One-pot azidochlorination of glycals

Article abstract of DOI:10.1021/ol102750h

A simple one-pot azidochlorination for the preparation of nitrogen-containing Koenigs-Knorr glycosyl donors proceeds upon reaction of protected glycals with sodium azide, ferric chloride, and hydrogen peroxide. Different mono-and disaccharide galactals an

Full text of DOI:10.1021/ol102750h

ORGANIC
LETTERS
2011
Vol. 13, No. 4
545–547
One-Pot Azidochlorination of Glycals
€
Carolin Plattner, Michael Hofener, and Norbert Sewald*
Department of Chemistry, Organic and Bioorganic Chemistry, Bielefeld University,
€
Universitatsstr. 25, 33615 Bielefeld, Germany
norbert.sewald@uni-bielefeld.de
Received November 12, 2010
ABSTRACT
A simple one-pot azidochlorination for the preparation of nitrogen-containing Koenigs-Knorr glycosyl donors proceeds upon reaction of
protected glycals with sodium azide, ferric chloride, and hydrogen peroxide. Different mono- and disaccharide galactals and glucals are converted
in a highly R-selective manner to the 2-azido glycosyl chlorides. Starting from disaccharide galactals, building blocks for the synthesis of the
T-antigen are obtained in a straightforward manner. The simplicity of the reaction conditions allows for an efficient and scalable R-selective
synthesis of 2-azido substituted glycosyl chlorides.
2-N-Acetamido-2-deoxygalactosides, among other
2-acetamido-2-deoxysugars, are key components of
naturally occurring glycoconjugates and oligosaccha-
rides.1,2 They are present in glycoproteins on the cell
surface playing major roles in biological recognition
processes, such as cell adhesion, cell differentiation,
and immuno-recognition.3 The aminosugars serve as
receptor ligands for enzymes,4 antibodies,5 and lectins;6
are the key moiety of tumor-associated antigens (TN-antigen
and T-antigen, Figure 1);7 and are present in antifreeze
glycoproteins.8
Figure 1. Structures of the TN- and the T-antigen.
Hence, an efficient preparation of 2-acetamido galacto-
side precursors and, in a more general way, for 2-acetami-
do functionalizedglycosyl donors is of high importancefor
oligosaccharide and glycopeptide syntheses. There are
various methods for the preparation, starting from pro-
tected glycals as reagents. The azidonitration,9 the nitra-
tion of glycals,10,11 and the azidophenylselenation
reaction12,13 have to be mentioned in this context. A one-
pot azidochlorination resulting directly in 2-azido substituted
(1) Herzner, H.; Reipen, T.; Schultz, M.; Kunz, H. Chem. Rev. 2000,
100, 4495–4537.
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1017–1029.
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Chem. 1968, 46, 405–411.
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1994, 59, 8256–8260.
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Rudiger, H. ChemBioChem 2004, 5, 740–764.
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r
10.1021/ol102750h
2011 American Chemical Society
Published on Web 01/18/2011

Koenigs-Knorr donors has been claimed in a patent.14
According to this procedure, a mixture of ferric chloride,
ferrous sulfate, ammonium peroxodisulfate, hydrogen
peroxide, and sodium azide is used for the conversion of
galactals to 2-azido galactosyl chlorides. All these proce-
dures suffer from specific problems such as low yields, the
requirement of a large reagent excess, and hazardous
reaction conditions.
We have developed a one-pot azidochlorination procedure
that uses few, nontoxic, and simple reagents in practically
stoichiometric amounts. The synthesis uses protected gly-
cals like, e.g., 3,4,6-tri-O-acetyl-D-galactal 1a as the star-
ting material and ferric chloride hexahydrate (0.8 equiv),
sodium azide (1.1 equiv), and hydrogen peroxide (1.1 equiv)
(Table 1) as reagents. The reaction is easily reproduced
on different reaction scales and provides high yields (up
to 78%).
The method was repeatedly applied up to 15.0 g of the
starting material giving reproducibly good yields of about
70% of the protected 2-azido galactosyl chloride 2a. The
crude mixture consisted of the R-anomer as the major
product (85-90%) and different byproducts in low amounts.
Minute amounts of the β-anomer could only be detected in
the samples after purification by SiO2 column chromato-
graphy. However, chromatographic purification is detri-
mental as it results in a considerable loss of material due to
hydrolysis and/or decomposition.
Scheme 1. Synthesis of a TN-Antigen Building Block
Table 1. Azidochlorination of 3,4,6-Tri-O-acetyl-D-galactal 1a
The crude azido chlorides can be used under typical
Koenigs-Knorr activation conditions to prepare glycosy-
lated amino acid building blocks or glyco conjugates
(Scheme 1).15 The azido derivative 2a was used to prepare
the glycosylated threonine building block 4. The yields and
diastereoselectivities of the threonine glycosylation are
comparable to those reported for the corresponding bro-
mide 3 obtained from an azidonitration reaction followed
by bromination.9,18
We have furthermore subjected a series of differently
protected galactals and other glycals to the reaction con-
ditions to explore the scope of method. Generally, other
protecting groups of the benzyl, benzoyl, and silyl type are
also tolerated in glycals (Table 2). However, it must be
stated that incomplete conversion occurred in the case of
glucal derivative 5 and the galactal 1d. Adding larger
amounts of reagents did not improve the results. Instead,
larger amounts of byproduct were formed.
In particular, the high yields in the case of the protected
disaccharide glycals 7 have to be stressed as they represent
precursors of the T-antigen moiety.7 The protected galac-
tal 7a was completely converted to a yield of 69% of the
corresponding 2-azido galactal 8a without significant am-
ounts of byproduct. Notably, one hydroxyl group was un-
protected. Likewise, the peracetylated galactal 7b gave
78% of crude chloride 8b. As for the azido chloride 2a,
the crude material could be used in subsequent reactions
without purification.
molar ratio
FeCl3 H2O/NaN3/H2O2
conditions
yielda
3
3.0/2.0/2.0
1.1/1.1/1.5
0.8/1.2/1.5
0.8/1.1/1.1
0.8/1.2/1.5
0.8/1.2/1.5
CH3CN, -30 °C, 3 h
CH3CN, -30 °C, 3 h
CH3CN, -30 °C, 7 h
CH3CN, -20 °C, 7 h
CH3CN, 0 °C, 6 h
78%
71%
74%
70%
62%
-
CH3CN, rt, 16 h
a Unpurified product. Yield determined by 1H NMR after complete
conversion of starting material.
Variation of the reaction conditions revealed that
larger amounts of the reagents do not distinctly influ-
ence the reaction time and the yield. Strikingly, no
reaction occurred at room temperature, while the reac-
tion proceeded smoothly at 0 °C with a slightly reduced
yield compared to the reaction at -30 °C. Acetonitrile is
the solvent of choice, as all reagents are dissolved at the
chosen concentration. Stirring and subsequent workup
of the homogeneous reaction is clearly facilitated com-
pared to working with a suspension. No conversion was
observed in THF, dioxane, and methylene chloride.
Moreover, the yields are not improved under strictly
anhydrous reaction conditions. Large amounts of inor-
ganic salts are employed in the literature procedures of
azidonitration and azidochlorination and have to be
removed in the workup.9,14 In contrast, our protocol
only employs stoichiometric amounts or a slight excess
of the inorganic components which can be easily re-
moved by aqueous workup.
(15) Paulsen, H.; Adermann, K. Liebigs Ann. Chem. 1989, 751–769.
(16) Park, M. H.; Takeda, R.; Nakanishi, K. Tetrahedron Lett. 1987,
28, 3823–3824.
ꢀ
ꢀ
(17) Padron, J. I.; Vazquez, J. T. Tetrahedron: Asymmetry 1995, 6,
857–858.
(18) Broddefalk, J.; Nilsson, U.; Kihlberg, J. J. Carbohydr. Chem.
1994, 13, 129–132.
(14) Naicker, S.; Noujaim, A. Patent US4935503, 1990.
546
Org. Lett., Vol. 13, No. 4, 2011

Table 2. Azidochlorination of Different Glycalsa
a Reaction conditions: 0.8 equiv of FeCl3 H2O, 1.1 equiv of NaN3, 1.1 equiv of H2O2 in CH3CN, -35 °C, 4-8 h. b Determined by 1H NMR.
3
c Unpurified product.
In conclusion, the one-pot azidochlorination described
here clearly improves and simplifies the preparation of
2-azido glycosyl donors. For many interesting substrates,
the reaction gives reproducibly good yields between 60 and
90% and can be easily upscaled to multigram reactions.
Not only the acetyl protected monosaccharide glycals but
also disaccharide glycals can be used as substrates leading
mainly to the R-configured products. A relatively broad
variety of starting glycals is accepted, though incomplete
conversion occurs occasionally. This efficient and conve-
nient method is an attractive alternative for the preparation
of T- and TN-antigen precursors compared to the methods
employed so far.
Acknowledgment. We thank Deutsche Forschungsge-
meinschaft (SFB 613) for financial support.
Supporting Information Available. A general experi-
mental procedure and full spectroscopic data for com-
pounds 2a-d, 4, 6, 8a, and 8b. This material is available
free of charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 4, 2011
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