 M toluene solution at 4 °C for several
weeks. The reaction could be applied to per-O-benzyl-
ated-glycosyl azides in the fuco-, gluco- and galacto-
series with good yields and selectivity. Further studies
are in progress to extend the scope of this reaction to
other acylating agents and to investigate the reaction
mechanism.
€
ꢁ
9. Gyorgydeak, Z.; Szitagyi, L.; Paulsen, H. J. Carbohydr.
Chem. 1993, 12, 139–163, and references cited therein.
10. Soli, E. D.; Manoso, A. S.; Patterson, M. C.; DeShong, P.;
Favor, D. A.; Hirshmann, R.; Smith, A. B., III. J. Org.
Chem. 1999, 64, 3171–3177.
11. Gervay, J.; Nguyen, T. N.; Hadd, M. J. Carbohydr. Res.
1997, 300, 119–125.
Acknowledgements
12. Hadd, M. J.; Gervay, J. Carbohydr. Res. 1999, 320, 161–
169.
13. Scriven, E. F. V.; Turnbull, K. Chem. Rev. 1988, 88, 351–
368.
14. A phosphotriazene is the first intermediate of the Stau-
dinger azide reduction. Acylation of this intermediate,
followed byelimination of N 2 and Ph3PO could also occur
(see Ref. 2).
We thank Andrea Colombo for suggestions in the initial
phases of this project, and Andrea Russo for preparing
the azides 9 and 10. Funding was provided in part bythe
European CommunityÕs Human Potential Programme
under contract HPRN-CT-2002-00173.
15. Curtis, N. J.; Brown, R. S. J. Org. Chem. 1980, 45, 4038–
4046.
References and notes
16. Rauchfuss, T. B. Inorg. Chem. 1977, 16, 2966–2968.
17. All new compounds were fullycharacterized by 1H and
13C NMR and byMS spectrometry(FAB). General
procedure for the Staudinger reduction–acylation: To a
solution of the a-azide (1 equiv) in CCl4 (0.1 M) at room
temperature under Ar, was added the phosphine 8
(1.2 equiv) (1 M solution in drytoluene). The reaction
mixture was stirred for the time and at the temperature
indicated in Table 2. The solvent was then evaporated
under reduced pressure. The residue was dissolved in
AcOEt and extracted with water: the organic layer was
dried over Na2SO4 and concentrated. The crude product
was purified byflash chromatographyusing 6:4 toluene/
AcOEt as the eluent.
1. Nair, L. G.; Fraser-Reid, B.; Szardenings, A. K. Org. Lett.
2001, 3, 317–319, and references cited therein.
2. Mizuno, M.; Muramoto, I.; Kobayashi, K.; Yaginuma,
H.; Inazu, T. Synthesis 1999, 162–165, and references cited
therein.
3. Boullanger, P.; Maunier, V.; Lafont, D. V. Carbohydr.
Res. 2000, 324, 97–106.
€
4. Kovacs, L.; Osz, E.; Domokos, V.; Holzer, W.;
ꢁ
Gyorgydeak, Z. Tetrahedron 2001, 57, 4609–4621, and
€
references cited therein.
ꢁ
5. Damkaci, F.; DeShong, P. J. Am. Chem. Soc. 2003, 125,
4408–4409.