Optimized procedure for the synthesis of 6-azido-6-deoxy-galactopyranosides from 6-O-tosyl-galactopyranosides

Article abstract of DOI:10.1080/00397910500408787

The reaction conditions for preparation of 6-azido-6-deoxy-glycoside remain elusive, although there are many successful cases in hand. After careful investigation of the reaction conditions, a practical procedure for the preparation of 6-azido-6-deoxy-gal

Full text of DOI:10.1080/00397910500408787

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Optimized Procedure for the Synthesis of
6‐Azido‐6‐deoxy‐galactopyranosides From
6‐O‐Tosyl‐galactopyranosides
Shu‐Chun Li a , Xiang‐Bao Meng a , Meng‐Shen Cai a & Zhong‐Jun Li a
a Department of Chemical Biology, School of Pharmaceutical Sciences, State
Key Laboratory of Natural and Biomimetic Drugs , Peking University Health
Science Center , Beijing, China
Published online: 16 Aug 2006.
To cite this article: Shu‐Chun Li , Xiang‐Bao Meng , Meng‐Shen Cai & Zhong‐Jun Li (2006) Optimized
Procedure for the Synthesis of 6‐Azido‐6‐deoxy‐galactopyranosides From 6‐O‐Tosyl‐galactopyranosides,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
36:5, 637-643
To link to this article: http://dx.doi.org/10.1080/00397910500408787
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Synthetic Communicationsw, 36: 637–643, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500408787
Optimized Procedure for the Synthesis of
6-Azido-6-deoxy-galactopyranosides From
6-O-Tosyl-galactopyranosides
Shu-Chun Li, Xiang-Bao Meng, Meng-Shen Cai, and
Zhong-Jun Li
Department of Chemical Biology, School of Pharmaceutical Sciences,
State Key Laboratory of Natural and Biomimetic Drugs, Peking
University Health Science Center, Beijing, China
Abstract: The reaction conditions for preparation of 6-azido-6-deoxy-glycoside
remain elusive, although there are many successful cases in hand. After careful inves-
tigation of the reaction conditions, a practical procedure for the preparation of 6-azido-
6-deoxy-galactopyranoside derivatives was demonstrated.
Keywords: Aqueous DMF, 6-azido-6-deoxy-galactoside, nucleophilic substitution
INTRODUCTION
Synthetic approaches to azidodeoxysugars have been widely described in the
literature because since these compounds are precursors of aminoglycoside
antibiotics. Several efficient methods for the introduction of an azido group
at sugar C-6 have been developed: 1) The displacement reactions of C-6
halides[1] with sodium azide; 2) the displacement reactions of 6-O-
tosylates,[1,2] mesylates,[3] and triflates,[4] of sugars with sodium azide; 3)
the direct selective reactions of primary hydroxyl groups with PPh3/CBr4/
[5]
NaN3, or a Mitsunobu procedure;[6] 4) The displacement reactions of
sugar isoureas with NaN3.[7]
Received in Japan July 30, 2005
Address correspondence to Zhong-Jun Li, Department of Chemical Biology, School
of Pharmaceutical Sciences, State Key Laboratory of Natural and Biomimetic Drugs,
Peking University Health Science Center, Beijing 100083, China.
637

638
S.-C. Li et al.
Among all these methods, the displacement of sulfonates with azido ions
are by far the most common procedures, because the 6-O-sulfonates can be
obtained readily by treatment of sugar with a sulfonyl chloride in the
presence of pyridine or triethylamine.
It is well known that the rates of the bimolecular replacements involving
anionic nucleophiles are enchanced in polar aprotic solvent. N,N-dimethyl
formamide (DMF) is frequently used in preparation of carbohydrate azide
because it has a lower boiling point than dimethyl sulfoxide (DMSO) or hex-
amethylphosphortriamide (HMPT). Most researchers employ the anhydrous
solvents, whereas others add water.[2c,8]
The substitution of 6-O-sulfonate group by azide is widely used but not
universally applicable, being subject to the following restrictions. The
incoming nucleophile is hindered when the C4-O-substituent is in an axial
position[9] (i.e, 6-O-tosyl-galactosides), thus the rates and yields of the displa-
cement of 6-O-tosyl-galactosides with sodium azide are always lower than
those of 6-O-tosyl-glucosides or -mannosides; the nucleophilic substitution
may also be frustrated by acyl migration or formation of 3,6-[1,10] or
4,6-anhydro derivatives[2b] under anhydrous conditions, where sodium azide
acts as a weak Lewis base; the discrepant results from different groups may
be due, at least in part, to the subtle factors controlled by the investigators.
Anderson reported that the addition of an amount of water to DMF
increases the solubility of sodium azide enough to more than offset the
intrinsic rate-depressing effect of the water.[8] In the present article, to
overcome the unfavorable factors and seek for a reproducible procedure, the
displacement reactions of several 6-O-tosyl-galactosides with sodium azide
were studied under various conditions in detail. We found that the yields of
the displacement reactions of 6-O-tosyl-galactosides with sodium azide in
aqueous DMF are considerable better than those in anhydrous solvent.
RESULTS AND DISCUSSION
Because 6-O-tosylate and 6-azido-6-deoxy galactoside derivatives are both
subject to elimination, decomposition, and even carbonization at high temp-
erature, we found that a yellow to dark brown solution was obtained after
24 h if the reaction temperature is between 90 and 140 8C. All the reactions
were carried out at 80 8C. We firstly choose 6-O-tosyl-1,2,3,4-di-O-isopropy-
lidenegalactopyranoside[8,11] (Figure 1) as the substrate to optimize the
reaction in various solvents. 1,2,3,4-di-O-isopropylidence-d-D In Table 1 it
may be seen that the best yield (88%) of the nucleophilic displacement of
6-O-tosyl galactoside was obtained at 80 8C in DMF containing 10% water.
6-Azido-6-deoxy-1,2,3,4-di-O-isopropylidene-a-D-galactopyranoside
can
also be prepared in quantitive yield in DMSO at 160 8C.[12] It should be
pointed out that the high-boiling-point solvent cannot be used universally;
for example, the synthesis of methyl 6-azido-6-deoxy-a-D-galactopyranoside

Synthesis of 6-Azido-6-deoxy-galactopyranosides
639
Figure 1.
was frustrated by working up and formation of anhydro sugar. The additive,
tetrabutylammonium iodide (TBAI), does not seem to improve the yield of
this reaction. The yield was decreased in DMF containing more or less
water than 10%. In DMF containing some other protic solvent, such as
ethanol, the yield was lower than that in the solvent of DMF containing
water. The reactions did not work at all in protic solvent, such as ethanol or
aqueous ethanol under reflux.
To further extend the scope of the substrates, other three 6-O-tosyl-galac-
tosides (2,[10a] 3,[3b] and 4,[10a] Figure 1) derivatives were prepared and tried
under selected conditions (Table 2). The yields of the displacement
reactions in DMF containing 10% water improved more obviously than
those in anhydrous solvent, especially substrate 4.
The typical SN2 reaction may be transformed into a pseudo-first-order
process in aqueous DMF. The reaction rate increased after the solubility of
nucleophile increased.[8] The solubility of sodium azide increased in DMF con-
taining more than 10% water, but the solubility of the substrates decreased. At
the same time, the hydrolysis rate heightened dramatically. As a compromise,
Table 1.
Solvent
(additive)
NaN3
(eqiv)
Temp
(8C)
Time
(h)
Isolated
yield (%)
Entry
1
2
Dry DMF
Dry DMF
Dry DMF
1.0
2.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
80
80
24.0
24.0
24.0
24.0
24.0
24.0
24.0
24.0
24.0
24.0
24.0
24.0
48
56
58
76
88
71
65
65
0
3
80
80
4
DMF (5% H2O)
DMF (10% H2O)
DMF (15% H2O)
DMF (20% H2O)
DMF (10% ethanol)
95% ethanol
5
80
80
6
7
80
80
8
9
Reflux
Reflux
80
10
11
12
Ethanol (10% H2O)
DMF/(TBAI)
0
69
85
DMF/(10% H2O þ
80
5% mol TBAI)

640
Table 2.
S.-C. Li et al.
Solvent
(additive)
Temp
(8C)
Time
(h)
Isolated
yield (%)
Entry Substrate
1
2
3
4
5
6
7
8
2
2
3
3
4
4
4
4
Dry DMF
DMF (10% H2O)
Dry DMF
80
80
80
80
80
80
80
80
30
30
30
30
30
30
30
30
65
88
57
85
35
78
46
78
DMF (10% H2O)
Dry DMF
DMF (10% H2O)
DMF (TBAI)
DMF (10% H2O þ
5% mol TBAI)
the reaction yield and rate is better in DMF containing 10% water than in any
other conditions. The unfavorable reactions (acyl migration and formation of
anhydro sugar) catalyzed by the weak Lewis base, NaN3, under anhydrous
conditions, were also avoided in the aqueous solution.
All the reactions (listed in Tables 1 and 2) were carried out in parallel in a
100-mg scale. Grams-scale of 6-deoxy-6-deoxy galactosides can be prepared
under the optimized condition and give consistent and satisfied isolated yields.
In conclusion, we have found a practical procedure for the preparation of
6-azido-6-deoxy-galactopyranoside derivatives under simple conditions. The
optimized procedure is reproducible, does not need the anhydrous DMF,
and gives the desired products in good yields.
EXPERIMENTAL
General Methods
1H and 13C NMR spectra were recorded on a Varian VXR 300 spectrometer
with Me4Si as the internal standard and CDCl3 or Me2SO-d6 as solvent.
Optical rotations were measured at 25 8C with an Optical Activity AA-10R
polarimeter. The progress of reactions was monitored by TLC on silica-gel
GF254 plates. Detection was performed by examination under UV light and
by charring with 5% phosphomolybdic acid hydrate in EtOH or 15% concd.
H2SO4 in EtOH. Preparative TLC was performed on silica-gel GF254 plates
and column chromatography on silica-gel H. Only the desired product was
isolated, and the by-products were omitted.
Preparation of 6-O-Tosyl-galactopyranoside: 1, 2, 3, and 4
6-O-Tosyl-1,2,3,4-di-O-isopropylidene-a-D-galactopyranoside
(1)
was
prepared according to Ref. 8. Methyl 6-O-tosyl-a-D-galactopyranoside (4)

Synthesis of 6-Azido-6-deoxy-galactopyranosides
641
and methyl 6-O-tosyl-2,3,4-tri-O-acetyl-a-D-galactopyranoside (2) were
prepared following the known procedure.[10a] Methyl 6-O-tosyl-2,3,4-tri-O-
benzyl-a-D-galactopyranoside (3) was prepared from methyl a-D-galactopyr-
anoside via four steps.[3b] Data for compound 3: [a]D25 þ51.48 (c 0.70 CHCl3).
1H NMR (300 MHz; CDCl3): d ¼ 2.39 (s, 3H, PhCH3), 3.43 (s, 3H, H3CO–),
3.44–4.90 (m, 12H, H-2~6, 3 ꢀ PhCH2), 4.92 (d, 1H, J1,2 3.3 Hz, H-1), 7.13–
7.33 (m, 15H, 3 ꢀ Ph), 7.38 (d, 2H, J 8.1 Hz), 7.84 (d, 2H); 13C NMR
(75 MHz, CDCl3): d 21.67 (CH3Ph), 55.42 (CH3O), 69.17, 73.13, 73.38,
75.23, 76.04 (sugar C-2ꢀ6), 80.16, 80.17, 80.17 (3 ꢀ CH2Ph), 98.34 (C-1),
127.34, 127.51, 127.92, 128.18, 128.32, 128.47, 128.50, 128.62, 128.80,
129.57, 129.72, 133.42, 137.35, 137.57, 138.11, 144.84 (Ph); ESI-TOF MS
m/z: 636.24 (M þ NH4). Calcd. for C35H38O8S: 618.23.
General Procedure for 6-Azido-6-deoxy-1,2,3,4-di-O-
Isopropylidene-a-D-galacto-pyranoside
A suspension of 6-O-tosyl-1,2,3,4-di-O-isopropylidene-a-D-galactopyrano-
side (1, 100 mg, 0.32 mmol) and sodium azide in various solvents (2 mL,
listed in Table 1) was heated for 24 h at 80 8C. The cooled solution was
poured into ice water (10 mL) and extracted with chloroform (10 mL ꢀ 3).
The combined extracts was washed with water, dried (MgSO4), and evapor-
ated to leave a syrup. The pure product was obtained as a colorless oil after
separation on a preparative TLC (petroleum ether–ethyl acetate 4 : 1). The
spectral data was the same as reported.[8]
General Procedure for Methyl 6-Azido-6-deoxy-2,3,4-tri-O-acetyl-
a-D-galacto-pyranoside
A suspension of methyl 6-O-tosyl-2,3,4-tri-O-acetyl-a-D-galactopyranoside
(100 mg, 0.21 mmol) and sodium azide (42 mg, 0.64 mmol) in the solvent
(2 mL, listed in Table 2, entries 1 and 2) was heated for 30 h at 80 8C. The
cooled solution was poured into ice water (10 mL) and extracted with ethyl
ether (10 mL ꢀ 3). The combined extracts was washed with brine, dried
(MgSO4), and evaporated to give the crude product, which was purified on
a preparative TLC (petroleum ether–ethyl acetate, 2 : 1) to give a white
solid. The spectral data was the same as reported.[10a]
General Procedure for Methyl 6-Azido-6-deoxy-2,3,4-tri-O-benzyl-
a-D-galactopyrano-side
A suspension of methyl 6-O-tosyl-2,3,4-tri-O-benzyl-a-D-galactopyranoside
(100 mg, 0.16 mmol) and sodium azide (32 mg, 0.48 mmol) in the solvent
(2 mL, listed in Table 2, entries 3 and 4) was heated for 30 h at 80 8C. The

642
S.-C. Li et al.
cooled solution was poured into ice water (10 mL) and extracted with ethyl
ether (10 mL ꢀ 3). The extract was washed with brine, dried (MgSO4), and
evaporated to give the crude product, which was purified on a preparative
TLC (petroleum ether–ethyl acetate, 4 : 1) to give a colorless syrup. The
spectral data was the same as reported.[3b]
General Procedure for Methyl 6-Azido-6-deoxy-a-D-
galactopyranoside
A suspension of methyl-6-tosyl-6-deoxy-a-D-galactopyranoside (100 mg,
0.29 mmol) and sodium azide (57 mg, 0.87 mmol) in the solvent (2.0 mL,
listed in Table 2, entries 5–8; in entries 7 and 8, 6 mg of TBAI was added)
was heated for 30 h at 80 8C. The reaction mixture was evaporated in
vacuum. The residue was purified on PTLC (CHCl3–CH3OH, 8 : 1) and the
desired product was obtained as a colorless syrup. The spectral data was the
same as reported.[10a]
Scaled-Up Reactions
A suspension of 1 (2, 3, or 4) (5–10 mmol) and sodium azide (3 eq) in DMF–
H2O (9 : 1, enough to dissolve the tosylate) was heated for 24 h (30 h) at 80 8C.
The reaction solutions were worked up conventionally, and the crude products
were purified on flash column chromatography to give the desired products in
75–90% yields.
ACKNOWLEDGMENTS
We are grateful the financial support from the National Nature Sciences foun-
dation of China (No. 30330690 and 20372003).
REFERENCES
1. Maunier, V.; Boullanger, P.; Lafont, D.; Chevalier, Y. Synthesis and surface-active
properties of amphiphilic 6-aminocarbonyl derivatives of D-glucose. Carbohydr.
Res. 1997, 299, 49–57.
2. (a) Kieburg, C.; Sadalapure, K.; Lindhorst, T. K. Glucose-based AB2-building
blocks for the construction of branched glycopeptidomimetics. Eur. J. Org.
Chem. 2000, 2035–2040; (b) Hansen, H. C.; Magnusson, G. Synthesis of
selected aminodeoxy analogues of galabiose and globotriose. Carbohydr. Res.
1999, 322, 166–180; (c) Szarek, W. A.; Jones, J. K. N. Carbohydrates containing
nitrogen in a five-membered ring and an attempted synthesis of a carbohydrate
with nitrogen in a seven-membered ring. Can. J. Chem. 1965, 43, 2345–2356.

Synthesis of 6-Azido-6-deoxy-galactopyranosides
643
3. (a) Bullock, C.; Hough, L.; Richardson, A. C. A novel route to 1,4-anhydro deriva-
tives of b-D-galactopyranose. Carbohydr. Res. 1990, 197, 131–138;
(b) Yoshimura, J.; Asano, K.; Umemura, K.; Horito, S.; Hashimoto, H.
Synthesis of methyl 2,3-O-D-glycopyranosylidene-a-D-mannopyranosides
having various substituents. Carbohydr. Res. 1983, 121, 187–204.
4. Hui, Y.; Chang, C. T. Convenient divergent synthesis of a library of trehalosamine
analogues. Org. Lett. 2002, 4 (13), 2245–2248.
5. Blanco, J. L. J.; Fernandez, J. M. G.; Gadelle, A.; Defaye, J. A mild one-step
selective conversion of primary hydroxyl groups into azides in mono- and oligo-
saccharides. Carbohydr. Res. 1997, 303, 367–372.
6. (a) Moris-Varas, F.; Qian, X. H.; Wong, C. H. Enzymatic/chemical synthesis and
biological evaluation of seven-membered iminocyclitols. J. Am. Chem. Soc. 1996,
118, 7647–7652; (b) Lafont, D.; Boullanger, P. Preparation of primary and
secondary azidosugars from diols using the dioxaphosphorane methodology.
J. Carbohydr. Chem. 1999, 18, 675–688; (c) Kobayashi, Y.; Shiozaki, M.
Syntheses of trehazolin derivatives and evaluation as glycosides inhibitors.
J. Org. Chem. 1995, 60, 2570–2580.
7. Christian, S.; Ralf, M.; Helmut, R. Non-anomeric sugar isoureas. J. Carbohydr.
Chem. 2002, 21, 293–304.
8. Wu, M.; Anderson, L.; Slife, C. W.; Jenson, L. J. Effect of solvent, temperature,
and nature of sulfonate group on the azide displacement reaction of sugar sulfo-
nates. J. Org. Chem. 1974, 39 (20), 3014–3019.
9. Sugihara, J. M.; Teerlink, W. J.; MacLeod, R.; Dorrence, S. M.; Springer, C. Direct
syntheses of some cyano and nitro derivatives of carbohydrates by nucleophilic
displacement. J. Org. Chem. 1963, 28, 2079–2082.
10. (a) Carmen, L.; Romero, Z.; Oscar, V. Synthesis of 6-amino-6-deoxy-2,3,4,5-tetra-
O-methyl-D-galactonic acide, a key precursor of a steroregular polyamide.
J. Carbohydr. Chem. 2001, 20, 689–701; (b) Patel, A.; Lindhorst, T. K.
Synthesis of “mixed type” oligosaccharide mimetics based on a carbohydrate
scaffold. Eur. J. Org. Chem. 2002, 79–86.
11. 1,2,3, 4-di-O-isopropylidene-a-D-galactopyranoside adopted a skew-boat confor-
¨
mation. See Roslund, M. U.; Klika, K. D.; Lehtila, R. L.; Tahtinen, P.;
Sillanpaa, R.; Leino, R. Conformation of the galactose ring adopted in solution
¨
¨¨
1
and in crystalline form as determined by experimental and DFT H NMR and
single-crystal X-ray analysis. J. Org. Chem. 2004, 69, 18–25.
12. Joosten, J. A. F.; Evers, B.; van Summeren, R. P.; Kamerling, J. P.;
Vliegenthart, J. F. G. Synthesis of b-D-Galp-(1 ! 4)-b-D-GlcpNAc-(1 ! 2)-a-
D-Manp-(1 ! O)-(CH2)7CH3 mimics to explore the substrate specificity of sialyl-
transferases and trans-sialidases. Eur. J. Org. Chem. 2003 (18), 3569–3586.