Unexpected formation of complex bridged tetrazoles via intramolecular 1,3-dipolar cycloaddition of 1,2-O-cyanoalkylidene derivatives of 3-azido-3-deoxy-d-allose

Article abstract of DOI:10.1016/j.carres.2007.10.034

An unexpected and interesting intramolecular side reaction occurred during the attempted synthesis of glycosyl cyanides upon treatment of 1-O-acetyl-3-azido-3-deoxyallose derivatives with TMSCN and different Lewis acids. Exo-1,2-O-cyanoalkylidene derivatives formed by neighboring group participation and attack of cyanide underwent, after Lewis-acid mediated isomerization to the endo-isomer, intramolecular azide-cyanide cycloaddition leading to the formation of tetrazoles embedded in bridged tetracyclic ring systems. The efficiency of cycloaddition is dependent on the ring structure of the sugar (pyranose or furanose). Of the studied molecules, 3-azido-1,2-O-cyanoethylidene-3-deoxy-allopyranose provides the most suitable scaffold for intramolecular [2+3] cycloaddition under exceptionally mild conditions. Our results highlight the capability of carbohydrates to act as scaffolds for the precise positioning of functional groups productive for a specific chemical reaction.

Full text of DOI:10.1016/j.carres.2007.10.034

Available online at www.sciencedirect.com
Carbohydrate Research 343 (2008) 2118–2129
Unexpected formation of complex bridged tetrazoles
via intramolecular 1,3-dipolar cycloaddition of
1,2-O-cyanoalkylidene derivatives of 3-azido-3-deoxy-D-allose
Marco Worch and Valentin Wittmann*
Fachbereich Chemie, Universita¨t Konstanz, D-78457 Konstanz, Germany
Received 1 October 2007; accepted 23 October 2007
Available online 6 November 2007
Presented at Eurocarb 14th Lubeck, Germany, September 2007
¨
Abstract—An unexpected and interesting intramolecular side reaction occurred during the attempted synthesis of glycosyl cyanides
upon treatment of 1-O-acetyl-3-azido-3-deoxyallose derivatives with TMSCN and different Lewis acids. Exo-1,2-O-cyanoalkylidene
derivatives formed by neighboring group participation and attack of cyanide underwent, after Lewis-acid mediated isomerization to
the endo-isomer, intramolecular azide–cyanide cycloaddition leading to the formation of tetrazoles embedded in bridged tetracyclic
ring systems. The efficiency of cycloaddition is dependent on the ring structure of the sugar (pyranose or furanose). Of the studied
molecules, 3-azido-1,2-O-cyanoethylidene-3-deoxy-allopyranose provides the most suitable scaffold for intramolecular [2+3] cyclo-
addition under exceptionally mild conditions. Our results highlight the capability of carbohydrates to act as scaffolds for the precise
positioning of functional groups productive for a specific chemical reaction.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: C-Glycosyl compounds; Cyanides; Cyanoethylidene; Cycloaddition; Neighboring group participation
1. Introduction
addition reactions of organic azides to nitriles occur
more readily.13–17 Still, they require high reaction tem-
peratures to proceed and yields are with few excep-
tions18 not satisfactory. In the course of our
investigations toward the Lewis-acid promoted synthesis
of glycosyl cyanides, we now observed an unexpected
side reaction leading for the first time to complex
bridged tetracyclic ring systems via 1,3-dipolar cyclo-
addition of intermediate cyanoethylidene derivatives of
3-azidoallose even at room temperature.
The formation of cyanoethylidene compounds is a
common side reaction in C-glycosylation reactions. They
are formed when ester protecting groups are used at O-2
and the C-nucleophile is cyanide.19–21 Kochetkov and
coworkers utilized cyanoethylidene compounds in O-
glycosylation reactions and showed that the C–C bond
between the dioxolane carbon and the carbon of the
cyano group is relatively weak and can be cleaved with
catalytic amounts of Lewis acids such as trityl per-
chlorate.22–24 Myers et al. showed that cyanoethylidene
Tetrazoles are becoming an increasingly popular func-
tionality. They can serve as bioisosteres of carboxylic
acids,1,2 as precursors of nitrogen-containing hetero-
cycles, and as lipophilic spacers in pharmaceuticals.
Recently reported was their use as b-secretase inhibi-
tors,3,4 Kv1.5 blockers,5 and as carboxylate bioisosteres
of gabapentin and pregabalin.6,7 A potentially useful
method for the preparation of 1,5-disubstituted tetra-
zoles is the [2+3] cycloaddition of organic azides to
nitriles. To date, however, only a few electron deficient
nitriles are known that undergo this reaction in an inter-
molecular way under very forcing conditions.8–10 High
yields have been reported for the reaction of sulfonyl
and acyl cyanides with unhindered aliphatic azides by
neat, thermal fusion.11,12 Intramolecular [2+3] cyclo-
*
Corresponding author. Tel.: +49 7531 88 4572; fax: +49 7531 88
4573; e-mail: mail@valentin-wittmann.de
0008-6215/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2007.10.034

M. Worch, V. Wittmann / Carbohydrate Research 343 (2008) 2118–2129
2119
compounds of mannose, glucose, and galactose can be
converted to anomeric cyanides under acid promotion
without an exogenous cyanide source.19 Intra- or inter-
molecular cycloaddition reactions of cyanoethylidene
compounds have not been reported before.
nose. Treatment with acetic anhydride in pyridine affor-
ded peracetylated b-pyranose 3 in 91% yield over 3 steps
besides small amounts of the corresponding a- and b-
furanose and a-pyranose forms. Alternatively, stirring
of 1 with 2 M HCl directly resulted in the formation
of 2, which was again peracetylated under the same con-
ditions. In this case, however, the yield of b-pyranose 3
was somewhat lower (70% over 2 steps). For both reac-
tion pathways the amounts of a-pyranose and the a- and
b-furanose forms were negligible and completely separa-
ble by HPLC purification.
To synthesize glycosyl cyanide 4, peracetate 3 was
treated with excess of trimethylsilyl cyanide (TMSCN)
and equimolar amounts of tin tetrachloride as Lewis
acid promoter. However, we were not able to find even
traces of the desired C-glycosyl compounds under these
conditions. Instead, we observed a new compound that,
after extensive analysis by NMR and IR spectroscopy
and mass spectrometry, turned out to be tetrazole 6.
As an intermediate, exo-cyanoethylidene derivative 5
was identified (see below). Figure 1 depicts characteristic
NMR data of 5 and 6. Tetrazole 6 shows a 13C NMR
2. Results and discussion
In the course of our program directed at the synthesis of
sugar diamino acids (SDAs) as building blocks of oligo-
saccharide mimetics,25 we were interested in glycosyl
cyanide 4 of 3-azido-3-deoxy-D-allopyranose (Scheme
1). Starting from 3-azido-3-deoxy-1,2:5,6-di-O-isopro-
pylidene-a-D-allofuranose 126 we obtained the peracet-
ylated allopyranose derivative 3 using two different
pathways. When using 60% formic acid for the cleavage
of the isopropylidene protecting groups of 1, we ob-
served the formation of two different formylated side
products, which could subsequently be converted with
NaOMe/MeOH to the completely deprotected 3-azido-
3-deoxy-D-allose 2 existing predominantly as b-pyra-
O
O
OH
OAc
O
OAc
O
c
d
O
a or b
O
HO
AcO
AcO
OH
OAc
CN
O
OH
OAc
OAc
N3
N3
d
N3
N3 O
2
3
4
1
OH
O
OAc
O
OAc
O
HO
AcO
AcO
e
O
O
O
O
N
N
O
O
N
N
N3
N N
N N
CN
7
6
5
Scheme 1. Reagents and conditions: (a) (i) 60% HCOOH, 16 h; (ii) NaOMe, MeOH, 2 h; (b) 2 M HCl, 6 h; (c) Ac2O, pyr, overnight, 91% [(a) + (c)],
70% [(b) + (c)]; (d) 5 equiv TMSCN, 1.2 equiv SnCl4, CH2Cl2, 60 °C, 65%; (e) NaOMe, MeOH, 14 h, 84%.
OAc
O
OAc
O
AcO
98.41 ppm
99.05 ppm
H
100.97 ppm
97.85 ppm
AcO
3.50 ppm
H
H
O
5.59 ppm
O
N3
O
O
N
NOE
N
3J
H3C
CN
N N
155.20 ppm
116.39 ppm
5
6
Figure 1. Comparison of significant 1H and 13C NMR chemical shifts of compounds 5 and 6. Also indicated are an NOE between H-5 and the
cyanoethylidene methyl group of 5 indicative for the exo-configuration and a 3JC,H long-range coupling observed in a 1H,13C HMBC NMR spectrum
characteristic for tetrazole 6.

2120
M. Worch, V. Wittmann/ Carbohydrate Research 343 (2008) 2118–2129
resonance at 155.20 ppm, which is typical for a tetrazole
carbon27,28 and a strong signal in a 1H,13C HMBC NMR
spectrum due to a 3JC,H long-range coupling between the
tetrazole carbon and H-3. In addition, the cyanide reso-
nance in a 13C NMR spectrum and the nitrile and azide
resonances in an IR spectrum (between 2100 and
2130 cmꢀ1, medium intensity) were missing for 6. Tetra-
zole 6 could be deacetylated with NaOMe in methanol
leading to the formation of diol 7 in 84% yield. Further
investigations of the tetrazole formation using different
solvents and Lewis acids at different temperatures
revealed that 6 emerged as the major product in every case
and no anomeric cyanide 4 was formed. Table 1 gives an
overview over some of the experiments we carried out.
To isolate and characterize cyanoethylidene interme-
diate 5, we reacted 3 with TMSCN (5 equiv) and cata-
lytic amounts of Lewis acid (0.2 equiv SnCl4) at room
temperature. After column chromatography, 5 was iso-
lated in 22% yield beside tetrazole 6 (33%) and starting
material 3 (12%). NOE experiments carried out with
cyanoethylidene derivative 5 using a mixing time of
300 ms revealed an NOE between the dioxolane methyl
group and H-5 indicating that 5 is the exo-cyanoethylid-
ene isomer. Pure 5 was treated with TMSCN and SnCl4
or with SnCl4 alone. In both cases we observed that
tetrazole 6 was formed as the only product beside some
decomposition. Addition of TMSCN to a solution of
SnCl4 and 5 in CH2Cl2 increased the speed of reaction
but had no effect on the yield, which was approximately
70%. We always had to use at least equimolar amounts
of Lewis acid to effect complete consumption of starting
material 5.
Scheme 2 shows the proposed mechanism by which
tetrazole 6 is formed. Starting from 3, neighboring
group participation leads to acetoxonium ion 8 that
can be attacked by cyanide either from the exo or the
endo side. Formation of exo-cyanoethylidene 5 is
expected to be kinetically favored due to an attack from
the sterically less hindered convex side of bicyclic 8.
Formation of exo-cyanoethylidenes has been described
earlier by others to be favored over the formation of
endo-cyanoethylidenes22–24,29 and also corresponds to
the preferred formation of exo-isomeric forms of ortho
esters.30 Under the reaction conditions, however,
cyanide attack is reversible giving also access to endo-
cyanoethylidene 9. Proper spatial orientation of azido
and cyano groups within endo-cyanoethylidene 9 obvi-
ously leads to a fast irreversible intramolecular cycload-
dition forming tetrazole 6. In agreement with a fast
cycloaddition step is the observation that we were never
able to detect any of the endo-cyanoethylidene isomer 9.
To investigate whether tetrazole formation also
occurs with protecting groups that are known to reduce
the amount of cyanoethylidene formation,31,32 we
Table 1. Results of reactions of 3-azido-3-deoxy-allopyranose 3 with 5 equiv of TMSCN under varying conditions
Solvent
Lewis acid
T (°C)
Time
Yield 5 (%)
Yield 6 (%)
Recovered 3 (%)
CH2Cl2
CH2Cl2
CH2Cl2
H3CNO2
H3CNO2
0.4 equiv SnCl4
1.2 equiv SnCl4
0.2 equiv SnCl4
0.9 equiv BF3ꢁOEt2
1.2 equiv BF3ꢁOEt2
60
60
20
20
60
5 h
2 h
18 h
1 h 20 min
20 min
14
—
22
8
8
65
9
60
35
52
—
65
—
—
—
2
2
3
3
3
Scheme 2. Proposed mechanism for intramolecular tetrazole formation.

M. Worch, V. Wittmann / Carbohydrate Research 343 (2008) 2118–2129
2121
OH
O
OBz
O
OBz
O
OBz
O
a
b
c
HO
BzO
BzO
BzO
OH
OBz
CN
OAc
OH
OBz
OBz
OBz
N3
N3
N3
c
N3
2
10
11
12
OBz
O
OBz
BzO
O
BzO
O
O
N
O
O
N
N3
Ph
13
Ph
N N
CN
14
Scheme 3. Reagents and conditions: (a) BzCl, pyr, 24 h, 77%; (b) (i) H2N–NH2ꢁHOAc, DMF, 50 °C, 3 h; (ii) Ac2O, pyr, 12 h, 41% (2 steps); (c)
10 equiv TMSCN, 1.6 equiv BF3ꢁOEt2, H3CNO2, 50%.
decided to introduce a benzoyl group as protection for
O-2. Azidoallose 2 was perbenzoylated with benzoyl
chloride in pyridine to give 10 in a yield of 77% (Scheme
3). Experiments to react 10 directly with TMSCN and
SnCl4 failed. Obviously, the anomeric benzoyl group
cannot act as a leaving group under these conditions
and starting material was recovered completely. Ano-
meric deprotection of 10 by treatment with hydrazinium
acetate for 3 h at 50 °C and subsequent acetylation with
pyridine/Ac2O led to the formation of 11 as a mixture of
anomers (a:b = 1:2.9) in 41% yield over 2 steps. Com-
pound 11 was treated with TMSCN and BF3ꢁOEt2 in
nitromethane and, again, the formation of a tetrazole
(14) was observed (50% yield). Glycosyl cyanide 12
was not found. In this case, the yield of 14 dropped to
12% when dichloromethane was used instead of
nitromethane.
Since we observed tetrazole formation even with a
benzoyl group at O-2, we wanted to know if azidoallose
acts as a template for the intramolecular cycloaddition
reaction only in its pyranose constitution or if this cycli-
zation can also be achieved with the corresponding acet-
ylated furanose (17). To synthesize 17, furanose 1 was
treated with a solution of HCl in methanol (Scheme
4). After stirring for 48 h, the formation of a mixture
of methyl glycosides 15 and 16 was observed. Quenching
of the reaction mixture with triethylamine and subse-
quent chromatographic purification afforded the desired
triol 15 in a yield of 56% and 5,6-O-isopropylidene
derivative 16 in 34% yield. Neutralization of the reaction
mixture was necessary, as direct solvent removal gave
small amounts of the corresponding methyl a- and b-
D-3-azido-3-deoxy-allopyranosides, which were not sep-
arable from 15 by column chromatography. Conversion
of 16 into 15 was possible using the same conditions as
before, thus raising the overall yield of 15 to 78%. Sub-
sequently 15 was converted into the peracetylated fura-
nose 17 in 2 steps in a yield of 83% (Scheme 5).
Treatment of 17 with 5 equiv of TMSCN and
1.1 equiv of SnCl4 in CH2Cl2 at 60 °C led to complete
consumption of the starting material and a product mix-
ture of glycosyl cyanide 18 (27%) and tetrazole 19 (52%)
was isolated. NMR studies of this reaction in CD2Cl2
revealed that two major intermediates were formed.
To isolate these intermediates, 17 was treated with
5 equiv of TMSCN and only 0.5 equiv of SnCl4 at room
temperature. Under these conditions we were able to
isolate the two intermediates 20 (19%) and 21 (6%) by
HPLC beside 18 (19%) and 19 (37%). Analysis by
NMR spectroscopy revealed that the intermediates were
the two isomeric cyanoethylidenes (Scheme 1), which
were formed in an exo/endo ratio of approximately
3:1. Since the endo-cyanoethylidene derivative 21 could
be isolated in the allofuranose case, we conclude that
O
O
O
O
HO
HO
a
O
O
O
OMe
OMe
O
N3 OH
N3 O
N3 OH
16
15
1
a
Scheme 4. Reagents and conditions: (a) (i) MeOH, HCl, 48 h; (ii) Et3N, pH 7, 78%.

2122
M. Worch, V. Wittmann/ Carbohydrate Research 343 (2008) 2118–2129
AcO
AcO
HO
HO
AcO
AcO
AcO
AcO
O
CN
a, b
O
c
O
O
OMe
OAc
O
O
N
N3 OH
N3 OAc
N3 OAc
18
N
N
N
15
17
19
52%
27%
AcO
AcO
AcO
AcO
d
O
O
18
19%
19
O
O
N3 O
N3 O
20
19%
37%
CN
NC
21
6%
Scheme 5. Reagents and conditions: (a) Ac2O, pyr, 12 h; (b) 75 equiv HOAc, 12 equiv Ac2O, 6 equiv concd H2SO4, 30 min, 83% (2 steps); (c) 5 equiv
TMSCN, 1.1 equiv SnCl4, CH2Cl2, 60 °C; (d) 5 equiv TMSCN, 0.5 equiv SnCl4, CH2Cl2, rt.
BzO
BzO
HO
HO
BzO
BzO
BzO
BzO
CN
a
b
c
O
O
O
O
OMe
OMe
OAc
N3 OBz
N3 OH
N3 OBz
N3 OBz
15
22
23
24
Scheme 6. Reagents and conditions: (a) BzCl, pyr, 24 h, 89%; (b) 70 equiv HOAc, 10 equiv Ac2O, 5 equiv concd H2SO4, 36 min, 90%; (c) 5 equiv
TMSCN, 1.1 equiv SnCl4, CH2Cl2, 4 h, 60 °C, 65%.
in this case the spatial orientation of the cyano and
azido groups is not as favorable for a subsequent cyclo-
addition as in the allopyranose case, leading to a slower
rate of the tetrazole formation.
Lewis acids. exo-1,2-O-Cyanoalkylidene derivatives
formed by neighboring group participation and attack
of cyanide underwent, after Lewis-acid mediated iso-
merization to the endo-isomer, intramolecular azide–
cyanide cycloaddition leading to the formation of
tetrazoles embedded in bridged tetracyclic ring systems.
The efficiency of cycloaddition is dependent on the ring
structure of the sugar. Of the studied molecules, 3-azido-
1,2-O-cyanoethylidene-3-deoxy-allopyranose provides
the most suitable scaffold for intramolecular [2+3]
cycloaddition under exceptionally mild conditions.
Tetrazole formation is even observed with a 2-O-benzoyl
protecting group that is known to give diminished
amounts of cyanoalkylidene derivatives. In the case of
3-azido-3-deoxy-allofuranose, production of a glycosyl
cyanide was observed beside tetrazole formation when
O-2 was acetylated indicating a less precise positioning
of azide and cyanide. Tetrazole formation can be com-
pletely prevented in the furanose case by introducing a
benzoyl group at O-2. In this case, the glycosyl cyanide
is the major product.
The observation, that glycosyl cyanide 18 was formed
beside tetrazole 19 in the allofuranose case, led us to the
speculation that the introduction of a benzoyl group at
O-2 this time could lead to the formation of the ano-
meric cyanide as the major product. To prove this, 15
was perbenzoylated with benzoyl chloride in pyridine
to yield 22 in 89% yield (Scheme 6). Subsequently, the
anomeric acetyl group was introduced by acetolysis of
22 with concd H2SO4, HOAc and Ac2O to give 23 in
90% yield. Treatment of 23 with 5 equiv of TMSCN
and 1.1 equiv of SnCl4 in CH2Cl2 led to the formation
of the glycosyl cyanide 24 as the major product (65%),
as expected. This time, we did not observe any tetrazole
formation.
3. Conclusion
It has been shown that carbohydrates can function as
scaffolds for the spatially defined presentation of phar-
macophores.33 Our results highlight the capability of
carbohydrates to act as scaffolds for the precise position-
ing of functional groups productive for a specific
In summary, we investigated an unexpected and inter-
esting side reaction during the attempted synthesis of
glycosyl cyanides by treatment of 1-O-acetyl-3-azido-3-
deoxyallose derivatives with TMSCN and different

M. Worch, V. Wittmann / Carbohydrate Research 343 (2008) 2118–2129
2123
chemical reaction. It is conceivable that pyranose forms
of other sugars, having a similar stereochemical struc-
ture at C-2 and C-3, like gulose or ribose, could also
act as scaffolds for the same reaction.
(C-4), 62.33 (C-6). MALDIMS (positive mode, DHB,
MeCN/H2O 1:1) m/z calcd for C6H11N3O5: 228.1
[M+Na]+. Found: 228.0. Anal. Calcd for C6H11N3O5ꢁ
0.75H2O: C, 32.95; H, 5.76; N, 19.22. Found: C,
33.04; H, 5.71; N, 19.25.
4. Experimental
4.3. 1,2,4,6-Tetra-O-acetyl-3-azido-3-deoxy-b-D-allo-
pyranose (3)
4.1. General methods
Compound 3 was synthesized in two different ways.
(a) Compound 1 (5.3 g, 18.57 mmol) was suspended in
60% formic acid (180 mL) and stirred at room tempera-
ture for 16 h. The solvent was removed under dimi-
nished pressure and the completely deprotected
product was separated from formylated side product
by column chromatography (EtOAc). The side product
was then dissolved in MeOH (70 mL) and a 0.4 M soln
of NaOMe in MeOH (2.15 mL) was added. After 2 h ion
exchange resin Amberlite IR-120 (H+ form) was added
until the soln showed a pH of 7. The solvent was re-
moved under diminished pressure and the white crystal-
line residue was combined with the completely
deprotected product. Combined products were dissolved
in pyridine (260 mL) followed by the addition of Ac2O
(130 mL) and stirred overnight. Solvent removal under
diminished pressure followed by chromatographic puri-
fication (4:1 petroleum ether–EtOAc) afforded 3 as a
colorless oil (6.31 g, 16.91 mmol, 91%).
(b) Compound 1 (2.18 g, 7.64 mmol) was dissolved
under ultrasonic agitation in 2 M HCl (76.4 mL) and
stirred for 6 h at room temperature. The solvent was re-
moved under diminished pressure. The remaining dark
brown oil was redissolved in pyridine (110 mL) under
ultrasonic agitation. Subsequently, Ac2O (55 mL) was
added and the soln was stirred overnight. Solvent
removal under diminished pressure followed by chro-
matographic purification (4:1 petroleum ether–EtOAc)
afforded 3 as a colorless oil (2.0 g, 5.35 mmol, 70%).
In both cases (a) and (b) minor signals from the a-
pyranose and the a- and b-furanose forms were detected
in the NMR spectrum of compound 3.
All solvents were dried and freshly distilled using stan-
dard procedures.34 Organic solutions were concentrated
under diminished pressure with bath temperatures
<40 °C. Cation exchange resin Amberlite IR-120 (H+)
was pre-washed with dry MeOH before use. Thin-layer
chromatography (TLC) was performed on aluminum-
backed, pre-coated silica gel plates (Silica Gel 60 F254
,
E. Merck). Silica Gel 60 (200–400 mesh) was used for
column chromatography. MALDI-TOF mass spectra
were recorded on a Bruker Biflex III spectrometer in po-
sitive, linear mode. High resolution ESI mass spectra
were recorded on an Apex II spectrometer using an
Apollo ESI source. FT-IR spectra were recorded on a
Perkin Elmer System 2000 FT-IR spectrometer. NMR
spectra were recorded either with a Bruker DRX 600
1
(600 MHz for H and 150 MHz for 13C) or a Bruker
1
AC 250 (250 MHz for H and 62.5 MHz for 13C) spec-
trometer. Resonance assignments were made by the
aid of COSY, HSQC, HMQC, HMBC, and NOESY
experiments, when necessary. Chemical shifts are
reported relative to CHCl3 (dH 7.26, dC 77.0 ppm), DMSO
(dH 2.50, dC 39.43 ppm), or MeOH (dC 49.50 ppm) as
internal standard for D2O. In the case of a/b and
endo/exo mixtures, elemental analysis was carried out
using a mixture of both isomers, even when the isomers
were separated for the recording of NMR spectra.
4.2. 3-Azido-3-deoxy-b-D-allopyranose (2)
A 0.4 M soln of NaOMe in MeOH (2.6 mL, 0.1 equiv)
was added to a stirred soln of 3 (3.9 g, 10.45 mmol) in
dry MeOH (20 mL). After 6 h, ion exchange resin
Amberlite IR-120 (H+ form) was added until the pH
was 7. Evaporation to dryness afforded 2 as a white
wax-like solid (1.93 g, 9.4 mmol, 90%). Beside the b-
pyranose form, minor signals from the a-pyranose and
the a- and b-furanose forms were detected in the
Rf 0.26 (3:1 petroleum ether–EtOAc). IR (film): m 2109
1
(N3), 1751 cmꢀ1 (CO). H NMR (CDCl3, 250 MHz): d
5.96 (d, 1H, J1,2 8.5 Hz, H-1), 4.92–4.99 (m, 2 H, H-2,
H-4), 4.47 (t, 1H, J2,3 ꢂ J3,4 3.4 Hz, H-3), 4.29 (dd,
0
1H, J5,6 4.2 Hz, J6;6 12:3 Hz, H-6), 4.10–4.21 (m, 2H,
J5;6 1:9 Hz, H-5, H-60), 2.13 (s, 3H, CH3CO), 2.12 (s,
0
NMR spectrum of compound 2 in a ratio of bPyr: aPyr
Fur:aFur = 100:4:3: < 1. These minor products were
not completely characterized.
Rf 0.33 (EtOAc/MeOH). H NMR (D2O, 250 MHz):
d 4.76 (dd, 1H, J1,2 8.2 Hz, H-1), 4.19 (t, 1H, J2,3 ꢂ J3,4
3.5 Hz, H-3), 3.75–3.82 (m, 2H, H-6, H-4), 3.58–3.69 (m,
2H, H-5, H-60), 3.51 (dd, 1H, J2,3 3.5 Hz, H-2); 13C
NMR (D2O + 2 drops MeOH-d4, 150 MHz): d 94.97
(C-1), 75.56 (C-5), 72.11 (C-2), 68.00 (C-3), 67.93
:
3H, CH3CO), 2.11 (s, 3H, CH3CO), 2.08 (s, 3H,
CH3CO); 13C NMR (CDCl3, 150 MHz): d 170.57
(CO), 169.32 (CO), 169.21 (CO), 168.90 (CO), 89.81
(C-1), 70.88 (C-5b), 69.30 (C-2), 66.87 (C-4), 61.82 (C-
6), 60.79 (C-3), 20.82 (CH3CO), 20.67 (CH3CO), 20.48
(CH3CO), 20.45 (CH3CO). MALDIMS (positive mode,
DHB, dioxane) m/z calcd for C14H19N3O9: 396.2
[M+Na]+. Found: 396.2. Anal. Calcd: C, 45.04; H,
5.13; N, 11.26. Found: C, 45.24; H, 5.23; N, 11.17.
b
1

2124
M. Worch, V. Wittmann/ Carbohydrate Research 343 (2008) 2118–2129
4.4. 4,6-Di-O-acetyl-3-azido-3-deoxy-1,2-O-(1-exo-cya-
noethylidene)-a-D-allopyranose (5)
CH3); 13C NMR (DMSO-d6, 150 MHz): d 169.97
(CO), 169.13 (CO), 155.20 (C-tetrazole), 100.97 (dioxo-
lane C), 97.85 (C-1), 68.32 (C-2), 65.22 (C-4), 63.68
(C-5), 61.38 (C-6), 55.52 (C-3), 20.67 (CH3CO), 20.51
(CH3CO), 19.73 (dioxolane CH3). MALDIMS (positive
mode, CHCA, dioxane) m/z calcd for C13H16N4O7:
363.1 [M+Na]+. Found: 363.1. Anal. Calcd: C, 45.88;
H, 4.74; N, 16.46. Found: C, 45.83; H, 4.79; N, 16.52.
Trimethylsilyl cyanide (316.7 lL, 2.53 mmol, 5 equiv)
and a 1 M soln of SnCl4 in CH2Cl2 (101 lL, 101 lmol,
0.2 equiv) were added to a stirred soln of 3 (189 mg,
506 lmol) in dry CH2Cl2 (7.5 mL) under argon. After
18 h the reaction soln was poured on a satd aq NaHCO3
soln (23 mL). The aq layer was extracted with CH2Cl2
(3 ꢃ 30 mL). The combined extracts were concentrated
and the dark brown residue was subjected to column
chromatography to yield 5 (37.8 mg, 110.8 lmol, 22%)
as colorless crystals, 6 (57 mg, 168 lmol, 33%) as pale
4.6. Tetrazole 7
A 0.05 M soln of NaOMe in MeOH (0.41 mL,
0.05 equiv) was added to a stirred soln of compound 6
(140.2 g, 0.412 mmol) in dry MeOH (4.1 mL). After
14 h ion exchange resin Amberlite IR-120 (H+ form)
was added until the soln showed a pH of 7. Evaporation
to dryness and subsequent chromatographic purification
(1:9 petroleum ether–EtOAc) afforded compound 6 as a
white wax-like solid (88.3 mg, 0.345 mmol, 84%).
Rf 0.19 (1:9 petroleum ether–EtOAc). 1H NMR (D2O,
600 MHz): d 5.85 (d, 1H, J1,2 4.0 Hz, H-1), 5.57 (dd, 1H,
J2,3 5.5 Hz, J3,4 3.0 Hz, H-3), 5.23 (dd, 1H, H-2), 4.30
(dd, 1H, J4,5 10.2 Hz, H-4), 3.74–3.80 (m, 2H, H-6, H-
60), 3.07 (m, 1H, H-5), 2.07 (dioxolane CH3); 13C
NMR (D2O + 2 drops MeOH-d4, 150 MHz): d 156.41
(C-tetrazole), 102.15 (dioxolane C), 99.16 (C-1), 70.35
(C-2), 68.88 (C-5), 65.27 (C-4), 60.63 (C-6), 59.83 (C-
3), 19.87 (dioxolane CH3). Anal. Calcd for
C9H12N4O5ꢁH2O: C, 41.46; H, 4.83; N, 21.49. Found:
C, 41.62; H, 5.12; N, 21.54.
yellow needles and starting material
3
(23 mg,
61.7 lmol, 12%).
Rf 0.34 (3:1 petroleum ether–EtOAc). 1H NMR
(CDCl3, 250 MHz): d 5.81 (d, 1H, J1,2 5.6 Hz, H-1),
5.35 (m, 1H, J3,4 ꢂ J4,5 6.4 Hz, H-4), 4.69 (ddd, 1H,
J2,3 2.72 Hz, J2,4 1.0 Hz, H-2), 4.26 (dd, 1H, J5,6
0
0
3.4 Hz, J6;6 12:1 Hz, H-6), 4.18 (dd, 1H, J5;6 5:2 Hz,
H-60), 3.97 (ddd, 1H, H-5), 3.50 (dd, 1H, H-3), 2.16 (s,
3H, CH3CO), 2.09 (s, 3H, CH3CO), 1.96 (s, 3H, dioxo-
lane CH3); 13C NMR (CDCl3, 150 MHz): d 170.35
(CO), 169.93 (CO), 116.39 (CN), 99.08 (dioxolane C),
98.48 (C-1), 74.13 (C-2), 70.25 (C-5), 65.50 (C-4),
63.48 (C-6), 55.03 (C-3), 24.01 (dioxolane CH3), 20.61
(CH3CO), 20.60 (CH3CO). MALDIMS (positive mode,
CHCA, MeCN) m/z calcd for C13H16N4O7: 363.1
[M+Na]+. Found: 363.1. Anal. Calcd: C, 45.88; H,
4.74; N, 16.46. Found: C, 45.62; H, 4.55; N, 16.31.
4.5. Tetrazole 6
4.7. 3-Azido-1,2,4,6-tetra-O-benzoyl-3-deoxy-b-D-allo-
pyranose (10)
Trimethylsilyl cyanide (263 lL, 2.10 mmol, 5 equiv) and
a 1 M soln of SnCl4 in CH2Cl2 (505 lL, 505 lmol,
1.2 equiv) were added to a stirred soln of 3 (157 mg,
420.5 lmol) in dry CH2Cl2 (4 mL) under argon at
60 °C. After 2 h the reaction soln was poured on a satd
aq NaHCO3 soln. The aq layer was extracted with
CH2Cl2. The combined extracts were dried (MgSO4) con-
centrated and the dark brown residue was subjected to
column chromatography (2:1 petroleum ether–EtOAc)
to yield 6 (93.0 mg, 273 lmol, 65%) as a yellow oil.
Rf 0.32 (2:1 petroleum ether–EtOAc). 1H NMR
(CDCl3, 250 MHz): d 5.73 (d, 1H, J1,2 3.9 Hz, H-1),
5.59 (dd, 1H, J2,3 5.8, J3,4 3.1 Hz, H-3), 5.08 (dd, 1H,
J4,5 10.5 Hz, H-4), 4.89 (dd, 1H, H-2), 4.28 (dd, 1H,
Compound 2 (1.01 g, 4.92 mmol) was dissolved in pyri-
dine (8 mL) at room temperature. The colorless soln was
cooled in an ice bath and benzoyl chloride (11.44 mL,
98.5 mmol, 5 equiv per OH group) was added. After
stirring for 24 h at room temperature, the soln was
concentrated under diminished pressure. The residue
was suspended in EtOAc and washed with water
(80 mL) and satd aq NaHCO3 soln (100 mL). The
organic phase was dried (MgSO4) and concentrated.
Chromatographic purification (8:1?5:1?3:1 petroleum
ether–EtOAc) afforded 10 (2.34 g, 3.78 mmol, 77%) as a
colorless foam. Minor amounts of the corresponding a-
and b-furanose were formed as side products. They were
completely separable by column chromatography.
0
J5,6 3.9 Hz, J6;6 12:4 Hz, H-6), 4.16 (dd, 1H,
J5;6 2:1 Hz, H-60), 3.45 (m, 1H, H-5), 2.16 (s, 3H,
Rf 0.42 (4:1 petroleum ether–EtOAc). 1H NMR
(CDCl3, 250 MHz): d 7.99–8.09 (m, 8H, Ph), 7,36–7,65
(m, 12H, Ph) 6.49 (d, 1H, J1,2 8.5 Hz, H-1), 5.59 (dd,
1H, J2,3 3.4 Hz, H-2), 5.52 (dd, 1H, J3,4 3.3 Hz, J4,5
9.7 Hz, H-4), 4.82 (t, 1H, H-3), 4.62–4.69 (m, 2H, H-5,
0
CH3CO), 1.98 (s, 3H, CH3CO), 1.95 (s, 3H, dioxolane
CH3); 1H NMR (DMSO-d6 600 MHz): d = 5.76 (d,
1H, J1,2 3.9 Hz, H-1), 5.74 (dd, 1H, J2,3 5.6 Hz, J3,4
3.1 Hz, H-3), 5.43 (dd, 1H, H-2), 5.20 (dd, 1H, H-4),
4.15 (dd, 1H, J5,6 4.3 Hz, J6;6 12:5 Hz, H-6), 4.03 (dd,
H-6), 4.47 (dd, 1H, J5;6 5:0 Hz, J6;6 12:9 Hz, H-60, Hz);
13C NMR (CDCl3, 150 MHz): d 166.10 (CO), 165.02
(CO), 164.98 (CO), 164.67 (CO), 133.85, 133.74,
0
0
0
1H, J5;6 1:5 Hz, H-60), 3.34 (m, 1H, H-5), 2.16 (s, 3H,
CH3CO), 1.98 (s, 3H, CH3CO), 1.95 (s, 3H, dioxolane
0

M. Worch, V. Wittmann / Carbohydrate Research 343 (2008) 2118–2129
2125
133.70, 133.09, 130.14, 130.03, 129.81, 129.65, 128.75,
128.64, 128.60, 128.58, 128.51, 128.47, 128.40, 128.36
(24 C, C-arom.), 90.81 (C-1), 71.24 (C-5), 69.81 (C-2),
68.05 (C-4), 62.97 (C-6), 61.56 (C-3). MALDIMS (posi-
tive mode, DHB, dioxane) m/z calcd for C34H27N3O9:
644.2 [M+Na]+. Found: 644.5. ESIHRMS m/z calcd
for C34H27N3O9: 644.1645 [M+Na]+. Found: 644.1663.
in nitromethane (2 mL) at room temperature under
argon. BF3ꢁOEt2 was added in portions of 2 lL every
30 min, until TLC indicated complete consumption of
starting material. The soln was poured on a satd aq
NaHCO3 soln (20 mL) and the aq layer was extracted
with CH2Cl2 (3 ꢃ 30 mL). The combined extracts were
concentrated and the dark brown residue was subjected
to column chromatography (4:1 petroleum ether–
EtOAc) to yield 14 (23.4 mg, 44.2 lmol, 50%) as a pale
yellow syrup.
4.8. 1-O-Acetyl-3-azido-2,4,6-tri-O-benzoyl-3-deoxy-a,b-
D-allopyranose 11
Rf 0.28 (4:1 petroleum ether–EtOAc). 1H NMR
(CDCl3, 250 MHz): d 7.41–8.17 (4m, 15H, arom.), 5.94
(d, 1H, J1,2 3.9 Hz, H-1), 5.79 (dd, 1H, J2,3 5.8 Hz, J3,4
3.0 Hz, H-3), 5.68 (dd, 1H, J4,5 10.4 Hz, H-4), 5.17
Compound 10 (1.54 g, 2.48 mmol) was dissolved in
DMF (10 mL) at 50 °C and stirred for 10 min. Hydrazi-
nium acetate (274.4 mg, 2.97 mmol, 1.2 equiv) sus-
pended in DMF (2 mL) was added and the resulting
soln was stirred for 3 h at 50 °C. The reaction mixture
was diluted with 70 mL EtOAc and washed with
50 mL portions of a satd aq NaCl soln until the precip-
itation of salt had stopped. The organic phase was dried
(MgSO4) and concentrated. After passing the residue
through a short bed of silica (3:1 petroleum ether–
EtOAc), the solvent mixture was removed under dimi-
nished pressure and dried for 3 days under vacuum over
P2O5. The remaining pale yellow solid was dissolved in
pyridine (2.5 mL) and then stirred with Ac2O (3 mL)
for 12 h. The soln was concentrated and coevaporated
three times with toluene. The crude product was purified
by column chromatography to yield 11 (470 mg,
0.84 mmol, 41%, a:b = 1:2.9) as a colorless foam.
0
(dd, 1H, H-2), 4.68 (dd, 1H, J5,6 4.1 Hz, J6;6 12:5 Hz,
H-6), 4.44 (dd, 1H, H-60), 3.86 (m, 1H, H-5); 13C
NMR (CDCl3, 150 MHz): d 165.9 (CO), 165.3 (CO),
134.14, 133.33, 131.83, 130.85, 130.30, 129.74, 129.32,
128.74, 128.62, 128.45, 128.36, 126.38 (18 C, C-arom.),
102.9 (dioxolane C), 98.6 (C-1), 69.4 (C-2), 66.4 (C-4),
64.7 (C-5), 62.0 (C-6), 56.1 (C-3). MALDIMS (positive
mode, DHB, dioxane) m/z calcd for C28H22N4O7:
549.2 [M+Na]+. Found: 549.2. ESIHRMS m/z
calcd for C28H22N4O7: 565.1112 [M+K]+. Found:
565.1111.
4.10. Methyl 3-azido-3-deoxy-a,b-D-allofuranoside (15)
and methyl 3-azido-3-deoxy-5,6-O-isopropylidene-a,b-
D-allofuranoside (16)
Rf 0.37 (3:1 petroleum ether–EtOAc). 1H NMR
(CDCl3, 250 MHz): d 7.41–8.09 (3m, 3Pha, 3Phb), 6.48
(d, J1,2 3.9 Hz, H-1a), 6.28 (d, J1,2 8.4 Hz, H-1b), 5.54
(t, J2,3 ꢂ 3.8 Hz, H-2a), 5.46 (dd, J3,4 3.2 Hz, J4,5
10.0 Hz, H-4b), 5.40 (dd, J3,4 3.3 Hz, J4,5 10.1 Hz,
H-4a), 5.33 (dd, H-2b, J2,3 3.4 Hz), 4.80 (t, H-3a), 4.77
(t, 3-Hb), 4.69 (m, H-5a), 4.66 (dd, J5,6 2.5 Hz,
Acetyl chloride (86 lL, 1.2 mmol) was added to a stirred
soln of compound 1 (857 mg, 3 mmol) in 11.8 mL of
MeOH under nitrogen at 0 °C. The ice bath was re-
moved and the reaction mixture was stirred for 48 h at
room temperature. The soln was neutralized with Et3N
and concentrated under diminished pressure. The pale
yellow residue was subjected to column chromatography
to yield 15 (367 mg, 1.69 mmol, 56%) and 16 (250 mg,
0.97 mmol, 34%) as colorless crystals.
0
0
J6;6 12:4 Hz, H-6a), 4.62 (dd, J5,6 2.2 Hz, J6;6 12:3 Hz,
H-6b), 4.56 (m, H-5b), 4.48 (dd, J5;6 4:1 Hz, H-60a),
0
4.43 (dd, J5;6 4:6 Hz, H-60 ), 2.24 (s, 3H, CH3COa),
0
b
2.07 (s, 3H, CH3COb); 13C NMR (CDCl3, 150 MHz):
Compound 15: Rf 0.23 (1:4 petroleum ether–EtOAc).
1H NMR (MeOH-d4, 600 MHz): d 4.82 (d, J1,2 4.4 Hz,
H-1a), 4.74 (s, J1,2 < 1 Hz, H-1b), 4.22 (dd, J2,3 7.6 Hz,
H-2a), 4.10 (d, J2,3 4.2 Hz, H-2b), 3.92–3.97 (m, H-3a,
H-3b, H-4b), 3.90 (t, J3,4 ꢂ J4,5 4.2 Hz, H-4a), 3.75 (dd,
d 169.12 (COa), 169.07 (COb), 166.11 (COb), 166.09
(COa), 164.89 (COa), 164.87 (2 ꢃ COb), 164.85 (COa),
128.39–133.89 (36C, 3 ꢃ Pha, 3 ꢃ Phb), 89.99 (C-1b),
88.46 (C-1a), 71.05 (C-5b), 69.75 (C-2b), 68.40 (C-2a),
67.75 (C-4b), 67.21 (C-4a), 66.14 (C-5a), 62.84 (C-6b),
62.54 (C-6a), 61.25 (C-3b), 58.88 (C-3a), 20.98
(CH3COa), 20.87 (CH3COb). MALDIMS (positive
mode, DHB, dioxane) m/z calcd for C29H25N3O9:
582.2 [M+Na]+. Found: 582.3. Anal. Calcd for
C29H25N3O9: C, 62.25; H, 4.50; N, 7.51. Found: C,
62.22; H, 4.41; N, 7.65.
0
J5,6 3.3 Hz, J6,6 11.4 Hz, H-6b), 3.56–3.63 (m, H-5a,
H-60 , H-6a, H-60 ), 3.51 (m, H-5a), 3.39 (s, OMea),
b
a
3.32 (OMeb); 13C NMR (MeOH-d4, 150 MHz): d
109.76 (C-1b), 103.64 (C-1a), 83.72 (C-4a), 81.65 (C-
4b), 77.16 (C-2b), 75.39 (C-5b), 74.20 (C-2a), 73.28 (C-
5a), 65.39 (C-3b), 64.82 (2 C, C-6a, C-6b), 61.60 (C-3a),
55.37 (OMeb), 55.31 (OMea). Anal. Calcd: C, 38.36;
H, 5.98; N, 19.17. Found: C, 38.50; H, 6.05; N, 19.01.
Compound 16: Rf 0.27 (1:2 petroleum ether–EtOAc).
1H NMR (CDCl3, 600 MHz): d 4.80 (d, J1a,2a 4.5 Hz,
H-1a), 4.75 (s, J1b,2b < 1 Hz, H-1b), 4.20 (m, H-2a),
4.02–4.12 (m, H-6b, H-2b, H-3b, H-5a, H-6a), 3.89–3.97
4.9. Tetrazole 14
Trimethylsilyl cyanide (110.5 lL, 883 lmol, 10 equiv)
was added to a stirred soln of 11 (49.4 mg, 88.3 lmol)

2126
M. Worch, V. Wittmann/ Carbohydrate Research 343 (2008) 2118–2129
(m, H-60 , H-5b, H-4b, H-3a, H-6a), 3.84 (dd, J3a,4a
3.4 Hz, J4a,5a 5.9 Hz, H-4a), 3.80 (m, H-6a), 3.40 (s,
OMea), 3.26 (OMeb), 1.41 (s, 1CH3b, 1CH3a), 1.31 (s,
CH3b), 1.30 (s, CH3a); 13C NMR (CDCl3, 150 MHz):
17 (81 mg, 217 lmol) in dry CH2Cl2 (4 mL) under
argon. The mixture was heated in an oil bath (60 °C).
After 90 min the reaction soln was poured on a satd
aq NaHCO3 soln (30 mL). The aq layer was extracted
with CH2Cl2 (3 ꢃ 50 mL). The combined extracts were
concentrated and the dark brown residue was subjected
to column chromatography to yield 18 (20 mg,
58.8 lmol, 27%) as a colorless oil and 19 (38 mg,
112 lmol, 52%) as a pale yellow oil.
Compound 18: Rf 0.44 (3:2 petroleum ether–EtOAc).
1H NMR (CDCl3, 250 MHz): d 5.55 (dd, 1H, J1,2
3.2 Hz, J2,3 5.2 Hz, H-2), 5.34 (dd, 1H, H-5), 4.67 (d,
1H, H-1), 4.35–4.43 (m, 2H, H-3, H-6), 4.12–4.21 (m,
2H, H-4, H-60), 2.21 (s, 3H, CH3CO), 2.17 (s, 3H,
CH3CO), 2.10 (s, 3H, CH3CO); 13C NMR (CDCl3,
150 MHz): d 170.329 (CO), 169.76 (CO), 169.38 (CO),
115.41 (CN), 80.95 (C-4), 75.82 (C-2), 69.71 (C-5),
69.32 (C-1), 61.59 (C-6), 60.75 (C-3), 20.91 (CH3CO),
20.61 (CH3CO), 20.35 (CH3CO). MALDIMS (positive
mode, CHCA, MeCN) m/z calcd for C13H16N4O7:
363.1 [M+Na]+. Found: 363.1. Anal. Calcd: C, 45.88;
H, 4.74; N, 16.46. Found: C, 45.78; H, 4.80; N, 16.51.
Compound 19: Rf 0.28 (1:1 petroleum ether–EtOAc).
1H NMR (CDCl3, 600 MHz): d 5.84 (d, 1H, J1,2 3.9 Hz,
H-1), 5.62 (dd, 1H, J2,3 5.5 Hz, H-2), 5.41 (d, 1H,
J3,4 < 1 Hz, H-3), 5.02 (m, 1H, H-5), 4.55 (d, 1H, J4,5
b
d
109.86 (C-isopropylidenea), 109.77 (C-isopropyl-
ideneb), 107.83 (C-1b), 101.92 (C-1a), 82.58 (C-4a),
81.99 (C-4b), 77.56 (C-5b), 75.50 (C-5a), 75.48 (C-2b),
72.38 (C-2a), 67.67 (C-6b), 66.34 (C-6a), 65.31 (C-3b),
60.95 (C-3a), 55.33 (OMea), 54.82 (OMeb), 26.33
(CH3b), 26.27 (CH3a), 25.03 (CH3b), 24.61 (CH3a). Anal.
Calcd: C, 46.33; H, 6.61; N, 16.21. Found: C, 46.41; H,
6.74; N, 16.00.
4.11. 1,2,5,6-Tetra-O-acetyl-3-azido-3-deoxy-a,b-D-allo-
furanose (17)
Ac2O (5 mL) was added to a stirred soln of compound
15 (271 mg, 1.24 mmol) in pyridine (10 mL). After 12 h
the reaction mixture was concentrated under diminished
pressure and the yellow residue was filtered through a
short silica column (2:1 petroleum ether–EE). The com-
bined product fractions were dried and subsequently dis-
solved in a mixture of Ac2O (1.29 mL), HOAc (4.92 mL)
and concd H2SO4 (360 lL). After 90 min, the reaction
mixture was poured on a satd aq NaHCO3 soln. The
aq layer was extracted with CH2Cl2 (3 ꢃ 30 mL). The
combined extracts were concentrated and the dark
brown residue was subjected to column chromatography
to yield 17 (386 mg, 1.03 mmol, 83%) as a colorless oil.
Rf 0.26 (2:1 petroleum ether–EtOAc). 1H NMR
(CDCl3, 600 MHz): d 6.31 (d, J1,2 4.4 Hz, H-1a), 6.12
(s, J1,2 < 1 Hz, H-1b), 5.31 (d, J2,3 4.9 Hz, H-2b), 5.09–
0
6.5 Hz, H-4), 4.44 (dd, 1H, J5,6 3.3 Hz, J6;6 12:5 Hz,
H-6), 4.20 (dd, 1H, J5;6 4:6 Hz, H-60), 2.19 (s, 3H,
0
CH3CO), 2.12 (s, 3H, CH3CO), 2.05 (s, 3H, dioxolane
CH3); 13C NMR (CDCl3, 150 MHz): d 170.24 (CO),
169.79 (CO), 154.60 (C-tetrazole), 103.43 (C-1), 102.79
(dioxolane C), 84.78 (C-4), 77.73 (C-2), 70.27 (C-5),
61.90 (C-6), 57.414 (C-3), 20.93 (dioxolane CH3), 20.63
(CH3CO), 19.04 (CH3CO). MALDIMS (positive mode,
CHCA, MeCN) m/z calcd for C13H16N4O7: 363.1
[M+Na]+. Found: 363.1. Anal. Calcd: C, 45.88; H,
4.74; N, 16.46. Found: C, 45.80; H, 4.76; N, 16.48.
0
5.18 (m, H-2a, H-5b, H-5a), 4.45 (dd, J5,6 3.2 Hz, J6,6
0
12.2 Hz, H-6b), 4.38 (dd, J5,6 3.9 Hz, J6;6 12:3 Hz,
H-6a), 4.26 (t, J3,4 ꢂ J4,5 4.3 Hz, H-4a), 4.17–4.22 (m,
H-4b, H-3a), 4.11–4.16 (m, H-3b, H-60 ), 4.08 (dd,
a
J5;6 5:6 Hz, H-60b), 2.16 (s, 1CH3b, 1CH3a), 2.12 (s,
0
1CH3b, 1CH3a), 2.09 (s, CH3a), 2.08 (s, 1CH3b,
1CH3a), 2.06 (s, CH3b). 13C NMR (CDCl3, 150 MHz):
d 170.42 (COb), 170.27 (COa), 169.96 (2C, 1COa,
1COb), 169.63 (COa), 169.62 (COa), 169.39 (COb),
168.57 (COb), 98.03 (C-1b), 93.29 (C-1a), 82.13 (C-4a),
79.80 (C-4b), 75.74 (C-2b), 71.75 (2 C, C-5b, C-2a),
70.34 (C-5a), 62.24 (C-6b), 61.97 (C-6a), 61.53
(C-3b), 58.24 (C-3a), 20.94, 20.77, 20.56, 20.15 (4C,
CH3COa), 20.89, 20.78, 20.62, 20.43 (4 C, CH3COb).
MALDI-HRMS (positive mode, DHB, dioxane) m/z
calcd for C14H19N3O9: 396.1091 [M+Na]+. Found:
396.0990.
4.13. 5,6-Di-O-acetyl-3-azido-3-deoxy-1,2-O-(1-exo-cya-
noethylidene)-a-D-allofuranose (20) and 5,6-Di-O-acetyl-
3-azido-3-deoxy-1,2-O-(1-endo-cyanoethylidene)-a-D-
allofuranose (21)
Trimethylsilyl cyanide (150 lL, 0.1.20 mmol, 6 equiv)
and a 1 M soln of SnCl4 in CH2Cl2 (100 lL, 100 lmol,
0.5 equiv) were added to a stirred soln of compound
17 (75 mg, 201 lmol) in dry CH2Cl2 (4 mL) under
argon. After 15 h the reaction soln was poured on satd
aq NaHCO3 soln (25 mL). The aq layer was extracted
with CH2Cl2 (3 ꢃ 20 mL). The combined extracts were
concentrated and the dark brown residue was taken up
in acetonitrile and filtered. Purification of the remaining
soln by HPLC afforded 21 (13 mg, 38 lmol, 19%) as a
white powder and 21 (4 mg, 12 lmol, 6%) as a colorless
oil. In addition, cyanide 18 (13 mg, 38 lmol, 19%) and
tetrazole 19 (25 mg, 73.5 lmol, 37%) were isolated.
4.12. 2,5,6-Tri-O-acetyl-3-azido-3-deoxy-b-D-allofuran-
osyl cyanide (18) and tetrazole 19
Trimethylsilyl cyanide (136 lL, 1.09 mmol, 5 equiv) and
a 1 M soln of SnCl4 in CH2Cl2 (239 lL, 239 lmol,
1.1 equiv) were added to a stirred soln of compound

M. Worch, V. Wittmann / Carbohydrate Research 343 (2008) 2118–2129
2127
Compound 20: Rf 0.34 (3:1 petroleum ether–EtOAc).
1H NMR (CDCl3, 250 MHz): d 5.99 (d, 1H, J1,2 4.0 Hz,
H-1), 5.32 (m, 1H, H-5), 4.94 (dd, 1H, J2,3 4.93 Hz,
61.75 (C-3b), 55.19 (OMeb). MALDIMS (positive mode,
CHCA, dioxane) m/z calcd for C28H25N3O8: 554.2
[M+Na]+. Found: 554.4. Anal. Calcd: C, 63.27; H,
4.74; N, 7.91. Found: C, 63.13; H, 4.86; N, 7.76.
Compound a-22: Rf 0.38 (4:1 petroleum ether–
EtOAc). H NMR (CDCl3, 250 MHz): d 7.99–8.09 (m,
Pha), 7.38–7.56 (m, Pha), 5.75 (m, H-5a), 5.29 (d, J1,2
4.2 Hz, H-1a), 5.25 (dd, J2,3 4.2, H-2a), 4.82 (dd, J5,6
0
H-2), 4.40 (dd, 1H, J5,6 3.8 Hz, J6;6 12:1 Hz, H-6),
4.17 (dd, 1H, J5;6 6:5 Hz, H-60), 4.11 (dd, 1H, J3,4
0
1
9.6 Hz, J4,5 5.7 Hz, H-4), 3.62 (dd, 1H, H-3), 2.14
(s, 3H, CH3CO), 2.08 (s, 3H, CH3CO), 1.91 (s, 3H,
dioxolane CH3); 13C NMR (CDCl3, 150 MHz): d
170.36 (CO), 169.83 (CO), 116.38 (CN), 104.74
(C-1), 100.84 (dioxolane C), 81.11 (C-2), 76.11 (C-4),
69.97 (C-5), 62.17 (C-6), 61.47 (C-3), 24.31 (dioxolane
CH3), 20.71 (CH3CO), 20.59 (CH3CO). MALDIMS
(positive mode, CHCA, MeCN) m/z calcd for
C13H16N4O7: 363.1 [M+Na]+. Found: 363.1. Anal.
Calcd: C, 45.88; H, 4.74; N, 16.46. Found: C, 45.62;
H, 4.55; N, 16.31.
3.4 Hz, J6,6 12.2, H-6a), 4.69 (dd, J5;6 6:2 Hz, H-60a),
4.55 (dd, J3,4 7.2 Hz, H-3a), 4.46 (t, H-4a), 3.44 (s,
OMea). 13C NMR (CDCl3, 150 MHz): d 128.36—
133.37 (12 C, C-arom.), 100.93 (C-1a), 79.71 (C-4a),
73.02 (C-2a), 71.22 (C-5a), 62.70 (C-6a), 58.87 (C-3a),
55.19 (OMea). MALDIMS (positive mode, CHCA,
dioxane) m/z calcd for C28H25N3O8: 554.2 [M+Na]+.
Found: 554.4.
0
0
Compound 21: Rf 0.34 (3:1 petroleum ether–EtOAc).
1H NMR (CDCl3, 600 MHz): d 6.14 (d, 1H, J1,2
3.8 Hz, H-1), 5.29 (m, 1H, H-5), 5.18 (t, 1H, H-2), 4.41
4.15. 1-O-Acetyl-3-azido-2,5,6-tri-O-benzoyl-3-deoxy-
a,b-D-allofuranose (23)
0
(dd, 1H, J5,6 3.5 Hz, J6;6 12:2 Hz, H-6), 4.19 (dd, 1H,
J5;6 6:1 Hz, H-60), 4.13 (dd, 1H, J3,4 9.5 Hz, J4,5 6.1 Hz,
Compound 22 (2.01 g, 3.78 mmol) was dissolved in
Ac2O (3.55 mL), HOAc (15.12 mL), and concd H2SO4
(990 lL). After 35 min the reaction mixture was poured
on a satd aq NaHCO3 soln. The aq layer was extracted
with CH2Cl2 (3 ꢃ 50 mL). The combined extracts were
dried (MgSO4), concentrated, and the dark brown resi-
due was subjected to column chromatography to yield
23 (1.90 g, 3.40 mmol, 90%) as a colorless oil.
0
H-4), 3.47 (dd, 1H, J2,3 5.1 Hz, H-3), 2.14 (s, 3H,
CH3CO), 2.09 (s, 3H, CH3CO), 1.87 (s, 3H, dioxolane
CH3); 13C NMR (CDCl3, 150 MHz): d 170.44 (CO),
169.93 (CO), 115.59 (CN), 106.11 (C-1), 104.67 (dioxo-
lane C), 83.60 (C-2), 76.40 (C-4), 70.18 (C-5), 62.18
(C-6), 61.86 (C-3), 20.77 (CH3), 20.66 (CH3), 20.63
(CH3). MALDIMS (positive mode, CHCA, MeCN) m/z
calcd for C13H16N4O7: 363.1 [M+Na]+. Found: 363.1.
Compound b-23: Rf 0.38 (4:1 petroleum ether–
1
EtOAc). H NMR (CDCl3, 250 MHz): d 8.07–8.11 (m,
4.14. Methyl 3-azido-2,5,6-tri-O-benzoyl-3-deoxy-a,b-D-
allofuranoside (22)
4H, arom.), 8.00–8.03 (m, 2H, arom.), 7.54–7.63 (m,
3H, arom.), 7.41–7.50 (m, 6H, arom.), 6.34 (s, 1H,
J1,2 < 1 Hz, H-1), 5.76 (m, 1H, H-5), 5.62 (d, 1H, J2,3
0
Compound 15 (948 mg, 4.32 mmol) was dissolved in
pyridine (10 mL) at room temperature. The colorless
soln was cooled in an ice bath and benzoyl chloride
(2.26 mL, 19.44 mmol, 4.5 equiv per OH group) was
added. After stirring for 48 h at room temperature the
soln was concentrated under diminished pressure. The
residue was suspended in EtOAc (100 mL) and washed
with water (100 mL) and sat. NaCl soln (100 mL). The
organic phase was dried (MgSO4) and concentrated.
Chromatographic purification (8:1?5:1 petroleum
ether–EtOAc) afforded 22 (2.05 g, 3.86 mmol, 89%) as
a colorless foam.
4.3 Hz, H-2), 4.79 (dd, 1H, J5,6 3.6 Hz, J6;6 12:1 Hz,
H-6), 4.60 (dd, 1H, J5;6 6:4 Hz, H-60), 4.50–4.56 (m,
0
2H, H-4, H-3), 1.92 (s, 3H, CH3CO). 13C NMR (CDCl3,
150 MHz): d 168.70 (CO), 168.03 (CO), 165.51 (CO),
165.18 (CO), 133.87, 133.64, 133.27, 130.03, 129.89,
129.69, 129.45, 129.15, 128.61, 128.58, 128.50, 128.47
(18 C, C-arom.), 98.21 (C-1), 80.36 (C-4), 76.39 (C-2),
71.81 (C-5), 62.92 (C-6), 61.36 (C-3), 20.67 (CH3).
MALDIMS (positive mode, CHCA, dioxane) m/z calcd
for C29H25N3O9: 582.2 [M+Na]+. Found: 582.4. Anal.
Calcd: C, 62.25; H, 4.50; N, 7.51. Found: C, 62.13; H,
4.70; N, 7.56.
Compound b-22: Rf 0.38 (4:1 petroleum ether–
EtOAc). IR (thin film): m 2113 (N3), 1725 cmꢀ1 (CO).
1H NMR (CDCl3, 250 MHz): d 7.99–8.09 (m, Phb),
7.36–7.65 (m, Phb), 5.75 (m, H-5b), 5.54 (d,
J1,2 < 1 Hz, J2,3 4.7 Hz, H-2b), 5.07 (s, H-1b), 4.88 (dd,
Compound a-23: Rf 0.38 (4:1 petroleum ether–
EtOAc). H NMR (CDCl3, 250 MHz): d 8.01–8.09 (m,
6H, arom.), 7.55–7.64 (m, 3H, arom.), 7.43–7.50 (m,
6H, arom.), 6.57 (s, 1H J1,2 4.4 Hz, H-1), 5.68 (m, 1H,
H-5), 5.45 (dd, 1H, J2,3 7.6 Hz, H-2), 4.76 (dd, 1H, J5,6
1
0
0
0
0
J5,6 3.1 Hz, J6;6 12:1 Hz, H-6b), 4.68 (dd, J5;6 6:3 Hz,
3.9 Hz, J6;6 12:3 Hz, H-6), 4.63 (dd, 1H, J5;6 5:5 Hz,
H-60), 4.58 (t, 1H, J4,5 ꢂ 4.4 Hz, H-4), 4.54 (dd, 1H,
J3,4 4.0 Hz, H-3), 2.14 (s, 3H, CH3CO). 13C NMR
(CDCl3, 150 MHz): d 169.39 (CO), 165.98 (CO), 165.35
(CO), 165.32 (CO), 133.88, 133.70, 133.36, 129.95,
129.83, 129.71, 129.34, 129.02, 128.68, 128.55, 128.43
H-60 ), 4.57 (t, J3,4 ꢂ J4,5 ꢂ 7.6 Hz, H-4b), 4.51 (dd, J2,3
b
4.7 Hz, H-3b), 4.47 (s, OMeb). 13C NMR (CDCl3,
150 MHz): d 165.74 (COb), 165.37 (COb), 164.98
(COb), 128.36–134.26 (12 C, C-arom.), 106.11 (C-1b),
78.76 (C-4b), 76.61 (C-2b), 72.33 (C-5b), 62.93 (C-6b),

2128
M. Worch, V. Wittmann/ Carbohydrate Research 343 (2008) 2118–2129
5. Wu, S.; Fluxe, A.; Sheffer, J.; Janusz, J. M.; Blass, B. E.;
White, R.; Jackson, C.; Hedges, R.; Murawsky, M.; Fang,
B.; Fadayel, G. M.; Hare, M.; Djandjighian, L. Bioorg.
Med. Chem. 2006, 16, 6213–6218.
6. Burgos-Lepley, C. E.; Thompson, L. R.; Kneen, C. O.;
Osborne, S. A.; Bryans, J. S.; Capiris, T.; Suman-Chau-
han, N.; Dooley, D. J.; Donovan, C. M.; Field, M. J.;
Vartanian, M. G.; Kinsora, J. J.; Lotarski, S. M.;
El-Kattan, A.; Walters, K.; Cherukury, M.; Taylor, C.
P.; Wustrow, D. J.; Schwarz, J. B. Bioorg. Med. Chem.
2006, 16, 2333–2336.
7. Schwarz, J. B.; Colbry, N. L.; Zhu, Z.; Nichelson, B.;
Barta, N. S.; Lin, K.; Hudack, R. A.; Gibbons, S. E.;
Galatsis, P.; DeOrazio, R. J.; Manning, D. D.; Vartanian,
M. G.; Kinsora, J. J.; Lotarski, S. M.; Li, Z.; R., D. M.; El-
Kattan, A.; Thorpe, A. J.; Donevan, S. D.; Taylor, C. P.;
Wustrow, D. J. Bioorg. Med. Chem. 2006, 16, 3559–3563.
8. Carpenter, W. R. J. Org. Chem. 1962, 27, 2085–2088.
9. Quast, H.; Bieber, L. Tetrahedron Lett. 1976, 17, 1485–
1486.
10. Krayushkin, M. M.; Beskopyl’nyi, A. M.; Zlotin, S. G.;
Luk’yanov, O. A.; Zhulin, V. M. Izv. Akad. Nauk SSSR,
Ser. Khim. 1980, 2668.
11. Demko, Z. P.; Sharpless, K. B. Angew. Chem., Int. Ed.
2002, 41, 2110–2113.
12. Demko, Z. P.; Sharpless, K. B. Angew. Chem., Int. Ed.
2002, 41, 2113–2116.
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(18 C, C-arom.), 93.63 (C-1), 82.50 (C-4), 72.49 (C-2),
71.19 (C-5), 62.78 (C-6), 58.68 (C-3), 21.04 (CH3).
MALDIMS (positive mode, CHCA, dioxane) m/z calcd
for C29H25N3O9: 582.2 [M+Na]+. Found: 582.4.
4.16. 3-Azido-2,5,6-tri-O-benzoyl-3-deoxy-b-D-allofuran-
osyl cyanide (24)
Trimethylsilyl cyanide (369 lL, 2.95 mmol, 5 equiv) and
a 1 M soln of SnCl4 in CH2Cl2 (650 lL, 650 lmol,
1.1 equiv) were added to a stirred soln of 23 (331 mg,
591 lmol) in dry CH2Cl2 (12 mL) under argon. The mix-
ture was heated in an oil bath (60 °C). After 4 h the reac-
tion soln was poured on a satd aq NaHCO3 solution
(60 mL). The aq layer was extracted with CH2Cl2
(3 ꢃ 50 mL). The combined extracts were dried
(MgSO4), concentrated, and the dark brown residue
was subjected to column chromatography to yield 24
(202 mg, 384 lmol, 65%) as a colorless oil.
Rf 0.33 (5:1 petroleum ether–EtOAc). IR (thin film):
m 2116 (N3), 1728 cmꢀ1 (CO). 1H NMR (CDCl3,
250 MHz): d 8.02–8.11 (m, 6H, arom.), 7.43–7.51 (m,
9H, arom.), 5.83 (dd, J1,2 3.8 Hz, J2,3 5.2 Hz, H-2),
5.76 (m, H-5), 4.86 (d, H-1), 4.78 (dd, J5,6 3.8 Hz,
J6;6 12:3 Hz, H-6), 4.65–4.69 (m, H-60, H-3), 4.45
14. Fusco, R.; Garanti, L.; Zecchi, G. J. Org. Chem. 1975, 40,
1906–1909.
15. Garanti, L.; Zecchi, G. J. Org. Chem. 1980, 45, 4767–4769.
16. Korakas, D.; Kimbaris, A.; Varvounis, G. Tetrahedron
1996, 52, 10751–10760.
0
(t, J3,4 ꢂ J4,5 6.4 Hz, H-4). 13C NMR (CDCl3,
150 MHz): d 165.96 (CO), 165.49 (CO), 165.15 (CO),
134.27, 133.75, 133.38, 130.08, 129.90, 129.69, 129.28,
128.85, 128.75, 128.60, 128.52, 127.79 (18 C, C-arom.),
115.28 (CN), 80.91 (C-4), 76.10 (C-2), 71.00 (C-5),
69.35 (C-1), 62.59 (C-6), 61.96 (C-3). MALDIMS (posi-
tive mode, DHB, dioxane) m/z calcd for C28H22N4O7:
549.1 [M+Na]+. Found: 549.2. ESIHRMS m/z calcd
549.1386 [M+Na]+. Found: 549.1367. Anal. Calcd: C,
63.87; H, 4.21; N, 10.64. Found: C, 63.20; H, 4.49; N,
10.04.
17. Porter, T. C.; Smalley, R. K.; Teguiche, M.; Purwono, B.
Synthesis 1997, 773–777.
18. Davis, B. G.; Brandstetter, T. W.; Hackett, L.; Winchester,
B. G.; Nash, R. J.; Watson, A. A.; Griffiths, R. C.; Smith,
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Acknowledgment
24. Kochetkov, N. K. Tetrahedron 1987, 43, 2389–2436.
25. Sicherl, F.; Wittmann, V. Angew. Chem., Int. Ed. 2005, 44,
2096–2099.
Financial support by the Deutsche Forschungsgemeins-
chaft is gratefully acknowledged.
26. Gruner, S. A. W.; Truffault, V.; Voll, G.; Locardi, E.;
Sto¨ckle, M.; Kessler, H. Chem. Eur. J. 2002, 8, 4365–4376.
27. Semenov, V. V.; Bogdanov, V. S.; El’yanov, B. S.;
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Fainzil’berg, A. A. Khim. Geterotsikl. Soedin. 1982,
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