Conversion of reducing carbohydrates into hydrophilic substituted imidazoles

Article abstract of DOI:10.1039/c3gc41203b

Carbohydrates, as cheap mass-products, promise to be outstanding candidates as sustainable raw materials. To achieve the goal of carbohydrate utilisation as industry raw materials, environmental low impact conversions from sugars to high value products are needed. Here we present the conversion of reducing sugars into imidazole heterocycles. Imidazole formation was achieved by a one-pot conversion of reducing mono and disaccharides with amidines in a melt of ammonium carbonate. A range of disaccharides were converted into different 2-substituted imidazoles carrying a varying glycosylation pattern on the 4-tetrahydroxy butyl side chain. All conversions were performed without the need of protecting groups, using benign reagents and solvents.

Full text of DOI:10.1039/c3gc41203b

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Conversion of reducing carbohydrates into hydrophilic
substituted imidazoles
Andreas Brust,a,b,* and Eckehrd Cunyb
Glyco-diversity library: Disaccharide based benign green synthesis of
tetrahydroxybutyl imidazole building blocks with a diverse glycosylation pattern.

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Full Paper
Conversion of reducing carbohydrates into hydrophilic substituted
imidazoles
Andreas Brust,a,b,* and Eckehard Cunyb
5
a Institute of Molecular Bioscience, University of Queensland, Brisbane, Australia. E-mail: a.brust@imb.uq.edu.au
b Clemens-Schoepf Institut für Organische Chemie und Biochemie, Technische Universität Darmstadt,
Darmstadt, Germany 97321.
10 Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
Carbohydrates, as cheap massꢀproducts, promise to be outstanding candidates as sustainable raw
materials. To achieve the goal of carbohydrate utilisation as industry raw materials, environmental low
impact conversions from sugars to high value products are needed. Here we present the conversion of
15 reducing sugars into imidazole heterocycles. Imidazole formation was achieved by a oneꢀpot conversion
of reducing mono and disaccharides with amidines in a melt of ammonium carbonate. A range of
disaccharides were converted into different 2ꢀsubstituted imidazoles carrying a varying glycosylation
pattern on the 4ꢀtetrahydroxy butyl side chain. All conversions were performed without the need of
protecting groups, using benign reagents and solvents.
40 blocks of the chemical industry and their refinement leads
to drugs, pesticides, polymers, pigments, ionic liquids and
other high value materials. The partial transformation of
the carbon chain of sugars into N-heterocycles, polymers
and other synthesis building blocks is of interest to release
45 the raw material pressure and to reach a sustainable
chemical industry.
20 Introduction
Mankind is facing the end of cheap oil, with the peak of
production already passed.1 The chemical industry is heavily
reliant on oil or coal based hydrocarbons, which form the
foundation of our modern lifestyle. This discrepancy creates
25 the inevitable necessity for a progressive changeover towards
renewable and hence, sustainable feedstock to fulfil the
industry’s raw material needs.2 Carbohydrates are by far
the most abundant organic compounds and represent the
major portion of the renewable biomass. Carbohydrate
30 utilization for the production of low cost, sustainable and
eco-friendly chemicals or polymers of versatile industrial
applicability is of central importance for relieving the
industry reliance on petrochemical raw materials.2-7
The key to the utilization of carbohydrates is the ability to
chemically arm the poly hydroxylated sugar framework by
introducing reactive moieties like e.g. carbonyl function or
50 amine groups suitable for follow on chemistries. The
9
utilization of sugar derived furfurals8, as raw materials
was previously demonstrated, leading to reactive 1,4-
diketo compounds10 or γ-keto-carboxylic acid analogues11
and these were converted into N-heterocycles of the
55 pyrrole-, thiophene-, pyridazine-, diazepinone-, pyridinol-,
benzodiazepinone-
and
pyridazinone-
type.10,12,13
35 The conversion of bulk scale produced sustainable
carbohydrates into building blocks for fine chemical
production requires entry reactions with broad
applicability and reaction pathways using benign reagents
and solvents. Aromatic N-heterocycles are key building
Furthermore, Lichtenthaler and coworkers13-15 expanded
on the utilization of sugar phenyl osazones as building
blocks for the synthesis of pyrrazoles.13-15
60 Other rare examples of direct single step conversions of
natural reducing sugars into aromatic N-heterocycles has
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lead to quinoxalines,16, 17 pyrazines,18 imidazoles,19, 20 fused
ring and
pyrazolo[3,4-b]quinoxalines16,21,22
benzimidazoles.23-25
In this work we were particularly interested in the
synthesis of imidazoles. This class of N-heterocycles
appears widely in a range of high value products in
particular in bioactive molecules like histidine, histamine
and in commercial drug molecules.26, 27 Nꢀcontaining polyꢀ
cyclic structures have been reported to be associated with a
Results
In the synthetic access of imidazole 2 developed by Streith
et al19, compressed ammonia plays the role of solvent, to
set formamidine free from its salt, as well as base,
60 assisting in tautomeric rearrangement and aromatization.
While high-pressure operations in liquid ammonia are
common for industrial applications we aimed to develop a
more convenient methodology that would give us access
to a library of molecules in a short time frame.
5
10 wide range of biological activity. In particular the
imidazole/benzimidazole ring system is considered as a
privileged structure for the modulation of biological
response. 28, 29
Simple imidazoles are industrially produced with the
15 Radziszewski reaction,30 condensing 1,2-dicarbony
compounds with aldehydes and ammonia. Based on
glucose was the access to 4(5)-hydroxymethyl-imidazole
possible, but only in a complicated multistep process.20
Rather then interested in simple imidazoles, we are aiming
20 here for imidazole products with poly-hydroxylated /
glycosylated side chains introduced by the sugar building
block used.
65 To accomplish this we have experimented with
D-glucose
and -fructose using different ammonia sources. E.g.
D
aqueous-ammonia solution, solutions of ammonium
carbonate, ammonium hydrogen carbonate, ammonium
acetate was used, employing varying temperature. The
70 best results we finally achieved when employing melts of
ammonium carbonate. A mixture of ammonium carbonate,
formamidine acetate and fructose or glucose (5/1.6/1) was
producing a low viscosity melt above 60°C allowing for
easy magnetic steering. The ammonium carbonate
75 decomposes during heating with the formation of
ammonia, water and release of carbon dioxide to the
atmosphere, resulting overall in large ammonia excess
compared to the use of aqueous solutions. Under these
condition the amidines, which are either released from
80 their salts by ammonia or are formed by aminolysis of
imido esters react under imine formation with the
carbonyl moiety of the reducing sugar (see scheme 2; →
a). This initial step is then followed by Amadori
rearrangement38 under formation of an adjacent carbonyl
85 moiety (a → b → c), which finally allows for cyclization
and tautomeric aromatization to yield the imidazole
moiety 2.
An example of carbohydrate based bioactive imidazoles is
the 2-acetyl-4-tetrahydroxy-butyl imidazole 1 which has
25 been found as a Maillard product caramel color31 in e.g.
roasted coffee32 and is synthetically accessible from
D-
glucosone,33
D Dꢀ
-Glucoseamine34 or 1ꢀaminoꢀ1ꢀdeoxyꢀ
fructose.35 The imidazole 1 is highly interesting due to its
pharmacological properties as a potent sphingosin-1-
30 phospahate lyase inhibitor making it herewith
commercially valuable in the treatment of autoimmune
diseases36 and rheumatoid arthritis.37
The non acetylated parent molecule 2 is accessible in a
high pressure reaction from
D-fructose or D-glucose in
35 liquid ammonia with formamidine acetate.19 These
amidine based cyclization methods incorporate the α-
hydroxy-carbonyl C-2
functionality of reducing
saccharides into the imidazole ring system (see scheme 2).
40
Scheme 1: D-Glucose and D-Fructose based N-heterocycles of the
imidazole type
45 These straightforward one-pot procedures19 caught our
attention as an interesting gateway to imidazole raw
materials that still contain parts of the carbohydrate
skeleton. These reaction pathways may offer a bulk scale
access to interesting starting materials for imidazole
50 containing high value products.
Here we present a straightforward procedure that allows
the conversion of generally all reducing disaccharides and
monosaccharides into side chain poly-hydroxylated
imidazoles with a varying glycosylation pattern as well as
55 2-substitution on the aromatic imidazole ring system.
90 Scheme 2: Proposed mechanism of imidazole (2) formation from D-
glucose and formamidine
2
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The reactions were worked up after approximately 2h
when the carbon dioxide formation had stopped.
Glcp), cellobiose (β-
D
-Glcp-(1→4)-
D
-Glcp), lactose (β-
D
-
-
Galp-(1→4)- -Glcp) and lactuloses (β-
D
D
-Galp-(1→4)-
D
The obtained brown syrup-like solutions were dissolved
in methanol and decolorized with activated charcoal and
purified by column chromatography on silica gel. The
imidazole 2 was obtained in a 50% yield similar to the
method described by Streith. 19
Fruf) could be transformed into imidazoles 6-12 resulting
in imidazole products with a variety of glycosylation
65 patterns (scheme 3) on the tetrahydroxybutyl side chain
(3-12).
All products were purified by silica gel chromatography
using an ethanol / ammonia mixture as eluent. Observed
yields were moderate (25-50%) most likely due to losses
70 during chromatography, amidine hydrolysis as well as
formation of unwanted Maillard products. Table 1 shows a
summary of the imidazole products (2-12) obtained and
related product yields. In light of the cheap availability of
most reducing disaccharides, the obtained moderate
5
With this facile method in hand we were interested to
expand the chemistry towards bulk scale available
10 disaccharides5 and to herewith produce hydrophilic
tetrahydroxybutyl imidazoles of type 2 with different
glycosylation pattern, effectively introduced, based on the
disaccharide used. Disaccharides investigated were the
reducing dissacharide-pyranoses melibiose (α-
-Glcp), leucrose (α- -Glcp-(1→5)-
-Glcp-(1→4)- -Glcp), cellobiose (β-
Glcp) and lactose (β- -Galp-(1→4)- -Glcp) as well as the
furanose disaccharides lactuloses (β-
and the industrial produced isomaltulose (α-
D-Galp-
15 (1→6)-
D
D
D-Frup), maltose 75 yields are still satisfactory in particular for 2 position
unmodified or methylated products.
(α-
D
D
D-Glcp-(1→4)-D-
D
D
D
-Galp-(1→4)-
D
-Fruf)
-Glcp-
D
20 (1→6)-D-Fruf). Most of these, in particular maltose,
cellobiose, lactose, isomaltulose and lactulose are mass
scale produced, sustainable, low cost raw materials.5
To further broaden the scope of the developed one pot
25 procedure, (see scheme 3) different nitrogen donor
molecules were investigated, to give access to ring
Scheme 3: One pot condensation of carbohydrates with amidines in a
80 ammonium carbonate melt, yielding tetrahydroxybutyl substituted
position
2-substituted
imidazoles.
Other
than
imidazoles with
a variable α/β-D-Glc/Gal- glycosylation sphere
formamidine acetate, we investigated ethylacetimidate
and benzylamidine hydrochloride as cyclization partner to
30 introduce a 2-methyl or 2-phenyl moiety into the formed
imidazoles.
depending on used starting disaccharide (see table 1)
Table 1: Product yields obtained from “one pot” transformation of
85 sugars into imidazoles (scheme 3). Matrix shows obtained variable
glycosylation pattern of the tetrahydroxyl side chain and imidazole ring
substitution.
Due to its low cost as an industrial produced bulk sugar
derived from sucrose we focused our initial efforts on
35 isomaltulose (α-D-Glcp-(1→6)-D-Fruf). This model sugar
Sugar
R
Product
R4
R3
R2
R1
Yield
[%]
50
47
49
30
5
was used to evaluate the stability of the glycosidic linkage
under the used reaction conditions and to investigate if a
dissacharide ketose is a suitable starting material for
imidazole formation.
Fructose
Glucose
Ha
2
2
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
α-D-Glc
α-D-Glc
α-D-Glc
α-D-Glc
α-D-Glc
H
Isomaltulose
Isomaltulose
Isomaltulose
Melibiose
Melibiose
Leucrose
Leucrose
Maltose
H
3
Meb
Phc
H
4
40 We applied the one pot imidazole formation procedure to
isomaltulose using formamidine acetate, ethylacetimidate
as well as benzylamidine hydrochloride under the same
conditions used for the synthesis of 2 starting from
glucose or fructose. In all cases we could obtain the
45 envisaged imidazoles (3-5) in decreasing yields of 48%,
30%, and 5% for the 2-H (3), 2-Me (4) and 2-Ph (5)
substituted imidazole respectively. This results show that
the one pot procedure is generally suitable for the
conversion of reducing dissaccharides into imidazoles but
50 the introduction of 2-substitution into the imidazole
moiety is hampered by the hydrolytic instability (R = H, <
Me, < Ph) of the applied amidines, under the ammonium
carbonate melt conditions. This was in particular
prominent and confirmed when using benzamidine (R =
55 Ph). In this case large quantities of benzoic acid amide
were isolated as a major hydrolysis side product.
5
6
38
27
38
26
28
25
40
Me
H
7
8
α-D-Glc
Me
H
9
H
α-D-Glc
10
11
12
H
H
H
H
α-D-Glc
β-D-Glc
β-D-Gal
Cellobiose
Lactose
H
H
H
H
a
b
c
Amidines introduced as: formamidine acetate, ethylacetimidate,
90 benzamidine hydrochloride
Conclusion
Carbohydrates provide a sustainable source of carbon, which
can replace petrochemical raw materials.2, 7 The incorporation
of the carbohydrate backbone carbons into imidazoles, while
95 maintaining the residual carbohydrate integrity was aim of
this work, and delivered hybrid products with hydrophilic,
polyꢀhydroxylated side chain substitution. The envisaged
Not only isomaltulose (α-
successfully deliver imidazoles 3-5 but also all other used
disaccharides melibiose (α- -Galp-(1→6)- -Glcp), leucrose
-Glcp-(1→5)- -Frup), maltose (α- -Glcp-(1→4)-
D-Glcp-(1→6)-D-Fruf) did
D
D
60 (α-
D
D
D
D-
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imidazole class of Nꢀheterocycles, finds a multitude of
[Previously published data.19: [α]D20 = ꢀ 12.0° (c 1.0, H2O), 38
60 % employing chromatography on a ion exchange column].
(Found: C, 44.72; H, 6.50; N, 14.90% C7H12N2O4 requires C,
44.68; H, 6.43; N, 14.89%); 1H NMR (300 MHz, D2O): δ 3.60
ꢀ 3.89 (m, 4 H, 2’ꢀH, 3’ꢀH, 4’ꢀH2), 5.15 (d, 1 H, 1’ꢀH), 7.38 (s,
1 H, 5ꢀH), 8.44 (s, 1 H, 2ꢀH). J1’,2’ = 1.1 Hz. 13C NMR (75.5
65 MHz, D2O): δ 65.3 (Cꢀ4’), 67.4 (Cꢀ1’), 73.2 (Cꢀ3’), 75.5 (Cꢀ
2’), 118.5 (Cꢀ5), 136.6 (Cꢀ2), 137.4 (Cꢀ4).
technical applications and is known to be a privileged
27
structure for bioactive molecules.26, Thus we ventured to
find an improved and general applicable route towards
imidazoles, derived from low cost, renewable sugars.
We developed a protecting group free process, employing
benign solvents and reagents throughout synthesis and
purification. We could show that reducing sugars in general
and in particular reducing disaccharides can be cyclized to
10 tetrahydroxybutyl substituted imidazoles (2ꢀ12). The reaction
media of molten ammonium carbonate enabled the synthesis
of 2ꢀsubstituted imidazoles by employing different amidines
as nitrogen source. Furthermore the process was gentle
enough to allow for the use of a range of dissacharides with
15 different glycosidic linkage resulting in a wide variety of
products with a diverse glycosylation pattern. The developed
synthesis can be easily transferred into largeꢀscale production
and the produced imidazoles 2ꢀ 12 may provide suitable raw
materials for novel high value products with unique properties
20 based on their carbohydrate origin. Future development of
follow on chemistry for these products will show how suitable
the developed entry reactions might be to provide a raw
material source for novel fine chemical production strategies.
5
4-[(1'R,2'S,3'R)-4'-(α-D-Glucopyranosyloxy)-1',2',3'-
trihydroxy-butyl]-imidazole (3) was obtained from
isomaltulose with formamidine acetate. Evaporation of
70 product containing chromatography fractions yielded
imidazole 3 (1.75 g, 49 %) as a colourless hard foam. — Rf
0.19 [EtOH / conc. NH3ꢀsol. (3 : 1)]. — [α]D20 + 77.2 (c 1.0,
DMSO). (Found: C, 44.52; H, 6.30; N, 8.05% C13H22N2O9
1
requires C, 44.57; H, 6.33; N, 8.00%); H NMR (300 MHz,
75 D2O): δ 3.42 (dd, 1 H, 4’’ꢀH), 3.57 (dd, 1 H, 2’’ꢀH), 3.67 (m,
1 H, 4’ꢀHa), 3.72 (m, 2 H, 3’’ꢀH, 5’’ꢀH), 3.78 (m, 1 H, 6’’ꢀ
Ha), 3.83 (m, 1 H, 6’’ꢀHb), 3.90 (m, 1 H, 4’ꢀHb), 3.95 (m, 2
H, 2’ꢀH, 3’ꢀH), 4.93 (d, 1 H, 1’’ꢀH), 5.03 (d, 1 H, 1’ꢀH), 7.18
(s, 1 H, 5ꢀH), 7.82 (s, 1 H, 2ꢀH). — J1’,2’ = 2.6, J1’’,2’’ = 3.7,
80 J2’’,3’’ = 9.8, J3’’,4’’ = 9.3, J4’’,5’’ = 9.3 Hz. 13C NMR (75.5 MHz,
D2O): δ 63.3 (Cꢀ6’’), 69.7 (Cꢀ1’), 71.1 (Cꢀ4’), 72.3 (Cꢀ3’),
72.4 (Cꢀ4’’), 74.4 (Cꢀ2’’), 74.6 (Cꢀ3’’), 75.9 (Cꢀ2’, Cꢀ5’’),
100.9 (Cꢀ1’’), 119.1 (Cꢀ5), 138.6 (Cꢀ2), 140.9 (Cꢀ4). MS
(FD): m/z = 351 [M++H], 373 [M++Na].
25 Experimental
85 4-[(1'R,2'S,3'R)-4'-(α-D-Glucopyranosyloxy)-1',2',3'-
trihydroxybutyl]-2-methylimidazole (4) was obtained from
isomaltulose with ethylacetimidatꢀhydrochlorid. Evaporation
of product containing fractions, yielded 2ꢀmethyl imidazole 4
(1.05 g, 30 %) as a yellow hard foam. — Rf 0.25 [EtOH /
90 conc. NH3ꢀsol. (3 : 1)]. — [α]D20 + 75.3 (c 1.0, DMSO).
(Found: C, 46.19; H, 6.68; N, 7.65% C14H24N2O9 requires C,
46.15; H, 6.64; N, 7.69%);
Analytical instrumentation used: Melting points (uncorrected
values) recorded on a Bock monoskop instrument. Spectral
measurements were performed on: Perkin Elmer 241
(rotations), Varian MAT 311 A (MS), Bruker WM 300
30 instruments (1H at 300, 13C NMR at 75.5 MHz, respectively).
PerkinꢀElmer 240 elemental analyzer was used for compound
microanalysis and purity confirmation. TLC on silica gel 60
1H NMR (300 MHz, D2O): δ 2.37 (s, 3 H, 2ꢀCH3), 3.42 (dd, 1
H, 4’’ꢀH), 3.57 (dd, 1 H, 2’’ꢀH), 3.65 (m, 1 H, 4’ꢀHa), 3.72
95 (m, 2 H, 3’’ꢀH, 5’’ꢀH), 3.77 (m, 1 H, 6’’ꢀHa), 3.82 (m, 1 H,
6’’ꢀHb), 3.88 (m, 1 H, 4’ꢀHb), 3.92 (bs, 2 H, 2’ꢀH, 3’ꢀH), 4.92
(d, 1 H, 1’’ꢀH), 4.95 (d, 1 H, 1’ꢀH), 7.02 (s, 1 H, 5ꢀH). — J1’,2’
= 1.8, J1’’,2’’ = 3.7, J2’’,3’’ = 9.8, J3’’,4’’ = 9.3, J4’’,5’’ = 9.3 Hz.
13C NMR (75.5 MHz, D2O): δ 14.6 (2ꢀCH3), 62.8 (Cꢀ6’’),
100 69.0 (Cꢀ1’), 70.6 (Cꢀ4’), 71.7 (Cꢀ3’), 71.8 (Cꢀ4’’), 73.8 (Cꢀ
2’’), 74.0 (Cꢀ3’’), 75.4 (Cꢀ2’, Cꢀ5’’), 100.4 (Cꢀ1’’), 118.1 (Cꢀ
5), 139.5 (Cꢀ2), 148.0 (Cꢀ4). MS (FD): m/z = 365 [M+], 366
[M+1+].
F254 plastic sheets (Merck) was used to monitor the reactions
and to ascertain the purity of the products (single point on
35 TLC plate); eluents employed and Rf values observed are
given in the appropriate experiment; detection of TLC plates
was performed with UVꢀlight or by charring with sulfuric
acid. Column chromatography: silica gel 60 (63ꢀ200 mesh,
MachereyꢀNagel).
40
General Procedure for the synthesis of imidazoles (2-12):
A mixture of 10 mmol of carbohydrate was heated at 65ꢀ80°C
with (NH4)2CO3 (4.8 g, 50 mmol) and 16 mmol of a amidine
4-[(1'R,2'S,3'R)-4'-(α-D-Glucopyranosyloxy)-1',2',3'-
105 trihydroxybutyl]-2-phenylimidazole (5) was obtained from
isomaltulose with benzamidine hydrochloride hydrate
Evaporation of product containing fractions, yielded 2ꢀphenyl
imidazole 5 (213 mg, 5 %) as a yellowꢀbrown hard foam — Rf
0.42 [EtOH / conc. NH3ꢀsol. (3 : 1)]. (Found: C, 53.62; H,
110 6.20; N, 6.55% C19H26N2O9 requires C, 53.52; H, 6.15; N,
45 source
of either formamidine acetate (1.7g) or
ethylacetimidate hydrochloride (1.9g) or benzamidine
hydrochloride hydrate (2.8g) until no further gas development
could be observed. The obtained brownꢀred melts were
dissolved in methanol and decolorized with activated
50 charcoal. The obtained pale yellow solutions were
concentrated and purified on silica gel (5 x 30 cm) employing
ethanol / concentrated (25%) ammonia (3 : 1) as eluent.
4-[(1'R,2'S,3'R)-1',2',3',4'-Tetrahydroxybutyl]-imidazole
(2): was obtained from
55 formamidine acetate. Evaporation of fractions with Rf 0.37
[EtOH / conc. NH3ꢀsol. (3 : 1)] yielded product imidazole 2
1
6.57%); H NMR (300 MHz, D2O): δ 3.47 (dd, 1 H, 4’’ꢀH),
3.60 (dd, 1 H, 2’’ꢀH), 3.70 (m, 1 H, 4’ꢀHa), 3.75 (m, 2 H, 3’’ꢀ
H, 5’’ꢀH), 3.78 (m, 1 H, 6’’ꢀHa), 3.84 (m, 1 H, 6’’ꢀHb), 3.96
(m, 1 H, 4’ꢀHb), 3.98 (m, 1 H, 2’ꢀH), 4.01 (m, 1 H, 3’ꢀH),
115 4.98 (d, 1 H, 1’’ꢀH), 5.17 (d, 1 H, 1’ꢀH), 7.36 (s, 1 H, 5ꢀH);
Dꢀfructose or Dꢀglucose with
7.52 ꢀ 7.85 (m, 5 H, C6H5). — J1’,2’ = 2.2, J1’’,2’’ = 3.7, J2’’,3’’
=
9.7, J3’’,4’’ = 9.3, J4’’,5’’ = 9.3 Hz. 13C NMR (75.5 MHz, D2O): δ
63.4 (Cꢀ6’’), 68.7 (Cꢀ1’), 71.3 (Cꢀ4’), 72.2 (Cꢀ3’), 72.4 (Cꢀ
4’’), 74.4 (Cꢀ2’’), 74.7 (Cꢀ3’’), 75.6 (Cꢀ2’), 76.0 (Cꢀ5’’),
(470 mg, 50 % from fructose; 442mg, 47% from glucose) as a
yellowish hard foam. — [α]D = ꢀ 12.2 (c 1.0, H2O).
20
–
4
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DOI: 10.1039/C3GC41203B
101.0 (Cꢀ1’’), 120.3 (Cꢀ5), 128.8ꢀ137.0 (C6H5), 140.0 (Cꢀ4),
148.6 (Cꢀ2). MS (FD): m/z = 427.2 [M++H], 450.2 [M++Na].
4-[(1'R,2'S,3'R)-4'-(α-D-Galactopyranosyloxy)-1',2',3'-
102.1 (Cꢀ1’’), 117.6 (Cꢀ5), 135.3 (Cꢀ2), 147.0 (Cꢀ4). MS
(FD): m/z = 365 [M+], 366 [M+1+].
4-[(1'R,2'S,3'R)-2'-(α-D-Glucopyranosyloxy)-1',3',4'-
trihydroxybutyl]-imidazole (6) from melibiose with 65 trihydroxybutyl]-imidazole (10) from maltose with
5
formamidine acetate yielded imidazole 6 (1.33 g, 38 %) as a
formamidine acetate yielded imidazole 10 (1.3 g, 28 %) as a
yellowꢀbrown hard foam. — Rf 0.24 [EtOH / conc. NH3ꢀsol.
(3 : 1)]. (Found: C, 44.59; H, 6.29; N, 8.08% C13H22N2O9
yellowꢀbrown hard foam. — Rf 0.16 [EtOH / conc. NH3ꢀsol.
1
(3 : 1)]. H NMR (300 MHz, D2O): δ 3.60 (m, 1 H, 4’ꢀHa),
1
requires C, 44.57; H, 6.33; N, 8.00%); H NMR (300 MHz,
3.74 (m, 1 H, 6’’ꢀH), 3.84 (dd, 1 H, 2’’ꢀH), 3.86 (m, 1 H, 4’ꢀ
Hb), 3.88 (m, 1 H, 4’’ꢀH), 3.91 (m, 1 H, 2’ꢀH), 3.94 (m, 1 H, 70 D2O): δ 3.43 (dd, 1 H, 4’’ꢀH), 3.61 (dd, 1 H, 2’’ꢀH), 3.55 ꢀ
10 5’’ꢀH), 3.96 (m, 1 H, 3’’ꢀH), 3.98 (m, 1 H, 3’ꢀH), 4.98 (d, 1 H,
1’’ꢀH), 5.15 (d, 1 H, 1’—H), 7.32 (s, 1 H, 5ꢀH), 8.25 (d, 1 H,
2ꢀH). — J1’,2’ = 2.3, J1’’,2’’ = 3.3, J2’’,3’’ = 7.5, J3’’,4’’ = 3.4, J4’’,5’’
=3.4, Jgem, 6’’ꢀH2 = 14.5 Hz. 13C NMR (75.5 MHz, D2O): δ
64.0 (Cꢀ6’’), 68.4 (Cꢀ1’), 71.4 (Cꢀ4’, Cꢀ2’’), 72.1 (Cꢀ3’), 72.2
15 (Cꢀ3’’), 72.3 (Cꢀ4’’), 73.8 (Cꢀ5’’), 75.7 (Cꢀ2’), 101.2 (Cꢀ1’’),
119.0 (Cꢀ5), 137.6 (Cꢀ2), 138.9 (Cꢀ4). MS (FD): m/z = 351
[M++H], 373 [M++Na].
3.61 (m, 1 H, 4’ꢀHa ), 3.67 ꢀ 3.79 (m, 2 H; 4’ꢀHb , 6’’ꢀHa),
3.80 ꢀ 3.84 (m, 3 H, 3’ꢀH, 3’’ꢀH, 5’’ꢀH), 3.89 ꢀ 3.92 (m, 1 H,
6’’ꢀHb), 4.19 (dd, 1 H, 2’ꢀH), 5.10 (d, 1 H, 1’’ꢀH), 5.21 (d, 1
H, 1’ꢀH), 7.24 (s, 1 H, 5ꢀH), 8.00 (s, 1 H, 2ꢀH). — J1’,2’ = 3.8,
75 J2’,3’ = 5.4, J1’’,2’’ = 3.9, J2’’,3’’ = 10.0, J3’’,4’’ = 9.6, J4’’,5’’ = 9.3 Hz.
13C NMR (75.5 MHz, D2O): δ 63.2 (Cꢀ6’’), 63.7 (Cꢀ4’), 69.1
(Cꢀ1’), 72.4 (Cꢀ4’’), 74.3 (Cꢀ3’), 74.6 (Cꢀ2’’), 74.9 (Cꢀ3’’),
75.5 (Cꢀ5’’), 85.1 (Cꢀ2’) 101.8 (Cꢀ1’’), 119.0 (Cꢀ5), 136.7 (Cꢀ
2), 137.3 (Cꢀ4). MS (FD): m/z =351 [M++H], 373 [M++Na].
4-[(1'R,2'S,3'R)-4'-(α-D-Galactopyranosyloxy)-1',2',3'-
trihydroxybutyl]-2-methylimidazole (7) from melibiose 80 4-[(1'R,2'S,3'R)-2'-(β-D-Glucopyranosyloxy)-1',3',4'-
20 with ethylacetimidate hydrochloride yielded 2ꢀmethylꢀ
imidazole 7 (979 mg, 27 %) as a yellowꢀbrown hard foam. —
Rf 0.20 [EtOH / conc. NH3ꢀsol. (3 : 1)]. (Found: C, 44.62; H,
trihydroxybutyl]-imidazole (11) from cellobiose with
formamidine acetate yielded imidazole 11 (875 mg, 25 %) as
a yellowꢀbrown hard foam. — Rf 0.20 [EtOH / conc. NH3ꢀsol.
(3 : 1)]. 1H NMR (300 MHz, D2O): δ 3.30 ꢀ 3.35 (m, 3 H, 2’’ꢀ
6.35; N, 8.10% C13H22N2O9 requires C, 44.57; H, 6.33; N,
1
8.00%); H NMR (300 MHz, D2O): δ 2.62 (s, 3 H, 2ꢀCH3), 85 H, 5’’ꢀH, 4’’ꢀH), 3.44 ꢀ 3.50 (m, 1 H, 3’’ꢀH ), 3.68 ꢀ 3.77 (m,
25 3.75 (m, 1 H, 4’’ꢀH), 3.76 (m, 2 H, 6’’ꢀH), 3.82 (m, 1 H, 2’ꢀ
H), 3.82 ꢀ 3.89 (m, 2 H, 2’’ꢀH, 4’’ꢀH), 3.95 ꢀ 3.99 (m, 3 H,
3’ꢀH, 3’’ꢀH, 5’’ꢀH), 5.00 (d, 1 H, 1’’ꢀH), 5.17 (d, 1 H, 1’ꢀH),
7.26 (s, 1 H, 5ꢀH). — J1’,2’ = 1.5, J1’’,2’’ = 3.5, J2’’,3’’ = 8.1, J3’’,4’’
4 H, 6’’ꢀH2, 4’ꢀH2), 3.78 ꢀ 3.86 (m, 1 H, 3’ꢀH), 4.11 (dd, 1 H,
2’ꢀH), 4.51 (d, 1 H, 1’’ꢀH), 5.10 (d, 1 H, 1’ꢀH), 7.33 (s, 1 H,
5ꢀH), 8.27 (s, 1 H, 2ꢀH). — J2,5 = 1.3, J1’,2’ = 4.1, J2’,3’ = 6.4,
J1’’,2’’ = 8.2 Hz. 13C NMR (75.5 MHz, D2O): δ 63.4 (Cꢀ4’),
= 3.5, J4’’,5’’ = 3.5 Hz. 13C NMR (75.5 MHz, D2O): δ 13.5 (2ꢀ 90 64.7 (Cꢀ6’’), 68.4 (Cꢀ1’), 71.8 (Cꢀ4’’), 74.0 (Cꢀ3’), 76.1 (Cꢀ
30 CH3), 64.0 (Cꢀ6’’), 67.1 (Cꢀ1’), 71.4 (Cꢀ4’, Cꢀ2’’), 71.9, 72.1
(Cꢀ3’, Cꢀ3’’), 72.4 (Cꢀ4’’), 73.8 (Cꢀ5’’), 75.4 (Cꢀ2’), 101.2
(Cꢀ1’’), 118.0 (Cꢀ5), 135.9 (Cꢀ2), 148.2 (Cꢀ4). MS (FD): m/z
= 365 [M+], 366 [M+1+].
5’’), 78.3 (Cꢀ2’’, Cꢀ3’’), 84.0 (Cꢀ2’) 105.2 (Cꢀ1’’), 119.3 (Cꢀ
5), 137.3 (Cꢀ2), 137.9 (Cꢀ4). MS (FD): m/z = 351 [M++H],
373 [M++Na].
4-[(1'R,2'S,3'R)-2'-(β-D-Galactopyranosyloxy)-1',3',4'-
95 trihydroxybutyl]-imidazole (12) from lactose with
formamidine acetate yielded imidazole 12 (1.40 g, 40 %) as a
yellowꢀbrown hard foam. — Rf 0.13 EtOH / conc. NH3ꢀsol. (3
: 1). 1H NMR (300 MHz, D2O): δ 3.55 ꢀ 3.61 (m, 2 H, 4’ꢀHa,
6’’ꢀHa), 3.63 ꢀ 3.65 (m, 2 H, 2’’ꢀH, 3’’ꢀH ), 3.65 ꢀ 3.67 (m, 1
4-[(1'R,2'S,3'R)-3'-(α-D-Glucopyranosyloxy)-1',2',4'-
35 trihydroxybutyl]-imidazole (8) from leucrose with
formamidine acetate yielded imidazole 8 (1.7 g, 38 %) as a
yellowꢀbrown hard foam. — Rf 0.21 [EtOH / conc. NH3ꢀsol.
1
(3 : 1)]. H NMR (300 MHz, D2O): δ 3.44 (dd, 1 H, 4’’ꢀH),
3.61 (dd, 1 H, 2’’ꢀH), 3.75ꢀ3.79 (m, 2 H, 4’ꢀHa ,6’’ꢀHa), 3.80ꢀ 100 H, 5’’ꢀH ), 3.67 ꢀ 3.70 (m, 2 H; 4’ꢀHb , 6’’ꢀHb), 3.77 ꢀ 3.86
40 3.86 (m, 4 H, 3’ꢀH, 2’’ꢀH, 3’’ꢀH, 5’’ꢀH), 3.90ꢀ3.93 (m, 2 H,
4’ꢀHb, 6’’ꢀHb), 4.00 (dd, 1 H, 2’ꢀH), 5.13 (d, 1 H, 1’’ꢀH),
5.23 (d, 1 H, 1’ꢀH), 7.42 (s, 1 H, 5ꢀH), 8.52 (s, 1 H, 2ꢀH). —
(m, 1 H, 3’ꢀH), 3.91 (dd, 1 H, 4’’ꢀH), 4.17 (dd, 1 H, 2’ꢀH),
4.51 (d, 1 H, 1’’ꢀH), 5.07 (d, 1 H, 1’ꢀH), 7.27 (s, 1 H, 5ꢀH),
8.05 (s, 1 H, 2ꢀH). — J2,5 = 0.8, J1’,2’ = 5.4, J2’,3’ = 5.4, J1’’,2’’
=
7.6, J3’’,4’’ = J4’’,5’’ = 3.4 Hz. 13C NMR (75.5 MHz, D2O): δ 63.6
J2,5 = 1.0, J1’,2’ = 2.3, J2’,3’ = 7.9, J1’’,2’’ = 3.9, J3’’,4’’ = 9.6, J4’’,5’’
=
9.6 Hz. 13C NMR (75.5 MHz, D2O): δ 63.3 (Cꢀ6’’), 63.9 (Cꢀ 105 (Cꢀ4’), 64.6 (Cꢀ6’’), 69.0 (Cꢀ1’), 71.3 (Cꢀ4’’), 73.9 (Cꢀ4’),
45 4’), 67.4 (Cꢀ1’), 72.4 (Cꢀ4’’), 74.2 (Cꢀ2’), 74.4 (Cꢀ2’’), 75.0
(Cꢀ3’’), 75.6 (Cꢀ5’’), 82.0 (Cꢀ3’) 102.5 (Cꢀ1’’), 119.0 (Cꢀ5),
136.9 (Cꢀ2), 137.5 (Cꢀ4). MS (FD): m/z = 351 [M++H], 373
[M++Na].
74.4 (Cꢀ3’), 75.4 (Cꢀ5’’), 77.7 (Cꢀ2’’), 85.0 (Cꢀ2’) 105.9 (Cꢀ
1’’), 119.6 (Cꢀ5), 138.1 (Cꢀ2), 138.5 (Cꢀ4).
MS (FD): m/z = 351 [M+1+], 373 [M+Na+].
4-[(1'R,2'S,3'R)-3'-(α-D-Glucopyranosyloxy)-1',2',4'-
50 trihydroxybutyl]-2-methyl-imidazole (9) from leucrose with
ethylacetimidate hydrochloride yielded imidazole 9 (940 mg,
26 %) as a yellowꢀbrown hard foam. — Rf 0.27 [EtOH /
conc. NH3ꢀSol. (3 : 1)]. 1H NMR (300 MHz, D2O): δ 2.62 (s,
3 H, 2ꢀCH3), 3.44 (t, 1 H, 4’’ꢀH), 3.62 (dd, 1 H, 2’’ꢀH), 3.75 ꢀ
55 3.80 (m, 2 H, 4’ꢀHa, 6’’ꢀHa), 3.80 ꢀ 3ꢀ86 (m, 4 H, 3’ꢀH, 2’’ꢀH,
3’’ꢀH, 5’’ꢀH), 3.90 ꢀ 3.93 (m, 2 H, 4’ꢀHb, 6’’ꢀHb), 4.00 (dd, 1
H, 2’ꢀH), 5.13 (d, 1 H, 1’’ꢀH), 5.24 (d, 1 H, 1’ꢀH), 7.28 (s, 1
H, 5ꢀH). — J1’,2’ = 2.2, J2’,3’ = 7.9, J1’’,2’’ = 3.8, J2’’,3’’ = 10.0,
J3’’,4’’ = J4’’,5’’ = 9.6 Hz. 13C NMR (75.5 MHz, D2O): δ 13.0 (2ꢀ
60 CH3), 62.7 (Cꢀ6’’), 63.3 (Cꢀ4’), 66.3 (Cꢀ1’), 71.9 (Cꢀ4’’), 73.4
(Cꢀ2’), 73.8 (Cꢀ2’’), 74.5 (Cꢀ3’’), 75.0 (Cꢀ5’’), 81.6 (Cꢀ3’),
110 Acknowledgment
This work was financially supported by Grant 94 NR 078ꢀF
and 99 NR 063 from the Ministry of Nutrition, Agriculture
and Forestry, Bonn, administered by the Fachagentur
Nachwachsende Rohstoffe, Gu lzow, Germany 18276.
115 Notes and references
a Institute of Molecular Bioscience, Brisbane, Australia.; Tel:
+61 7 3346 2985; E-mail: a.brust@imb.uq.edu.au
bClemens-Schöpf Institut fu r Organische Chemie und
Biochemie, Technische Universität Darmstadt, Darmstadt,
120 Germany 97321.
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Green Chemistry
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DOI: 10.1039/C3GC41203B
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