Epimerisation of carbohydrates and cyclitols, 17. Synthesis of glycosyl azides and N-acetyl glycosyl amines of rare monosaccharides

Article abstract of DOI:10.1055/s-2000-6250

The glycosyl azides 1 (D-arabino), 3 (L-fuco), 5 (D-manno), and 7 (D- galacto) were epimerised in a one-pot procedure by heating with chloral/DCC/1,2-dichloroethane in good yields. The respective products, epimerised at the C-3 atom, have D-lyxo (2), L-gulo (4), D-altro (6), and D- gulo (8, 9) configuration. Compound 8, directly generated or obtained by deformylation of its 6-O-formyl derivative 9, was used as the key intermediate for further syntheses. Besides the acetylation of 8 to 10, and decarbamoylation to the 4,6-dihydroxy derivative 11, the latter 11 was acetylated to 12 and benzylated to 13. Moreover, the azide function of 8 was converted into an amino group using tributyltin hydride/AIBN or Staudinger conditions. The amino derivatives were isolated in the form of their N-acetyl derivatives 14 and 15, respectively. Finally, the dichloroethylidene (14) and the trichloroethylidene (15) groups were hydrodechlorinated forming the same ethylidene derivative 16. Crystal structures are given for the gulopyranoses 4 and 12.

Full text of DOI:10.1055/s-2000-6250

226
PAPER
Epimerisation of Carbohydrates and Cyclitols, 17.1 Synthesis of Glycosyl
Azides and N-Acetyl Glycosyl Amines of Rare Monosaccharides
Christian Hager, Ralf Miethchen,* Helmut Reinke
Universität Rostock, Lehrstuhl Organische Chemie II, Buchbinderstrasse 9, D-18051 Rostock, Germany
Fax +49(381)4981819; E-mail: ralf.miethchen@chemie.uni-rostock.de
Received 4 August 1999; revised 6 October 1999
Dedicated to Prof. Dr. Klaus Peseke on the occasion of his 60th birthday.
α-D-Arabinopyranosyl azide (1), β-L-fucopyranosyl azide
(3), β-D-mannopyranosyl azide (5), and β-D-galactopyra-
nosyl azide (7) were selected as starting materials. On re-
fluxing the solutions of these compounds with anhydrous
Abstract: The glycosyl azides 1 (D-arabino), 3 (L-fuco), 5 (D-man-
no), and 7 (D-galacto) were epimerised in a one-pot procedure by
heating with chloral/DCC/1,2-dichloroethane in good yields. The
respective products, epimerised at the C-3 atom , have D-lyxo (2), L-
gulo (4), D-altro (6), and D-gulo (8, 9) configuration. Compound 8, chloral and DCC in 1,2-dichloroethane for 7−12 hours the
directly generated or obtained by deformylation of its 6-O-formyl
D-lyxo-, L-gulo-, D-altro-, and D-gulo-configurated azides
derivative 9, was used as the key intermediate for further syntheses.
2, 4, 6 and 8/9, respectively, were obtained in yields of 52-
Besides the acetylation of 8 to 10, and decarbamoylation to the 4,6-
70% (Scheme 1). The azide function of the sugars was not
dihydroxy derivative 11, the latter 11 was acetylated to 12 and ben-
attacked by DCC.16 It is noticeable that the primary OH-
zylated to 13. Moreover, the azide function of 8 was converted into
group of hexoses is also formylated, caused by a haloform
reaction.12 Thus, the mannosyl azide 5 and the galactosyl
azide 7 yielded mixtures of 6 and 8, respectively, with the
corresponding 6-O-formyl derivatives on treatment with
chloral/DCC. Because a formyl group can be selectively
cleaved by heating the corresponding sugar with methan-
olic triethylamine,12 the crude product mixture obtained
from 5 was treated with this reagent (20:1, v/v) generating
the uniform product 6 (yield: 69%). In the case of 8/9 the
two products were separated by column chromatography
and then characterised.
an amino group using tributyltin hydride/ AIBN or Staudinger con-
ditions. The amino derivatives were isolated in the form of their N-
acetyl derivatives 14 and 15, respectively. Finally, the dichloroeth-
ylidene (14) and the trichloroethylidene (15) groups were hydro-
dechlorinated forming the same ethylidene derivative 16. Crystal
structures are given for the gulopyranoses 4 and 12.
Key words: carbohydrates, azides, acetals, amides, stereoselectivi-
ty
Glycosyl azides are useful precursors and building blocks
in carbohydrate chemistry. Thus, glycosylamines, valu-
able intermediates for the synthesis of glycoconjugates,
are accessible by catalytic hydrogenation of glycosyl
azides2 or by reductive conversion with phosphines
(Staudinger reaction),3,4 thiols4 or trimethyl chlorosilane5
in the presence of acylation reagents. A disadvantage of
the latter reactions is the 1-N-acylation, i.e., deactivated
glycosyl amines are obtained.4,6,7 However, glycosylated
phosphinimines, the key intermediates of the Staudinger
reaction with glycosyl azides, were also used to synthesise
other interesting products.8 1,3-Dipolar cycloadditions,
generating nucleoside analogs or derivatives in which the
heterocyclic group is placed at positions other than the
anomeric position of the sugar moiety (e.g. ref.9), are a
further possibility for using azido sugars.
In this paper we report about syntheses of glycosyl azides
of rare monosaccharides using a non-conventional one-
pot acetalation/epimerisation procedure which is applica-
ble to cyclic polyols with three contiguous hydroxyl
groups in a cis-trans sequence,1,10-13 for the mechanism
see ref.12, 13 This method requires a carbodiimide as co-re-
agent. However, carbodiimides tend to undergo cycload-
ditions with azides at reaction conditions similar to the
above-mentioned one-pot procedure.14,15 Thus, we have to Scheme 1
clear up whether glycosyl azides allow an epimerisation.
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PAPER
Epimerisation of Carbohydrates and Cyclitols
227
As expected, the products 2, 4, 6, 8, and 9 are mixtures of
two diastereomers, because a new stereogenic centre was
formed by the chloral acetalation. The ratio of endo-H
(major) to exo-H form was determined by integration of
1
the acetal-H signals in the H NMR spectra of the mix-
tures, always after the column chromatographic separa-
tion: the ratio of endo-H/exo-H for compounds 2 (9:1), 6
(12:1), 8 (6:1) and 9 (6:1). In the case of the L-gulo-deriv-
ative 4 and of the D-gulo-derivatives 8 and 9 the pure
endo-H diastereomers were obtained from the mixtures by
fractionated crystallisation from diethyl ether-heptane
mixtures. The compounds 2 and 6 could only be isolated
as amorphous solids; attempts of recrystallisation from
methanol, isopropanol, nitromethane or from diethyl
ether-heptane mixtures were not successful.
The structures of the acetalated glycosyl azides 2, 4, 6, 8
1
and 9 are supported by their H- and 13C NMR spectral
data in comparison with literature data of similar com-
pounds, e.g. ref.10,12 Complete spectral data, only for the
major diastereomers, are given in Table 3. The spectra of
the five compounds show the characteristic signals of a Figure 1 X-ray structure of 4-O-cyclohexylcarbamoyl-6-deoxy-
2,3-O-(2,2,2-trichloroethylidene)-b-L-gulopyranosyl azide (4)
carbamoyl and a chloral acetal function. The location of
these groups is detectable by the downfield shifts of the
nearest ring protons (comparison with the spectra of the
starting materials 1, 3, 5, and 7, respectively). The formyl
proton (9: δ = 7.47 ppm) and the cyclic acetal functions (δ
≈ 5.1−5.5 ppm) are represented by characteristic singlets.
It is noticeable that the signal of the endo-H form is al-
ways shifted downfield compared to the corresponding
exo-H singlet, see also ref.1,10-13,20
ylidene)-β-D-gulopyranosyl azide (12) were suitable for
an X-ray measurement (Figure 2).
Like the L-gulo derivative 4 compound 12 does not adopt
an ideal chair conformation. Based on its Puckering pa-
rameters (Q = 0.512 Å, q = 18.1°, j = 344°) the ring con-
4
O
formation fits in between a C1-chair, E-half-boat, and
OH5-half-chair conformation. The extent of torsion re-
flected by q = 18.1° indicates the structure to be nearer to
Additionally, the structure of 4-O-cyclohexylcarbamoyl-
6-deoxy-2,3-O-(2,2,2-trichloroethylidene)-β-L-gulopyra-
nosyl azide (4) was confirmed by X-ray analysis Figure 1,
Table 1. The Puckering parameters17,18 (Q = 0.541 Å,
q = 159.0°, j = 172.0°) of 4 indicate that the pyranose
ring adopts a distorted 1C4-chair conformation. The value
q = 159.0°, reflecting the extent of torsion of a chair con-
formation, is only slightly nearer to an ideal 1C4-chair con-
formation (q = 180.0°, j = 0∞) than to an EO-half-boat
4
a C1-chair (q = 0.0°, j = 0°) than to an OE-half-boat
O
(q = 54.7°, j = 360°) or to an H5-half-chair (q = 50.8°,
j = 330°). The kind of torsion reflected by the value for
j = 344° is unspecific, because this value is exactly be-
O
tween the corresponding values of the E-half-boat and
the OH5-half-chair conformations. For selected X-ray-data
see Table 1.
3
(q = 125.3°, j = 180.0°) or a H2-half-chair (q = 129.2°,
A comparison of the structural data of the D-gulo deriva-
tive 12 and the L-gulo derivative 4 shows that in
spite of different protecting groups the two compounds
adopt virtually the same conformation probably caused
by the relatively stiff bicyclic segment of a trioxabicyc-
lo[4.3.0]nonane.
j = 150.0°) conformation. The value j = 172° reflecting
the manner of torsion, indicates that the deformation of
the 1C4-chair tends more to an EO-half-boat than to a 3H2-
half-chair conformation.
Scheme 2 shows some selected examples of protecting
group chemistry with 4-O-cyclohexylcarbamoyl-2,3-O-
(2,2,2-trichloroethylidene)-β-D-gulopyranosyl azide (8)
using standard methods like acetylation, benzylation, and
decarbamoylation.1,12,13 Besides the direct preparation of
8 from 7 (Scheme 1), deformylation of 9 by heating with
a 5% methanolic triethylamine solution also yielded this
compound (Scheme 2). In the search for a crystalline D-
gulo derivative, which allows for an X-ray analysis, com-
pound 8 was modified. Thus, the 6-O-acetyl derivative 10,
the 4,6-di-O-acetyl derivative 12 (via 11), and the 4,6-di-
O-benzyl derivative 13 (via 11) were prepared from 8.
The crystals of 4,6-di-O-acetyl-2,3-O-(2,2,2-trichloroeth-
Table 1 Selected X-ray Data for Compounds 4 and 12
4 (C15H21Cl3N4O5)
12 (C12H14Cl3N3O7)
Monoclinic, C2
a = 26.795(5) Å
b = 5.5190(11) Å
c = 15.699(3) Å
b = 116.85(3)
V = 2071.4(7) Å3
Z = 4
Monoclinic, P21
a = 10.618(3) Å
b = 6.925(2) Å
c = 13.011(4) Å
b = 106.770(10)
V = 916.0(5) Å3
Z = 2
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228
C. Hager et al.
PAPER
Scheme 2
Selective conversion of the trichloroethylidene function
of 8 into an ethylidene group by treatment with Bu3SnH/
AIBN, as reported in ref.,1,13,19,20 can only be carried out
after the conversion of the azido group. That is, in a later
synthetic step because the reagent preferentially attacks
the glycosidic azide function.21 The resulting glycosyl
amine is not stable under the reaction conditions. Only af-
ter modification of the reaction conditions, i.e., decreasing
the reaction temperature to 50 °C, and reducing the reac-
tion time to 3 hours, was a major product detectable by
TLC. Because glycosyl amines are stabilised by acylation
the product mixture was acetylated using acetic anhy-
dride/pyridine. In this way the major product could be
isolated as N-(6-O-acetyl-4-O-cyclohexylcarbamoyl-
2,3-O-(2,2-dichloroethylidene)-β-D-gulopyranosyl)ace-
tamide (14) by column chromatography (yield: 49%),
Scheme 2. However, N-acylated glycosyl amines are not
very valuable N-nucleophiles in carbohydrate chemistry.
The structure of 14 is supported by various NMR data
(Table 3). Thus, the acetal-H couples with the proton of
the vicinal dichloromethyl group giving doublets (3J ≈
3.2). Because of the relatively small difference in their
chemical shifts (dCHCl = 5.45 ppm, dH-acetal = 5.57 ppm) a
2
significant roof-shaped effect is observed for both cou-
pling participants. The H-1 signal of 14 (δ = 5.12 ppm,
3J1,2 ≈ 8.7, 3J1,HAc ≈ 9.4) is a double doublet that is signif-
Figure 2 X-ray structure of 4,6-di-O-acetyl-2,3-O-(2,2,2-trichlo-
roethylidene)-b-D-gulopyranosyl azide (12)
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PAPER
Epimerisation of Carbohydrates and Cyclitols
229
Table 2 Data of the Glycosyl Azides 2, 4, 6, 8–13 and the Glycosyl Amides 14–16a
Prod- Precursor Yield Mp / °C
Formula (molar mass)
[a]2D2CHCl3 (c )
Rf
uct
%
(solvent)
(heptane:EtOAc, 5:1, v/v)
b
2
1
3
52
70
69
58
13
89
61
82
64
49
65
94
amorphous solid
128–130 (iPrOH);
68–70, amorphous solid
138–140 (heptane:Et2O)
76–78 (heptane:Et2O)
122–124 (heptane)
75 (iPrOH)
C14H19Cl3N4O5 (429.68)
C15H21Cl3N4O5 (443.71)
C15H21Cl3N4O6 (459.69)
C15H21Cl3N4O6 (459.69)
C16H21Cl3N4O7 (487.70)
C17H23Cl3N4O7 (501.75)
C8H10Cl3N3O5 (334.54)
C12H14Cl3N3O7 (418.61)
C22H22Cl3N3O5 (514.79)
C19H28Cl2N2O8 (483.34)
C19H27Cl3N2O8 (517.79)
C19H30N2O8 (414.46)
0.32
0.33
0.10
0.11
0.24
0.15
0.20d
0.16
0.32f
0.24g
0.10h
0.12g
4
–77.3 (1.25)
b
6
5
8
7
–60.3 (1.19)
–99.0 (1.07)
–75.8 (1.15)
–85.0 (1.04)c
–82.4 (1.02)e
–81.1 (1.03)c
–43.9 (1.04)c
–40.1 (1.01)c
–53.9 (1.00)
9
7
10
11
12
13
14
15
16
8
8
11
11
8
103–104 (iPrOH)
colourless syrup
107–110 (iPrOH)
amorphous solid 116–121
97–99
8
14
a Satisfactory C, H, N microanalyses: C 0.37, H 0.18, N 0.41
b [a]D-value was not determined because the compound is an endo-H / exo-H diastereomeric mixture.
c [a]2D3
d Toluene:EtOAc, 3:1, v/v.
e [a]2D4
f
Heptane:EtOAc, 10:1, v/v.
g Toluene:EtOAc, 1:1, v/v.
h Toluene:EtOAc, 2:1, v/v.
X-ray analysis: The data were collected in routine ω-scan on a
Siemens P4 four circle diffractometer equipped with a graphite
monochromator using Mo-Kα radiation. The structures were solved
by direct methods and the refinement calculations were done using
the full-matrix least-squares method of SHELXL-93. Crystallo-
graphic data (excluding structure factors) for the structures reported
in this paper have been deposited with the Cambridge Crystallo-
graphic Data Centre as supplementary publication no. CCDC-133
113 (4) and 133 114 (12). Copies of the data can be obtained
free of charge on application to The Director, CCDC, 12 Union
Road, Cambridge, CB2 1EZ, UK (fax +(1223)336033; E-mail:
deposit@ccdc.cam.ac.uk).
icantly shifted down field compared to the H-1 doublet of
the starting material 8 (δ = 4.78, 3J1,2 ≈ 7.3). The acetami-
no group shows a broad doublet for NH at d = 6.34 ppm
(Table 3).
Now, the conversion of the dichloroethylidene acetal of
14 into an ethylidene function is possible without any
problems. On heating 14 with Bu3SnH/AIBN in toluene
for 4 hours at 65 °C, N-(6-O-acetyl-4-O-cyclohexylcar-
bamoyl-2,3-O-ethylidene-b-D-gulopyranosyl)acetamide
(16) was generated and isolated in a yield of 94%. A sec-
ond pathway to synthesise compound 16 from 8, as shown
in Scheme 2, gives some better overall yields than the
former (8 via 14). At first the azide 8 was converted into
the amide 15 (yield 65%) using Ph3P / Ac2O / pyridine22
followed by reduction of the trichloroethylidene group
with Bu3SnH/AIBN. The ethylidene acetal 16 was isolat-
ed in a yield of 89%.
4-O-Cyclohexylcarbamoyl-2,3-O-(2,2,2-trichloroethylidene)-a-
D-lyxopyranosyl Azide (2); Typical Procedure
To a suspension of a-D-arabinopyranosyl azide (1)23 (0.88 g, 5
mmol) in dry (ClCH2)2 (10 mL), chloral (2.58 g, 17.5 mmol) and
DCC (2.58 g, 12.5 mmol) were sequentially added. The mixture
was then refluxed with stirring for 7−8 h (TLC control); meanwhile
the azide dissolved gradually. After cooling to r.t. and addition of
10% aq HOAc (15 mL), the mixture was shaken for 45 min to de-
stroy excess DCC. The precipitated N,N′-dicyclohexylurea was re-
moved by filtration, the organic phase was separated, and the
aqueous phase was washed with CH2Cl2 (2 ¥ 15 mL). The com-
bined extracts were washed with sat. aq NaHCO3 (15 mL), H2O
(2 x 15 mL), dried (Na2SO4) and concentrated under reduced pres-
sure. The residue was purified by column chromatography giving a
mixture of the endo-H / exo-H diastereomers (9:1) of 2, Tables 2
and 3.
Mps were obtained using a Leitz Laborlux 12 Pol equipped with a
hot stage Mettler FP 90. 1H and 13C{H} NMR spectra were recorded
on Bruker instruments: AC 250, ARX 300, and ARX 400, internal
standard TMS. Optical rotations were measured on a Polar LµP
(IBZ Meßtechnik) instrument. Column chromatography: E. Merck
Silica Gel 60 (63−200 µm); TLC: E. Merck Silica Gel 60 F254 foils.
Chemicals: Chloral (Fluka), DCC (Aldrich), 60% suspension NaH
in oil (Fluka), AIBN (Fluka), Bu3SnH (Aldrich), Amberlite IR 120
(Fluka).
Synthesis 2000, No. 2, 226–232 ISSN 0039-7881 © Thieme Stuttgart · New York

230
C. Hager et al.
PAPER
a
Table 3 1H and 13C NMR Data [CDCl3/TMS, δ, J (Hz)] of the Azides 2, 4, 6, 8–13 and the Glycosyl Amides 14–16
Prod- H-1 H-2
H-3
H-4
H-5
H-5′ H-6
H-6′
NH
H-Ab C-1, C-2, C-3 ,C-4 ,C-5, C-6, CCl3 C-Ac
uct
(d)
(dd) (dd) (ddd)
(s)
acetyl, benzyl, carbamoyl,
formyl
3J1,2 3J2,3 3J3,4 3J4,5
3J4,5’ 2J5,5’ 3J5,6
3J5,6’ 2J6,6’ 3JNH/CH
2
5.16 4.33 4.62 4.94 3.90 3.81
4.2 5.3 5.3 4.0 6.2 12.3
4.68
7.9
5.48
87.1 (C-1), 76.6, 76.2, 67.0
98.8
98.8
99.0
98.7
106.9
106.8
107.0
106.7
(5.30) (C-2, 3, 4), 62.3 (C-2, 3, 4, 5),
153.9 (carbamoyl-C=O)
4
6
4.74 4.25 4.67 5.09 3.99
7.5 5.2 2.3 1.5
1.27d
6.3
4.78
8.0
5.47
5.44
87.8 (C-1), 76.7, 75.9, 70.3,
68.1 (C-2, 3, 4, 5), 15.5 (C-6),
154.1 (carbamoyl-C=O)
5.10 5.20 4.75 4.68 3.65
2.1 3.9 5.7 8.9
3.99 3.81
2.7 4.7
4.83
12.3 8.1
85.1 (C-1), 76.7, 75.9, 70.3,
(5.30) 68.1 (C-2, 3, 4, 5), 62.2 (C-6),
153.5 (carbamoyl-C=O)
8e 4.78 4.29 4.72 5.24 3.93
7.3 5.6 2.7 1.6
3.73 3.53
5.7 8.2
4.90
11.8 8.2
5.49
87.8 (C-1), 76.4 (C-3), 76.0
(5.31) (C-2), 74.1 (C-5), 65.8 (C-4),
59.7 (C-6), 155.4 (carbamoyl-
C=O)
9f
4.15 4.09 4.63 5.21 3.64
7.4 4.9 2.5 1.7
4.29 4.07
5.12
87.5 (C-1), 76.1 (C-3), 75.7
98.5
106.7
106.8
7.5
5.2
11.6
(4.83) (C-2), 71.7 (C-5), 65.5 (C-4),
61.3 (C-6), 160.2 (formyl-
C=O), 153.4 (carbamoyl-
C=O)
10
4.79 4.30 4.76 4.22 mg
7.4 5.4 2.5 1.1
mh
mh
4.75
8.0
5.47
87.5 (C-1), 76.1, 75.8 (C-2, C- 98.7
3), 71.8 (C-5), 65.8 (C-4), 61.8
(C-6), 170.4 (acetyl-C=O),
153.5 (carbamoyl-C=O), 20.7
(CH3)
2.07 (CH3)
4.89 4.43 4.76 4.22 3.83
11i
12
mk
4.2
mk
4.2
5.48
5.49
88.2 (C-1), 78.1, 75.7, 73.5,
67.2 (C-2, 3, 4, 5), 63.2 (C-6)
99.0
98.6
107.1
106.8
6.9 5.6 2.6 1.6
4.84 4.32 4.64 5.31 ml
7.2 5.5 2.5 1.5
ml
ml
87.3 (C-1), 75.7, 75.7, 71.2,
65.5 (C-2, 3, 4 ,5), 61.5 (C-6),
170.5, 169.5 (CH3CO), 20.7,
20.7 (CH3CO)
2.14, 2.07 (CH3CO)
13n 4.67 4.25 4.64 3.82 3.91
3.65 3.58
5.36
87.4 (C-1), 76.3, 75.7, 73.8,
73.6, 73.5, 71.9 (C-2, 3, 4, 5,
benzyl-CH2), 68.1 (C-6)m
99.0
106.8
103.7
7.4 5.5 2.4 2.0
6.0
6.5
9.7
14
5.12 4.22 4.47 5.19 mo
8.7 4.9 2.4 1.1
mo
mo
4.79
8.1
5.57
3.2p
76.4, 76.1, 75.0, 72.3, 71.1,
66.4 (C-1, 2, 3, 4, 5, CHCl2),
61.7 (C-6) 170.6, 170.6
(C=O), 153.7 (carbamoyl-
C=O), 23.4, 20.7 (CH3)
5.45 (d, CHCl2), 6.34 (d, 3J1/NH ≈ 9.4, amide), 2.04 (s, 6H, acetyl-CH3, amide-CH3)
15
5.09 4.37 4.66 5.17 mr
8.8 5.1 2.4
mr
mr
4.97
8.2
5.46
76.7 (C-1), 76.7 (C-3), 75.5
(C-2), 72.2 (C-5), 66.2 (C-4),
61.6 (C-6), 171.1, 170.7
(C=O), 153.8 (carbamoyl-
C=O), 23.7, 20.8 (CH3)
98.6
106.4
6.88 (d, 3J1,NH ≈ 9.1, amide-NH), 2.01, 1.99 (CH3)
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Epimerisation of Carbohydrates and Cyclitols
231
Table 3 (continued)
Prod- H-1 H-2
H-3
H-4
H-5
H-5′ H-6
H-6′
NH
H-Ab C-1, C-2, C-3 ,C-4 ,C-5, C-6, CCl3 C-Ac
uct
(d)
(dd) (dd) (ddd)
(s)
acetyl, benzyl, carbamoyl,
formyl
3J1,2 3J2,3
3J3,4
3J4,5
3J4,5’ 2J5,5’ 3J5,6
3J5,6’ 2J6,6’ 3JNH/CH
16
5.19 ms
8.8
ms
2.4
5.17 ms
1.1
ms
ms
4.88
7.7
5.50
5.0t
76.1, 74.2, 74.1, 72.4, 67.1
(C-1, 2, 3, 4, 5), 62.0 (C-6),
170.6, 170.6 (C=O), 153.8
(carbamoyl-C=O), 23.2, 21.5,
20.7 (CH3)
102.4
6.44 (d, 3J1/NH ≈ 9.4, amide-NH), 2.03, 2.00 (CH3), 1.32 (d, 3H, ethylidene-CH3)
a The cyclohexyl ring of 2, 4, 6, 8, 10, 14-16 gives 4 proton multiplets: 3.35–3.60 (CH), 1.85–2.00 (CH2), 1.52–1.80 (CH2), 1.00–1.46 (CH2),
4 carbon signals: CH/CH2 50.2, 33.2, 25.4, 24.7.
b Acetal-H, (acetal-H of the exo-H form in brackets).
c Acetal-C.
d Doublet CH3.
e 3.17 (dd, 6-OH), 3J6,OH ≈ 8.5 Hz, 3J6′/OH ≈ 6.3 Hz.
f Benzene-d6, 1H NMR: cyclohexyl CH 3.31–3.50 (m), CH2 1.59–1.79 (m), 1.18–1.48 (m), 0.62–1.12 (m), 7.47 (s, formyl-H). 13C NMR: cy-
clohexyl 50.3, 33.1, 25.3, 24.7.
g 4.07–4.16 (m, H-2).
h Multiplet 4.18–4.26 (H-6, 6′′).
i 3.66 (d, 3J4,4-OH ≈ 5.1 Hz, 4-OH), 2.51 (t, 3J6,6-OH ≈3J6′,6-OH ≈ 6.1 Hz, 6-OH).
k Multiplet 3.93–4.09 (H-6, 6′).
l Multiplet 4.10–4.24 (H-5, 6, 6′).
m 137.7, 137.1, 3 x 128.6, 2 x 128.4, 128.2, 128.0, 2 x 127.8, 127.7 (phenyl).
n 7.06-7.35 (phenyl), 4.58, 4.49 (d, 2J ≈ 11.8 Hz, benzyl-CH2), 4.48, 4.40 (d, 2J ≈ 12.0 Hz, benzyl-CH2).
o Multiplet 4.05–4.19 (H-5, 6, 6′).
p d, 3Jacetal-H/CHCl
.
2
r 3.97–4.20 (m, H-5, 6, 6′).
s 4.04–4.22 (H-2, 3, 5, 6, 6′).
t q, 3Jacetal-H/CH
.
3
4-O-Cyclohexylcarbamoyl-6-deoxy-2,3-O-(2,2,2-trichloroeth-
ylidene)-b-L-gulopyranosyl Azide (4)
separation (heptane: EtOAc, 5:1) two products were isolated; major
product 8 and by-product 9, Tables 2 and 3.
b-L-Fucopyranosyl azide (3)24 (0.95 g, 5 mmol), chloral (2.58 g,
17.5 mmol), DCC (2.58 g, 12.5 mmol) and (ClCH2)2 (15 mL) were
refluxed for about 8 h (TLC control). Then the mixture was worked
up as described for compound 2. After column chromatography, af-
forded the pure endo-H diastereomer of 4, Tables 2 and 3.
4-O-Cyclohexylcarbamoyl-2,3-O-(2,2,2-trichloroethylidene)-β-
D-gulopyranosyl Azide (8)
A solution of the formyl derivative 9 (0.20 g, 0.41 mmol) in 5%
methanolic Et3N (5 mL) was refluxed for about 10 min (TLC con-
trol, Rf ≈ 0.25, toluene: EtOAc, 8:1, v/v) and then concentrated un-
der reduced pressure. The syrupy residue was crystallised from a
heptane/Et2O mixture, mp: 138−140 °C, yield: 0.18 g (94%), Tables
2 and 3.
2-O-Cyclohexylcarbamoyl-3,4-O-(2,2,2-trichloroethylidene)-b-
D-altropyranosyl Azide (6)
b-D-Mannopyranosyl azide (5)25 (1.0 g, 5 mmol), chloral (2.58 g,
17.5 mmol), DCC (2.58 g, 12.5 mmol) and (ClCH2)2 (15 mL) were
refluxed for about 12 h (TLC control). Then the mixture was
worked up as described for compound 2. The crude product, a mix-
ture of compound 6 (Rf ≈ 0.28, toluene: EtOAc, 8:1) and its 6-O-
formyl derivative (Rf ≈ 0.61), was refluxed in 5% methanolic Et3N
solution (25 mL) for about 10 min (TLC control) to deformylate the
by-product. After evaporation of the solvents and column chro-
matographic purification compound 6 was isolated as an amorphous
solid (diastereomeric mixture of the endo-H / exo-H form, 12:1),
Tables 2 and 3.
6-O-Acetyl-4-O-cyclohexylcarbamoyl-2,3-O-(2,2,2-trichloro-
ethylidene)-b-D-gulopyranosyl Azide (10)
A solution of D-gulosyl azide 8 (1.0 g, 2.18 mmol) in pyridine/Ac2O
(10 mL, 1:1 v/v) was stirred at r.t. for 12 h. After concentration of
the mixture under reduced pressure, the syrupy residue was dis-
solved in Et2O (15 mL). This solution was washed with 3% aq
NaHSO4 (2 x 5 mL), H2O (2 ¥ 5 mL) and dried (MgSO4). After
evaporation of the solvent and column chromatographic purifica-
tion of the residue the crystalline compound 10 was isolated, Tables
2 and 3.
4-O-Cyclohexylcarbamoyl-2,3-O-(2,2,2-trichloroethylidene)-b-
D-gulopyranosyl Azide (8) and 4-O-Cyclohexylcarbamoyl-6-O-
formyl-2,3-O-(2,2,2-trichloroethylidene)-b-D-gulo pyranosyl
Azide (9)
2,3-O-(2,2,2-Trichloroethylidene)-b-D-gulopyranosyl Azide (11)
Compound 8 (2.55 g, 5.55 mmol) dissolved in 1% methanolic
NaOMe (60 mL) was decarbamoylated by heating the solution un-
der reflux for 6h. Subsequently, the mixture was cooled and neutr-
alised with an acidic ion exchanger resin (Amberlite IR-120). After
evaporation of the solvent under reduced pressure and column chro-
matographic purification, the crystalline compound 11 was ob-
tained, Tables 2 and 3.
b-D-Galactopyranosyl azide (7)26 (1.0 g, 5 mmol), chloral (2.58 g,
17.5 mmol), DCC (2.58 g, 12.5 mmol) and (ClCH2)2 (15 mL) were
refluxed for about 8 h (TLC control). Then the mixture was worked
up as described for compound 2. After column chromatographic
Synthesis 2000, No. 2, 226–232 ISSN 0039-7881 © Thieme Stuttgart · New York

232
C. Hager et al.
PAPER
4,6-Di-O-acetyl-2,3-O-(2,2,2-trichloroethylidene)-b-D-gulopyr-
anosyl Azide (12)
Procedure B: N-(6-O-acetyl-4-O-cyclohexylcarbamoyl-2,3-O-
(2,2,2-trichloroethylidene)-b-D-gulopyranosyl)acetamide
(15)
Compound 11 (0.50 g, 1.49 mmol) was acetylated in pyridine/Ac2O
(10 mL, 1:1, v/v) as described for 10. After column chromatography
the crystalline product 12 was isolated, Tables 2 and 3.
(0.23 g, 0.44 mmol) dissolved in toluene (20 mL) was treated with
Bu3SnH (0.51 g, 0.47 mL, 1.76 mmol) and AIBN (0.01 g, 0.06
mmol) as described in procedure A; yield of 16: 0.16 g (89%), Ta-
bles 2 and 3.
4,6-Di-O-benzyl-2,3-O-(2,2,2-trichloroethylidene)-b-D-gulopyr-
anosyl Azide (13)
Acknowledgement
To a stirred solution of the endo-H diastereomer 11 (0.50 g, 1.49
mmol) in dry THF (10 mL), a 60% suspension of NaH (0.19 g, 4.66
mmol) in oil was added in small doses at r.t. followed by benzyl bro-
mide (0.44 g, 0.31 mL, 3.73 mmol). After stirring of the suspension
for about 8 h and addition of Et2O (15 mL), the mixture was care-
fully hydrolysed by the dropwise addition of dist. H2O (15 mL).
Then the organic phase was separated, washed with 3% aq NaHSO4
(2 x 5 mL) and water (2 x 5 mL), dried (MgSO4) and concentrated
under reduced pressure. Column chromatographic purification of
the residue yielded a colourless syrupy product 13, Tables 2 and 3.
The authors are grateful to Dr. Zoltàn Györgydeàk, (Kossuth Lajos
University of Debrecen, Hungary) for interesting discussions and
for the gift of glycosyl azide samples. We also thank Dr. Manfred
Michalik (Institut für Organische Katalyseforschung e.V., Rostock)
for recording the NMR spectra. The Fonds der Chemischen Indu-
strie promoted our research by financial support.
References
(1) Part 16. M. Frank, R. Miethchen, D. Degenring, Carbohydr.
Res. 1999, 318, 167.
N-[6-O-Acetyl-4-O-cyclohexylcarbamoyl-2,3-O-(2,2-dichloro-
ethylidene)-b-D-gulopyranosyl]acetamide (14)
(2) Paulsen, H.; Pflughaupt, K.-W., The Carbohydrates, Chem.
and Biochem., 2nd ed., Vol. IB; Academic Press: New York/
London, 1980; pp 881−927 and papers cited therein.
(3) Gololobov, Y. G.; Kasukhin, L. F. Tetrahedron 1992, 48,
1353.
(4) Garcia-López, J. J.; Santoyo-Gonzáles, F.; Vargas-Berenguel,
A. Synlett 1997, 265.
(5) Barua, A.; Bez, G.; Barua, N. C. Synlett 1999, 553.
(6) Paul, B.; Korytnyk, W., Carbohydr. Res. 1978, 67, 457.
(7) Nakabayashi, S.; Warren, C. D.; Jeanloz, R. W. Carbohydr.
Res. 1988, 174, 279.
(8) Zbiral, E.; Schörkhuber, W. Liebigs Ann. Chem. 1982, 1870.
Hiebl, J.; Zbiral, E. Liebigs Ann. Chem. 1988, 765.
Pintér, I.; Kovác, J.; Tóth, G. Carbohydr. Res. 1995, 273, 99.
Garcia-López, J. J.; Santoyo-Gonzáles, F.; Vargas-Berenguel,
A.; Gimenez-Martinez, J. J. Chem. Eur. J. 1999, 5, 1775.
(9) Norris, P.; Horton, D.; Levine, B. R. Heterocycles 1996, 43,
2643.
(10) Miethchen, R.; Rentsch, D. Synthesis 1994, 827.
(11) Miethchen, R.; Rentsch, D. Liebigs Ann. Chem. 1994, 1191.
(12) Miethchen, R.; Rentsch, D.; Frank, M. J. Carbohydr. Chem.
1996, 15, 15.
To a stirred solution of 4-O-cyclohexylcarbamoyl-2,3-O-(2,2,2-
trichloroethylidene)-b-D-gulopyranosyl azide (8) (3.0 g, 6.53
mmol) in toluene (100 mL), Bu3SnH (5.70 g, 5.18 ml, 19.59 mmol)
and AIBN (0.10 g, 0.61 mmol) were added at 50 °C (Ar atm) and
stirring was continued for 3 h at this temperature (TLC control). Af-
ter evaporation of the solvent under reduced pressure, the oily resi-
due was dissolved in heptane (20 mL). The precipitate that formed
after a short time was separated by filtration and dissolved in Ac2O/
pyridine (30 mL, 1:1, v/v). After stirring of this mixture for 12 h at
r.t., the solvents were evaporated under reduced pressure. The oily
residue was dissolved in Et2O (30 mL), the solution was washed
with 3% aq NaHSO4 (2 ¥ 10 mL) and H2O (2 ¥ 10 mL), and dried
(MgSO4). The crude product obtained after evaporation of the sol-
vent was purified by column chromatography giving the crystalline
product 14, Tables 2 and 3.
N-[6-O-Acetyl-4-O-cyclohexylcarbamoyl-2,3-O-(2,2,2-trichlo-
roethylidene)-b-D-gulopyranosyl]acetamide (15)
To a solution of 4-O-cyclohexylcarbamoyl-2,3-O-(2,2,2-trichloro-
ethylidene)-b-D-gulopyranosyl azide (8) (1.0 g, 2.18 mmol) in dry
pyridine (10 mL), PPh3 (1.14 g, 4.36 mmol) was added and the mix-
ture stirred for 2 h at r.t. (TLC control). Then Ac2O (10 mL) was
added and stirring was continued for 12 h. The solvents were evap-
orated under reduced pressure and the residue was dissolved in Et2O
(25 mL). After washing with 3% aq NaHSO4 (2 ¥ 5 mL) and H2O
(2 ¥ 5 mL) the ethereal solution was dried (MgSO4) and concentrat-
ed under reduced pressure. Column chromatographic purification of
the residue (Rf ≈ 0.38, heptane:EtOAc, 1:2, v/v), followed by HPLC
separation to remove Ph3PO completely, yielded the amorphous
product 15, Tables 2 and 3.
(13) Frank, M.; Miethchen, R.; Reinke, H. Eur. J. Org. Chem.
1999, 1259.
(14) Tsuge, O.; Urano, S.; Oe, K. J. Org. Chem. 1980, 45, 5130.
(15) Percival, D. M.; Herbst, R. M. J. Org. Chem. 1957, 22, 925.
(16) Chr. Hager, Dissertation; Universitaet Rostock, 1999.
(17) Cremer, D.; Pople, J. A. J. Am. Chem. Soc. 1975, 97, 1354.
(18) Jeffrey, G. A.; Yates, J. H. Carbohydr. Res. 1979, 74, 319.
(19) Jacobsen, S.; Sløk, F. Acta Chem. Scand. 1993, 47, 1012.
(20) Rentsch, D.; Miethchen, R. Carbohydr. Res. 1996, 293, 139.
(21) see also: Vlahov, I. R.; Vlahova, P. I.; Schmidt, R. R.
Tetrahedron Lett. 1992, 33, 7503.
Vlahov, I. R.; Vlahova, P. I.; Schmidt, R. R. Tetrahedron
Asymm. 1993, 4, 293.
(22) Mungall, W. S.; Greene, G. L.; Heavner, G. A.; Letzinger, R.
L. J. Org. Chem. 1975, 40, 1659.
N-(6-O-Acetyl-4-O-cyclohexylcarbamoyl-2,3-O-ethylidene-b-D-
gulopyranosyl)acetamide (16)
Procedure A: To a solution of N-(6-O-acetyl-4-O-cyclohexylcar-
bamoyl-2,3-O-(2,2-dichloroethylidene)-b-D-gulopyranosyl)aceta-
mide (14) (0.50 g, 1.03 mmol) in toluene (20 mL), Bu3SnH (0.90 g,
0.82 ml, 3.09 mmol) and AIBN (0.02 g, 0.13 mmol) was added at
65 °C with stirring. After about 4 h the reaction is finished (TLC
control) and the mixture was shaken with 10% aq KF (10 mL) for
45 min. Thus, Bu3SnF formed from the soluble chloride precipitated
and was removed by filtration. The organic phase was washed with
3% aq NaHSO4 (5 mL) and H2O (2 ¥ 5 mL), dried (MgSO4) and
concentrated under reduced pressure. The residue was purified by
column chromatography yielding the crystalline product 16, Tables
2 and 3.
(23) Kunz, H.; Pfrengle, W.; Rueck, K.; Sager, W. Synthesis 1991,
1039.
(24) Györgydeák, Z.; Szilágyi, L. Liebigs Ann. Chem. 1995, 103.
(25) Györgydeák, Z.; Paulsen, H. Liebigs Ann. Chem. 1977, 1987.
(26) Györgydeák, Z.; Szilágyi, L. Liebigs Ann. Chem. 1987, 235.
Article Identifier:
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Synthesis 2000, No. 2, 226–232 ISSN 0039-7881 © Thieme Stuttgart · New York