Click chemistry inspired highly facile synthesis of triazolyl ethisterone glycoconjugates

Article abstract of DOI:10.1016/j.steroids.2013.11.022

Numerous deoxy-azido sugars 3 were prepared by the reaction of tosyl/bromo sugars with NaN₃ in dry DMF under heating condition. The 1,3-dipolar cycloaddition of deoxy-azido sugars 3 with ethisterone 4 to afford regioselective triazole-linked ethisterone glycoconjugates 5 was investigated in the presence of CuI and DIPEA in dichloromethane or CuSO₄· 5H₂O and sodium ascorbate in aqueous medium. All the developed compounds were characterized by spectroscopic analysis (IR, ¹H & ¹³C NMR, and MS spectra). Structure of triazolyl ethisterone glycoconjugate 5a has been further confirmed by its Single Crystal X-ray analysis.

Full text of DOI:10.1016/j.steroids.2013.11.022

Steroids 80 (2014) 71–79
Contents lists available at ScienceDirect
Steroids
journal homepage: www.elsevier.com/locate/steroids
Click chemistry inspired highly facile synthesis of triazolyl ethisterone
glycoconjugates
1
1
2
⇑
Dhananjay Kumar , Kunj B. Mishra , Bhuwan B. Mishra, Saheli Mondal , Vinod K. Tiwari
Department of Chemistry, Centre of Advanced Study, Faculty of Science, Banaras Hindu University, Varanasi 221005, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Numerous deoxy-azido sugars 3 were prepared by the reaction of tosyl/bromo sugars with NaN3 in dry
DMF under heating condition. The 1,3-dipolar cycloaddition of deoxy-azido sugars 3 with ethisterone 4 to
afford regioselective triazole-linked ethisterone glycoconjugates 5 was investigated in the presence of CuI
and DIPEA in dichloromethane or CuSO4ꢀ5H2O and sodium ascorbate in aqueous medium. All the devel-
oped compounds were characterized by spectroscopic analysis (IR, 1H & 13C NMR, and MS spectra). Struc-
ture of triazolyl ethisterone glycoconjugate 5a has been further confirmed by its Single Crystal X-ray
analysis.
Received 16 September 2013
Received in revised form 5 November 2013
Accepted 23 November 2013
Available online 5 December 2013
Keywords:
Click chemistry
Ethisterone
Ó 2013 Elsevier Ltd. All rights reserved.
Carbohydrate
Glycoconjugate
1. Introduction
inhibitor is among the best-known examples of triazole containing
structures with the broad-spectrum antibiotic piperacillin [10,11].
Steroids, due to their rigid framework and potential for diverse
range of functionalization, broad biological activity profile, and
ability to penetrate the cell membrane and bind to specific
hormonal receptors, have become preferred synthons for the
development of diverse bioconjugates [1,2]. Many representatives
of this group are widely used in medicine as essentials of anti-
inflammatory, anabolic, and contraceptive drugs. For example,
ethisterone is known to compete for androgen receptor (AR) bind-
ing, and suppresses levels of AR transcriptional activation relative
to dihydrotestosterone (DHT) [3]. Several conjugates have been
prepared from steroids through integration and/or linkage with
other biomolecules and drugs for numerous pharmacological
applications [4–7]. Recently, Levine et al. identified potential
biomedical significance of multivalent peptoid conjugates for ad-
vanced prostate cancer [8]. Thus, development of triazole-linked
ethisterone glycoconjugates would be crucial in AR pharmacology
and chemical biology.
Also several members of the 1,2,3-triazole family have indeed
shown interesting biological properties, such as anti-allergic, anti-
bacterial and anti-HIV activity [12,13].
The coupling of two or more molecular entities with distinct
properties to form novel conjugates with combined properties of
parent components, has emerged as a fast growing technology in
recent years [14–16]. Several new conjugates arising via such
bioconjugation have been found to exhibit unusual biological prop-
erties and activities as the different molecular segments act coop-
eratively [17–19]. In this prospective, the ‘Click’-chemistry [20] is a
newer approach for the synthesis of drug-like molecules that can
accelerate the drug discovery process by utilizing a few practical
and reliable reactions [21–23].
Among the reactions comprising the click universe, the perfect
example is the Huisgen 1,3-dipolar cycloaddition of terminal
alkynes and organic azides to form 1,4-disubstituted-1,2,3-tria-
zoles [20–25]. In addition, because of important role of carbohy-
drate in biological system [26], and their great chemotherapeutic
potential [27], a wide variety of glycoconjugates so far has been
synthesized using azide–alkyne cycloaddition approach [28–35].
However, the synthesis of steroid-glycoconjugates using ‘click’
chemistry has yet to be realized fully. Thus, in view of numerous
In medicinal chemistry, the triazoles are known to possess a
number of desirable features including sufficient stability to
acidic/basic hydrolysis and reductive/oxidative conditions, indica-
tive of a high aromatic stabilization [9]. This moiety is relatively
resistant to metabolic degradation. Tazobactam, a b-lactamase
medicinal effects of ethisterone, a 17a-ethynyl analog of testoster-
one, and the utility of carbohydrates in numerous chemical,
biological, medicinal, and pharmacological investigations, we here-
in report the high-yielding synthesis of novel triazole-linked ethis-
terone glycoconjugates (5a–i) using 1,3-dipolar cycloaddition
⇑
Corresponding author. Tel.: +91 542 6702466; fax: +91 542 2368174.
E-mail addresses: vtiwari@ucdavis.edu, tiwari_chem@yahoo.co.in (V.K. Tiwari).
Equal contribution.
1
2
Present address: Chembiotek Research International, Salt Lake Electronics
Complex, Sector V, Kolkata, WB 700091, India.
0039-128X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.steroids.2013.11.022

72
D. Kumar et al. / Steroids 80 (2014) 71–79
reaction of azido-sugars (3a–i) with ethisterone (4) in the presence
2.6. General procedure for synthesis of ethisterone glycoconjugates
of Cu(I) catalyst at room temperature.
(5a–j)
2.6.1. 1-(3-O-Benzyl-5-deoxy-1,2-O-isopropylidene-a-D-xylofuranos-
5-yl)-4-ethisterone-1,2,3-triazole (5a)
2. Experimental
A solution of 3a (1.20 g, 3.9 mmol), and ethisterone 4 (1.35 g,
4.3 mmol) in presence of DIPEA (0.55 ml, 4.3 mmol) and CuI
(0.37 g, 1.9 mmol) in dry CH2Cl2 was sttired at room temparature
under argon atmosphenre for 12 h. After completion of reaction
(monitored by TLC), the reaction mixture was in vacuo concen-
trated to obtain a crude residue which was further purified by
silica gel (100–200 mesh) column chromatography to afford com-
2.1. General methods
All of the reactions were executed using anhydrous solvents un-
der an argon atmosphere in one-hour oven-dried glassware at
100 °C. All reagents and solvents were of pure analytical grade.
Thin-layer chromatography (TLC) was performed on 60 F254 silica
gel, pre-coated on aluminum plates and revealed with either a UV
lamp (kmax = 254 nm) or a specific color reagent (iodine vapors) or
by spraying with methanolic H2SO4 solution and subsequent heat-
ing at 60 °C. 1H and 13C NMR were recorded at 300 and 75 MHz,
respectively. Chemical shifts given in ppm downfield from internal
TMS; J values in Hz. Mass spectra recorded using electrospray ion-
ization mass spectrometry (ESI–MS). Infrared spectra recorded as
Nujol mulls in KBr plates. Elemental analysis was performed using
a C, H, N analyzer, and results were found to be within 0.4% of the
calculated values. Reaction under microwave condition was carried
out on Microwave CEM Discover R Lab Mate. Polarimeter with
general tungsten lamp having tube of 2 dm and 20 ml capacity.
Single-crystal X-ray data collected on Xcalibur Eos (Oxford) CCD-
diffractometer.
pound 5a. Yellow crystalline solid (2.2 g, 90% yield); [
a]D = +20.0 (c
0.20 CHCl3); IR (KBr) max: 3412, 3174, 2976, 2946, 1658, 1454,
m
1382, 1080 cmꢁ1; 1H NMR (300 MHz, CDCl3): d 7.43 (s, 1H, triazol-
yl-H), 7.35–7.33 (m, 5H, Ar–H), 5.96 (d, J = 3.9 Hz, 1H, H-1), 5.69 (s,
1H, ethisterone-H), 4.73–4.65 (m, 3H, H-2 and OCH2Ph), 4.54–4.47
(m, 3H, H-4 and H-5), 4.00 (m, H-3), 2.92 (s, 1H, ethisterone-H),
2.38–2.13 (m, 5H, ethisterone-H), 2.04 (m, 1H, ethisterone-H),
1.95–1.78 (m, 3H, ethisterone-H), 1.60–1.42 (m, 10H, 1 ꢂ CH3 of
>C(CH3)2 and ethisterone-7H), 1.31 (m, 3H, 1 ꢂ CH3 of >C(CH3)2),
1.16 (s, 3H, ethisterone-CH3), 1.05 (s, 3H, ethisterone-CH3), 0.72–
0.64 (m, 1H, ethisterone-H), 0.48–0.38 (m, 1H, ethisterone-H);
13C NMR (75 MHz, CDCl3): 199.4, 171.1, 153.3, 136.8, 128.6,
128.3, 127.7, 123.7, 122.1, 112.1, 105.1, 81.9, 81.8, 81.7, 78.8,
72.0, 53.2, 49.3, 49.0, 46.8, 38.5, 37.4, 36.2, 35.5, 33.8, 32.7, 32.6,
31.5, 26.7, 26.2, 23.4, 20.5, 17.3, 14.2; MS: m/z 618 [M+H]+; Anal.
Calcd for C36H47N3O6: C, 69.99; H, 7.67; N, 6.80. Found: C, 70.37;
H, 7.98; N, 7.09.
2.2. Procedure for synthesis of protected sugars (1a–i)
The compounds 1a–i were prepared from readily available
Click reaction between glycosyl azide 3a and ethisterone 4
using CuSO4ꢀ5H2O/sodium ascorbate in aqueous medium at room
temperature afford ethisterone triazolyl glycoconjugate 5a in good
yield. Furthermore, an equimolar mixture of glycosyl azide 3a
(35 mg) and ethisterone 4 (50 mg), in anhydrous toluene (10 ml)
carbohydrates
-lactose) using standard protection and modification methodolo-
gies [36–44].
(D-glucose, D-galactose, D-ribose, D-xylose, and
D
2.3. General procedure for synthesis of tosyl-sugars (2a–e)
was added DIPEA (25 lL) and CuI (9 mg) as described above under
inert atmosphere. The reaction was carried out under microwave
heating condition (Microwave CEM Discover R Lab Mate) at
100 °C for 15 min. After completion of reaction (monitored by
TLC), the reaction mixture was in vacuo concentrated, extracted
with CH2Cl2 and washed with water. After drying over anhydrous
Na2SO4, the organic layer was in vacuo concentrated. Purification
using flash column chromatography afforded ethisterone triazolyl
glycoconjugate 5a. The physical data is closely matched with the
developed molecule 5a, where the reaction was carried out at room
temperature.
The stirring solutions of compounds 1a–e in pyridine at 0 °C
were added with p-toluene sulphonyl chloride under anhydrous
condition. The reactions was allowed to come at room temperature
and further stirred for 12 h. After completion (monitered by TLC),
the reaction mixtures were in vacuo concentrated and the crude
obtained were purified by flash column chromatography to afford
tosyl-sugars 2a–e in good yields.
2.4. General procedure for synthesis of bromo-sugars (2f-j)
The stirring solutions of compounds 1f–j at 0 °C were treated
with 33% HBr solution in glacial acetic acid under anhydous condi-
tion. The reation mixture was further stirred for 2 h at 0 °C. After
completion of reaction (monitored by TLC), the reaction mixtures
were neutralized with saturated NaHCO3 solution followed by
extraction in dichloromethane. The organic layers were dried over
anhydrous Na2SO4 and concentrated under reduced pressure to af-
ford compounds 2f–j. Because of low stability at room temperature,
all the developed bromo-sugars 2f–j was subsequently utilized for
the synthesis of sugar azides 3f–j without further purification.
2.6.2. 4-Ethisterone-1-(methyl-5-azido-5-deoxy-2,3-O-
isopropylidene-b- -ribofuranosid-5-yl)-1,2,3-triazole (5b)
D
A solution of azide 3b (1.0 g, 4.1 mmol), and ethisterone 4
(1.4 g, 4.6 mmol) in presence of DIPEA (0.75 ml, 4.6 mmol) and
CuI (0.4 g, 2 mmol) in dry CH2Cl2 was sttired at room temparature
under argon atmosphenre for 12 h followed purification described
earlier afforded compound 5b. Yellowish solid (2.1 g, 95% yield);
[a]
D = ꢁ15.5 (c 0.19 CHCl3); IR (KBr)
mmax: 3453, 3140, 2939,
2856, 1667, 1330, 868 cmꢁ1 1H NMR (300 MHz, CDCl3): d 7.48
;
(s, 1H, triazolyl-H), 5.69 (s, 1H, ethisterone-H), 5.01 (s, 1H, H-1),
4.74–4.38 (m, 5H, H-2, H-3, H-4, H-5), 3.38 (s, 3H, –OCH3), 2.82
(s, 1H, ethisterone-H), 2.37–2.29 (m, 5H, ethisterone-H), 2.14–
2.10 (m, 1H, ethisterone-H), 1.91–1.86 (3H, ethisterone-H), 1.61–
1.05 (m, 19H, ethisterone-H), 0.73 (m, 1H, ethisterone-H), 0.47
(m, 1H, ethisterone-H); 13C NMR (75 MHz, CDCl3): 199.4, 171.1,
153.6, 123.7, 121.4, 112.9, 110.0, 85.1, 84.9, 82.1, 81.7, 55.5, 53.1,
53.1, 48.8, 46.8, 38.5, 37.8, 36.2, 35.5, 33.8, 32.7, 32.6, 31.5, 26.3,
24.8, 23.6, 20.5, 17.3, 14.2; MS: m/z 542 [M+H]+; Anal. Calcd for
2.5. General procedure for synthesis of sugar azides (3a–j)
The stirring solutions of compounds 2a–j in dry DMF were trea-
ted with NaN3 [45–52]. The reaction mixtures were further heated
at 80 °C under anhydrous condition followed by constant stirring
over night. After completion of reaction (monitored by TLC), the
reaction mixtures were in vacuo concentrated followed by silica
gel column chromatography to afford compounds 3a–j in good
yields.
C30H43N3O6: C, 66.52; H, 8.00; N, 7.76. Found: C, 66.77; H, 8.33;
N, 7.37.

D. Kumar et al. / Steroids 80 (2014) 71–79
73
2.6.3. 1-(6-Deoxy-1,2:3,4-di-O-isopropylidene-
yl)-4-ethisterone-1,2,3-triazole (5c)
a
-
D
-galactopyranos-50-
CDCl3): 199.5, 171.3, 153.1, 137.1, 128.6, 128.1, 127.7, 123.7,
122.9, 111.9, 105.1, 82.2, 81.8, 81.1, 80.1, 72.2, 67.5, 53.6, 53.0,
48.9, 46.8, 38.5, 37.5, 36.1, 35.4, 33.8, 32.7, 32.5, 31.4, 26.7, 26.1,
23.4, 20.4, 17.3, 14.1 ppm; MS: m/z 648 [M+H]+; Anal. Calcd for
A solution of azide 3c (0.75 g, 2.6 mmol), and ethisterone 4
(0.9 g, 2.8 mmol) in presence of DIPEA (0.5 ml, 2.8 mmol) and CuI
(0.25 g, 1.3 mmol) in dry CH2Cl2 was sttired at room temparature
under argon atmosphenre for 12 h followed purification described
earlier afforded compound 5c. Yellowish solid (1.4 g, 92% yield);
C37H49N3O7: C, 68.60; H, 7.62; N, 6.49. Found: C, 68.86; H, 8.01;
N, 6.68.
[
a]
D = ꢁ16.2 (c 0.20 CHCl3); IR (KBr)
m
max: 3458, 3156, 2979,
2.6.6. 4-Ethisterone-1-(2,3,4,6-tetra-O-acetyl-b-
1,2,3-triazole(5f)
D-glucoopyranosyl)-
2940, 2869, 1667, 1384, 1068 cmꢁ1 1H NMR (300 MHz, CDCl3): d
;
7.57 (s, 1H, triazolyl-H), 5.69 (s, 1H, ethisterone-H), 5.49 (d,
J = 3.9 Hz, 1H, H-1), 4.65–4.60 (m, 2H, H-2 and H-3), 4.47–4.32
(m, 2H, H-4 and H-5), 4.22–4.12 (m, 2H, H-6), 2.38–2.30 (m, 6H,
ethisterone-H), 2.15–2.04 (m, 2H, ethisterone-H), 1.97–1.87 (m,
2H, ethisterone-H), 1.65–1.17 (m, 22H, 4 ꢂ CH3 of >C(CH3)2 and
ethisterone-H), 1.05 (s, 3H, ethisterone-CH3), 0.70 (m, 1H, ethister-
one-H), 0.47 (m, 1H, ethisterone-H); 13C NMR (75 MHz, CDCl3):
199.4, 171.3, 152.9, 123.6, 122.3, 109.8, 108.9, 96.1, 81.9, 71.1,
70.6, 70.3, 67.3, 53.2, 50.5, 48.8, 46.8, 38.5, 37.5, 36.2, 35.5, 33.8,
32.7, 32.5, 31.5, 25.9, 24.8, 24.3, 23.5, 20.5, 17.3, 14.1 ppm; MS:
m/z 598 [M+H]+; Anal. Calcd for C33H47N3O7: C, 66.31; H, 7.93; N,
7.03. Found: C, 65.99; H, 8.16; N, 7.40.
A solution of azide 3f (100 mg, 0.26 mmol), and ethisterone 4
(92 mg, 0.29 mmol) in presence of DIPEA (0.045 ml, 0.26 mmol)
and CuI (25 mg, 0.13 mmol) in dry CH2Cl2 was sttired at room tem-
parature under argon atmosphenre for 12 h followed purification
described earlier afforded compound 5f. White crystline (142 mg,
80% yield); IR (KBr)
mmax: 3436, 2926, 2857, 1756, 1662, 1370,
1038 cmꢁ1 1H NMR (300 MHz, CDCl3): d 7.70 (s,1H, triazolyl-H),
;
5.87 (d, J = 8.1 Hz, 1H), 5.69 (s, 1H), 5.44–5.41 (m, 2H), 5.24 (t,
J = 9.0 Hz, 1H), 4.31 (dd, J = 5.1 Hz, 12.6 Hz, 1H), 4.17–4.13 (m,
1H), 4.02 (d, J = 8.1 Hz, 1H), 2.44–2.29 (m, 5H), 2.07–1.82 (m,
17H), 1.60–1.05 (m, 17H), 0.70 (m, 1H), 0.37 (m, 1H); 13C NMR
(75 MHz, CDCl3): 199.4, 171.2, 170.3, 169.7, 169.3, 168.6, 154.2,
123.7, 119.6, 85.5, 82.1, 74.9, 72.5, 70.2, 67.6, 61.4, 53.3, 48.6,
46.7, 38.4, 37.6, 36.1, 35.5, 33.7, 32.7, 32.4, 31.4, 23.8, 20.6, 20.4,
20.0, 17.3, 14.0 ppm.
2.6.4. 4-Ethisterone-1-(methyl-2,3,4-tri-O-benzyl-6-deoxy-a-D-
glucopyranos-5-yl)-1,2,3-triazole (5d)
A solution of azide 3d (1.08 g, 2.2 mmol), and ethisterone 4
(0.75 g, 2.4 mmol) in presence of DIPEA (0.5 ml, 2.4 mmol) and
CuI (0.2 g, 1 mmol) in dry CH2Cl2 was sttired at room temparature
under argon atmosphenre for 12 h followed purification described
earlier afforded compound 5d. Yellowish solid (1.55 g, 88% yield);
2.6.7. 4-Ethisterone-1-(2,3,4,6-Tetra-O-benzoyl-b-
1,2,3-triazole (5g)
D-glucopyranosyl)-
A solution of azide 3g (1 g, 1.5 mmol), and ethisterone 4 (0.55 g,
1.7 mmol) in presence of DIPEA (0.35 ml, 1.7 mmol) and CuI
(0.15 g, 0.7 mmol) in dry CH2Cl2 was sttired at room temparature
under argon atmosphenre for 12 h followed purification described
earlier afforded compound 5g. Yellowish solid (1.2 g, 82% yield);
[
a]
D = ꢁ18.8 (c 0.20 CHCl3); IR (KBr)
m
max: 3438, 3147, 3088,
3062, 3030, 2939, 2857, 1667, 1359, 1055 cmꢁ1
;
1H NMR
(300 MHz, CDCl3): d 7.44 (s, 1H, triazolyl-H), 7.33–7.31 (m, 15H,
Ar–H), 5.68 (s, 1H, ethisterone-H), 4.99–4.89 (m, 2H, OCH2Ph),
4.82–4.68 (m, 3H, H-1 and OCH2Ph), 4.62–4.54 (m, 4H, OCH2Ph
and H-6), 4.00–3.97 (m, 2H, H-3 and H-5), 3.43–3.40 (m, 1H, H-
2), 3.16–3.12 (m, 4H, OCH3 and H-4), 2.61 (s, 1H, ethisterone-H),
2.37–2.23 (m, 5H, ethisterone-H), 2.12–2.04 (m, 1H, ethisterone-
H), 1.93–1.86 (m, 3H, ethisterone-H), 1.57–1.47 (m, 5H, ethister-
one-H), 1.38–1.25 (m, 2H, ethisterone-H), 1.16 (s, 3H, ethister-
one-CH3), 1.04 (s, 3H, ethisterone-CH3), 0.69–0.65 (m, 1H,
ethisterone-H), 0.47–0.40 (m, 1H, ethisterone-H); 13C NMR
(75 MHz, CDCl3): 199.3, 171.0, 153.3, 138.2, 137.7, 128.6, 128.4,
128.0, 127.9, 127.7, 123.7, 122.4, 97.9, 82.0, 81.6, 79.9, 78.0, 75.7,
74.9, 73.4, 69.1, 55.2, 53.2, 50.7, 48.7, 46.7, 38.4, 37.7, 36.1, 35.5,
33.7, 32.6, 32.6, 31.4, 23.6, 20.5, 17.3, 14.1 ppm; MS: m/z 802
[M+H]+; Anal. Calcd for C49H59N3O7: C, 73.38; H, 7.41; N, 5.24.
Found: C, 73.02; H, 7.63; N, 4.93.
[a
]
D = ꢁ23.2 (c 0.20 CHCl3); IR (KBr)
m
max: 3446, 3158, 3064,
3033, 2926, 2854, 1729, 1663, 1316, 1092 cmꢁ1
;
1H NMR
(300 MHz, CDCl3): d 8.01–7.70 (m, 9H, Ar–H and triazolyl-H),
7.55–7.22 (m, 12H, Ar–H), 6.25 (d, J = 9.6 Hz, 1H, H-1), 6.08 (t,
J = 9.6 Hz, 1H, H-3), 5.97–5.83 (m, 2H, H-2 and H-4), 5.66 (s, 1H,
ethisterone-H), 4.66 (d, J = 10.5 Hz, 1H, H-5), 4.52–4.48 (m, 2H,
H-6), 2.52 (s, 1H, ethisterone-H), 2.27–2.21 (m, 5H, ethisterone-
H), 2.02–1.66 (m, 4H, ethisterone-H), 1.54–1.39 (m, 1H, ethister-
one-H), 1.34–1.25 (m, 7H, ethisterone-H), 1.10 (s, 3H,
ethisterone-CH3), 0.99 (s, 3H, ethisterone-CH3), 0.37 (m, 1H, ethis-
terone-H), 0.16 (m, 1H, ethisterone-H); 13C NMR (75 MHz, CDCl3):
199.3, 171.2, 166.0, 165.4, 165.0, 164.7, 154.4, 133.7, 133.4, 133.2,
129.8, 129.7, 129.6, 128.4, 127.9, 123.6, 119.7, 86.0, 82.3, 75.5,
72.9, 70.9, 68.8, 62.6, 52.9, 48.4, 46.7, 38.4, 37.8, 36.0, 35.6, 33.8,
32.7, 32.3, 31.3, 23.9, 20.4, 17.2, 14.0 ppm; MS: m/z 934 [M+H]+;
Anal. Calcd for C55H55N3O11: C, 70.72; H, 5.94; N, 4.50. Found: C,
70.38; H, 5.67; N, 4.71.
2.6.5. 4-Ethisterone-1-(3-O-benzyl-6-deoxy-1,2-O-isopropylidene-
-glucofuranos-5-yl)-1,2,3-triazole (5e)
A solution of azide 3e (305 mg, 0.9 mmol), and ethisterone 4
a-
D
2.6.8. 4-Ethisterone-1-(2,3,4-tri-O-acetyl-b-
triazole (5h)
D-xylopyranosyl)-1,2,3-
(312 mg, 1 mmol) in presence of DIPEA (0.171 ml, 1 mmol) and
CuI (86 mg, 0.45 mmol) in dry CH2Cl2 was sttired at room tempar-
ature under argon atmosphenre for 12 h followed purification de-
scribed earlier afforded compound 5e. Yellowish solid (550 mg,
A solution of azide 3h (98 mg, 0.32 mmol), and ethisterone 4
(111 mg, 0.35 mmol) in presence of DIPEA (0.06 ml, 0.35 mmol)
and CuI (30 mg, 0.16 mmol) in dry CH2Cl2 was sttired at room tem-
parature under argon atmosphenre for 10 h followed purification
described earlier afforded compound 5h. Yellowish solid
93% yield); [
a]
D = ꢁ17.0 (c 0.19 CHCl3); IR (KBr)
mmax: 3316, 2973,
2936, 2886, 1674, 1385, 1080 cmꢁ1
;
1H NMR (300 MHz, CDCl3): d
7.44 (s, 1H, triazolyl-H), 7.33–7.26 (m, 5H, Ar–H), 5.92 (d,
J = 3.3 Hz, 1H, H-1), 5.69 (s, 1H, ethisterone-H), 4.73–4.54 (m, 4H,
OCH2Ph, H-2, H-4), 4.43–4.37 (m, 2H, H-6), 4.12–4.07 (m, 1H, H-
5), 4.84 (d, J = 5.4 Hz, H-3), 3.02 (d, J = 5.4 Hz, -OH at C-5), 2.87 (s,
1H, ethisterone-H), 2.42–2.25 (m, 5H, ethisterone-H), 2.14–2.07
(m, 1H, ethisterone-H), 1.96–1.86 (m, 3H, ethisterone-H), 1.63–
1.25 (m, 13H, 2 ꢂ CH3 of > C(CH3)2 and ethisterone-H), 1.17 (s,
3H, ethisterone-CH3), 1.05 (s, 3H, ethisterone-CH3), 0.74 (m, 1H,
ethisterone-H), 0.47 (m, 1H, ethisterone-H); 13C NMR (75 MHz,
(175 mg, 88% yield); [
a
]
D = ꢁ12.5 (c 0.20 CHCl3); IR (KBr) mmax
:
3472, 3148, 2927, 2856, 1759, 1666, 1371, 1038 cmꢁ1
;
1H NMR
(300 MHz, CDCl3): d 7.59 (s,1H, triazolyl-H), 5.76 (d, J = 8.4 Hz,
1H, H-1), 5.69 (s, 1H, ethisterone-H), 5.44–5.34 (m, 2H, H-2 and
H-3), 5.16–5.14 (m, 1H, H-4), 4.30 (dd, J = 5.4, 11.1 Hz, 1H, HA-5),
3.62–3.65 (m, 1H, HB-5), 2.57 (s, 1H, ethisterone-H), 2.38–2.24
(m, 5H, ethisterone-H), 2.07–2.04 (m, 11H, 3 ꢂ OAc, 2H, ethister-
one-H), 1.92–1.84 (m, 2H, ethisterone-H), 1.60–1.34 (m, 7H,
ethisterone-H), 1.17 (s, 3H, ethisterone-CH3), 1.05 (s, 3H,

74
D. Kumar et al. / Steroids 80 (2014) 71–79
Table 1
Synthesis of deoxy-azido sugars 3a–j from protected sugars 1a–j.
(i)TsCl,Py,12h,rt or
HBr-AcOH,2h,rt
Sugar
N3
Sugar
OH
(ii) NaN3, DMF, 80oC, 18h
3 (a-j)
yield = 80-93%
Sugar azidesb
1 (a-j)
Entry
1
Compound 1a
Tosyl/bromo sugars
Yield (%)c
90
BnO
BnO
O
BnO
O
O
TsO
O
HO
N3
N3
O
O
O
O
O
2a
O
1a
3a
2
3
85
85
O
O
OMe
OMe
OMe
HO
TsO
TsO
O
O
O
O
O
O
1b
2b
O
3b
O
O
HO
N3
O
O
O
O
O
O
O
O
O
O
O
O
1c
2c
3c
4
5
93
85
OH
OTs
N3
O
O
O
BnO
BnO
BnO
BnO
BnO
BnO
BnO
2d
BnO
OMe
BnO
3d
OMe
OMe
1d
6
7
88
90
OBz
OBz
OBz
O
O
O
BzO
BzO
BzO
BzO
BzO
BzO
OBz
OAc
N3
OBz
BzO
2g
BzO
3g
Br
1g
8
9
80
92
O
O
O
AcO
AcO
AcO
AcO
AcO
N3
AcO
OAc
AcO
2h
OAc
Br
3h
1h
OAc
OAc
OAc
AcO
AcO
AcO
AcO
AcO
AcO
O
O
O
OAc
N3
OAc
1i
AcO
2i
AcO
3i
Br
10
90
OAc
OAc
AcO
AcO
AcO
AcO
OAc
AcO
OAc
OAc
OAc
O
O
O
O
O
O
O
O
O
OAc
N3
AcO
AcO
AcO
AcO
AcO
AcO
OAc
OAc
AcO
AcO
Br
3j
1j
2j
a
b
c
Protected sugars.
deoxy-azido sugars.
over all yield.

D. Kumar et al. / Steroids 80 (2014) 71–79
75
ethisterone-CH3), 0.72–0.69 (m, 1H, ethisterone-H), 0.39–0.33 (m,
1H, ethisterone-H); 13C NMR (75 MHz, CDCl3): 199.4, 171.2,
169.7, 169.7, 168.7, 154.1, 123.7, 119.4, 86.2, 82.0, 71.9, 70.3,
68.3, 65.4, 53.3, 48.8, 46.8, 38.4, 37.6, 36.1, 35.5, 33.8, 32.7, 32.4,
31.5, 23.6, 20.5 (2 ꢂ C), 20.5, 20.1, 17.3, 14.1 ppm; MS: m/z 614
[M+H]+; Anal. Calcd for C32H43N3O9: C, 62.63; H, 7.06; N, 6.85.
Found: C, 62.94; H, 6.79; N, 6.49.
described earlier afforded compound 5j. Yellowish solid (397 mg,
90% yield); [ max: 3473, 3153,
D = ꢁ40.4 (c 0.15 CHCl3); IR (KBr)
2926, 2855, 1755, 1661, 1371, 1053 cmꢁ1 1H NMR (300 MHz,
a]
m
;
CDCl3): d 7.59 (s,1H, triazolyl-H), 5.81–5.79 (m, 1H), 5.69 (s, 1H,
ethisterone-H), 5.39–5.37 (m, 3H), 5.16–5.10 (m, 1H), 4.99–4.95
(m, 1H), 4.53–4.48 (m, 2H), 4.14–4.09 (m, 3H), 3.96–3.89 (m,
3H), 2.37–2.29 (m, 6H, ethisterone-H), 2.16–1.82 (m, 25H,
21 ꢂ OAc), 1.56–1.41 (m, 7H, ethisterone-H), 1.17 (s, 3H, ethister-
one-CH3), 1.04 (s, 3H, ethisterone-CH3), 0.73–0.65 (m, 1H, ethister-
one-H), 0.38–0.29 (m, 1H, ethisterone-H); 13C NMR (75 MHz,
CDCl3): 199.4, 171.2, 170.3, 170.1, 170.0, 170.0, 169.4, 169.0,
168.9, 154.1, 123.7, 119.6, 100.9, 85.3, 82.1, 75.8, 75.5, 72.4, 70.8,
70.7, 70.4, 68.9, 66.5, 61.5, 60.7, 53.3, 48.6, 46.7, 38.4, 37.7, 36.1,
35.5, 33.8, 32.7, 32.4, 31.4, 23.7, 20.7, 20.5, 20.4, 20.1, 17.3,
14.0 ppm; MS: m/z 974 [M+H]+; Anal. Calcd for C47H63N3O19: C,
57.96; H, 6.52; N, 4.31. Found: C, 57.77; H, 6.23; N, 4.01.
2.6.9. 4-Ethisterone-1-(2,3,4,6-tetra-O-acetyl-b-
1,2,3-triazole (5i)
D-galactopyranosyl)-
A solution of azide 3i (200 mg, 0.53 mmol), and ethisterone 4
(184 mg, 0.58 mmol) in presence of DIPEA (0.1 ml, 0.58 mmol)
and CuI (51 mg, 0.2 mmol) in dry CH2Cl2 was sttired at room tem-
parature under argon atmosphenre for 12 h followed purification
described earlier afforded compound 5i. Yellowish solid (348 mg,
95% yield); [
a
]
D = ꢁ14.6 (c 0.20 CHCl3); IR (KBr)
mmax: 3470, 3139,
2926, 2853, 1756, 1668, 1369, 1040 cmꢁ1
;
1H NMR (300 MHz,
CDCl3): d 7.71 (s, 1H, triazolyl-H), 5.81 (d, J = 9.3 Hz, 1H, H-1),
5.70 (s, 1H, ethisterone-H), 5.59–5.54 (m, 2H, H-2 and H-4), 5.23
(dd, J = 3.3, 10.2 Hz, 1H, H-3), 4.21–4.16 (m, 3H, H-5 and H-6),
2.52–2.22 (m, 9H, 1 ꢂ OAc and ethisterone-H), 2.09–1.83 (m,
13H, 3 ꢂ OAc and ethisterone-H), 1.57–1.36 (m, 7H, ethisterone-
H), 1.18 (s, 3H, ethisterone-CH3), 1.06 (s, 3H, ethisterone-CH3),
0.70 (m, 1H, ethisterone-H), 0.42–0.38 (m, 1H, ethisterone-H);
13C NMR (75 MHz, CDCl3): 199.4, 171.2, 170.3, 169.9, 169.7,
168.8, 154.2, 123.7, 119.7, 86.1, 82.3, 74.0, 70.7, 67.8, 66.8, 61.0,
53.4, 48.6, 46.8, 38.5, 37.8, 36.1, 35.6, 33.8, 32.7, 32.4, 31.5, 23.8,
20.6 (3 ꢂ C), 20.4, 20.1, 17.3, 14.1 ppm; MS: m/z 686 [M+H]+; Anal.
Calcd for C35H47N3O11: C, 61.30; H, 6.91; N, 6.13. Found: C, 61.57;
H, 6.56; N, 6.41.
3. Results and discussion
The synthetic strategy starts from cheap and readily available
monosaccharides (D-glucose, D-galactose, D-ribose, D-xylose, and
D-lactose), which after processing to a number of high-yielding
steps for protection and modification, afforded suitably protected
sugars 1a–j. The compounds 1a–j were further converted to their
respective tosyl/bromo-derivatives 2a–j, which on reaction with
sodium azide in dry DMF at 80 °C under anhydrous condition re-
sulted in the formation of respective deoxy-azido sugars 3a–j in
good yields (Table 1). Thus, the treatment of 3-O-benzyl-1,2-O-iso-
propylidene-a-D-xylofuranose 1a with p-toluenesulfonyl chloride
in the presence of pyridine under anhydrous condition at room
temperature for 12 h afforded benzyl-1,2-O-isopropylidene-5-O-
2.6.10. 4-Ethisterone-1-(2,3,6-tri-O-acetyl-4-O-(2,3,4,6-tetra-O-
tosyl-a-D-xylo-furanose 2a, which on further treatment with
acetyl-b-
D-galactopyrano- syl)-1-deoxy-1-azido-b-D-glucopyranose)-
sodium azide in anhydrous DMF at 80 °C led to the formation of
1,2,3-triazole (5j)
5-azido-3-O-benzyl-5-deoxy-1,2-O-isopropylidene-a-D-xylofuranose
A solution of azide 3j (300 mg, 0.45 mmol), and ethisterone 4
(155 mg, 0.49 mmol) in presence of DIPEA (0.085 ml, 0.49 mmol)
and CuI (43 mg, 0.22 mmol) in dry CH2Cl2 was sttired at room tem-
parature under argon atmosphenre for 12 h followed purification
3a in 90% yield.
Once the synthesis of azido-sugars 3a–j was achieved, we next
turned our attention towards the CuAAC click reaction of devel-
oped compounds 3a-j with ethisterone 4. Generally, such reactions
Table 2
Study of the solvent effect on click reaction of azido-sugar 3a
OH
H
BnO
N
N
H
H
HO
O
BnO
N
O
O
O
4
N3
H
O
O
CuSO4.5H2O (5 mol %)
Sodium ascorbate (10 mol %)
O
H
H
O
5a
3a
12 h, rt
.
Entry
Reaction condition
Yield (%)a
1
2
3
4
5
6
7
8
9
10
MeOH/H2O (1:1)
t-BuOH/H2O (1:1)
CH2Cl2/H2O (1:1)
Et2O/H2O (1:1)
Acetone/H2O (1:1)
H2O/THF (1:1)
H2O/THF (0.5:1)
THF
65
60
50
35
40
70
45
ta
H2O
75
70
THF/H2O (1:1)b
a
Isolated yields in 10 h.
Reaction under argon atmosphere, ta = trace amount, nd = not detected.
b

76
D. Kumar et al. / Steroids 80 (2014) 71–79
require the generation of Cu(I) species in situ starting from CuI and
DIPEA in dichloromethane or CuSO4ꢀ5H2O and sodium ascorbate in
aqueous medium or other copper catalyst. We primarily investi-
gated the reactions using the mixtures of MeOH/H2O, t-BuOH/
H2O, CH2Cl2/H2O, Et2O/H2O, acetone/H2O, and THF/H2O. It is simple
to verify that most of the reactions afforded corresponding ethis-
terone triazolyl glycoconjugate 5a using a variety of organic sol-
vents in combination with H2O (Table 2). However, optimal yield
of 5a was achieved using a mixture of THF/H2O (1:1) as a solvent.
A remarkable feature of this reaction was the H2O dependence in
the triazolyl glycoconjugate synthesis. Reactions using a mixture
of THF/H2O (1:0.5) or just THF resulted into the poor yield of the
desired product 5a (Table 2, entry 7 and 8). This may be due to
the decreased solubility of sodium ascorbate and copper salt in this
solvent. It is important to note that the reactions are not very much
air sensitive, allowing the preparation of the respective triazole 5a
in an open atmosphere (Table 2, entry 10).
of ethisterone in addition to six protons of isopropylidene moiety
resonated in the range of d 2.92–0.38. In the 13C NMR spectrum,
a carbon resonance signal observed at d 199.4 was evidenced for
carbonyl carbon of ethisterone while the anomeric carbon (C-1)
of furanose sugar resonated at d 105.1. A single-crystal X-ray
analysis evidenced the unambiguous structure of compound 5a
(Fig. 1) [53]. The crystallographic refinement data of compound
5a has been given in Table 3.
Having established the reaction conditions for the regioselec-
tive cycloaddition of the terminal alkyne 4 and the xylofuranosyl
azide 3a, we further explored the scope of other sugar azides in
such cycloaddition and developed a library of ethisterone glyco-
conjugates 5a–j in efficient yields (Table 4). Furthermore, we
investigated the reaction under microwave (MW) condition, where
Table 3
Crystallographic refinement data for compound 5a.
Earlier, several reports have established dichloromethane as a
solvent of choice for CuAAC click transformations, hence the click
reaction of deoxy-azido sugar 3a (0.3 mmol) with 4 (0.3 mmol) in
presence of CuI (5 mol%) and DIPEA (10 mol%) is carried out in
anhydrous DCM under argon atmosphere at rt. Reaction gave
regioselectively the desired 1,4 triazole i.e.1-(3-O-benzyl-
Compound
Empirical formula
Formula weight
Crystal system
Space group
a (Å)
5a
C
36H47N3O6
617.79
Orthorhombic
P212121
9.4468(8)
9.5061(7)
36.792(4)
90
b (Å)
c (Å)
5-deoxy-1,2-O-isopropylidene-a-D-xylofuranos-5-yl)-4-ethister-
one-1,2,3-triazole 5a in 90% yield. The regioisomeric nature of the
compound 5a was established based on its spectroscopic data. In
mass spectrum, the compound 5a displayed a molecular ion peak
[M+H]+ at m/z 618. In 300 MHz 1H NMR spectrum, the signal for
triazolyl proton appeared as singlet at d 7.43. The signals corre-
sponding to five phenyl protons were observed as multiplet in
the range of d 7.35–7.33. The anomeric proton of furanose sugar
(H-1) appeared as doublet at d 5.96 (J = 3.9 Hz). A siglet observed
at d 5.69 was identified for the methyne resonance of ethisterone
while a three proton multiplet observed in the range of d 4.73–
4.65 was accounted for the H-2 and oxymethylene (–OCH2–)
protons. A signal integrated to three protons appeared in the range
of d 4.54–4.47 was established for H-5 and H-4 protons of the
xylofuranosyl sugar. Likewise, a one-proton multiplet appeared
at d 4.00 was evidenced for H-4. The remaining twenty-six protons
b (°)
V (Å3)
3304.0(5)
4
Z
Density (calc)
1.242
1328, 1328.60
0.084
F(000), F0(000)
l
(mmꢁ1
)
Crystal Size [mm]
Temperature (K)
Radiation
0.11 ꢂ 0.15 ꢂ 0.18
293
MoKa 0.71073
h Min–Max [°]
h, k, l
Tot.,UniqData, R(int)
Obs. data [I > 2.0
Nref, Npar
R1, wR2, S
CCDC
3.07, 28.87
ꢁ4:12; ꢁ7:10; ꢁ17:47
8080, 6224, 0.033
3957
8734, 414
0.0881, 0.2574, 1.028
949197
r(I)]
Fig. 1. Molecular structure of 5a. Thermal ellipsoids of C, N, and O are set at 40% probability.

D. Kumar et al. / Steroids 80 (2014) 71–79
77
Table 4
Synthesis of ethisterone glycoconjugates 5a-i via Cu-catalyzed click chemistry.
Entrya
1
Sugar azide
Click productb
Yield (%)c
90
Yield (%)d
88
3a
BnO
N
N
N
N
N
HO
O
O
N
N
N
N
O
H
H
H
O
H
H
H
H
O
5a
N
2
3b
95
92
HO
OMe
O
O
H
O
O
5b
3
3c
92
92
N
HO
O
O
O
O
O
H
5c
N
4
3d
90
92
HO
H
H
O
BnO
BnO
BnO
H
H
OMe
H
O
O
5d
5
3e
94
nd
N
N
HO
N
OBn
O
HO
O
O
H
5e
6
3f
92
nd
AcO
O
N
N
N
HO
OAc
OAc
OAc
H
5f
H
H
O
(continued on next page)

78
D. Kumar et al. / Steroids 80 (2014) 71–79
Table 4 (continued)
Entrya
7
Sugar azide
Click productb
Yield (%)c
82
Yield (%)d
86
3g
BzO
N
N
N
O
OBz
OBz
HO
N
N
OBz
H
H
H
H
H
O
5g
N
8
3h
89
90
O
OAc
OAc
HO
AcO
H
O
O
5h
9
3i
95
nd
AcO
O
OAc
OAc
N
N
HO
N
OAc
H
H
H
5i
10
3j
90
92
AcO
O
OAc
OAc
AcO
O
N
N
HO
O
N
OAc
OAc
AcO
H
H
H
O
5j
a
Molar ratios: deoxy-azido sugar (1.1 equiv), ethisterone (1.0 equiv), CuI (5 mol %) and DIPEA (10 mol %).
Ethisterone glycoconjugates.
b
c
Isolated yield at r.t. (time 10 h). nd = not done.
d
Isolated yield through reaction under microwave at 100 °C with a stirring rate 200 rpm in 15 min.
significant reduction in reaction time 15 min was observed for
of steroidal carbohydrate based potential chemotherapeutic agent
is under progress in our laboratory.
comparative reaction yield at room temperature for 10–12 h. Using
extensive spectral studies (IR, MS, 1H, and 13C NMR), the structures
of all the developed glycoconjugates 5a–j were elucidated.
Acknowledgement
4. Conclusion
Author gratefully acknowledge Council of Scientific & Industrial
Research (CSIR), New Delhi (Grant No. 02(0173)/13/EMR-II) for the
funding. Author thanks CISC, Department of Chemistry, Banaras
Hindu University and RSIC, Central Drug Research Institute, Luc-
know for providing spectroscopic data of synthesized compounds.
A number of deoxy-azido sugars were prepared by nucleophilic
substitution from O-p-toluenesulfonyl glycofurano/pyranoses
using sodium azide in anhydrous DMF under inert condition. The
deoxy-azido sugars were further subjected to CuAAC click reaction
with ethisterone, a naturally occurring steroid alkyne to afford
numerous ethisterone glycoconjugates in excellent yields. The
reaction time has been significantly reduced (15 min) under micro-
wave heating. This methodology is efficient to synthesize novel
steroidal triazolyl glycoconjugates with potential application in
biological studies. Further work in this direction on development
Appendix A. Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.steroids.
2013.11.022.

D. Kumar et al. / Steroids 80 (2014) 71–79
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