Reactions of several monosaccharide-derived alcohols with p-acetamidobenzenesulfonyl azide and DBU

Article abstract of DOI:10.1016/j.tetlet.2011.03.066

Attempted diazo transfer to 1-O-(2-phenylacetyl)-2,3;5,6-di-O- isopropylidene-α-d-mannofuranose using p-acetamidobenzenesulfonyl azide (p-ABSA) and DBU as base affords 1-O-(2-diazo-2-phenylacetyl)-2,3;5,6-di-O- isopropylidene-α-d-mannofuranose in low yield along with 2,3;5,6-di-O-isopropylidene-α-d-mannofuranose, 1-azido-2,3;5,6-di-O- isopropylidene-β-d-mannofuranose, as well as the unreacted starting material. The azido sugar likely arises from α-mannofuranosyl sulfonate ester formation, through displacement of azide from p-ABSA by the sugar lactol, followed by stereospecific displacement by azide anion on the furanosyl sulfonate ester. This outcome has been studied further with the conditions being applied to several common monosaccharide derivatives. Accessible substrates afford the azido sugar in an overall one-pot alcohol-to-azide conversion, while hindered substrates yield the sulfonate esters.

Full text of DOI:10.1016/j.tetlet.2011.03.066

Tetrahedron Letters 52 (2011) 2670–2672
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Reactions of several monosaccharide-derived alcohols
with p-acetamidobenzenesulfonyl azide and DBU
⇑
Iulia A. Sacui, Peter Norris
Department of Chemistry, Youngstown State University, 1 University Plaza, Youngstown, OH 44555, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Attempted diazo transfer to 1-O-(2-phenylacetyl)-2,3;5,6-di-O-isopropylidene-a-D-mannofuranose using
Received 15 January 2011
Revised 13 March 2011
Accepted 14 March 2011
Available online 23 March 2011
p-acetamidobenzenesulfonyl azide (p-ABSA) and DBU as base affords 1-O-(2-diazo-2-phenylacetyl)-
2,3;5,6-di-O-isopropylidene- -mannofuranose in low yield along with 2,3;5,6-di-O-isopropylidene-
-mannofuranose, 1-azido-2,3;5,6-di-O-isopropylidene-b- -mannofuranose, as well as the unreacted
starting material. The azido sugar likely arises from -mannofuranosyl sulfonate ester formation, through
a
-
D
a-
D
D
a
displacement of azide from p-ABSA by the sugar lactol, followed by stereospecific displacement by azide
anion on the furanosyl sulfonate ester. This outcome has been studied further with the conditions being
applied to several common monosaccharide derivatives. Accessible substrates afford the azido sugar in an
overall one-pot alcohol-to-azide conversion, while hindered substrates yield the sulfonate esters.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Sulfonyl azide
Monosaccharide
Diazo transfer
Azidation
Azidodeoxy sugar
1. Introduction
nose with acetone and crystallizes as the a-anomer as shown by
X-ray diffraction analysis.7 Solution NMR spectra of this lactol
show no evidence for the related b-anomer so this furanose serves
as a configurationally reliable platform upon which to introduce a
diazoester at the anomeric position for further study. The overall
goal was to build diazoester 3 and then treat it with Rh2(OAc)4 in
order to study the fate of the resultant metal-stabilized carbenoid
(Scheme 1). Here, we discuss the attempted synthesis of diazoester
3 and the unexpected formation of a glycosyl azide, the isolation of
which suggests a potentially useful one-pot conversion of repre-
sentative monosaccharide alcohols into azido sugars.
The occurrence of branched-chain sugars in various antibiotics,1
as well as the utility of compounds such as non-hydrolyzable
C-glycosides in the study of carbohydrate-associated proteins,2
requires the development of synthetic methods with which to
introduce C–C bonds on to sugars efficiently and in a stereo- and
regioselective fashion. The use of organometallic nucleophiles, or
nucleophiles derived from the sugar framework, is limited due to
the basicity of such species, and the application of (neutral) radical
chemistry requires the careful pre-assembly of suitable precur-
sors.3 Surprisingly, little attention has been paid so far to the use
of carbenoid insertion chemistry for introducing C–C bonds into car-
bohydrate platforms.4,5 Having a non-basic carbenoid intermediate
undergo C–H insertion could offer a convenient and quite direct
solution to the problems associated with more traditional
strategies.
2. Results and discussion
Standard esterification of
1 with phenylacetic acid was
accomplished using dicyclohexylcarbodiimide (DCC) and 4-
dimethylaminopyridine (4-DMAP); 1-O-(2-phenylacetyl)-2,3;5,6-
Our efforts in this area have focused on selectively protected
diazoesters derived from furanoses, which are designed to limit
the possibilities for intramolecular C–H insertion,5 and we have
published initial details of intermolecular carbenoid insertion
chemistry to afford chiral ethers.6 Here, we report on unexpected
results using 2,3;5,6-di-O-isopropylidene-a-D-mannofuranose (1)
as the scaffold in which the diazo precursor was to be assembled
at the anomeric position of the sugar (Scheme 1). Lactol 1 is the
thermodynamic product of acid-catalyzed acetalation of D-man-
di-O-isopropylidene-a-D-mannofuranose (2) being isolated in 90%
yield (Scheme 2) after recrystallization from ethanol. Crystals of
2 suitable for X-ray diffraction were obtained and the structure
of this compound proved that the
a-configuration of the precursor
had been retained.8
Subsequently, attempted traditional diazo transfer onto
2-phenylacetyl ester 2, using the commercially available solid
reagent p-acetamidobenzenesulfonyl azide (p-ABSA, 5) and DBU
as base, was not as straightforward as expected (Scheme 3). TLC
analysis of the orange reaction mixture showed four spots which,
after column chromatography, proved to be the unreacted starting
material 2, alcohol 1, the desired diazoester 3, and the unexpected
⇑
Corresponding author. Tel.: +1 330 941 1553; fax: +1 330 941 1579.
E-mail address: pnorris@ysu.edu (P. Norris).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.03.066

I. A. Sacui, P. Norris / Tetrahedron Letters 52 (2011) 2670–2672
2671
O
O
O
O
O
O
O
O
Rh2+
O
O
N2
Intra - or intermolecular
insertion chemistry?
OH
O
Ph
O
1
3
Scheme 1.
O
O
O
O
O
O
O
O
5
PhCH2CO2H
O
O
O
O
O
O
O
O
O
N3
O
O
O
DBU, CH3CN
reflux, 12h
56%
DCC, 4-DMAP
CH2Cl2, CH3CN
RT, 12 h
OH
O
OH
Ph
4
1
O
1
2
Scheme 4.
Scheme 2.
precursor 1 to beta in azide 4, strongly suggests that this is a bimo-
lecular substitution process.
1-azido-2,3;5,6-di-O-isopropylidene-b-D-mannofuranose (4). Hav-
Such a direct conversion of sugar alcohol groups to the corre-
sponding azidodeoxy derivative could prove useful in a general
sense, especially if the chemistry were to be applicable at non-
anomeric positions. We, therefore, explored the application of the
same reaction conditions to four representative monosaccharide
substrates, namely, the primary alcohols in methyl 2,3-O-isopro-
ing worked extensively with compound 4 in the past, we were
careful to make sure that our reactions were not contaminated
with this material and, after further work, we were satisfied that
this azide was actually formed under the described reaction condi-
tions. The 1H NMR spectrum of the diazoester 3 compared with
that of precursor 2 showed the disappearance of the 2H singlet
pylidene-b-
-galactopyranose (7), and the secondary alcohols in 1,2;5,
6-di-O-isopropylidene- -allofuranose (8) and 1,2;5,6-di-O-iso-
propylidene- -glucofuranose (9), with each system providing
D-ribofuranoside (6) and 1,2;4,5-di-O-isopropylidene-
at 3.6 ppm corresponding to the a-CH2 group and the IR spectrum
of 3 showed the distinctive diazo absorption at 2095 cmÀ1. Glyco-
syl azide 4 had the same physical characteristics as the previously
reported compound,9 and in these experiments only the b-anomer
of the azide was isolated which had implications for the mecha-
nism of its formation.
a-D
a
-D
a-D
useful results (Table 1). Ribofuranose-derived primary alcohol 6
was indeed converted to known methyl 5-azidodeoxy-2,3-O-iso-
propylidene-b-
aqueous workup and column chromatography. For
D
-ribofuranoside (10),14 isolated in 49% yield after
The synthesis of azidodeoxy sugars is of major importance in
carbohydrate chemistry and is usually accomplished by displace-
ment of leaving groups with azide salts,10 reaction with diphenyl-
phosphoryl azide,11 or diazo transfer to amino sugars,12 for
example. Since each of these methods has potential disadvantages
such as the use of potentially explosive azide salts or inconvenient
reagents like TfN3, we took care to analyze this unexpected azide
formation in more detail. There is literature precedence for de-
esterification with DBU,13 which could explain the formation of
alcohol 1, and subsequent reaction of 1 with p-ABSA could then
lead to azide 4 via a sequence of sulfonate ester formation followed
by intermolecular displacement by azide anion. To test this idea, an
experiment beginning with lactol 1 itself under the same condi-
tions (p-ABSA and DBU) also led to 4 in moderate yield after stir-
ring in CH3CN at room temperature overnight thus providing
additional evidence for the suggested mechanism. After some addi-
tional experimentation with different equivalents of p-ABSA, dif-
ferent solvents, and various reaction temperatures, azide 4 could
be isolated in 56% yield after refluxing alcohol 1 with 2.0 equiv of
p-ABSA and 2.0 equiv of DBU in CH3CN for 12 h (Scheme 4). Con-
version of 1 into 4 represents a one-pot synthesis of the glycosyl
azide using the easy to handle solid p-ABSA without having to first
form an activated glycosyl intermediate such as a glycosyl halide.
Inversion of configuration at the anomeric position, from alpha in
D-galactopyra-
nose-derived primary alcohol 7 the product, isolated in 82% yield,
proved to be sulfonate ester 11. Bimolecular nucleophilic substitu-
tion at C-6 of this galactopyranose system is known to be slow due
to the proximity of the axial substituent at C-4 of the pyranose ring.
Under the same conditions the secondary alcohols 8 and 9 also
yielded the sulfonate esters, 12 and 13, respectively (Table 1).
The isolation of sulfonate esters 11, 12, and 13 provides evi-
dence for the overall mechanism operating in the reaction between
these alcohols and p-ABSA in the presence of DBU. Most likely in
the mannofuranosyl system, i.e., the conversion of 1 to 4, the
cosyl sulfonate ester is formed from reaction of 1 with p-ABSA.
Whether or not there is equilibration between - and b- anomers
of the sulfonate ester, it is reasonable to expect that the -anomer
a-gly-
a
a
is significantly more stable than the b-anomer as is the case with
the precursor alcohol (1). Concomitant generation of azide anion
allows for displacement on the
a-sulfonate ester and, subse-
quently, the isolation of b-azide 4. Smooth conversion of the un-
crowded primary alcohol in 6 and isolation of sulfonate esters
11, 12, and 13, which derive from sterically hindered primary
(11) and secondary (12 and 13) systems, respectively, suggests that
p-ABSA is serving as a source of both sulfonate leaving group and
azide nucleophile in this chemistry.
O
S
AcHN
N3
O
O
O
O
O
O
O
O
O
N3
5
O
O
2
1 + 2 +
N2
+
DBU, CH3CN
RT, 12h
O
Ph
3
4
O
Scheme 3.

2672
I. A. Sacui, P. Norris / Tetrahedron Letters 52 (2011) 2670–2672
Table 1
phile under these conditions. We are currently exploring the de-
tailed mechanism of this process and expanding the scope of this
reaction to other systems.
Reaction of selected sugar alcohols with p-ABSA/DBUa
Sugar alcohol
Product
% Yield
49
HO
O
OCH3
N3
OCH3
O
Acknowledgments
O
O
O
O
10
6
This work is part of the M.S. thesis of I.A.S. and was supported
by a Teaching Assistantship from the School of Graduate Studies
and Research at Youngstown State University. The overall project
was funded by the Petroleum Research Fund of The American
Chemical Society (Award 43948-B1).
O
OH
O
O
S
O
O
NHAc
O
O
O
O
82
90
90
O
O
7
O
11
O
Supplementary data
O
O
O
O
Supplementary data (experimental procedures, analyses, and
spectra) associated with this article can be found, in the online ver-
sion, at doi:10.1016/j.tetlet.2011.03.066.
O
O
8
O
O
O
OH
O
AcHN
SO2
O
O
12
References and notes
O
O
O
O
O
SO2
NHAc
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4. Branderhorst, H. M.; Kemmink, J.; Liskamp, R. M. J.; Pieters, R. J. Tetrahedron
Lett. 2002, 43, 9601–9603.
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6. Sacui, I. A.; Zeller, M.; Norris, P. Carbohydr. Res. 2008, 343, 1819–1823.
7. Sheldrick, B.; Mackie, W.; Akrigg, D. Acta. Crystallogr., Sect. C: Cryst. Struct.
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OH
O
9
O
O
O
O
13
2.0 equiv p-ABSA, 2.0 equiv DBU, CH3CN, reflux 12 h.
a
8. Sacui, I. A.; Norris, P.; Zeller, M. Acta. Crystallogr., Sect. E: Struct. Rep. Online 2010,
E66, o2341.
3. Conclusion
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Following the unexpected isolation of glycosyl azide 4 during
attempted diazo transfer it has been shown that direct alcohol to
azide conversion, using the solid and commercially available or-
ganic reagent p-acetamidobenzenesulfonyl azide with DBU as base,
is facile at the anomeric carbon of 1 and the uncrowded primary
alcohol position in ribofuranosyl glycoside 6. More crowded sub-
strates afford the sulfonate esters, thus providing evidence that
p-ABSA serves as the source of both the leaving group and nucleo-
10. Elchert, B.; Li, J.; Wang, J.; Hui, Y.; Rai, R.; Ptak, R.; Ward, P.; Takemoto, J. Y.;
Bensaci, M.; Chang, C.-W. T. J. Org. Chem. 2004, 69, 1513–1523.
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