Synthesis of novel 3-deoxy-3-C-triazolylmethylallose derivatives and evaluation of their biological activity

Article abstract of DOI:10.2478/s11532-012-0002-9

Recently, monosaccharide-triazole conjugates have proved to possess a large variety of useful biological activities. This paper describes synthesis of a new series of 3-deoxy-3-C-triazolylmethyl-allose derivatives. These new compounds are obtained from ac

Full text of DOI:10.2478/s11532-012-0002-9

Cent. Eur. J. Chem. • 10(2) • 2012 • 386-394
DOI: 10.2478/s11532-012-0002-9
Central European Journal of Chemistry
Synthesis of novel 3-deoxy-3-C-triazolylmethyl-
allose derivatives and evaluation
of their biological activity
Research Article
Jekaterina Rjabova1,2, Vitālijs Rjabovs1, Antonio J. Moreno Vargas3,
Elena Moreno Clavijo3, Māris Turks1*
1Faculty of Material Science and Applied Chemistry,
Riga Technical University, LV-1007 Riga, Latvia
2Institute „BIOR”, LV-1076 Riga, Latvia
3Department of Organic Chemistry, Faculty of Chemistry,
University of Seville, 41012 Seville, Spain
Received 9 October 2011; Accepted 12 December 2011
Abstract:
Recently, monosaccharide-triazole conjugates have proved to possess
a large variety of useful biological activities.
This paper describes synthesis of a new series of 3-deoxy-3-C-triazolylmethyl-allose derivatives. These new compounds are obtained
from acetonide-protected 3-deoxy-3-azidomethyl allose and commercial alkynes via Cu(I) catalyzed 1,3-dipolar cycloaddition.
The obtained molecular scaffolds differ from those described earlier by the presence of a methylene linker (-CH2-) between
the C(3) of allose and the triazole moiety. It was demonstrated that acetonide-protected monosaccharide, 3-deoxy-3-C-(4-phenyl-1H-
1,2,3-triazol-1-yl)methyl-1,2:5,6-di-O-isopropylidene-α-d-allofuranose, inhibited α-L-fucosidase for 26% at 0.1 mM concentration,
but a deprotected analog, 3-deoxy-3-C-(4-(4-tert-butylphenyl)-1H-1,2,3-triazol-1-yl)methyl-β-d-allofuranose, showed 15% inhibition
of β-glucosidase at 1 mM concentration.
Keywords: 3-deoxy-3-C-triazolylmethyl-allose • Methylene linker • Triazolyl-monosaccharides • Click chemistry • Inhibitors of glycosidases
© Versita Sp. z o.o.
1. Introduction
sialidase [9], glycogen phosphorylase [10] inhibiting
activities (Fig. 1), antitubercular activity [11], and as
Nitrogen
containing
heterocycle-carbohydrate
nucleoside mimetics [12].
conjugates are widely represented in Nature in the form
of DNA and RNA, and as elements in many biologically
active compounds. 1,2,3-Triazoles became readily
available after the discovery of Cu(I) catalyzed Huisgen
cycloaddition [1] and a large array of compounds with
different substituents were synthesized [2]. Some of
them exhibited noticeable biological activity, such as
antibacterial [3], antiviral [4], COX-2 inhibiting [5], and
other activities [6].
The combination of both carbohydrate and 1,2,3-
triazole structural motifs has led to the flourishing field
of conjugates that have proved to possess various
biological activities [7]. Thus, sugar-triazole conjugates
were synthesized and tested for glycosidases [8], trans-
Among the compounds tested, 4-substituted 1,2,3-
triazolylglucosides 1 showed up to 90% inhibition of
yeast α-glucosidase at 1 mM concentration [8], and rabbit
muscle glycogen phosphorylase inhibition with Ki up to
26μM[10],whereasgalactosederivatives2and3showed
moderate (up to 40%) to weak inhibition of Trypanosoma
cruzi trans-sialidase at 0.5 – 1 mM level [9].
The field of triazolyl monosaccharides is dominated
by compounds which contain the triazole moiety either at
the glycosidic position or at the terminal exocyclic carbon,
namely at C(5) for furanoses and C(6) for pyranoses.
There are only a few reports dealing with 2- or 3-(1,2,3-
triazol-1-yl)furanoses [13] and 2-, 3- or 4-(1,2,3-triazol-1-
yl)pyranoses. Compounds that are easily derived from
* E-mail: maris_turks@ktf.rtu.lv
386

J. Rjabova et al.
Figure 1. Sugar-triazole conjugates with glycosidases (1), glycogen phosphorylase (1) and trans-sialidase (2, 3) inhibiting activities.
Figure 2. Acetonide-protected carbohydrates as mediocre inhibitors of α-glucosidase.
e.g. glucosamine or 3-amino-3-deoxy-galactose fall
As a result, we report here the synthesis and
into this last category [14]. In relation to this report, it is glycosidases inhibiting activity of novel triazole-3-
noteworthy that in the above mentioned molecules the deoxyallose conjugates, where triazoles are attached to
triazole moiety is directly attached to the sugar ring at the monosaccharide core via a CH2 linker.
the 2-, 3-, or 4-position.
Most of the classically driven projects were focused
2. Experimental procedure
on the synthesis and biological evaluation of fully
deprotected sugar derivatives or those containing acyl
groups that are easily cleaved by lipases within the cell.
2.1. General
However,arecentreportshowedacetonide-protected
allose and xylose derivatives (4 and 5) as glucosidase
inhibitors (Fig. 2) [15]. Specifically, diacetone-d-allose
derivative 4 showed 73% inhibition of α-glucosidase
at 0.5 mM concentration, while 5 appeared to be a
weaker inhibitor of the same enzyme (26% inhibition
at 0.1 mM). It was suggested, that compound 4 and its
ribose analogs are mimicking acarbose in the active
site of yeast maltase [15a]. Additionally, there have
been successful examples of pharmaceutically active
ingredients containing acetonide protecting groups.
Topiramate, an anticonvulsant drug, is possibly one of
the most prominent examples within the sugar series
[16].
Hence, we decided to modify the structures reported
by Ferreira and coworkers [15a] by introducing a
methylene (-CH2-) linker between the sugar core
and triazole moiety. It has been shown on several
occasions that incorporation of the latter has increased
the biological activity more than 600-fold [17]. In terms
of medicinal chemistry, variation of distance between
the pharmacophores is a well-established practice for
modification of the biological activity. Incorporation of
a methylene linker also addresses issues of enzymatic
lability connected with other linkers such as esters and
amides [18].
Reactions were carried out as described below using
solvents and reagents dried according to standard
procedures. Copper(II) sulfate pentahydrate, sodium
ascorbate, 2,2 M n-butyl lithium, oxalyl chloride were
purchased from Acros, mesyl chloride, methyltriphenyl
phosphonium bromide and alkynes were purchased
from Alfa Aesar and used without purification. Column
chromatography was carried out using Rocc silica gel
40-60 µm. HPLC was performed on Agilent Technologies
1200 Series chromatograph with UV-Vis diode array
detector; reverse phase C18, 2.6 μm, 4.6×100 mm,
0.8 mLmin-1; eluentA: 0.01 M KH2PO4 in water containing
6% MeOH; eluent B: MeOH; gradient: 10%→90% B
in 4 min., 90% B 9 min, 90%→10% B in 2 min.
Melting points are uncorrected. Specific rotation data
was recorded on Perkin Elmer polarimeter. 1H NMR
(300 MHz) and 13C NMR (75 MHz) were recorded in
CDCl3, D2O, or DMSOd6 (with solvent residual signal as
the internal standard).
2.2.
General procedure for preparation
of triazoles 12a-i
To a solution of azide 10 (0.1 g, 0.33 mmol) and
alkyne (0.50 mmol) in THF (5 ml) copper(II) sulfate
pentahydrate solution (7 mg, 0.03 mmol) in water
(0.5 mL) and sodium ascorbate solution (10 mg,
387

Synthesis of novel 3-deoxy-3-C-triazolylmethyl-allose
derivatives and evaluation of their biological activity
0.05 mmol) in water (0.5 mL) were added. The (d, J=3.5 Hz, 1H), 7.46 (d, J=8.2 Hz, 2H), 7.78
resulting reaction mixture was stirred overnight at (d, J=8.2 Hz, 2H), 7.85 (s, 1H); 13C NMR (75 MHz,
ambient temperature (12-24 h, monitored by TLC). CDCl3) δ 25.1, 26.4, 26.7, 26.8, 31.3, 34.7, 46.3, 49.7,
Then it was concentrated under reduced pressure and 68.0, 77.6, 79.8, 80.5, 105.0, 109.9, 112.4, 120.5, 125.5,
the residue was dissolved in ethyl acetate (50 mL). 125.8, 127.7, 147.4, 151.3. IR (KBr) 3150, 2975, 1460,
The organic phase was washed with brine (3×10 mL), 1370, 1265, 1215, 1065, 1020, 850. HRMS: Calculated
dried (Na2SO4) and evaporated under reduced pressure. for C25H36N3O5 m/z=458.2655. Found m/z=458.2617.
The product was purified by column chromatography
(eluent hexanes/ethyl acetate 1:1) to yield triazoles methyl-1,2:5,6-di-O-isopropylidene-α-d-allofuranose
12a-i (Table 1). (12d) Yield: 92%, white solid, m.p. 95°C. [α]D=+85
3-Deoxy-3-C-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)
3-Deoxy-3-C-(4-phenyl-1H-1,2,3-triazol-1-yl) (c=1.11, CH3OH) 1H NMR (300 MHz, CDCl3) δ 0.86
methyl-1,2:5,6-di-O-isopropylidene-α-d-allofuranose (m, 2H), 0.97 (m, 2H), 1.32 (s, 3H), 1.35 (s, 3H), 1.43
(12a) Yield: 95%, white solid, m.p. 142 – 144°C. [α] (s, 3H), 1.57 (s, 3H), 1.97 (m, 1H), 2.59 (tt, J=10.8 Hz,
1
D=+63 (c=1.00, CH3OH). H NMR (300 MHz, CDCl3) δ J=4.4 Hz, 1H), 3.78 (dd, J=9.8 Hz, J=8.0 Hz, 1H), 4.00
1.33 (s, 3H), 1.37 (s, 3H), 1.46 (s, 3H), 1.58 (s, 3H), 2.68 (m, 2H), 4.12 (dd, J=8.2 Hz, J=5.9 Hz, 1H), 4.42 (m, 2H),
(tt, J=10.2 Hz, J=4.2 Hz, 1H), 3.83 (dd, J=9.7 Hz, J=8.3 4.84 (dd, J=13.6 Hz, J=4.2 Hz, 1H), 5.75 (d, J=3.6 Hz,
Hz, 1H), 3.98 (dd, J=8.2 Hz, J=4.8 Hz, 1H), 4.08 (m, 1H), 1H), 7.36 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 6.6, 7.9,
4.17 (dd, J=8.3 Hz, J=6.0 Hz, 1H), 4.53 (m, 2H), 4.96 25.0, 26.4, 26.7, 26.8, 46.2, 49.6, 68.0, 77.6, 79.8, 80.5,
(dd, J=13.5 Hz, J=4.2 Hz, 1H), 5.78 (d, J=3.6 Hz, 1H), 105.0, 109.9, 112.4, 120.9, 149.8. IR (KBr) 3135, 2990,
7.35 (d, J=7.2 Hz, 1H), 7.44 (t, J=7.8 Hz, 2H), 7.84 (d, 2940, 2895, 1570, 1560, 1465, 1380, 1375, 1220, 1125,
J=8.2 Hz, 2H), 7.89 (s, 1H); 13C NMR (75 MHz, CDCl3) 1075, 1015, 880, 845. HRMS: Calculated for C18H28N3O5
δ 25.1, 26.4, 26.7, 26.8, 46.3, 49.7, 68.0, 77.6, 79.8, m/z=366.2029. Found m/z=366.2048.
80.5, 105.0, 109.9, 112.5, 120.7, 125.7, 128.1, 128.8,
3-Deoxy-3-C-(4-(3-cyanoprop-1-yl)-1H-1,2,3-
130.6, 154.3. IR (KBr) 3130, 2990, 2960, 2925, 2890, triazol-1-yl)methyl-1,2:5,6-di-O-isopropylidene-
1480, 1455, 1375, 1270, 1225, 1165, 1125, 1060, 1045, α-d-allofuranose (12e) Yield: 92%, white solid,
1
1020. HRMS: Calculated for C21H28N3O5 m/z=402.2029. m.p. 91 – 92°C. [α]D=+73 (c=1.16, CH3OH) H NMR
Found m/z=402.2025.
(300 MHz, CDCl3) δ 1.33 (3H, s), 1.36 (3H, s), 1.44 (3H,
3-Deoxy-3-C-(4-(4-methylphenyl)-1H-1,2,3- s), 1.58 (3H, s), 2.09 (2H, quint, J=7.1 Hz), 2.43 (2H, t,
triazol-1-yl)methyl-1,2:5,6-di-O-isopropylidene-α-d- J=6.9 Hz), 2.60 (1H, tt, J=10.0 Hz, J=4.3 Hz), 2.90
allofuranose (12b) Yield: 81%, white solid, m.p. 135°C. (2H, t, J=7.2 Hz), 3.79 (1H, dd, J=9.8 Hz, J=8.1 Hz),
1
[α]D=+71 (c=1.26, CH3OH) H NMR (300 MHz, CDCl3) 3.97 (1H, dd, J=8.2 Hz, J=4.9 Hz), 4.04 (1H, m), 4.15
(300 MHz, CDCl3) δ 1.32 (s, 3H), 1.37 (s, 3H), 1.46 (1H, dd, J=8.2 Hz, J=5.8 Hz), 4.45 (2H, m), 4.90 (1H,
(s, 3H), 1.59 (s, 3H), 2.38 (s, 3H), 2.67 (tt, J=9.9 Hz, dd, J=13.6 Hz, J=4.2 Hz), 5.76 (1H, d, J=3.6 Hz), 7.49
J=4.4 Hz, 1H), 3.83 (dd, J=9.8 Hz, J=8.1 Hz, 1H), 3.98 (1H, s); 13C NMR (75 MHz, CDCl3) δ 16.4, 24.1, 24.8,
(dd, J=8.3 Hz, J=4.9 Hz, 1H), 4.07 (m, 1H), 4.16 (dd, 25.0, 26.4, 26.7, 26.8, 46.2, 49.7, 68.0, 77.6, 79.8, 80.5,
J=8.3 Hz, J=6.0 Hz, 1H), 4.53 (m, 2H), 4.95 (dd, J=13.6 105.0, 109.9, 112.5, 119.3, 122.4, 145.1. IR (KBr) 3135,
Hz, J=4.2 Hz, 1H), 5.77 (d, J=3.6 Hz, 1H), 7.24 (d, J=8.1 2990, 2935, 2885, 2245, 1480, 1465, 1385, 1375, 1230,
Hz, 2H), 7.73 (d, J=8.1 Hz, 2H,), 7.84 (s, 1H); 13C NMR 1170, 1125, 1075, 1015, 985. HRMS: Calculated for
(75 MHz, CDCl3) δ 21.3, 25.1, 26.4, 26.7, 26.8, 46.3, C19H29N4O5 m/z=393.2138. Found m/z=393.2125.
49.7, 68.0, 77.6, 79.8, 80.5, 105.0, 109.9, 112.4, 120.4,
3-Deoxy-3-C-(4-(but-1-yl)-1H-1,2,3-triazol-1-yl)
125.6, 127.8, 129.5, 138.0, 147.5. IR (KBr) 3135, 2990, methyl-1,2:5,6-di-O-isopropylidene-α-d-allofuranose
2940, 2890, 2865, 1385, 1375, 1265, 1240, 1220, 1205, (12f) Yield 88%, white solid, m.p. 67 – 68°C. [α]D=+79
1
1170, 1125, 1020, 850. HRMS: Calculated for C22H30N3O5 (c=1.40, CH3OH) H NMR (300 MHz, CDCl3) δ 0.93
m/z=416.2185. Found m/z=416.2208.
(t, J=7.3 Hz, 3H), 1.31 (s, 3H), 1.36 (m, 5H), 1.43
3-Deoxy-3-C-(4-(4-tert-butylphenyl)-1H-1,2,3- (s, 3H), 1.57 (s, 3H), 1.65 (quint, J=7.7 Hz, 2H), 2.60
triazol-1-yl)methyl-1,2:5,6-di-O-isopropylidene-α- (tt, J=9.9 Hz, J=4.3 Hz, 1H), 2.73 (t, J=7.5 Hz, 2H),
d-allofuranose (12c) Yield: 93%, white solid, m.p. 3.80 (dd, J=9.8 Hz, J=7.9 Hz, 1H), 4.01 (m, 2H), 4.14
1
140°C. [α]D=+71 (c=1.13, CH3OH) H NMR (300 MHz, (dd, J=8.1 Hz, J=5.8 Hz, 1H), 4.43 (m, 2H), 4.87
CDCl3) δ 1.32 (s, 3H), 1.35 (s, 9H), 1.37 (s, 3H), 1.46 (dd, J=13.6 Hz, J=4.3 Hz, 1H), 5.75 (d, J=3.6 Hz, 1H),
(s, 3H), 1.60 (s, 3H), 2.67 (tt, J=10.7 Hz, J=4.6 Hz, 1H), 7.39 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 13.8, 22.2,
3.83 (t, J=8.9 Hz, 1H), 3.98 (dd, J=8.2 Hz, J=4.8 Hz,, 25.1, 25.3, 26.3, 26.7, 26.8, 31.6, 46.0, 49.8, 68.0, 77.6,
1H), 4.07 (m, 1H), 4.16 (dd, J=8.1 Hz, J=6.0 Hz, 1H), 79.8, 80.6, 105.0, 109.8, 112.4, 121.8, 148.1. IR (KBr)
4.50 (m, 2H), 4.96 (dd, J=13.6 Hz, J=4.3 Hz, 1H), 5.77 3130, 2995, 2950, 2935, 2875, 1460, 1385, 1375, 1225,
388

J. Rjabova et al.
1165, 1125, 1075, 1015, 980, 850. HRMS: Calculated (12j) Yield 81%, white solid, m.p. 81 – 82°C. [α]D=+77
1
for C19H32N3O5 m/z=382.2342. Found m/z=382.2385.
(c=1.26, CH3OH) H NMR (300 MHz, CDCl3) δ 0.88
3-Deoxy-3-C-(4-(hex-1-yl)-1H-1,2,3-triazol-1-yl) (t, J=6.9 Hz, 3H), 1.32 (m, 10H), 1.43 (s, 3H), 1.56
methyl-1,2:5,6-di-O-isopropylidene-α-d-allofuranose (s, 3H), 1.65 (m, 2H), 2.59 (tt, J=9.9 Hz, J=4.6 Hz, 1H),
(12g) Yield 92%, white solid, m.p. 71°C. [α]D=+75 2.71 (t, J=7.8 Hz, 2H), 3.79 (dd, J=9.8 Hz, J=8.0 Hz,
1
(c=1.19, CH3OH) H NMR (300 MHz, CDCl3) δ 0.87 1H), 3.95 (dd, J=8.2 Hz, J=4.9 Hz, 1H), 4.01 (m, 1H),
(t, J=7.0 Hz, 3H), 1.31 (m, 9H), 1.35 (s, 3H), 1.43 4.13 (dd, J=8.2 Hz, J=5.9 Hz, 1H), 4.43 (m, 2H), 4.87
(s, 3H), 1.57 (s, 3H), 1.65 (quint, J=7.5 Hz, 2H), 2.59 (dd, J=13.6 Hz, J=4.3 Hz, 1H), 5.74 (d, J=3.6 Hz, 1H),
(tt, J=9.9 Hz, J=4.4 Hz, 1H), 2.71 (t, J=7.6 Hz, 2H), 7.39 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 14.0, 22.4,
3.79 (dd, J=9.8 Hz, J=8.0 Hz, 1H), 4.00 (m, 2H), 25.0, 25.5, 26.3, 26.7, 26.8, 29.1, 31.3, 46.0, 49.7,
4.13 (dd, J=8.2 Hz, J=5.8 Hz, 1H), 4.43 (m, 2H), 4.87 68.0, 77.6, 79.8, 80.5, 105.0, 109.8, 112.4, 121.7,
(dd, J=13.6 Hz, J=4.3 Hz, 1H), 5.75 (d, J=3.6 Hz, 1H), 148.0. IR (KBr) 3130, 2995, 2950, 2935, 2875, 1460,
7.38 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 14.1, 22.6, 1385, 1375, 1225, 1165, 1125, 1075, 1015, 980, 850.
25.0, 25.6, 26.3, 26.7, 26.8, 28.9, 29.5, 31.6, 46.0, 49.8, HRMS: Calculated for C20H34N3O5 m/z=396.2498.
68.0, 77.6, 79.8, 80.6, 105.0, 109.8, 112.4, 121.7, 148.1. Found m/z=396.2470.
IR (KBr) 3130, 2995, 2935, 2860, 1455, 1385, 1375,
2.3. General
procedure
for
synthesis
1225, 1165, 1125, 1065, 1015, 850. HRMS: Calculated
for C21H36N3O5 m/z=410.2655. Found m/z=410.2644.
3-Deoxy-3-C-(4-(2-hydroxyprop-2-yl)-1H-1,2,3-
triazol-1-yl)methyl-1,2:5,6-di-O-isopropylidene-α-d-
allofuranose (12h) Yield 92%, white solid, m.p. 94°C.
of deprotected triazole-conjugates 13a-h.
Trifluoroacetic acid (0.5 mL) was added to a suspension
of triazole 12 (50 mg) in water (2 mL). The resulting
reaction mixture was stirred at ambient temperature
until only the product was detected by HPLC (210 and
254 nm UV detection). Then the reaction mixture was
evaporated to dryness followed by evaporation with
water (4 x 2 mL). Freeze-drying of the water solution
(1-2 mL) yielded an isomeric mixture of fully deprotected
allose derivatives as white hygroscopic foam with the
product 13 being the major component of this mixture.
3-Deoxy-3-C-(4-phenyl-1H-1,2,3-triazol-1-yl)
methyl-β-d-allofuranose (13a). Product 13a was
obtained as a major component (Table 1) during
acidic hydrolysis reaction of 12a. Its structure was
1
[α]D=+77 (c=1.10, CH3OH) H NMR (300 MHz, CDCl3)
δ 1.32 (s, 3H), 1.36 (s, 3H), 1.44 (s, 3H), 1.57
(s, 3H), 1.64 (s, 6H), 2.42 (br s, 1H), 2.61 (m, 1H),
3.79 (dd, J=9.7 Hz, J=8.1 Hz, 1H), 4.00 (m, 2H), 4.14
(dd, J=8.2 Hz, J=5.9 Hz, 1H), 4.48 (m, 2H), 4.87 (dd,
J=13.6 Hz, J=4.1 Hz, 1 H), 5.76 (d, J=3.5 Hz,1H), 7.56
(s, 1H); 13C NMR (75 MHz, CDCl3) δ 25.1, 26.4, 26.7,
26.8, 30.4, 30.6, 46.2, 49.6, 68.0, 68.5, 77.6, 79.7,
80.5, 105.0, 109.9, 112.4, 120.2, 155.2. IR (KBr) 3300,
3190, 2995, 2980, 2915, 1385, 1375, 1220, 1200, 1155,
1125, 1015, 850. HRMS: Calculated for C18H30N3O6
m/z=384.2135. Found m/z=384.2116.
1
elucidated from spectra of the mixture of isomers. H
3-Deoxy-3-C-(4-(3-aminophenyl)-1H-1,2,3-
triazol-1-yl)methyl-1,2:5,6-di-O-isopropylidene-
α-d-allofuranose (12i) Yield: 90%, white solid, m.p.
133 – 134°C. [α]D=+73 (c=1.28, CH3OH) 1H NMR
(300 MHz, CDCl3) δ 1.31 (s, 3H), 1.36 (s, 3H), 1.45 (s,
3H), 1.59 (s, 3H), 2.66 (tt, J=10.0 Hz, J=4.3 Hz, 1H), 3.81
(dd, J=9.8 Hz, J=8.1 Hz, 1H), 3.86 (br s, 1H.), 3.97
(dd, J=8.3 Hz, J=4.9 Hz, 1H), 4.06 (m, 1H), 4.15
(dd, J=8.3 Hz, J=6.0 Hz, 1H), 4.50 (m, 2H), 4.94
(dd, J=13.6 Hz, J=4.3 Hz, 1H), 5.76 (d, J=3.6 Hz, 1H),
6.69 (d, J=7.6 Hz, 1H), 7.17 (m, 2H), 7.29 (s, 1H), 7.83
(s, 1H); 13C NMR (75 MHz, CDCl3) δ 25.1, 26.4, 26.7,
26.8, 46.3, 49.7, 68.0, 77.6, 79.8, 80.5, 105.0, 109.9,
112.4, 112.5, 115.1, 116.2, 120.8, 129.7, 131.6, 146.5,
147.5. IR (KBr) 3490, 3380, 3130, 2985, 2910, 1625,
1610, 1590, 1495, 1455, 1380, 1375, 1255, 1220,
1065. HRMS: Calculated for C21H29N4O5 m/z=417.2138.
Found m/z=417.2143.
NMR (major isomer, 300 MHz, D2O) δ 2.99 (tt, J=9.2 Hz,
J=5.2 Hz, 1H), 3.63 (m, 2H), 3.78 (d, J=9.8 Hz, 1H), 3.95
(m, 2H), 4.69 (m, 2H), 5.25 (s, 1H), 7.45 (m, 3H), 7.74
(d, J=8.1 Hz, 2H), 8.28 (s, 1H). 13C NMR (major
isomer, 75 MHz, D2O) δ 45.2, 47.5, 62.9, 74.8, 75.0,
80.2, 101.8, 122.7, 125.6, 128.9, 129.1, 129.2, 147.1.
HRMS: Calculated for C15H20N3O5 m/z=322.13975.
Found m/z=322.13904.
3-Deoxy-3-C-(4-(4-methylphenyl)-1H-1,2,3-
triazol-1-yl)methyl-β-d-allofuranose (13b). Product
13b was obtained as a major component (Table 1)
during acidic hydrolysis reaction of 12b. Its structure
was elucidated from spectra of the mixture of isomers.
1H NMR (major isomer, 300 MHz, D2O) δ 3.06 (s, 3H),
3.71 (tt, J=9.2 Hz, J=5.1 Hz, 1H), 4.31 (dd, J=11.0 Hz,
J=5.9 Hz, 1H), 4.42 (m, 2H), 4.73 (m, 2H), 5.36 (m, 1H),
5.48 (m, 1H), 5.96 (s, 1H), 8.05 (d, J=8.0 Hz, 2H), 8.39
(d, J=8.4 Hz, 2H), 8.97 (s, 1H). 13C NMR (major isomer,
75 MHz, D2O) δ 20.4, 45.2, 47.6, 63.0, 74.9, 75.0,
80.4, 101.9, 122.5, 125.7, 126.3, 129.8, 139.5, 147.2.
3-Deoxy-3-C-(4-(pent-1-yl)-1H-1,2,3-triazol-1-yl)
methyl-1,2:5,6-di-O-isopropylidene-α-d-allofuranose
389

Synthesis of novel 3-deoxy-3-C-triazolylmethyl-allose
derivatives and evaluation of their biological activity
HRMS: Calculated for C16H22N3O5 m/z=336.15540.
Found m/z=336.15485.
3-Deoxy-3-C-(4-(but-1-yl)-1H-1,2,3-triazol-1-
yl)methyl-β-d-allofuranose (13f). Product 13f was
3-Deoxy-3-C-(4-(4-tert-butylphenyl)-1H-1,2,3- obtained as a major component (Table 1) during acidic
triazol-1-yl)methyl-β-d-allofuranose (13c). Product hydrolysis reaction of 12f. Its structure was elucidated
1
13c was obtained as a major component (Table 1) from spectra of the mixture of isomers. H NMR (major
during acidic hydrolysis reaction of 12c. Its structure isomer, 300 MHz, D2O) δ 0.86 (t, J=7.6 Hz, 3H), 1.29
was elucidated from spectra of the mixture of isomers. (sextet, J=7.4 Hz, 2H), 1.61 (quint., J=7.5 Hz, 2H), 2.76
1H NMR (major isomer, 300 MHz, D2O) δ 1.33 (s, 9H), (t, J=7.4 Hz, 2H), 2.98 (tt, J=8.8 Hz, J=5.3 Hz, 1H), 3.61
3.03 (tt, J=9.2 Hz, J=4.8 Hz, 1H), 3.64 (m, 2H), 3.80 (d, (m, 2H), 3.76 (d, J=9.7 Hz, 1H), 3.94 (m, 2H), 4.73 (m,
J=10.7 Hz, 1H), 3.99 (m, 2H), 4.85 (d, J=2.0 Hz, 1H), 2H), 5.24 (s, 1H), 8.07 (s, 1H). 13C NMR (major isomer,
4.92 (d, J=2.0 Hz, 1H), 5.27 (s, 1H), 7.62 (d, J=8.4 Hz, 75 MHz, D2O) δ 12.8, 21.2, 23.1, 30.1, 45.1, 48.6, 62.9,
2H), 7.77 (d, J=8.3 Hz, 2H), 8.35 (s, 1H). 13C NMR δ 74.7, 75.0, 80.0, 101.8, 125.3, 163.1. HRMS: Calculated
(major isomer, 75 MHz, DMSO-d6) 31.7, 31.8, 35.1, for C13H24N3O5 m/z=302.17105. Found m/z=302.17087.
45.8, 47.7, 75.1, 75.8, 80.7, 102.2, 125.9, 126.5, 126.8,
128.1, 147.1, 151.8. HRMS: Calculated for C19H29N3O5 methyl-β-d-allofuranose (13g). Product 13g was
m/z=378.20235. Found m/z=378.20242. obtained as a major component (Table 1) during acidic
3-Deoxy-3-C-(4-(hex-1-yl)-1H-1,2,3-triazol-1-yl)
3-Deoxy-3-C-(4-cyclopropyl-1H-1,2,3-triazol- hydrolysis reaction of 12g. Its structure was elucidated
1
1-yl)methyl-β-d-allofuranose (13d). Product 13d from spectra of the mixture of isomers. H NMR (major
was obtained as a major component (Table 1) during isomer, 300 MHz, DMSO-d6, 70 °C) δ 0.88 (t, J=7.2 Hz,
acidic hydrolysis reaction of 12d. Its structure was 3H, H-C(6’’)), 1.33 (m, 6H, H-C(3’’,4’’,5’’)), 1.62 (quint,
elucidated from spectra of the mixture of isomers. J=7.2 Hz, 2H, H-C(2’’)), 2.62 (t, J=7.8 Hz, 2H, H-C(1’’)),
1H NMR (major isomer, 300 MHz, DMSO-d6, 70°C) 2.75 (ddt, J=8.4 Hz, J=7.5 Hz, J=4.7 Hz, 1H, H-C(3)),
δ 0.71 (m, 2H, H-C(2’’)), 0.89 (m, 2H, H-C(2’’)), 1.93 3.43 (dd, J=10.3 Hz, J=5.4 Hz, 1H, Ha-C(6)), 3.52 (ddd,
(m, 2H, H-C(1’’)), 2.70 (ddt, J=10.2 Hz, J=8.6 Hz, J=6.6 Hz, J=5.4 Hz, J=3.8 Hz, 1H, H-C(5)), 3.58 (dd,
J=4.3Hz, 1H, H-C(3)), 3.38(dd, J=10.5Hz, J=6.2Hz, 1H, J=10.3 Hz, J=3.8, 1H, Hb-C(6)), 3.67 (d, J=4.7 Hz, 1H,
Ha-C(6)), 3.45 (dt, J=7.0 Hz, J=2.8 Hz, 1H, H-C(5)), 3.56 H-C(2)), 3.77 (dd, J=8.4 Hz, J=6.6 Hz, 1H, H-C(4)),
(dd, J=10.5 Hz, J=2.9, 1H, Hb-C(6)), 3.59 (d, J=4.4 Hz, 4.53 (m, 2H, H-C(3’)), 5.02 (s, 1H, H-C(1)), 7.71 (s, 1H,
1H, H-C(2)), 3.68 (dd, J=8.8 Hz, J=7.7 Hz, 1H, H-C(4)), triazole). 1H NMR (major isomer, 300 MHz, D2O) δ 0.82
4.44 (dd, J=13.0 Hz, J=10.6 Hz, 1H, H-C(3’)), 4.52 (m, 3H), 1.27 (m, 6H), 1.68 (m, 2H), 2.82 (t, J=7.5 Hz,
(dd, J=13.0 Hz, J=3.0 Hz, 1H, H-C(3’)), 4.98 2H), 3.02 (tt, J=8.8 Hz, J=5.5 Hz, 1H), 3.63 (m, 2H), 3.77
1
(s, 1H, H-C(1)), 7.74 (s, 1H, triazole). H NMR (major (d, J=11.1 Hz, 1H), 3.96 (m, 2H), 4.84 (m, 2H), 5.25 (s,
isomer, 300 MHz, D2O) δ 0.86 (m, 2H), 1.15 (m, 2H), 1H), 8.26 (s, 1H). 13C NMR (major isomer, 75 MHz, D2O)
2.06 (m, 1H), 2.98 (tt, J=8.8 Hz, J=5.2 Hz, 1H), 3.59 δ 13.3, 21.8, 22.9, 27.5, 27.6, 30.5, 45.0, 49.8, 63.1,
(m, 2H), 3.74 (d, J=9.4 Hz, 1H), 3.90 (t, J=7.9 Hz, 1H), 74.9, 75.1, 80.1, 101.9, 126.6, 145.3. HRMS: Calculated
3.96 (d, J=4.7 Hz, 1H), 4.72 (m, 2H), 5.15 (s, 1H), 8.17 for C15H28N3O5 m/z=330.20235. Found m/z=330.20203.
(s, 1H). 13C NMR (major isomer, 75 MHz, D2O) δ 4.0,
3-Deoxy-3-C-(4-(2-hydroxyprop-2-yl)-1H-1,2,3-
8.0 (2 carbons), 44.9, 49.9, 63.0, 74.7, 75.0, 79.9, triazol-1-yl)methyl-β-d-allofuranose (13h). Product
101.8, 125.3, 147.2. HRMS: Calculated for C12H20N3O5 13h was obtained as a major component (Table 1)
m/z=286.13975. Found m/z=286.13962.
during acidic hydrolysis reaction of 12h. Its structure
3-Deoxy-3-C-(4-(3-cyanoprop-1-yl)-1H-1,2,3- was elucidated from spectra of the mixture of isomers.
triazol-1-yl)methyl-β-d-allofuranose (13e). Product 1H NMR (major isomer, 300 MHz, D2O) δ 1.60 (s, 6H),
13e was obtained as a major component (Table 1) 2.96 (tt, J=8.8 Hz, J=5.6 Hz Hz, 1H), 3.59 (m, 2H), 3.7
during acidic hydrolysis reaction of 12e. Its structure (m, 1H), 3.93 (m, 2H), 4.68 (m, 2H), 5.24 (s, 1H), 8.04
was elucidated from spectra of the mixture of isomers. (s, 1H). 13C NMR (major isomer, 75 MHz, D2O) δ 28.9
1H NMR (major isomer, 300 MHz, DMSO-d6+D2O) (2 carbons), 45.1, 47.8, 62.9, 68.1, 74.9, 74.9, 80.3,
δ 1.88 (quint, J=7.8 Hz, 2H), 2.71 (m, 3H), 3.38 101.8, 122.7, 154.2. HRMS:CalculatedforC12H21N3O5Na
(m, 2H), 3.55 (m, 3H), 3.68 (t, J=7.4 Hz, 2H), 4.49 m/z=326.1328. Found m/z=326.1354.
(m, 2H), 4.97 (s, 1H), 7.81 (s, 1H). 13C NMR (major
isomer, 75 MHz, DMSOd6+D2O) δ 15.9, 24.0, 24.8, 45.6, 2.4. Glycosidases inhibition assays
46.7, 63.4, 74.7, 75.3, 79.7, 102.0, 120.6, 122.6, 145.1. The experiments were performed essentially as
HRMS: Calculated for C13H21N4O5 m/z=313.15065. previously described [19]. Briefly, the products were
Found m/z=313.15063.
solubilized in 9:1 mixture of water/methanol. Tests
390

J. Rjabova et al.
Scheme 1. Synthesis of the azidomethyl sugar 10.
were performed at 1 mM (with 1.7% of MeOH, final acetonide-protected products. All compounds were
concentration and a proportion of MeOH on the well) obtained as white solids and were stable during storage,
or 0.1 mM (with 0.17% of MeOH, final concentration except m-aminophenyl derivative 12i, which showed
and a proportion of MeOH on the well) concentration signs of oxidation characteristic for aniline derivatives.
1
depending on solubility of the products. For the assays, All products were fully characterized by their H-, 13C-
0.01–0.5 units/mL of enzyme and inhibitor were NMR spectra and HRMS analysis.
pre-incubated for 5 min at r.t., and the reaction started
Selected compounds of acetonide-protected
by addition of the substrate (O-p-nitrophenyl glycoside), carbohydrate-triazole conjugates 12 were subjected
buffered to the optimal pH of the enzyme. After 20 min of to in vitro tests of glycosidase inhibiting activities [19].
incubation at 37ºC, the reaction was stopped by addition The model compound 4 was also synthesized according
of sodium borate buffer pH 9.8. The p-nitrophenolate to the reported method [15a] in order to compare its
formedwasmeasuredbyvisibleabsorptionspectroscopy inhibitory activity with our triazolylmethyl derivatives
at 405 nm.
12. In our hands the inhibitory activity of compound
4 could not be tested because of its insufficient solubility,
whereas
3-deoxy-1,2:5,6-di-O-isopropylidene-D-
allose-derivatives were soluble in water upon addition
of a minimal amount of methanol (see experimental
section). Compounds 12a,b,f,g,i were tested
at 0.1 mM level and compounds 12d,e were tested
at 1 mM level for inhibition of α-L-fucosidase (EC
3.2.1.51, bovine kidney), α-galactosidase (EC
3.2.1.22, coffee beans), β-galactosidases (EC
3.2.1.23, Escherichia coli and Aspergillus oryzae),
α-glucosidases (EC 3.2.1.20, yeast and rice),
β-glucosidase (EC 3.2.1.21, almonds), α-mannosidase
(EC 3.2.1.24, jack beans), β-mannosidase (EC 3.2.1.25,
snail), β-xylosidase (EC 3.2.1.37, Aspergillus niger),
amyloglucosidase (EC 3.2.1.3, Aspergillus niger), and
β-N-acetylglucosaminidase (EC 3.2.1.30, jack beans).
However, only compound 12a had 26% inhibitory activity
towards α-L-fucosidase (EC 3.2.1.51, bovine kidney).
Compound 12c was not tested due to its insolubility in
water/MeOH mixtures. On the other hand, the n-pentyl
derivative 12j, which was not tested either, is anticipated
to have similar properties to those of 12f,g.
3. Results and discussion
Thesyntheticrouteinvolvedmodificationofcommercially
available diacetone-d-glucose 6 in order to synthesize
the necessary azide 10 via a previously reported
sequence (Scheme 1) [20]. It started with oxidation of
6 to the corresponding ketone 7 [21] and continued with
a Wittig reaction and hydroboration - oxidation. The
intermediate 3-deoxy-3-hydroxymethylallose derivative
9 was mesylated and transformed into the target
compound 10 upon treatment with NaN3. The azide 10
was used in a 1,3-dipolar cycloaddition reaction with
alkynes (Scheme 2).
We chose ten structurally different terminal alkynes
possessing aryl and alkyl substituents for use in the
cycloaddition reactions. A convenient method, involving
copper(II) sulfate pentahydrate as catalyst precursor with
sodium ascorbate as the reducing agent, seemed very
attractive due to its simplicity and robustness. Reactions
were successfully carried out at ambient temperature in
aqueous THF, and proceeded in 16 to 24 hours with
excellent yields of products 12a-j as summarized in
Table 1.
We next turned to acetonide deprotection in order
to obtain natural-like water soluble compounds of type
13 (Scheme 3, Table 1). Acidic hydrolysis reactions
proceeded cleanly in water with trifluoroacetic acid
giving isomeric mixtures of fully deprotected sugars
in quantitative yields. It was found that 3-deoxy-3-
In every case conversion was complete, and
standard extractive work-up followed by silica gel
column chromatography provided the aforementioned
*We were not able to reproduce results reported by Ferreira et al. [15a]. Compound 4 was neither soluble in water, nor in 9:1 mixture water/methanol
at 6 mM concentration. The compound was soluble at 1 mM concentration of 17:83 DMSO:H2O and the enzymatic assay revealed a 41% of inhibition
of a-glucosidases from yeast (EC 3.2.1.20) at this concentration. However, the blank experiment using the same proportion of DMSO and without
the inhibitor also showed a similar inhibition, which means that DMSO in this proportion is toxic for this enzyme.
391

Synthesis of novel 3-deoxy-3-C-triazolylmethyl-allose
derivatives and evaluation of their biological activity
Scheme 2. Synthesis of carbohydrate-triazole conjugates 12a-j (see Table 1).
Scheme 3. Deprotection of 3-deoxyallose-triazole conjugates 12a-h (see Table 1).
Table 1. Synthesis of protected (12a-j) and deprotected (13a-h) 3-deoxyallose − triazole conjugates.
Compound 13, Total yield of process 12→13,
Entry
R
Compound 12, Yield, %
(content of 13 in isomeric mixture, %)
1
2
12a,a 95
12b, 81
13a, quant., (76b)
13b, quant., (70b)
3
4
12c, 91
12d, 92
13c,c quant., (74b; 82d)
13d, quant., (75b; 83d)
5
6
7
12e, 92
12f, 88
12g, 92
13e, quant., (89d)
13f, quant., (72b)
CN
13g, quant., (76b; 80e)
OH
8
12h, 92
13h, quant., (71b)
9
12i, 90
12j, 81
-
-
NH2
10
a – Compound 12a reveals 26% inhibition of a-l-fucosidase at 0.1 mM level.
b – Determined by 1H-NMR (300 MHz, D2O, 25oC).
c – Compound 13c reveals 15% inhibition of β-glucosidase at 1 mM level.
d – Determined by 1H-NMR (300 MHz, DMSO-d6, 25oC).
e – Determined by 1H-NMR (300 MHz, DMSO-d6, 70oC).
392

J. Rjabova et al.
C-triazolylmethyl-allose derivatives exist mainly (up of the monosaccharide and the triazole core. Several
to 89%) in their β-furanose form as reported for their of these acetonide-protected allose-triazole conjugates
deprotected 3-C-azidomethyl-3-deoxy-allose congener 12 were subjected to glycosidases inhibiting activity
[20]. In every case the major components of compound tests, but only 4-phenyl-triazolyl derivative 12a showed
series 13 revealed pronounced cross-peaks between a moderate α-l-fucosidase inhibiting activity at 0.1 mM
H-C(3) and H-C(5) in their 2D-NOESY spectra. On concentration (26%). Acetal protecting groups in the
some occasions also H-C(1) − H-C(4) cross-peaks were obtained compounds were cleaved by acidic hydrolysis
observed.
in order to acquire the water soluble compounds.
Deprotected carbohydrates 13a-h were also Products 13 were also tested for their ability to inhibit
subjected to the inhibition activity tests at 1 mM level with various glycosidases, but only the 4-(4-t-butylphenyl)
the aforementioned set of enzymes. Of the compounds triazole conjugate 13c showed 15% β-glucosidase
tested, only 13c had 15% β-glucosidase (EC 3.2.1.21, inhibiting activity at 1 mM level. Additionally, it was found
almonds) inhibiting activity at 1 mM concentration. that protecting group free derivatives of 3-deoxy-3-C-
In a parallel experiment diacetonide 4 was also (1H-1,2,3-triazol-1-yl)methyl-d-allose exist mainly in β-d-
deprotected and submitted to glycosidases inhibiting furanoseform. Despiteofrecentliteraturereportsdealing
assays, but did not show any inhibitory activity. The with the use of isopropylidene-protected carbohydrate
latter product upon deprotection gave a mixture of all derivatives as glycosidases inhibitors, the present
four possible isomers: α- and β-pyranose and α- and compounds do not show significant aforementioned
β-furanose forms in the ratio of 6:21:35:38 (1H-NMR, biological activity. Our data clearly show the influence of
D2O). This ratio was changed to 3:16:55:26 in DMSOd6. CH2 linker on the glycosidases inhibiting activity of the
Due to the lack of glycosidases inhibiting activity the sugar-triazole conjugates.
constitution of this isomeric mixture was not studied in
detail.
Acknowledgements
4. Conclusions
This work has been supported by the European Social
Fund within the project «Support for the implementation
We have described the synthesis of novel carbohydrate of doctoral studies at Riga Technical University» and by
derivatives of 3-deoxy-d-allose with a 1,4-disubstituted the Latvian Council of Science grant 09.1557. Authors
1,2,3-triazole moiety in the side chain. The title thank JSC “Olainfarm” for kind donation of diacetone-
compounds differ from those reported previously by the d-glucose.
presence of a methylene linker (-CH2-) between C(3)
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