Improved preparation of 4(5)-aryl-2-(β-d-glucopyranosyl)-imidazoles, the most efficient glucose analogue inhibitors of glycogen phosphorylase

Article abstract of DOI:10.1039/c6ra21839c

The synthesis of 4(5)-aryl-2-(β-d-glucopyranosyl)-imidazoles, the currently most efficient glucose derived inhibitors of glycogen phosphorylase enzymes was amended and extended by using O-perbenzylated β-d-glucopyranosyl cyanide as the starting material.

Full text of DOI:10.1039/c6ra21839c

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DOI: 10.1039/C6RA21839C
Improved preparation of 4(5)-aryl-2-(β-D-glucopyranosyl)-imidazoles, the
most efficient glucose analogue inhibitors of glycogen phosphorylase
Eszter Szennyes,a Éva Bokor,a Gyula Batta,a Tibor Docsa,b Pál Gergely,b László Somsáka*
aDepartment of Organic Chemistry, University of Debrecen, POB 400, H-4002 Debrecen,
Hungary
bDepartment of Medical Chemistry, Faculty of Medicine, University of Debrecen, Egyetem tér
1, H-4032 Debrecen, Hungary
Abstract
The synthesis of 4(5)-aryl-2-(β-D-glucopyranosyl)-imidazoles, the currently most efficient
glucose derived inhibitors of glycogen phosphorylase enzymes was amended and extended by
using O-perbenzylated β-D-glucopyranosyl cyanide as the starting material. This compound
and its derivatives C-(β-D-glucopyranosyl)formimidate and formamidine were obtained in
large scale reactions to give the products in ~20 grams amounts. Ring closing reactions of the
formimidate and formamidine by α-amino- and α-bromoketones, respectively, produced the
O-perbenzylated imidazoles which were deprotected by catalytic hydrogenation or by
EtSH/BF3·OEt2. Newly prepared 4(5)-(4-nitro- and -aminophenyl)-2-(β-D-glucopyranosyl)-
imidazoles proved less efficient inhibitors (Ki values of 1141 and 411 nM, respectively) than
their unsubstituted counterpart (Ki = 280 nM).
Keywords
C-Glycosyl-compounds; cyanide; amidine; imidate; imidazole; glycogen phosphorylase;
inhibitor.
* Corresponding author: tel - +3652512900 ext 22348; fax - +3652512744; e-mail –
somsak.laszlo@science.unideb.hu
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DOI: 10.1039/C6RA21839C
Introduction
The imidazole ring is a frequent heterocyclic motif in essential biomolecules and other natural
products. It has emerged as an attractive building block in drug design because of its good
biocompatibility and multifaceted ability to make favourable interactions (e.g. hydrogen
bonds, van der Waals interactions, п-п stackings, ionic contacts and coordination to metal
ions) in various biological environments.1 A large array of compounds with an imidazole
scaffold are marketed drugs for the medication of prevalent diseases (e.g. cancer, viral,
fungal, bacterial and parasitic infections, neurodegenerative disorders, hypertension, allergy,
gastric ulcers, obesity etc.), and further representatives are under investigation not only in
therapeutic but also in diagnostic and pathologic fields.1
Among the bioactive imidazole derivatives some carbohydrate based conjugates, first of all N-
and C-nucleoside analogues can also be found with existing (e.g. AICAR and Mizoribine)2 or
possible pharmaceutical utilizations (e.g. imidazofurin).3 A 2-C-glycopyranosylated imidazole
was reported to inhibit some glycosidase enzymes.4
In our recent studies it has been shown that 4(5)-aryl-2-(β-D-glucopyranosyl)-imidazoles (7,
Scheme 1) exhibit nanomolar inhibitory activities towards glycogen phosphorylase enzymes
(GPs), and the very low Ki values (156 and 26 nM against human liver GPa, 280 and 31 nM
against rabbit muscle GPb, 226 and 65 nM against rabbit muscle GPa for 7a and 7b,
respectively) render these derivatives to be the best known glucose analogue inhibitors of
GPs.5,6 Based on these findings this type of compounds may have the potential to be applied
in diseased states wherein the action of GPs is essential (e.g. type 2 diabetes,7 ischemic
injuries,8,9 tumor growth10).
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DOI: 10.1039/C6RA21839C
The first syntheses of 7 were worked out starting from O-perbenzoylated glucopyranosyl
cyanide11 1 as outlined in Scheme 1.5,6 The cyclisation of amidine12 3, prepared from 1 via
amidoxime13,14 2, with α-bromo-ketones gave imidazoles 6 only in very low yields (route A)
primarily due to the lability of the benzoyl-protecting groups under the necessarily applied
basic conditions.5 In route B the transformation of amide11 4 to imidate15 5 and the subsequent
ring closure with α-amino-ketones required less basic conditions. Although this resulted in
somewhat better yields of 6,6 the overall yields for 7 seemed still unsatisfactory. Therefore,
we set out to find a more efficient route for the preparation of this promising class of
compounds first of all by changing the O-protecting groups to base stable benzyl ethers.
Scheme 1. Previous syntheses of 4(5)-aryl-2-(β-D-glucopyranosyl)-imidazoles
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DOI: 10.1039/C6RA21839C
Results and discussion
O-Perbenzylated D-glucopyranosyl cyanides both in α- and β-configurations are known from
the literature.16-19 While the pure α-configured cyanide could be obtained from glucosyl
trichloroacetimidate and TMSCN in a 1 gram scale reaction,17 no practicable, large scale
preparation of the β-anomer has yet been described. Small quantities of this compound (up to
300-400 mg) were achieved upon reaction of 1-O-acetate16 or 1-O-phosphate18 of 2,3,4,6-
tetra-O-benzyl-D-glucopyranose with TMSCN followed by preparative layer or flash column
chromatographic separation from the concomitant α-anomeric pair. Another method applying
debenzoylation of O-perbenzoylated β-D-glucopyranosyl cyanide11 followed by standard O-
perbenzylation was also reported.20
For the planned syntheses of the target C-glucosyl imidazoles several grams of the O-
perbenzylated β-D-glucopyranosyl cyanide were needed. To this end, the preparation of this
compound was effected by modifying the procedure of Garcia-Lopez et al.16 (Scheme 2).
Acetylation of commercially available 2,3,4,6-tetra-O-benzyl-D-glucopyranose (8) followed
by BF3∙Et2O promoted substitution of the resulting 1-O-acetyl-D-glucopyranose 9αβ with
TMSCN furnished an anomeric mixture of glucosyl cyanides 10αβ (α:β ~1.25:1) in high
yield. From the worked-up reaction mixture the pure cyanide 10β was separated by
crystallisation from EtOH. In this way ~18 g of 10β could be obtained from 50 g of 8 without
chromatographic purification.
Next, transformations of cyanide 10β into the corresponding amidine 11 and imidate 12 were
investigated (Scheme 2). Amidine hydrochloride 11 was prepared in excellent yield in a one-
pot two-step procedure from 10β by the addition21 of MeO– ion to the nitrile group (to give
the unisolated 12) followed by treatment22 with NH4Cl. Imidate 12 was also isolated in high
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yield by trituration of the worked-up mixture of the first reaction step (10β→12) with hexane.
DOI: 10.1039/C6RA21839C
Amidine 11 could also be obtained directly from 10αβ due to the poorer reactivity of 10α
under the applied conditions. Thus, addition of Et2O to the reaction mixture, obtained in a
consecutive treatment of 10αβ by NaOMe and NH4Cl containing 10α and 11, allowed
amidine salt 11 to crystallize and be isolated in 41 % yield. Finally, a large scale preparation
of 11 (~20 g pure product) was accomplished by a multistep reaction sequence
8→9αβ→10αβ→11 in 40 % overall yield without isolation of the intermediates.
Scheme 2. Reaction conditions: i) Ac2O, dry pyridine, rt; ii) TMSCN, BF3∙Et2O, dry CH3CN,
rt; iii) crystallization from EtOH; iv) 1. NaOMe in MeOH, CHCl3, rt, 2. NH4Cl, rt; v) NaOMe
in MeOH, CHCl3, rt.
Treatment of amidine 11 with α-bromo-ketones (Table 1, conditions i) afforded the desired O-
perbenzylated C-glucosyl imidazoles 13 in good yields accompanied by small amounts of N-
aroylmethyl imidazoles 14. The latter by-products were obviously formed by the reactions of
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13 with the α-bromo-ketones under the basic reaction conditions. Compounds 14a,b could be
DOI: 10.1039/C6RA21839C
separated by column chromatography, and HMBC NMR measurements (Fig. 1) proved the
depicted structures.
Table 1. Synthetic routes towards C-glucosyl imidazoles 7
i) THF-H2O 8:1, K2CO3, rt; ii) dry pyridine, rt; iii) Pd(OH)2/C, H2, ccHCl, EtOAc, EtOH, rt;
iv) BF3∙Et2O, EtSH, CH2Cl2, rt.
Ar
Conditions and yields (%)
13
14
7
i
ii
i
72
7
iii
89
a
b
c
33
69
47
‒
8
iii
iv
inseparable
82
ii
‒
i
36
traces
iv
45
66
iii
‒
‒
‒
d
(from 13c)
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DOI: 10.1039/C6RA21839C
Figure 1. Structure elucidation of compounds 14a,b by 2D 1H-13C HMBC measurements
(dashed lines indicate the observed cross peaks)
Extension of the above reaction to the synthesis of 4(5)-(4-nitrophenyl)imidazole 13c gave the
expected compound in acceptable yield. It is to be noted that under these conditions the O-
perbenzoylated counterpart of 13c could not be obtained from the corresponding amidine.
In order to exclude the possibility of the formation of by-products 14 the synthesis of
imidazoles 13a,b was also tried by cyclisation of imidate 12 with the corresponding α-amino-
ketones (Table 1, conditions ii), however, these reactions provided the desirable heterocycles
in significantly lower yields.
Finally, removal of the O-benzyl protecting groups of compounds 13 were studied. Catalytic
hydrogenation of 13a and 13c with Pd(OH)2/C in the presence of hydrochloric acid (to avoid
poisoning of the catalyst by protonation of the imidazole) was smoothly accomplished to
provide the phenyl and 4-aminophenyl derivatives 7a and 7d, respectively, in good yields
(Table 1, conditions iii). However, the same reaction of 2-naphthyl-imidazole 13b afforded
1
the expected deprotected derivative 7b together with inseparable by-products. The H-NMR
and MS measurements of this mixture revealed that beside O-debenzylation partial saturation
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of the naphthalene ring also took place. Further attempts to selectively cleave the benzyl
DOI: 10.1039/C6RA21839C
groups of 13b under reductive (Pd(OH)2/C, HCOONH4, MeOH), oxidative (CrO3, AcOH;
DDQ, CH2Cl2, H2O or MeOH) or other (TMSI, CH3CN; BBr3 or BBr3∙SMe2, CH2Cl2)
conditions failed. Finally, the treatment of 13b with ethanethiol in the presence of BF3∙OEt2
(Table 1, conditions iv) proved suitable to get 7b in high yield. By applying this method for
the deprotection of 13c the 4-nitrophenyl derivative 7c was also obtained, albeit in lower
yield.
The 4(5)-(4-nitro- and -aminophenyl)imidazoles 7c and 7d were assayed against rabbit
muscle GPb as described earlier23 to show Ki values of 1141 and 411 nM, respectively. This
finding revealed that substitution of the phenyl ring in the 4-position resulted in a weakening
of the inhibition (Ki = 280 nM for 7a), and this effect was smaller for the amino substituent in
comparison to that of the nitro group.
Conclusion
In conclusion, an improved method was elaborated for the synthesis of 4(5)-aryl-2-β-D-
glucopyranosyl imidazoles 7 from O-perbenzylated β-D-glucopyranosyl cyanide 10β. Cyanide
10β and its more reactive derivatives amidine 11 and imidate 12 were prepared in ~20 grams
scales. Ring closures of 11 and 12 by α-bromoketones or α-aminoketones, respectively, gave
the expected O-protected imidazoles 13 which were debenzylated by usual catalytic
hydrogenation (7a,d) or EtSH/BF3·OEt2 (7b,c). Overall yields for 7a and 7b were raised to 58
and 51 %, respectively, based on the starting 10β. Substitution of the phenyl ring of 7a in the
4-position by a nitro (7c) or an amino group (7d) resulted in somewhat less efficient inhibitors
of rabbit muscle glycogen phosphorylase b.
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DOI: 10.1039/C6RA21839C
Experimental
General Methods
Melting points were measured on a Kofler hot-stage and are uncorrected. Optical rotations
were determined with a Perkin-Elmer 241 polarimeter at rt. NMR spectra were recorded with
1
1
Bruker 360 (360/90 MHz for H/13C) or Bruker 400 (400/100 MHz for H/13C) or Avance II
1
500 (500/125 MHz for H/13C) spectrometers. Chemical shifts are referenced to the internal
TMS (1H), or to the residual solvent signals (13C). Proton-signal assigments for compounds 9-
14 are based on COSY correlations. Microanalyses were performed on an Elementar Vario
Micro cube instrument. Mass spectra were obtained by a Thermo Scientific LTQ XL
instrument. TLC was performed on DC-Alurolle Kieselgel 60 F254 (Merck), and the plates
were visualised under UV light and by gentle heating (generally no spray reagent was used
but, if more intense charring was necessary, the plate was sprayed with the following solution:
abs. EtOH (95 mL), ccH2SO4 (5 mL) anisaldehyde (1 mL)). For column chromatography
Kieselgel 60 (Merck, particle size 0.063-0.200 mm) was used. MeCN, CHCl3 and CH2Cl2
were distilled from P4O10 and stored over 4 Å molecular sieves. Pyridine was distilled from
KOH and stored over KOH pellets. MeOH was purified by distillation after refluxing for a
couple of hours with magnesium turnings and iodine. Organic solutions were dried over
anhydrous MgSO4 and concentrated under diminished pressure at 40-60 ºC (water bath).
2,3,4,6-Tetra-O-benzyl-β-D-glucopyranose (Carbosynth), TMSCN (ACROS), EtSH (TCI),
.
Pd(OH)2/C (Sigma Aldrich) and BF3 Et2O (Merck) were purchased from the indicated
suppliers. 2-Amino-1-arylethanones were synthesized according to literature procedures.6,24
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General procedure I for the synthesis of 4(5)-aryl-2-(2’,3’,4’,6’-tetra-O-DbOeIn: 1z0.y10l3-9β/-CD6R-A21839C
glucopyranosyl)-imidazoles (13a-c) from C-(2,3,4,6-tetra-O-benzyl-β-D-
glucopyranosyl)formamidine hydrochloride (11)
C-(2,3,4,6-Tetra-O-benzyl-β-D-glucopyranosyl)formamidine hydrochloride (11, 0.20 g, 0.33
mmol) and K2CO3 (0.09 g, 0.66 mmol, 2 equiv.) were stirred in a THF-H2O solvent mixture
(8 mL and 1 mL, respectively) at rt for 15 min. After that, 2-bromo-1-arylethanone (0.33
mmol, 1 equiv.) was added to the reaction mixture and the stirring was continued at rt. When
TLC (9:1 CHCl3-MeOH and 1:1 hexane-EtOAc) indicated total consumption of the starting
material (2 d) the mixture was diluted with EtOAc (20 mL) and extracted with water (2 × 10
mL). The organic phase was dried over MgSO4, the solvent was removed under reduced
pressure, and the residue was purified by column chromatography (2:1 hexane-EtOAc).
General procedure II for the synthesis of 4(5)-aryl-2-(2’,3’,4’,6’-tetra-O-benzyl-β-D-
glucopyranosyl)-imidazoles (13a,b) from methyl C-(2,3,4,6-tetra-O-benzyl-β-D-
glucopyranosyl)formimidate (12)
Methyl C-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)formimidate (12, 0.20 g, 0.34 mmol)
and the hydrochloride or hydrobromide salt of the corresponding 2-amino-1-arylethanone
(0.69 mmol, 2 equiv.) were dissolved in anhydrous pyridine (5 mL). The mixture was stirred
at rt and the reaction was monitored by TLC (2:1 hexane-acetone). After completion of the
reaction (2 d) the solution was diluted with EtOAc (20 mL) and extracted with water (3 × 10
mL). The organic phase was dried over MgSO4, filtered and the solvent was evaporated, then
the residue was purified by column chromatography (3:1 hexane-EtOAc).
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General procedure III for the removal of O-benzyl protecting groups by catalytic
DOI: 10.1039/C6RA21839C
hydrogenation
A degassed, vigorously stirred suspension of 20 % Pd(OH)2/C (50 weight % of substrate) in a
mixture of EtOAc (3 mL) and EtOH (15 mL) was saturated with H2 (3 ×), and a solution of
the corresponding O-perbenzylated β-D-glucopyranosyl imidazole 13 (0.42 mmol) in EtOAc
(3 mL) and a drop of concentrated HCl were added. After stirring the reaction mixture under
H2 atmosphere at rt for overnight it was neutralized with NaHCO3. The catalyst and the
inorganic precipitates were filtered off through a pad of celite and washed thoroughly with
MeOH (3 × 3 mL). The filtrate was then concentrated under reduced pressure and the residual
crude product was purified by column chromatography (5:1 CHCl3-MeOH).
General procedure IV for the removal of O-benzyl protecting groups by using
EtSH/BF3∙OEt2
To a solution of the corresponding O-perbenzylated β-D-glucopyranosyl imidazole 13 (0.54
mmol) in anhydrous CH2Cl2 (10 mL) EtSH (1.6 mL, 21.46 mmol, 40 equiv.) and BF3∙OEt2
(1.35 mL, 10.88 mmol, 20 equiv.) were added, and the reaction mixture was stirred at rt. After
completion of the reaction (3 d) monitored by TLC (1:1 hexane-EtOAc and 3:1 CHCl3-
MeOH) the mixture was diluted with EtOAc (10 mL) and extracted with water (3 × 3 mL).
The combined aqueous phases were concentrated under diminished pressure and the residue
was purified by column chromatography (19:1 → 9:1 CHCl3-MeOH).
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DOI: 10.1039/C6RA21839C
Syntheses and characterization of the compounds
2-(β-D-Glucopyranosyl)-4(5)-phenyl-imidazole (7a)
Prepared from compound 13a (0.24 g, 0.36 mmol) according to General procedure III.
Purification by column chromatography yielded 0.10 g (89 %) colourless syrup. Physical and
spectroscopic data were identical to those reported previously.5
2-(β-D-Glucopyranosyl)-4(5)-(2-naphthyl)-imidazole (7b)
Prepared from compound 13b (0.39 g, 0.54 mmol) according to General procedure IV.
Purification by column chromatography yielded 0.16 g (82 %) colourless syrup. Physical and
spectroscopic data were identical to those reported previously.5
2-(β-D-Glucopyranosyl)-4(5)-(4-nitrophenyl)-imidazole (7c)
Prepared from compound 13c (0.20 g, 0.28 mmol) according to General procedure IV.
Purification by column chromatography yielded 0.05 g (45 %) yellow syrup. Rf = 0.50 (7:3
CHCl3-MeOH); [α]D = +10 (c 0.50, MeOH); 1H NMR (400 MHz, CD3OD) δ (ppm): 8.22 (2H,
d, J = 8.9 Hz, aromatics), 7.94 (2H, d, J = 8.9 Hz, aromatics), 7.67 (1H, s, imidazole CH),
4.39 (1H, d, J = 9.6 Hz, H-1’), 3.90 (1H, dd, J = 12.0, 1.6 Hz, H-6’a), 3.74 (1H, dd, J = 12.0,
5.0 Hz, H-6’b), 3.66 (1H, pseudo t, J = 9.4, 9.0 Hz, H-2’ or H-3’ or H-4’), 3.55-3.46 (3H, m,
13
H-2’ and/or H-3’ and/or H-4’, H-5’); C NMR (100 MHz, CD3OD) δ (ppm): 149.4 (PhC4-
NO2), 147.5, 141.5 (imidazole C-2, C-4), 126.1, 125.1 (aromatics), 118.5 (imidazole C-5),
82.2, 79.3, 76.9, 74.6, 71.3 (C-1’ – C-5’), 62.8 (C-6’). ESI-MS positive mode (m/z): calcd for
+
C15H18N3O7 [M+H]+: 352.11. Found: 352.33.
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DOI: 10.1039/C6RA21839C
4(5)-(4-Aminophenyl)-2-(β-D-glucopyranosyl)-imidazole (7d)
Prepared from compound 13c (0.30 g, 0.42 mmol) according to General procedure III.
Purification by column chromatography yielded 0.10 g (66 %) pale yellow amorphous solid.
Rf = 0.37 (1:1 CHCl3-MeOH); [α]D = +2 (c 0.30, MeOH); 1H NMR (360 MHz, D2O) δ (ppm):
7.49 (2H, d, J = 8.2 Hz, aromatics), 7.31 (1H, s, imidazole CH), 6.89 (2H, d, J = 8.2 Hz,
aromatics), 4.52 (1H, d, J = 9.5 Hz, H-1’), 3.95 (1H, dd, J = 12.5, 1.8 Hz, H-6’a), 3.83 (1H,
dd, J = 12.5, 4.2 Hz, H-6’b), 3.75 (1H, pseudo t, J = 9.4, 9.0 Hz, H-2’ or H-3’ or H-4’) 3.70-
13
3.60 (3H, m, H-2’ and/or H-3’ and/or H-4’, H-5’); C NMR (90 MHz, D2O) δ (ppm): 145.9
(PhC4-NH2), 144.9, 137.5 (imidazole C-2, C-4), 126.2 (2), 122.4, 116.7 (2) (aromatics), 115.3
(imidazole C-5), 80.0, 77.1, 74.7, 72.8, 69.5 (C-1’ – C-5’), 60.9 (C-6’). ESI-MS positive
+
mode (m/z): calcd for C15H20N3O5 [M+H]+: 322.14. Found: 322.33.
1-O-Acetyl-2,3,4,6-tetra-O-benzyl-D-glucopyranose25,26 (9α,β)
2,3,4,6-Tetra-O-benzyl-β-D-glucopyranose (8, 5.00 g, 9.25 mmol) was dissolved in anhydrous
pyridine (15 mL) and cooled in an ice bath. To this stirred solution Ac2O (1.31 mL, 13.87
mmol; 1.5 equiv.) was added. The mixture was allowed to warm up to room temperature
while stirred, and the transformation was monitored by TLC (1:4 EtOAc-hexane). When the
reaction was complete (2 d) the mixture was poured into ice-water and extracted with CHCl3
(3 × 25 mL). The combined organic phase was washed with 10 % aq HCl solution (2 × 20
mL), satd aq NaHCO3 solution (20 mL) and brine (20 mL). The separated organic layer was
dried and concentrated to give the title compound as a colourless oil in quantitative yield. This
crude anomeric mixture was sufficiently pure for the next step. Rf: 0.36 (1:4 EtOAc-hexane);
1H NMR (CDCl3) δ (ppm): 7.35-7.12 (aromatics), 6.36 (d, J = 3.5 Hz, α-H-1), 5.61 (d, J = 8.1
Hz, β-H-1), 4.97-4.46 (PhCH2), 3.97-3.55 (sugar protons), 2.12 (s, α-CH3), 2.03 (s, β-CH3);
13C NMR (CDCl3) δ (ppm) 169.5 (α-C=O), 169.3 (β-C=O), 138.7, 138.5, 138.2, 138.1 (2),
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138.0, 137.9, 137.7, 128.6-127.7 (aromatics), 94.1, 84.9, 81.1, 77.3, 75.6 (β-C-1 – β-C-5),
DOI: 10.1039/C6RA21839C
90.1, 81.8, 79.0, 77.0, 72.9 (α-C-1 – α-C-5), 68.2 (β-C-6, α-C-6), 75.8, 75.1 (2), 73.6 (4 × β-
PhCH2), 75.8, 75.4, 73.6, 73.3 (4 × α-PhCH2), 21.2 (α-CH3), 21.1 (β-CH3).
2,3,4,6-Tetra-O-benzyl-α- and -β-D-glucopyranosyl cyanides (10αβ)
A: Trimethylsilyl cyanide (2.68 mL, 21.45 mmol, 2.5 equiv.) and BF3∙Et2O (53 μL, 0.43
mmol, 0.05 equiv.) were added to a solution of 1-O-acetyl-2,3,4,6-tetra-O-benzyl-D-
glucopyranose (9α,β, 5 g, 8.58 mmol) in anhydrous CH3CN (15 mL), and the reaction mixture
was stirred at room temperature. After disappearance of the starting material (~15 min, TLC,
1:5 EtOAc-hexane) the solvent was removed, and a solution of the resulting oil in EtOAc (50
mL) was extracted with satd aq NaHCO3 solution (2 × 20 mL) and brine (20 mL). The
organic phase was dried, concentrated, and column chromatography (1:7 EtOAc-hexane)
1
yielded 10αβ (3.82 g, 81 %) as a colourless oil. Rf: 0.3 (1:5 EtOAc-hexane); H NMR
(CDCl3) δ (ppm) 7.35-7.12 (aromatics), 4.96-4.42 (PhCH2), 4.61 (d, J = 6.2 Hz, α-H-1), 4.03
(d, J = 10.0 Hz, β-H-1), 3.89 (pseudo t, J = 9.3, 9.2 Hz, α-H-3), 3.82 (ddd, J = 9.4, 3.1, 2.3 Hz
α-H-5), 3.78-3.63 (α,β-H-2, α,β-H-4, α,β-H-6, α,β-H-6’), 3.58 (pseudo t, J = 9.3, 8.8 Hz, β-H-
13
3), 3.40 (ddd, J = 9.5, 3.5, 2.3 Hz, β-H-5). C NMR (CDCl3) δ (ppm) 138.3, 138.1, 138.0,
137.8, 137.7, 137.6, 137.3, 136.9, 128.8-127.8 (aromatics), 116.9 (β-C≡N), 115.5 (α-C≡N),
85.6, 83.2, 80.0, 79.7, 77.2, 77.0, 76.4, 76.2, 67.6, 67.0 (α,β-C-1 – α,β-C-5), 68.3, 67.9 (α,β-
C-6), 76.0, 75.9 (2), 75.3 (2), 74.0, 73.7, 73.6 (8 × PhCH2).
Analytically pure 10β could be obtained by crystallisation: an ethanolic solution of 10αβ (5
mL EtOH/1 g mixture) was kept at 5 °C for 30 min followed by sonication for 5-10 min and
this cycle was repeated 5 times. Then, the mixture was kept at rt for 2 days whereupon the
crystalline 10β (1.75 g, 37 %) was obtained. Mp: 85-87 °C (lit.16 mp: 76-78 °C); [α]D = +27 (c
1.00, CHCl3) (lit. [α]D = +29 (c 1, CHCl3);16 +16.7 (c 1.3, CHCl3);18 +25 (c 1.5, CHCl3)20); 1H
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NMR (CDCl3) δ (ppm): 7.33-7.12 (20H, m, aromatics), 4.93, 4.84 (2 × 1H, 2d, J = 10.2 Hz,
DOI: 10.1039/C6RA21839C
PhCH2), 4.87, 4.84 (2 × 1H, 2d, J = 10.5 Hz, PhCH2), 4.79, 4.54 (2 × 1H, 2d, J = 10.7 Hz,
PhCH2), 4.60, 4.53 (2 × 1H, 2d, J = 12.1 Hz, PhCH2), 4.06 (1H, d, J = 9.9 Hz, H-1), 3.77 (1H,
pseudo t, J = 9.9, 9.2 Hz, H-2), 3.73-3.68 (2H, m, H-6, H-6’), 3.65 (1H, pseudo t, J = 9.9, 9.2
Hz, H-4), 3.59 (1H, pseudo t, J = 9.2, 9.2 Hz, H-3) 3.42 (1H, ddd, J = 9.9, 4.6, 2.6 Hz, H-5);
13C NMR (CDCl3) δ (ppm): 138.1, 137.8, 137.7, 136.9, 128.6-127.8 (aromatics), 116.9
(C≡N), 85.6, 80.0, 79.8, 77.0, 67.6 (C-1 – C-5), 75.9 (2), 75.3, 73.7 (4 × PhCH2), 68.3 (C-6).
Anal. Calcd for C35H35NO5 (549.66): C, 76.48; H, 6.42; N, 2.55. Found: C, 76.67; H, 6.46; N,
2.49.
B: To a stirred solution of 8 (50 g, 92.47 mmol) in anhydrous pyridine (150 mL) Ac2O (13.1
mL, 138.71 mmol; 1.5 equiv.) was added at 0 ⁰C. The mixture was allowed to warm up to
room temperature and stirred until TLC (1:4 EtOAc-hexane) showed total consumption of the
starting material (2 d). The reaction mixture was then poured into ice-water and extracted with
CHCl3 (3 × 250 mL). The combined organic phase was extracted with 10 % aq HCl solution
(2 × 200 mL), satd aq NaHCO3 solution (200 mL) and brine (200 mL), respectively. The
separated organic layer was dried over MgSO4, filtered and concentrated to give compound
9α,β. Traces of pyridine were removed by repeated co-evaporations with toluene. The
obtained syrup was dissolved in anhydrous CH3CN (150 mL) and trimethylsilyl cyanide (28.9
mL, 231.18 mol, 2.5 equiv.) and BF3∙Et2O (571 μL, 4.62 mmol, 0.05 equiv.) were added, and
the stirrring was continued at rt. After disappearance of the starting material (~15 min, TLC
1:5 EtOAc-hexane) the solvent was removed. The resulting oil was diluted with EtOAc (500
mL) and extracted with satd aq NaHCO3 solution (2 × 200 mL) and brine (200 mL). The
organic phase was dried and concentrated to a syrup from which 18.73 g (37 %) of 10β was
obtained by crystallisation from EtOH as described above.
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DOI: 10.1039/C6RA21839C
C-(2,3,4,6-Tetra-O-benzyl-β-D-glucopyranosyl)formamidine hydrochloride (11)
A: To a solution of cyanide 10β (1 g, 1.82 mmol) in a mixture of anhydrous MeOH (5 mL)
and CHCl3 (1.5 mL) was added a 1M solution of NaOMe in MeOH (2.73 mL, 2.73 mmol, 1.5
equiv.). The mixture was stirred at rt and monitored by TLC (1:5 EtOAc–hexane). After
disappearance of the starting material (1 d) NH4Cl (0.24 g, 4.55 mmol, 2.5 equiv.) was added,
and when TLC (1:1 EtOAc-hexane and 9:1 CHCl3-MeOH) showed complete conversion (1 d)
of the intermediate formimidate 12 (Rf = 0.4 in 1:1 EtOAc-hexane) into a product (baseline,
1:1 EtOAc-hexane, Rf = 0.5 in 9:1 CHCl3-MeOH), the solvents were removed. The residue
was dissolved in EtOAc (10 mL), extracted with water (2 × 5 mL), dried, and concentrated.
The obtained syrup was triturated with Et2O to give 11 (1.00 g, 91 %) as a white crystalline
1
solid. Mp: 110-112 °C; [α]D = +35 (c 1.00, CHCl3); H NMR (CDCl3) δ (ppm): 9.84 (2H, s,
NH2), 7.52 (2H, s, NH2), 7.35-7.14 (20H, m, aromatics), 4.89, 4.84 (2 × 1H, 2d, J = 10.8 Hz,
PhCH2), 4.86, 4.54 (2 × 1H, 2d, J = 10.5 Hz, PhCH2), 4.78, 4.54 (2 × 1H, 2d, J = 11.0 Hz,
PhCH2), 4.52, 4.44 (2 × 1H, 2d, J = 11.8 Hz, PhCH2), 4.27 (1H, d, J = 9.4 Hz, H-1), 3.76 (1H,
pseudo t, J = 8.6, 8.6 Hz, H-3), 3.72 (1H, dd, J = 11.7, 3.1 Hz, H-6), 3.66-3.56 (3H, m, H-4,
H-5, H-6’), 3.47 (1H, pseudo t, J = 9.4, 8.6 Hz, H-2). 13C NMR (CDCl3) δ (ppm): 167.9
(C=N), 137.8, 137.6, 137.3, 136.3, 128.8-127.6 (aromatics), 86.0, 79.4, 78.4, 77.1, 73.3 (C-1
– C-5), 75.5 (2), 75.0, 73.6 (4 × PhCH2), 68.6 (C-6). MS-ESI (m/z, positive mode): Calcd. for
+
C35H39N2O5 [M + H]+: 567.29. Found: 567.75. Anal. Calcd for C35H39ClN2O5 (603.15): C,
69.70; H, 6.52; N, 4.64. Found: C, 69.00; H, 6.68; N, 4.60.
B: 1M NaOMe in MeOH (4.09 mL, 4.09 mmol, 0.75 equiv.) was added to a solution of
cyanides 10αβ (3 g, 5.46 mmol) in a mixture of anhydrous MeOH (15 mL) and CHCl3 (4.5
mL), and the reaction mixture was stirred at rt for 1 d (TLC, 1:5 EtOAc-hexane, Rf = 0.3 and
0.1 for 10α and 12, respectively, indicating the significantly poorer reactivity of 10α). NH4Cl
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(0.36 g, 6.82 mmol, 1.25 equiv.) was added, and the stirring was continued for aDnOIa: d10d.1i0t3i9o/nC6aRlA21839C
24 h at rt, when TLC (1:1 EtOAc–hexane and 9:1 CHCl3–MeOH) indicated complete
conversion of the intermediate formimidate 12 (Rf = 0.4, 1:1 EtOAc–hexane) into a more
polar product (baseline in 1:1 EtOAc–hexane, Rf = 0.5 in 9:1 CHCl3–MeOH). The solvents
were removed, the residue was dissolved in EtOAc (30 mL) and extracted with water (2 × 15
mL). The organic phase was dried and concentrated to an oil, which on trituration by Et2O
gave a solid which was filtered off and rinsed by Et2O to remove traces of unreacted 10α.
Yield of the title compound, identical with the material desribed above, was 1.35 g (41 %).
C: Starting from compound 8 (46.4 g, 85.81 mmol) the crude mixture of 10α,β was obtained
as described above. It was then dissolved in a mixture of anhydrous MeOH (250 mL) and
CHCl3 (75 mL), a 1M solution of NaOMe in MeOH (64.4 mL, 64.36 mmol, 0.75 equiv.) was
added, and the mixture was stirred at rt for 1 d. After that, NH4Cl (5.74 g, 107.26 mmol, 1.25
equiv.) was added to the reaction mixture, and stirred at rt for additional 24 h. The final
product 11 was obtained from this reaction mixture after work-up and crystallization steps
identical to those described above to give 20.7 g (40 %) white solid.
Methyl C-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)formimidate (12)
To a solution of cyanide 10β (3 g, 5.46 mmol) in a mixture of anhydrous MeOH (15 mL) and
CHCl3 (5 mL) was added a 1M solution of NaOMe in MeOH (2.73 mL, 2.73 mmol, 0.5
equiv.). The mixture was stirred at rt and monitored by TLC (1:5 EtOAc-hexane). After total
conversion of the starting material (1 d) the mixture was neutralized with a cation exchange
resin Amberlyst 15 (H+ form), then the resin was filtered off and the solvent was removed.
The residual syrup was triturated with hexane and the precipitate was filtered off. The
obtained white amorphous solid (2.89 g, 91 %) was pure enough for further transformation. Rf
= 0.4 (1:1 EtOAc-hexane); [α]D = +12 (c 0.60, CHCl3); 1H NMR (400 MHz, CDCl3) δ (ppm):
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7.72 (1H, broad s, NH), 7.34-7.15 (20H, m, aromatics), 4.90, 4.84 (2 × 1H, 2d, J = 11.1 Hz,
DOI: 10.1039/C6RA21839C
PhCH2), 4.81, 4.56 (2 × 1H, 2d, J = 10.8 Hz, PhCH2), 4.68, 4.54 (2 × 1H, 2d, J = 10.6 Hz,
PhCH2), 4.59, 4.54 (2 × 1H, 2d, J = 12.3 Hz, PhCH2), 3.78 (1H, d, J = 9.1 Hz, H-1’), 3.78
(3H, s, OCH3), 3.72-3.68 (3H, m, H-3’, H-6’a, H-6’b), 3.64 (1H, pseudo t, J = 9.4, 9.0 Hz, H-
4’), 3.53-3.49 (2H, m, H-2’, H-5’); 13C NMR (90 MHz, CDCl3) δ (ppm): 170.7 (C=N), 138.5,
138.1, 138.0, 137.8, 128.5-127.7 (aromatics), 86.3, 81.7, 78.9, 77.7, 77.5 (C-1’ – C-5’), 75.7,
75.1(2), 73.5 (4 × PhCH2), 68.8 (C-6’), 53.3 (OCH3). MS-ESI (m/z, positive mode): Calcd. for
+
C36H40NO6 [M + H]+: 582.29. Found: 582.58.
4(5)-Phenyl-2-(2’,3’,4’,6’-tetra-O-benzyl-β-D-glucopyranosyl)-imidazole (13a) and 1-(2-
oxo-2-phenylethyl)-4-phenyl-2-(2’,3’,4’,6’-tetra-O-benzyl-β-D-glucopyranosyl)-imidazole
(14a)
A: From amidine 11 (0.20 g, 0.33 mmol) and 2-bromo-1-phenylethanone (0.07 g, 0.33 mmol)
according to General procedure I. Purification by column chromatography yielded 14a as the
first and 13a as the second fraction.
Compound 13a: Yield: 0.16 g (72 %), colourless syrup. Rf = 0.47 (1:1 hexane-EtOAc); [α]D =
+6 (c 0.55, CHCl3); 1H NMR (400 MHz, CDCl3) δ (ppm): 10.19 (1H, broad s, NH), 7.64-7.01
(26H, m, aromatics, imidazole CH), 4.97, 4.86 (2 × 1H, 2d, J = 11.1 Hz, PhCH2), 4.85, 4.50
(2 × 1H, 2d, J = 10.9 Hz, PhCH2), 4.56 (1H, d, J = 9.3 Hz, H-1’), 4.50, 4.29 (2 × 1H, 2d, J =
10.5 Hz, PhCH2), 4.47, 4.41 (2 × 1H, 2d, J = 12.1 Hz, PhCH2), 3.88 (1H, pseudo t, J = 9.3,
9.2 Hz, H-2’), 3.80 (1H, pseudo t, J = 9.2, 9.1 Hz, H-3’), 3.70 (1H, pseudo t, J = 9.3, 9.1 Hz,
H-4’), 3.69 (1H, dd, J = 10.4, 2.2 Hz, H-6’a), 3.64 (1H, dd, J = 10.4, 4.4 Hz, H-6’b), 3.57
13
(1H, ddd, J = 9.3, 4.4, 2.2 Hz, H-5’); C NMR (100 MHz, CDCl3) δ (ppm): 145.4, 141.4
(imidazole C-2, C-4), 138.7, 138.1, 137.9, 137.6, 135.7, 128.7-125.0 (aromatics), 114.4
(imidazole C-5), 86.5, 81.7, 78.9, 77.8, 75.4 (C-1’ – C-5’), 75.7, 75.2, 74.9, 73.5 (4 × PhCH2),
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DOI: 10.1039/C6RA21839C
69.0 (C-6’). ESI-MS positive mode (m/z): calcd for C43H43N2O5 [M+H] : 667.32. Found:
667.44.
Compound 14a: Yield: 19 mg (7 %), colourless syrup. Rf = 0.55 (3:2 hexane-EtOAc); [α]D =
‒2 (c 0.50, CHCl3); 1H NMR (360 MHz, CDCl3) δ (ppm): 7.89, 7.82 (2 × 2H, 2d, J = 7.3 Hz
in each, aromatics), 7.57 (1H, t, J = 7.4 Hz, aromatic), 7.39-7.11 (26H, m, aromatics), 5.60,
5.44 (2 × 1H, 2d, J = 18.1 Hz, COCH2), 4.96, 4.84 (2 × 1H, 2d, J = 10.9 Hz, PhCH2), 4.81,
4.48 (2 × 1H, 2d, J = 10.8 Hz, PhCH2), 4.71, 4.62 (2 × 1H, 2d, J = 10.2 Hz, PhCH2), 4.57
(1H, d, J = 9.8 Hz, H-1’), 4.37, 4.32 (2 × 1H, 2d, J = 12.1 Hz, PhCH2), 3.98 (1H, pseudo t, J =
9.8, 9.0 Hz, H-2’), 3.77 (1H, pseudo t, J = 9.2, 9.0 Hz, H-3’), 3.64 (1H, pseudo t, J = 9.4, 9.2
Hz, H-4’), 3.63 (1H, dd, J = 10.4, 2.0 Hz, H-6’a), 3.58 (1H, dd, J = 10.4, 4.2 Hz, H-6’b), 3.52
(1H, ddd, J = 9.4, 4.2, 2.0 Hz, H-5’); 13C NMR (90 MHz, CDCl3) δ (ppm): 192.3 (CO), 144.5,
140.7 (imidazole C-2, C-4), 138.7, 138.3, 138.1 (2), 134.5, 134.3, 134.2-125.1 (aromatics),
118.4 (imidazole C-5), 86.8, 80.7, 79.1, 77.7, 75.6 (C-1’ – C-5’), 75.9, 75.2, 74.9, 73.4 (4 ×
+
PhCH2), 69.1 (C-6’), 52.3(CH2CO). ESI-MS positive mode (m/z): calcd for C51H49N2O6
[M+H]+: 785.36. Found: 785.50.
B: Imidate 12 (0.20 g, 0.34 mmol) and 2-amino-1-phenylethanone hydrochloride (0.12 g, 0.69
mmol) gave 0.08 g of 13a (33 %) according to General procedure II.
4(5)-(2-Naphthyl)-2-(2’,3’,4’,6’-tetra-O-benzyl-β-D-glucopyranosyl)-imidazole (13b) and
1-(2-(2-naphthyl)-2-oxoethyl)-4-phenyl-2-(2’,3’,4’,6’-tetra-O-benzyl-β-D-
glucopyranosyl)-imidazole (14b)
A: From amidine 11 (0.20 g, 0.33 mmol) and 2-bromo-1-(naphthalen-2-yl)ethanone (0.08 g,
0.33 mmol) according to General procedure I. Purification by column chromatography
yielded 14b as the first and 13b as the second fraction.
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Compound 13b: Yield: 0.16 g (69 %), white solid after trituration of the resulting syrup with
DOI: 10.1039/C6RA21839C
1
EtOH. Mp = 150-151 °C; Rf = 0.46 (1:1 hexane-EtOAc), [α]D = +23 (c 0.50, CHCl3); H
NMR (400 MHz, CDCl3) δ (ppm): 10.43 (1H, br s, NH), 8.21 (1H, s, aromatic), 7.78-7.02
(27H, m, aromatics, imidazole CH), 4.99, 4.87 (2 × 1H, 2d, J = 11.0 Hz, PhCH2), 4.86, 4.54
(2 × 1H, 2d, J = 10.9 Hz, PhCH2), 4.60 (1H, d, J = 9.4 Hz, H-1’), 4.52, 4.30 (2 × 1H, 2d, J =
10.3 Hz, PhCH2), 4.46, 4.40 (2 × 1H, 2d, J = 12.1 Hz, PhCH2), 3.91 (1H, pseudo t, J = 9.4,
9.1 Hz, H-2’), 3.83 (1H, pseudo t, J = 9.1, 9.0 Hz, H-3’), 3.71 (1H, pseudo t, J = 9.4, 9.0 Hz,
H-4’), 3.70 (1H, dd, J = 10.4, 2.2 Hz, H-6’a), 3.68 (1H, dd, J = 10.4, 4.4 Hz, H-6’b), 3.61
13
(1H, ddd, J = 9.4, 4.4, 2.2 Hz, H-5’). C NMR (100 MHz, CDCl3) δ (ppm): 145.4, 141.5
(imidazole C-2, C-4), 138.7, 138.1, 137.9, 137.6, 133.9, 132.7, 131.9, 128.6-127.7, 126.1,
125.3, 124.1, 123.2 (aromatics), 112.7 (imidazole C-5), 86.6, 81.6, 79.1, 77.9, 75.4 (C-1’ – C-
5’), 75.8, 75.2, 75.0, 73.5 (4 × PhCH2), 69.1 (C-6’). ESI-MS positive mode (m/z): calcd for
+
C47H45N2O5 [M+H]+: 717.33. Found: 717.42.
Compound 14b: Yield: 23 mg (8 %), colourless syrup. Rf = 0.49 (3:2 hexane-EtOAc); [α]D =
+7 (c 0.55, CHCl3); 1H NMR (400 MHz, CDCl3) δ (ppm): 8.47 (1H, s, aromatic), 8.36 (1H, s,
aromatic), 7.99-7.10 (32H, m, aromatics), 5.75, 5.62 (2 × 1H, 2d, J = 17.8 Hz, COCH2), 4.98,
4.86 (2 × 1H, 2d, J = 11.0 Hz, PhCH2), 4.79, 4.47 (2 × 1H, 2d, J = 10.8 Hz, PhCH2), 4.72,
4.66 (2 × 1H, 2d, J = 10.3 Hz, PhCH2), 4.67 (1H, d, J = 9.8 Hz, H-1’), 4.33, 4.29 (2 × 1H, d, J
= 12.3 Hz, PhCH2), 4.03 (1H, pseudo t, J = 9.8, 9.1 Hz, H-2’), 3.80 (1H, pseudo t, J = 9.1, 9.0
Hz, H-3’), 3.66 (1H, pseudo t, J = 9.5, 9.0 Hz, H-4’), 3.64 (1H, dd, J = 10.2, 2.0 Hz, H-6’b),
13
3.58 (1H, dd, J = 10.2, 4.3 Hz, H-6’a), 3.55 (1H, ddd, J = 9.5, 4.3, 2.0 Hz, H-5’); C NMR
(100 MHz, CDCl3) δ (ppm): 192.3 (CO), 144.7, 140.8 (imidazole C-2, C-4), 138.7, 138.2,
138.1, 138.0, 136.1, 134.0, 132.7, 132.6, 131.9, 131.7, 130.1-123.2 (aromatics), 118.9
(imidazole C-5), 86.8, 80.7, 79.2, 77.8, 75.8 (C-1’ – C-5’), 75.9, 75.2, 75.0, 73.4 (4 × PhCH2),
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69.1 (C-6’), 52.5 (CH2CO). ESI-MS positive mode (m/z): calcd for C59H53N2O6 [M+H] :
DOI: 10.1039/C6RA21839C
885.39. Found: 885.58.
B: Imidate 12 (0.20 g, 0.34 mmol) and 2-amino-1-(naphthalen-2-yl)ethanone hydrobromide
(0.18 g, 0.69 mmol) gave 0.12 g of 13b (47 %) according to General procedure II.
4(5)-(4-Nitrophenyl)-2-(2’,3’,4’,6’-tetra-O-benzyl-β-D-glucopyranosyl)-imidazole (13c)
Prepared from amidine 11 (0.20 g, 0.33 mmol) and 2-bromo-1-(4-nitrophenyl)ethanone (0.08
g, 0.33 mmol) according to General procedure I. Purification by column chromatography
yielded 0.09 g (36 %) yellow syrup. Rf = 0.42 (1:1 hexane-EtOAc); [α]D = +34 (c 0.50,
CHCl3); 1H NMR (400 MHz, CDCl3) δ (ppm): 10.41 (1H, s, NH), 8.14, 7.79 (2 × 2H, d, J =
8.7 Hz in each, aromatics), 7.35-6.98 (21H, m, aromatics, imdazole CH), 4.97, 4.89 (2 × 1H,
2d, J = 11.0 Hz, PhCH2), 4.87, 4.56 (2 × 1H, 2d, J = 10.9 Hz, PhCH2), 4.58 (1H, d, J = 9.3
Hz, H-1’), 4.53, 4.32 (2 × 1H, 2d, J = 10.5 Hz, PhCH2), 4.45, 4.41 (2 × 1H, 2d, J = 12.1 Hz,
PhCH2), 3.89 (1H, pseudo t, J = 9.3, 9.0 Hz, H-2’), 3.81 (1H, pseudo t, J = 9.0, 8.9 Hz, H-3’),
13
3.71 (1H, pseudo t, J = 9.3, 8.9 Hz, H-4’) 3.69-3.63 (3H, m, H-5’, H-6’a, H-6’b); C NMR
(101 MHz, CDCl3) δ (ppm): 146.2 (2), 140.9 (PhC4-NO2, imidazole C-2, C-4), 139.3 138.5,
138.0, 137.8, 137.4, 128.6-124.2 (aromatics), 114.8 (imidazole C-5), 86.5, 81.4, 79.0, 77.8,
75.1 (C-1’ – C-5’), 75.8, 75.2, 75.0, 73.5 (4 × PhCH2), 69.1 (C-6’). ESI-MS positive mode
+
(m/z): calcd for C43H42N3O7 [M+H]+: 712.30. Found: 712.25.
Acknowledgement
This work was supported by the Hungarian Scientific Research Fund (OTKA PD 105808). E.
Sz. thanks the International Visegrád Fund for a scholarship (V4EaP program, contracts
51300722 and 51401335) as well as Collegium Talentum (Edutus College, Tatabánya) for a
stipend.
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DOI: 10.1039/C6RA21839C
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