Syntheses and immunomodulatory activity of 3-O-[2′-hydroxy-3′-N,N-disubstituted aminopropan-1′-yl]-α-D-glucofuranoses

Article abstract of DOI:10.1016/S0223-5234(01)01234-X

A number of 3-O-[2′-hydroxy-3′-N,N-aminopropan-1′-yl]-α-D- glucofuranoses were synthesised by regioselective oxirane ring opening in compound 2 with different secondary amines followed by selective deacetalisation. All the compounds were tested for their immunomodulatory potential in vitro; seven of them expressed significant immunostimulant activity.

Full text of DOI:10.1016/S0223-5234(01)01234-X

Eur. J. Med. Chem. 36 (2001) 435–445
´
© 2001 Editions scientifiques et me´dicales Elsevier SAS. All rights reserved
PII: S0223-5234(01)01234-X/FLA
Original article
-glucofuranosesꢀ
Syntheses and immunomodulatory activity of
3-O-[2%-hydroxy-3%-N,N-disubstituted aminopropan-1%-yl]-a-
D
Abdul Rehman Khana, Rama Pati Tripathia,*, Amiya Prasad Bhaduri, Ragini Sahai,
Anju Purib, Lalit Mohan Tripathib, Vishwa Mohan Lal Srivastavab
aDivision of Medicinal Chemistry, Central Drug Research Institute, Lucknow 226001, India
bDivision of Biochemistry, Central Drug Research Institute, Lucknow 226001, India
Received 29 October 2000; revised 16 March 2001; accepted 20 March 2001
Abstract – A number of 3-O-[2%-hydroxy-3%-N,N-aminopropan-1%-yl]-a-D-glucofuranoses were synthesised by regioselective oxirane
ring opening in compound 2 with different secondary amines followed by selective deacetalisation. All the compounds were tested
´
for their immunomodulatory potential in vitro; seven of them expressed significant immunostimulant activity. © 2001 Editions
scientifiques et me´dicales Elsevier SAS
immunomodulation / glucofuranoses / allofuranoses
1. Introduction
therafectin (1), a candidate drug for the treatment of
rheumatoid arthritis, and its analogues are known to
be associated with antifungal [5], antiparasitic [6],
antiviral [7, 8] and various other biological activities
[9, 10]. In continuation of our work on aminoalkyl
derivatives of sugars we have synthesised b-hydroxy
aminopropyl ether derivatives of 1,2-O-isoproylidene-
The intricate modulatory interactions between vari-
ous components of the immune system are of
paramount importance in providing protection
against pathogens and resulting pathogenic condition
[1]. Consequently major efforts were devoted to de-
velop drugs that can modulate the immune system in
a beneficial manner.
a-D
-glucofuranoses and evaluated them for their im-
activities. Introduction of
munomodulatory
b-hydroxy functionality in the side chain increases the
water solubility and at the same time provides one
more binding site in the molecule.
A large number of compounds with diverse chemi-
cal structure and molecular weight are reported to be
effective immunomodulators [2]. In most of the infec-
tious diseases, the immune system is down regulated
and the body is prone to many opportunistic infec-
tions; the HIV infection (AIDS) being the glaring
example of such a case. Therefore, the need to de-
velop nontoxic and site-specific immunomodulators is
greatly felt. Low molecular weight sugar derivatives
with aminoalkyl appendages are known as potent
immunomodulators [3, 4]. One such compound,
2. Chemistry
The syntheses of compounds starts with diacetone-
a- -glucose (1a) [11] which on reaction with racemic
D
epichlorohydrin in organic or aq. medium at room
temperature in the presence of tetrabutyl ammonium-
bromide gave the corresponding 3-O-[2%(R/S)-3%-
epoxypropan-1%-yl] derivative (2) in quantitative yield.
The compound 2 on regioselective oxirane ring open-
ing with secondary amines, viz. dimethyl-, diethyl-,
di-isopropylamines, pyrrolidine, piperidine, N,N-dicy-
ꢀ CDRI communication no. 5832
* Correspondence and reprints
E-mail address: root@cscdri.ren.nic.in, rpt 56@yahoo.com
–
(R.P. Tripathi).

436
A.R. Khan et al. / European Journal of Medicinal Chemistry 36 (2001) 435–445
was prepared by reaction of diacetone-a- -allofura-
D
clohexyl amine, 1-methyl piperazine, morpholine and
1-[2-pyridyl] piperazine in refluxing methanol gave the
corresponding products (3–11) as a 1:1 diastereoiso-
meric mixture in moderate to good yield. The charac-
teristic H-1 and H-2 in 3 appeared as doublets at 5.90
and 4.56, respectively, besides other usual signals.
Compounds 3–11 on selective deacetalisation of 5,6-
O-isopropylidene with aq. HCl (3%) at room temper-
ature afforded the corresponding (2%R/S)-1,2-O-
isopropylidene-3-O-[2%-hydroxy-3%-(N-amino-propan-
nose (21) [12] with racemic epichlorohydrin to give
the intermediate (2%R/S)-O-[2%,3%-epoxypropan-1%-yl]-
a- -allofuranose (22), which on oxirane ring opening
D
with pyridyl piperazine gave compound 23, the latter
on selective deacetalisation with aq. HCl furnished
the corresponding allofuranose derivative (24) (figure
2).
The syntheses of pure diastereoisomers of com-
pound 20 were carried out by reacting alcohol 1a with
(S-) and (R-)-epichlorohydrins separately to afford
the corresponding compounds 3-O-[(2%S), 3%-
epoxypropan-1%-yl]-and 3-O-[(2%R), 3%-epoxypropan-
1%-yl]-a- -glucofuranose derivatives (12–20) as a (1:1)
D
diastereoisomeric mixture in good yield (figure 1).
The structures of all the compounds were determined
on the basis of spectroscopic data and elemental
analysis. The allofuranose analogue of compound 20
1%-yl]-a-
D
-glucofuranose derivatives 25 and 26,
respectively, in good yield (figure 3). The latter on
Figure 1. Syntheses of 3-O-[2%-hydroxy-N,N-disubstituted aminopropan-1%-yl]-a-D-glucofuranoses.

A.R. Khan et al. / European Journal of Medicinal Chemistry 36 (2001) 435–445
437
oxirane ring opening with 1-(2-pyridyl) piperazine in
refluxing methanol gave the corresponding 3-O-
[(2%S)- and (2%R)-b-hydroxy-3%-{1-(2-pyridyl) piper-
azin-4-yl}]-a- -glucofuranose derivatives 27 and 28,
D
respectively, in good yield. The above compounds, on
selective deacetalisation, gave the desired pure
diastereoisomers 29 and 30 in fair yield. The pure
diastereoisomers of compound 24 could be obtained
by the reaction of allofuranose derivative (21) with
(S)- and (R)-epichlorohydrins separately to give the
corresponding 3-O-[(2%S- and 2%R)-3%-epoxypropan-
1%-yl]-a- -allofuranose derivatives 31 and 32, respec-
D
tively. The latter on oxirane ring opening with
1-(2-pyridyl) piperazine followed by selective deac-
etalisation of 5,6-acetal in the intermediate com-
pounds 33 and 34 afforded, respectively, the required
pure diastereoisomers 35 and 36 in good yield (figure
2).
3. Immunomodulatory activity
Figure 2. Reagents and conditions: (i) racemic epichlorohy-
drin, 50% aq. NaOH, tetrabutyl ammonium bromide 0–30°C,
12 h; (ii) 1-(2-pyridyl) piperazine, methanol, reflux; (iii) 3% aq.
HC, 30°C, 6 h; and (iv) (S)-epichlorohydrin, 50% aq. NaOH,
tetrabutyl ammonium bromide 30°C, 6 h (R)-epichlorohydrin,
50% aq. NaOH, tetrabutyl ammonium bromide.
The immunomodulatory activity was assessed by
examining the effect of these compounds on mitogen-
induced lymphocyte proliferation (lymphocyte trans-
formation test, LTT) and mixed lymphocyte reaction
(MLR). For MLR splenocytes prepared from two
genetically different strains of mice (Swiss and Fawn
of both sexes, weighing 20–30 g) were co-cultured in
a 96-well flat bottom plate in the presence of RPMI-
1640 medium containing foetal calf serum (10%), glu-
tamine (2 mM), HEPES (10 mM), streptomycin (100
U mL−1), penicillin (100 mg mL−1) and gentamycin
(40 mg mL−1).
The compounds were added to the wells in 50, 10
and 1 mg mL−1 final concentrations in a total volume
of 200 mL, and three wells were used for each concen-
tration. The plate was placed in a humid CO2 incuba-
tor maintained at 37°C. After 72 h, each well was
pulsed with 0.5 mCi of [3H]-thymidine and the plate
was returned to the incubator. The cells, after 18 h,
were harvested on to glass fibre filters employing a
PHD cell harvester (Cambridge). Thymidine incorpo-
rated into the DNA was measured by liquid scintilla-
tion spectrometry.
Figure 3. Reagents and conditions: (i) (S)-epichlorohydrin,
50% aq. NaOH, tetrabutyl ammonium bromide; (ii) 1-(2-
pyridyl) piperazine, methanol, reflux; (iii) 3% aq. HCl 30°C, 6
h; and (iv) (R)-epichlorohydrin, 50% aq. NaOH, tetrabutyl
ammonium bromide.
For LTT, on the other hand, splenocytes obtained
from Swiss mouse only were cultured with or without
test compounds exactly as described for MLR. In this
case, however, concanavalin-A (con-A) at a subopti-

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A.R. Khan et al. / European Journal of Medicinal Chemistry 36 (2001) 435–445
mal concentration of 0.2 mg mL−1 was used as a
mitogen.
The results have been expressed as transformation
index (TI), which represents the ratio of thymidine
incorporation by splenocytes in presence of the com-
pound to that in the control (i.e. no drug).
3-O- position of the glucofuranose derivatives. The
side chain having one to two carbon flexible
aminoalkyl chains offers good immunostimulation
(compounds 12–14). However, restricting the flexibil-
ity of amine substituent in compound 13 results in the
loss of immunostimulatory activity, as is evident from
the observation that the compounds having pyrro-
lidine (15) and N-methyl piperazine (19) as terminal
amine substituent virtually produce no immunostimu-
lation. However, release of strain by introducing an
extra ꢀCH2 unit, piperidine (16) gave better immunos-
timulation. The replacement of alkyl amines with an
amine having hydrophobic as well as polar character
such as 1-(2-pyridylpiperazine (30) elicit the best im-
munostimulant response in the series. Further change
in configuration at C-3 from -(gluco) to a-(allo) in
compound 20 results in drastic loss of the activity
(compound 24). That the inactivity is not due to the
antagonistic effect of individual diastereoisomers has
also been ruled out, as even the individual
diastereoisomers 35 and 36 did not exhibit any signifi-
cant immunostimulation. Contrary to the configura-
tion at C-3, the immunomodulatory activity is
4. Results and discussion
The results of the various compounds on LTT and
MLR are given in table I. It is quite clear that
compounds other than 3–6, 10, 15, 18, 19 and 24
registered immunomodulatory activity at one or the
other concentration. However, taking a stimulation
index (SI) of 2.0 as a cut point only seven compounds,
i.e. 12–14, 16, 20, 29 and 30 qualify the criteria of
being good immunostimulants. On careful examina-
tion of the result it becomes clear that in general
deacetalisation of 5,6-O-isopropylidene group yields
better immunostimulants. The immune response
varies with the nature of the substituted amine in the
appended b-hydroxy aminopropyl side chain at the
Table I. Effect of compounds 3–20, 24, 29, 30 35 and 36 on lymphocyte proliferation (LTT) and mixed lymphocyte reaction (MLR)
Compd. No.
LTT (mg mL−1
)
MLR (mg mL−1
)
50
10
1
1
50
10
3
ND
ND
ND
1.1490.26
1.0690.14
1.1490.31
1.4990.27
1.0990.10
0.8690.19
1.0890.15
1.0190.30
1.5090.20
2.5690.32
2.4390.30
2.2190.35
1.1290.26
2.4190.26
1.1490.31
0.9890.28
0.9090.22
2.4190.32
ND
0.9090.21
1.1190.19
0.9790.03
1.0090.21
0.8290.16
0.8390.14
0.9790.24
1.1090.28
1.6390.20
1.7390.34
2.2690.65
1.9290.17
1.1490.15
1.9090.17
1.5290.29
0.9090.16
1.1090.25
2.2290.30
ND
0.8390.10
0.8590.12
1.9490.27
0.7590.19
1.5090.21
1.4990.20
1.0690.15
0.7790.16
1.6190.40
2.6090.15
2.4490.26
2.3990.17
0.7290.18
1.7190.12
2.5190.43
0.7090.27
0.8190.27
4.3490.81
ND
1.1890.24
1.3390.21
1.7290.32
0.7490.28
1.5290.28
0.9190.26
1.1590.20
0.8690.21
1.2090.10
2.6190.36
2.5890.23
3.1190.34
0.8990.21
3.1390.20
1.5190.27
0.7290.24
0.7890.15
3.1090.20
ND
1.3990.44
1.3290.31
1.6090.20
0.8090.14
1.5890.26
1.3290.21
1.5390.25
0.9090.23
1.3590.23
2.1390.32
1.5490.33
2.0290.15
0.7890.23
1.6290.18
2.7090.10
0.7890.15
0.8390.18
2.1090.20
ND
4
5
6
1.11090.31
ND
7
8
ND
ND
9
10
0.8690.19
1.9190.25
1.41090.26
2.2390.35
1.6690.15
1.4090.32
3.2390.52
1.3390.30
1.3090.39
0.9290.19
2.6390.36
0.6090.36
2.5090.73
2.1090.23
0.8090.34
0.6090.23
0.4790.18
11
12
13
14
15
16
17
18
19
20
24
29
2.3590.30
1.8590.25
0.8590.36
0.6590.25
0.7690.23
2.1290.13
2.1090.33
0.8290.32
0.6790.38
1.3590.12
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
30
35
36
Therafectin
0.6890.02
0.6990.01
0.7690.06

A.R. Khan et al. / European Journal of Medicinal Chemistry 36 (2001) 435–445
439
independent of the configuration at C-2% in the ap-
pended side chain as the immunostimulatory effect of
pure diastereoisomers (compounds 29 and 30) is al-
most equal to that of the diastereoisomeric mixture
(20). Detailed biological evaluation regarding the pos-
sible use of compound 20 in combating fungal infec-
tions has been studied and is the subject matter of
another communication.
over crushed ice and extracted with EtOAc (3×100 mL),
the organic layer was washed with aq. NH4Cl (10%,
2×20 mL) followed by water (2×20 mL) and dried
(Na2SO4). Evaporation of the organic solvent under
reduced pressure gave a syrup which was purified by
column chromatography (SiO2 60–120 mesh), using
CHCl3–MeOH (9:1) as the eluant to afford 2 [13] as
colourless oil, yield, 2.03 g, 90%.
6.1.1.2. (2%R/S)-1,2,5,6-di-O-isopropylidene-3-O-
5. Conclusions
(2%,3%-epoxypropan-1%-yl)-h- -allofuranose (22)
D
It was obtained by reaction of ( )epichlorohydrin
and allofuranose (21) as described in the case of 2 as
colourless syrup, yield 80%; [h]D (−) 42.18 (c, 0.014,
CHCl3); EIMS; 316 [M+1]+; IR (neat): 2900, 2800 (CꢀH
To summarise, we have synthesised ether deriva-
tives of 1,2-O-isopropylidene-a- -glucofuranoses
D
having 3-O-(b-hydroxy amino alkyl) chain as im-
munomodulators where the immunostimulant activity
is dependent on the configuration of C-3, but inde-
pendent of the absolute configuration in the side
chain.
1
stretching); H-NMR (CDCl3): l=5.80 and 5.78 (two
d, J=4.5 Hz, 1H, diastereoisomeric, H-1), 4.76 and 4.68
(two pseudo triplets, J=4.5 Hz, 1H, diastereoisomeric,
H-2), 4.38 (m, 1H, H-5), 4.12–4.08 (m, 2H, H-3 and
H-4), 4.02 (m, 2H, H-6), 3.90 and 3.52 (each m, each
1H, H-1%A and H-1%B), 3.20 (m, 1H, H-2%), 2.81 and 2.63
(each m, each 1H, H-3%A and H-3%B), 1.57, 1.48, 1.39
and 1.37 (each s, each 3H, 2×C(CH3)2); Anal. C15H24O7
(C, H, N).
6. Experimental
6.1. Chemistry
Melting points were determined on a Buchi 510 ap-
paratus and are uncorrected. Elemental analysis for all
new compounds were performed on a Carlo Erba Model
1108 elemental analyser and data of C, H, and N are
within 0.4% of calculated values. Thin layer chro-
matography was used to monitor the reactions. IR
spectra were recorded using a Perkin–Elmer 881 spec-
trophotometer and the values are expressed as wmax
cm−1. Mass spectral data were run on JEOL-300 spec-
trophotometer and 1H-NMR spectra were recorded on a
Brucker 200 and 400 MHz spectrophotometer.
6.1.1.3. (2%S)-1,2,5,6-di-O-isopropylidene-3-O-
(2%,3%-epoxypropan-1%-yl)-h- -glucofuranose (25)
D
Colourless oil, yield 60%; [h]D (+) 80.2 (c,
0.007,CHCl3); FABMS; 317 [M+1]+; IR: 2900, 2800
1
(CH3 and CH2 stretching); H-NMR (CDCl3): l=?5.87
(d, J=4.5 Hz, 1H, H-1), 4.55 (d, J=4.5 Hz, 1H, H-2),
4.31 (m, 2H, H-3, H-4), 4.00–3.90 (m, 3H, H-6, H-1%),
3.48 (d, J=12 Hz, J=8 Hz, 1H, H-1%), 3.15 (m, 1H,
H-2%), 2.82 and 2.62 (two dd, J=12 Hz, J=8 Hz, each
1H, H-3%), 1.59, 1.48, 1.39 and 1.31 (each s, each 3H,
2×C(CH3)2); Anal. C15H24O7 (C, H).
6.1.1. General procedure for the preparation of
compounds 2, 22, 25, 26, 31 and 32
6.1.1.4. (2%R)-1,2,5,6-di-O-isopropylidene-3-O-
(2%,3%-epoxypropan-1%-yl)-h- -glucofuranose (26)
D
6.1.1.1. (2%R/S)-1,2,5,6-di-O-isopropylidene-3-O-
Colourless oil, yield 75%; [h]D (−) 60.4 (c,
[2%,3%-epoxypropan-1%-yl]-h- -glucofuranose (2)
D
0.008,CHCl3); FABMS; 317 [M+1]+; IR: 2928, 2832
1
Epichlorohydrine (50 mL, 640 mmol) was magneti-
cally stirred with aq. NaOH (50%, 100 mL) for 0.5 h
with tetrabutyl ammonium bromide (5.0 g, 15.5 mmol).
To the stirring reaction mixture diacetone glucose (1a)
(20 g, 76.92 mmol) was slowly added at 0°C and stirring
continued at same temperature for 3 h followed by
additional 9 h at r.t. The reaction mixture was poured
(CH3 and CH2 stretching); H-NMR (CDCl3): l=5.89
(d, J=4.5 Hz, 1H, H-1), 4.61 (d, J=4.5 Hz, 1H, H-2),
4.32 (m, 2H, H-3, H-4), 4.00–3.90 (m, 3H, H-6, H-1%),
3.65 (d, J=12 Hz, J=8 Hz, 1H, H-1%), 3.15 (m, 1H,
H-2%), 2.82 and 2.65 (two dd, J=12 Hz, J=8 Hz, each
1H, H-3%), 1.51, 1.42, 1.36 and 1.31 (each s, each 3H,
2×C(CH3)2); Anal. C15H24O7 (C, H).

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A.R. Khan et al. / European Journal of Medicinal Chemistry 36 (2001) 435–445
6.1.1.5. (2%S)-1,2,5,6-di-O-isopropylidene-3-O-
(2%,3%-epoxypropan-1%-yl)-h- -allofuranose (31)
1.46, 1.38 and 1.32 (each s, each 3H, 2×(CH3)2); Anal.
C17H31NO7 (C, H, N).
D
Yield 85%; [h]D (−) 20.45 (c, 0.008,CHCl3); FABMS:
317 [M+1]+; IR: 2989, 2933 (CH3 and CH2 stretching);
1H-NMR (CDCl3): l=5.78 (d, J=4.5 Hz, 1H, H-1),
4.67 (pseudo-triplet, 1H, H-2), 4.40 (m, 1H, H-4), 4.06–
3.98 (m, 4H, H-3, H-5, H-6), 3.57 and 3.47 (two dd,
J=12 Hz, J=8 Hz, each 1H, H-1%), 3.20 (m, 1H, H-2%),
2.80 and 2.62 (two dd, J=12 Hz, J=8 Hz, each 1H,
H-3%), 1.57, 1.46, 1.37 and 1.35 (each s, each 3H, 2×
C(CH3)2); Anal. C15H24O7 (C, H).
6.1.2.2. (2%R/S)-1,2,5,6-di-O-isopropylidene-3-O-
[3%-(N,N-diethylamino)-2%-hydroxy-propan-1%-yl]-h-
glucofuranose (4)
Colourless oil, yield 60%; MS; m/z: 389 [M], IR
D-
(neat): 3000, 2940, 2900 and 2820 (CH3 and CH2
1
stretching); H-NMR (CDCl3): l=5.90 (d, J=4.5 Hz,
1H, H-1), 4.60 (d, J=4.5 Hz, 1H, H-2), 4.32 (m, 1H,
H-4), 4.12 (m, 2H, H-3 and H-5), 4.00 (m, 3H, H-1% and
H-6A), 3.81 (m, 2H, H-2% and H-6B), 3.65, 3.55 and 3.48
(three sets of dd, J=12 Hz, J=7 Hz, 2H, H-3%), 2.55
(m, 4H, N(CH2CH3)2), 1.50, 1.43, 1.36 and 1.32 (each s,
each 3H, 2×(C(CH3)2), 1.03 (two t merged with each
other, J=7.5 Hz, 6H, N(CH2CH3)2); Anal. C19H35NO7
(C, H, N).
6.1.1.6. (2%R)-1,2,5,6-di-O-isopropylidene-3-O-
(2%,3%-epoxypropan-1%-yl)-h- -allofuranose (32)
D
Colourless oil, yield 80%; [h]D (−) 25.14 (c, 0.05,
CHCl3); EIMS: 315 [M−1]+; FTIR: 2990, 2942 (CH3
and CH2 stretching); 1H-NMR (CDCl3): l=5.79 (d,
J=4.5 Hz, 1H, H-1%), 4.74 (pseudo triplet, 1H, H-2),
4.38 (dd, 1H, H-4), 4.00–4.10 (m, 4H, H-3, H-5 and
H-6), 3.94 (dd, J=12 Hz, J=8 Hz, 1H, H-3%A), 2.63
(dd, J=12 Hz, J=8 Hz, 1H, H-3%B), 1.59, 1.46, 1.39
and 1.35 (each s, each 3H, 2×C(CH3)2); Anal. C15H24O7
(C, H, N).
6.1.2.3. (2%R/S)-1,2,5,6-di-O-isopropylidene-3-O-
[3%-(N,N-disopropylamino)-2%-hydroxy-propan-1%-yl]-
h-D
-glucofuranose (5)
Colourless oil, yield 57%; [h]D (−) 21.10 (c, 0.01,
CHCl3); FABMS; m/z: 419 [M+2]+, 418 [M+1]+; IR
(neat): 3500, 2980, 2840, 2800 (CH3 and CH2 stretch-
ing); 1H-NMR (CDCl3): l=5.90 (d, J=4.5 Hz, 1H,
H-1), 4.62 (d, J=4.5 Hz, 1H, H-2), 4.35 (m, 1H, H-4),
4.13 (m, 2H, H-3 and H-5), 4.04 and 3.89 (two dd,
J=12 Hz, J=8 Hz, 2H, H-1%A and H-1%B), 3.75 and
3.68 (two m, 2H, H-6A and H-6B), 3.56 (m, 1H, H-2%),
3.51 and 3.40 (two dd, J=12 Hz, J=7 Hz, 2H, H-3%),
3.04 (sextet, J=7.5 Hz, 2H, [ꢀ{CH(CH3)2}2], 2.50 (bs,
1H, OH), 1.51, 4.46, 1.38 and 1.33 (each s, each 3H,
2×[C(CH3)2)], 1.08 and 1.01 (two d, J=7.5 Hz, 12H,
[ꢀ{CH(CH3)2}2]; Anal. C21H39NO7 (C, H, N).
6.1.2. General procedure for the preparation of
compounds 3–11, 23, 27, 28, 33 and 34
6.1.2.1. (2%R/S)-1,2,5,6-di-O-isopropylidene-3-O-
[3%-(N,N-dimethylamino)-2%-hydroxy-propan-1%-yl]-h-
D-
glucofuranose (3)
A solution of compound 2 (2.83 g, 8.95 mmol) in
methanol (20 mL) was refluxed with dimethyl amine
hydrochloride (0.73 g, 8.95 mmol) in the presence of
NaHCO3 (0.2 g, 2.38 mmol) for 8 h. The excess of
solvent was evaporated and residue dissolved in EtOAc
(50 mL), filtered. The organic layer was dried (Na2SO4)
and evaporated under reduced pressure to give an oil
which was purified by column chromatography (SiO2)
using CHCl3–MeOH (9:1) as the eluant to give com-
pound 3 (all other compounds of this series were pre-
pared similarly using corresponding amines) as
colourless oil yield, 2.03 g, 63%; [h]D (−) 25.94 (c,
0.001.CHCl3); FABMS; m/z: 362 [M+1]+; IR (neat):
2980, 2940 and 2780 (CH3 and CH2 stretching); 1H-
NMR (CDCl3): l=5.90 (d, J=4.5 Hz, 1H, H-1), 4.58
(d, J=4.5 Hz, 1H, H-2), 4.32 (m, 1H, H-5), 4.15 (m,
2H, H-3 and H-4), 4.00 (m, 2H, H-1%), 3.88 (m, 1H,
H-2%), 3.88 and 3.79 (m, 2H, H-6A and H-6B), 3.75,
3.64, and 3.58 (three sets of dd, J=12 Hz, J=8 Hz,
2H, diastereoisomeric H-3%), 2.39 (s, 6H, N(CH3)2), 1.51,
6.1.2.4. (2%-R/S)-1,2,5,6-di-O-isopropylidene-3-O-
[3%-(pyrrolidin-1-yl)-2%-hydroxy-propan-1%-yl]-h-
D-
glucofuranose (6)
Colourless oil, yield 57%; [h]D (−) 20.13 (c, 0.02,
CHCl3); EIMS; m/z: 387 [M+]; FTIR (neat): 3454 (OH),
1
3020, 2985, 2935, 2806 (CH3 and CH2 stretching); H-
NMR (CDCl3): l=5.90 (d, J=4.5 Hz, 1H, H-1), 4.58
(d, J=4.5 Hz, 1H, H-2), 4.32 (m, 1H, H-4), 4.12 (m,
2H, H-3 and H-5), 4.00 (m, 2H, H-1%), 3.92 (m, 1H,
H-2%), 3.82 and 3.67 (two m, 2H, H-6), 3.57 and 3.44
(two dd, J=12 Hz, J=7 Hz, 2H, H-3%), 2.72 (m, 4H,
pyrrolidin ring protons), 1.80 (bs, 4H, pyrrolidin ring
protons), 1.50, 1.42, 1.38 and 1.32 (each s, each 3H,
2×C(CH3)2); Anal. C19H33NO7 (C, H, N).

A.R. Khan et al. / European Journal of Medicinal Chemistry 36 (2001) 435–445
441
6.1.2.5. (2%R/S)-1,2,5,6-di-O-isopropylidene-3-O-
CHCl3); EIMS; m/z: 403 [M]+; IR (neat): 3452 (OH),
3018, 2933, 2868, 2819 (CH3 and CH2 stretching); H-
1
[3%-(piperidin-1-yl)-2%-hydroxy-propan-1%-yl]-h-
D
-
glucofuranose (7)
Colourless oil, yield 59%; [h]D (−) 20.12 (c, 0.016,
CHCl3); FABMS: 402 [M+1]+; IR (neat): 3450 (OH),
NMR (CDCl3): l=5.90 (d, J=4.5 Hz, 1H, H-1), 4.60
(d, J=4.5 Hz, 1H, H-2), 4.32 (m, 2H, H-3 and H-4),
4.15 (m, 5H, H-5 and morpholin ring protons), 4.02 (m,
3H, H-2% and H-6), 3.65 (m, 2H, H-3%), 2.51 (m, 4H, mor-
pholin ring protons), 1.50, 1.42, 1.35 and 1.30 (each s,
each 3H, 2×ꢀC(CH3)2); Anal. C19H33NO8 (C, H, N).
1
3000, 2950, 2800, 2790 (CH3 and CH2 stretching); H-
NMR (CDCl3): l=5.90 (d, J=4.5 Hz, 1H, H-1), 4.59
(d, J=4.5 Hz, 1H, H-2), 4.32 (m, 1H, H-4), 4.12 (m, 2H,
H-3 and H-5), 3.98 (m, 2H, H-1%), 3.90 (m, 1H, H-2%),
3.75 (m, 2H, H-6), 3.63, 3.57 and 3.48 (three dd, J=15
Hz, J=5 Hz, 2H, H-3%), 2.37 and 2.40 (m, 6H, piperidin
ring protons), 1.59 (bs, 4H, piperidin ring protons), 1.51,
1.46, 1.38 and 1.32 (each s, each 3H, 2×ꢀC(CH3)2); Anal.
C20H35NO7 (C, H, N).
6.1.2.9. (2%R/S)-1,2,5,6-di-O-isopropylidene-3-O-
[3%-{1-(2-pyridyl)-piperazin-4-yl}-2%-hydroxy-propan-
1%-yl]-h- -glucofuranose (11)
D
Colourless oil, yield 60%; [h]D (−) 13.55 (c, 0.017,
CHCl3); FABMS; m/z: 480 [M++1]; IR (neat): 3400
1
(OH), 3000, 2940, 2900, 2840 (CH stretching); H-NMR
6.1.2.6. (2%R/S)-1,2,5,6-di-O-isopropylidene-3-O-
[3%-(N,N-dicyclohexylamino)-2%-hydroxy-propan-1%-yl]-
(CDCl3): l=8.20 (d, J=5 Hz, 1H, pyridyl protons),
7.48 (dd, J=8 Hz, J=1.5 Hz, 1H, pyridyl protons), 6.63
(m, 2H, pyridyl protons), 5.90 (d, J=4.5 Hz, 1H, H-1),
4.60 (d, J=4.5 Hz, 1H, H-2), 4.33 (m, 1H, H-4), 4.12 (m,
2H, H-3 and H-5), 4.00 (two dd, J=12 Hz, J=8 Hz,
each 1H, H-1%), 3.85 (m, 1H, H-2%), 3.72 and 3.61 (each
dd, J=12 Hz, J=5 Hz, each 1H, H-6A and H-6B), 3.46
(two dd, J=12 Hz, J=7 Hz, 2H, H-3%), 2.70 (m, 2H,
piperazinyl ring protons), 2.62, 2.38 (m, 6H, piperazinyl
ring protons), 1.50, 1.43, 1.38 and 1.30 (each s, each 3H,
2×ꢀC(CH3)2); Anal. C24H37N3O7 (C, H, N).
h- -glucofuranose (8)
D
Colourless oil, yield 30%; [h]D (−) 20.57 (c, 0.06,
CHCl3); EIMS; m/z: 497 [M]+; IR (neat): 3500, 3000,
1
2950, 2850; H-NMR (CDCl3): l=5.89 (d, J=4.5 Hz,
1H, H-1), 4.61 (d, J=4.5 Hz, 1H, H-2), 4.32 (m, 1H, H-
4), 4.15 (m, 2H, H-3 and H-5), 3.95 and 3.86 (two dd,
J=12 Hz, J=8 Hz, 2H, H-1%), 3.65 and 3.61 (two dd,
J=10 Hz, J=5 Hz, 2H, H-6), 2.68 and 2.50 (two dd, J=
12 Hz, J=7 Hz, 2H, H-3%), 2.35 (bs, 1H, ꢀOH), 2.22 (m,
2H, cyclohexylprotons), 1.75 (m, 8H, cyclohexyl pro-
tons), 1.60 (m, 4H, cyclohexyl protons), 1.50, 1.42, 1.35
and 1.31 (each s, each 3H, 2×ꢀC(CH3)2), 1.15 (m, 8H,
cyclohexyl ring protons); Anal. C27H47NO7 (C, H, N).
6.1.2.10. (2%R/S)-1,2,5,6-di-O-isopropylidene-3-O-
[3%-{1-(2-pyridyl)-piperazin-4-yl}-2%-hydroxy-propan-
1%-yl]-h- -allofuranose (23)
D
Colourless oil, yield 66%; [h]D (−) 14.12 (c, 0.018,
CHCl3); FABMS; m/z: 480 [M++1]; FTIR: 3427, 2931,
2895, 2831 (CH3 and CH2 stretching); 1H-NMR
(CDCl3): l=8.20 (d, J=8 Hz, 1H, pyridyl proton), 7.48
(dd, J=8 Hz, J=4 Hz, 1H, pyridyl proton), 6.66 (m,
2H, pyridyl proton), 5.80 (d, J=4.5 Hz, 1H, H-1), 4.69
(pseudo triplet, J=4.5 Hz, 1H, H-2), 4.39 (m, 1H, H-4),
4.12 (m, 2H, H-3 and H-5), 4.06 and 4.00 (each dd, J=
12 Hz, J=8 Hz, each 1H, H-1%A and H-1%B), 3.86 (m,
1H, H-2%), 3.58 (m, 4H, H-3% and H-6), 2.72 (m, 2H,
piperazin ring protons), 2.60 (m, 6H, piperazin ring pro-
tons), 1.59, 1.49, 1.38 and 1.35 (each s, each 3H, 2×
C(CH3)2); Anal. C24H37N3O7 (C, H, N).
6.1.2.7. (2%R/S)-1,2,5,6-di-O-isopropylidene-3-O-
[3%-(4-methylpiperazin-1-yl)-2-hydroxy-propan-1%-yl]-
h- -glucofuranose (9)
D
Colourless oil, yield 60%; [h]D (−) 17.89 (c, 0.016,
CHCl3); FABMS; m/z: 417 [M+1]+; IR (neat): 3500,
1
3000, 2980, 2960, 2800; H-NMR (CDCl3): l=5.89 (d,
J=4.5 Hz, 1H, H-1), 4.58 (d, J=4.5 Hz, 1H, H-2), 4.31
(m, 1H, H-4), 4.12 (m, 2H, H-3 and H-5), 4.00 (m, 2H,
H-1%), 3.90 (m, 1H, H-2%), 3.78 and 3.65 (two dd, J=14
Hz, J=8 Hz, 2H, H-6), 3.58 and 3.42 (each dd, J=12
Hz, J=7 Hz, each 1H, H-3%A and H-3%B), 2.48 (m, 8H,
piperazinyl protons), 2.30 (s, 3H, NꢀCH3), 1.50, 1.43,
1.38 and 1.32 (each s, each 3H, 2×ꢀC(CH3)2); Anal.
C17H32NO7 (C, H, N).
6.1.2.11. (2%S)-1,2,5,6-di-O-isopropylidene-3-O-
[3%-{1-(2-pyridyl)-piperazin-4-yl}-2%-hydroxy-propan-
6.1.2.8. (2%R/S)-1,2,5,6-di-O-isopropylidene-3-O-
1%-yl]-h-D-glucofuranose (27)
[3%-(morpholin-4-yl)-2%-hydroxy-propan-1%-yl]-h-
glucofuranose (10)
Colourless oil, yield 80%; [h]D (−) 21.16 (c, 0.018,
D
-
Colourless oil, yield 60%; [h]D (−) 14.16 (c, 0.005,
CHCl3); FABMS; m/z: 479 [M+1]+; FTIR: 3450 (ꢀOH),
1
2980, 2900, 2880 (CH3 and CH2 stretching); H-NMR

442
A.R. Khan et al. / European Journal of Medicinal Chemistry 36 (2001) 435–445
(CDCl3): l=8.20 (d, J=5 Hz, 1H, pyridyl proton),
7.80 (dd, J=8 Hz, J=1.5 Hz, 1H, pyridyl proton), 6.65
(m, 2H, pyridyl proton), 5.90 (d, J=4.5 Hz, 1H, H-1%),
4.58 (d, J=4.5 Hz, 1H, H-2), 4.32 (m, 1H, H-4), 4.12
(m, 2H, H-3, H-5), 4.02 (two dd, J=12 Hz, J=8 Hz,
2H, H-1%), 3.85 (dd, J=14 Hz, J=3.5 Hz, 1H, H-2%),
3.60–3.42 (m, 4H, H-3%, H-6), 3.00 (m, 2H, piperazinyl
protons), 2.70, 2.55, 2.40 (each m, each 2H, piperazinyl
ring proton), 1.50, 1.43, 1.38, 1.32 (each s, each 3H,
2×C(CH3)2); Anal. C24H37N3O7 (C, H, N).
NMR (CDCl3): l=8.20 (d, J=5 Hz, 1H, pyridyl pro-
ton), 7.50 (dd, J=8 Hz, J=4 Hz, 1H, pyridyl proton),
6.66 (m, 2H, pyridyl proton), 5.79 (d, J=4.5 Hz, 1H,
H-1%), 4.69 (pseudo triplet, 1H, H-2), 4.37 (m, 1H, H-4),
4.07 (m, 3H, H-3, H-5 and H-1%A), 3.98 (m, 1H, H-1%B),
3.93 (m, 1H, H-2%), 3.75 (m, 2H, H-6), 3.64 (dd, J=12
Hz, J=8 Hz, 1H, H-3%A), 3.52 (dd, J=12 Hz, J=8
Hz, 1H, H-3%B), 2.90 (m, 5H, piperazinyl proton), 2.75
and 2.65 (two m, 3H, piperazinyl proton), 1.58, 1.48,
1.37, 1.34 (each s, each 3H, 2×C(CH3)2); Anal.
C24H37N3O7 (C, H, N).
6.1.2.12. (2%R)-1,2,5,6-di-O-isopropylidene-3-O-
[3%-{1-(2-pyridyl)-piperazin-4-yl}-2%-hydroxy-propan-
6.1.3. General Procedure for the preparation of
compounds 12–20, 24, 29, 30, 35, 36
1%-yl-h- -glucofuranose (28)
D
Colourless oil, yield 60%; [h]D (−) 12.18 (c, 0.06,
CHCl3); FABMS; m/z: 480 [M+1]+; FTIR: 3450 (ꢀOH),
6.1.3.1. (2%R/S)-1,2-O-isopropylidene-3-O-
[3%-(N,N-dimethylamino)-2%-hydroxy-propan-1%-yl]-h-
glucofuranose (12)
1
2985, 2935, 2885 (CH3 and CH2 stretching); H-NMR
D-
(CDCl3): l=8.20 (d, J=4.5 Hz, 1H, pyridyl proton),
7.80 (dd, J=8 Hz, J=1.5 Hz, 1H, pyridyl proton), 6.62
(m, 2H, pyridyl proton), 5.90 (d, J=4.5 Hz, 1H, H-1%),
4.58 (d, J=4.5 Hz, 1H, H-2), 4.32 (m, 1H, H-4), 4.12
(m, 2H, H-3, H-5), 4.00 (two dd, J=12 Hz, J=8 Hz,
2H, H-1%), 3.67 (m, 1H, H-2%), 3.60–3.45 (m, 4H, H-3%,
H-6), 3.00 (m, 2H, piperazinyl protons), 2.75–2.40 (m,
6H, piperazinyl ring proton), 1.50,1.45, 1.38, 1.32 (each
s, each 3H, 2×C(CH3)2); Anal. C24H37N3O7 (C, H, N).
The compound 4 (2.7 g, 7.47 mmol) was magnetically
stirred with aq. HCl (3%, 12 mL, pH 1–2) at r.t. (35°C)
for 3 h. Reaction mixture neutralised with solid
NaHCO3 till the pH is 7. It was filtered, solvent evapo-
rated under reduced pressure to give a residual mass,
which was extracted with chloroform (3×50 mL). Or-
ganic layer dried (Na2SO4) and evaporated under re-
duced pressure to give a syrup, which was purified by
column (SiO2) chromatography using CHCl3–MeOH
(95:5) as the eluant to give the desired compound 22 as
colourless oil (all other compounds of this series were
prepared similarly from the corresponding intermedi-
ates). Yield 75%; [h]D (−) 39.40 (c, 0.012, CHCl3);
FABMS; m/z: 321 [M]+; IR (neat): 3400 (OH), 2990,
6.1.2.13. (2%S)-1,2,5,6-di-O-isopropylidene-3-O-
[3%-{1-(2-pyridyl)-piperazin-4-yl}-2%-hydroxy-propan-
1%-yl]-h- -allofuranose (33)
D
Colourless oil, yield 60%; [h]D (−) 14.61 (c, 0.004,
CHCl3); FABMS; m/z: 479 [M+1]+; FTIR: 3390 (ꢀOH),
1
3025, 2935, 2850 (CH3 and CH2 stretching); H-NMR
1
2940, 2860, 2800 (CꢀH stretching); H-NMR (CDCl3):
(CDCl3): l=8.20 (d, J=5 Hz, 1H, pyridyl proton),
7.50 (dd, J=8 Hz, J=5 Hz, 1H, pyridyl proton), 6.66
(dd, J=5 Hz, J=1.5 Hz, 2H, pyridyl proton), 5.79 (d,
J=4.5 Hz, 1H, H-1%), 4.69 (pseudo triplet, J=4.5 Hz,
1H, H-2), 4.37 (m, 1H, H-4), 4.07–3.98 (m, 4H, H-3,
H-5, H-1%), 3.75 (m, 2H, H-6), 3.64 and 3.52 (each dd,
J=12 Hz, J=8 Hz, each 1H, H-3%), 3.00–2.89 (m, 5H,
piperazinyl ring proton), 2.75, 2.65 (two m, 3H, piper-
azinyl ring proton), 1.58, 1.48, 1.37, 1.34 (each s, each
3H, 2×C(CH3)2); Anal. C21 H33 N3 O7 (C, H, N).
l=5.96 (d, J=4.5 Hz, 1H, H-1), 4.54 (d, J=4.5 Hz,
1H, H-2), 4.15 (m, 1H, H-4), 4.10 (m, 2H, H-3, OH),
4.00 (m, 2H, H-1%), 3.87 (m, 3H, H-5 and H-6), 3.78 (m,
1H, H-2%), 3.56 and 3.52 (two dd, J=8 Hz, J=5 Hz,
2H, H-3%), 2.30 (s, 6H, N(CH3)2), 1.51, 1.33 (each s, each
3H, ꢀC(CH3)2); Anal. C24H27NO7 (C, H, N).
6.1.3.2. (2%R/S)-1,2-O-isopropylidene-3-O-
[3%-(N,N-diethylamino)-2%-hydroxy-propan-1%-yl]-h-
D-
glucofuranose (13)
6.1.2.14. (2%R)-1,2,5,6-di-O-isopropylidene-3-O-
[3%-{1-(2-pyridyl-piperazin-4-yl}-2%-hydroxy-propan-
Colourless oil, yield 89%; [h]D (−) 29.86 (c, 0.016,
CHCl3); EIMS; 349 [M]+; IR (neat): 3400 (OH), 3000,
1
1%-yl]-h-
D
-allofuranose (34)
2940, 2900, 2840 (CH3 and CH2 stretching); H-NMR
Colourless oil, yield 60%; [h]D (−) 14.61 (c, 0.04,
CHCl3); FABMS; 479 [M]+; FTIR: 3363 (ꢀOH), 3020,
2987, 2937 and 2844 (CH3 and CH2 stretching); 1H-
(CDCl3): l=5.94 (d, J=4.5 Hz, 1H, H-1), 4.55 (d,
J=4.5 Hz, 1H, H-2), 4.19 (m, 1H, H-4), 4.12 (m, 1H,
H-3), 4.05 and 3.99 (two dd, J=12 Hz, J=4 Hz, 2H,

A.R. Khan et al. / European Journal of Medicinal Chemistry 36 (2001) 435–445
443
H-1%), 3.85 (m, 3H, H-5 and H-6), 3.76 (m, 1H, H-2%),
3.68, 3.60, 3.52 (three dd, J=12 Hz, J=8 Hz, 2H,
H-3%), 3.30 (bs, 1H, OH), 2.65 (m, 4H, Nꢀ(CH26 ꢀCH3)2],
2.4 and 2.28 (bs, OH), 1.50 and 1.42 (each s, each 3H,
C(CH3)2), 1.10 and 1.07 (each t, J=7.5 Hz, each 3H,
NꢀCH2 (CH3)2); Anal. C16H31NO7 (C, H, N).
protons), 1.57 (m, 4H, piperidin ring protons), 1.49 and
1.32 (each s, each 3H, C(CH3)2), 1.48 (m, 2H, piperidin
ring protons); Anal. C17H31NO7 (C, H, N).
6.1.3.6. (2%R/S)-1,2-O-isopropylidene-3-O-
[3%-(N,N-dicyclohexylamino)-2%-hydroxy-propan-1%-yl]-
h-D
-glucofuranose (17)
Colourless oil, yield 57%; [h]D (−) 31.14 (c, 0.028,
6.1.3.3. (2%R/S)-1,2-O-isopropylidene-3-O-
[3%-(N,N-diisopropylamino)-2%-hydroxy-propan-1%-yl]-
CHCl3); EIMS; m/z: 457 [M++1]; IR (neat): 3400 (OH),
2940, 2850 (CꢀH stretching); 1H-NMR (CDCl3): l=
5.97 (d, J=4.5 Hz, 1H, H-1), 4.57 (d, J=4.5 Hz, 1H,
H-2), 4.34 (m, 2H, H-4), 4.18 (m, 2H, H-3 and H-5),
3.96 and 3.85 (each dd, J=12 Hz, J=4.5 Hz, each 1H,
H-1%A and H-1%B), 3.68 (m, 1H, H-2%), 3.54 and 3.46 (m,
2H, H-6), 3.22 (bs, ꢀOH), 2.79 and 2.62 (each dd, J=11
Hz, J=4.5 Hz, each 1H, H-3%A and H-3%B), 2.42 (m,
2H, cyclohexyl proton), 2.18 (bs, OH), 1.78 and 1.60
(two m, 6H and 4H cyclohexyl protons), 1.50 and 1.32
(each s, each 3H, ꢀC(CH3)2), 1.25 (m, 10H, cyclohexyl
protons); Anal. C24H43NO7 (C, H, N).
h-D
-glucofuranose (14)
Colourless oil, yield 70%; [h]D (−) 29.81 (c, 0.011,
CHCl3); FABMS; m/z: 378 [M+1]+; IR (neat): 3400
(OH), 2990, 2860, 2800 (CꢀH stretching); 1H-NMR
(CDCl3): l=5.94 (d, J=4.5 Hz, 1H, H-1), 4.55 (d,
J=4.5 Hz, 1H, H-2), 4.13 (m, 2H, H-3 and H-4), 4.05
and 3.96 (m, 2H, H-1%), 3.89 and 3.76 (m, 3H, H-5 and
H-6), 3.67 (m, 3H, H-2%, H-3%), 3.29 (bs, 1H, ꢀOH), 2.60
(bs, 1H, OH), 2.48 (sextet, J=7.5 Hz, 2H,
Nꢀ{CHꢀ(CH3)2}2), 2.25 (bs, 1H, ꢀOH), 1.49 and 1.32
(each s, each 3H, C(CH3)2), 0.80 and 0.78 (each d, each
6H, J=7.5 Hz, 2×Nꢀ[CH(CH36 )2]; Anal. C18H35NO7 (C,
H, N).
6.1.3.7. (2%R/S)-1,2-O-isopropylidene-3-O-
[3%-(4-methyl-piperazin-1-yl)-2%-hydroxy-propan-1%-yl]-
h- -glucofuranose (18)
D
6.1.3.4. (2%R/S)-1,2-O-isopropylidene-3-O-
[3%(-pyrrolidin-1-yl)-2%-hydroxy-propan-1%-yl]-h-
glucofuranose (15)
Colourless oil, yield 89%; [h]D (−) 24.26 (c, 0.08,
D-
CHCl3); FABMS; 377 [M++1]; IR (neat): 3400 (OH),
1
2990, 2920, 2800 (CꢀH stretching); H-NMR (CDCl3):
Colourless oil, yield 80%; [h]D (−) 23.02 (c, 0.016,
CHCl3); FABMS; m/z: 348 [M+1]+; IR (neat): 3400
(OH), 3000, 2950, 2850, 2800 (CꢀH stretching); 1H-
NMR (CDCl3): l=5.91 (d, J=4.5 Hz, 1H, H-1), 4.54
(d, J=4.5 Hz, 1H, H-2), 4.14 (m, 2H, H-3 and H-4),
4.00 (m, 1H, H-2%), 3.92 (m, 3H, H-3 and H-5), 3.66 (m,
2H, H-6), 3.36 and 2.85 (each dd, J=12 Hz, J=4.5 Hz,
each 1H, H-3%A and H-3%B), 2.68 (m, 4H, pyrolidin ring
protons), 2.49 (m, 4H, pyrrolidin ring protons), 1.49 and
1.32 (each s, each 3H, C(CH3)2); Anal. C16H29NO7 (C,
H, N).
l=5.94 (d, J=4.5 Hz, 1H, H-1), 4.53 (d, J=4.5 Hz,
1H, H-2), 4.35 (m, 1H, H-5), 4.14 (m, 2H, H-3 and
H-5), 4.15 (dd, J=12 Hz, J=5 Hz, 2H, H-1%), 3.89 (m,
1H, H-2%), 3.68 (m, 2H, H-6), 3.48 and 3.56 (each dd,
J=15 Hz, J=7 Hz, each 1H, H-3%A and H-3%B), 3.30
(bs, OH), 2.54 (m, 8H, piperazin ring protons), 2.30 (s,
3H, NꢀCH3), 1.50 and 1.32 (each s, each 3H, ꢀC(CH3)2);
Anal. C17H32N2O7 (C, H, N).
6.1.3.8. (2%R/S)-1,2-O-isopropylidene-3-O-
[3%-(morpholin-4-yl)-2%-hydroxy-propan-1%-yl]-h-
D-
6.1.3.5. (2%R/S)-1,2-O-isopropylidene-3-O-
glucofuranose (19)
[3%-(piperidin-1-yl)-2%-hydroxy-propan-1%-yl]-h-
glucofuranose (16)
D
-
Colourless oil, yield 80%; [h]D (−) 26.28 (c, 0.014,
CHCl3); FABMS; m/z: 364 [M+1]+; IR (neat): 3420
(OH), 2980, 2920, 2800 (CꢀH stretching); 1H-NMR
(CDCl3): l=5.94 (d, J=4.5 Hz, 1H, H-1), 4.54 (d,
J=4.5 Hz, 1H, H-2), 4.15 (m, 2H, H-3 and H-4), 4.02
(m, 3H, H-5 and H-1%), 3.90 (m, 3H, H-6 and H-2%), 3.75
(m, 6H, H-3% and morpholin ring protons), 2.64 and
2.42 (m, 4H, morpholin ringl protons), 1.52, 1.32 (each
s, each 3H, C(CH3)2); Anal. C16H29NO8 (C, H, N).
Colourless oil, yield 70%; [h]D (−) 26.23 (c, 0.016,
CHCl3); FABMS; m/z: 362 [M+1]+; IR (neat): 3400
(OH), 3000, 2950, 2850, 2800 (CꢀH stretching); 1H-
NMR (CDCl3): l=5.91 (d, J=4.5 Hz, 1H, H-1), 4.54
(d, J=4.5 Hz, 1H, H-2), 4.14 (m, 2H, H-3 and H-4),
3.90 (m, 4H, H-5, H-1% and H-2%), 3.68 (m, 2H, H-6),
3.30 (bs, ꢀOH), 2.60, 2.30, 2.21 (m, 6H, piperidin ring

444
A.R. Khan et al. / European Journal of Medicinal Chemistry 36 (2001) 435–445
6.1.3.9. (2%R/S)-1,2-O-isopropylidene-3-O-
[3%-(1-(2-pyridyl)-piperazin-4-yl)-2%-hydroxy-
6.1.3.12. (2%R)-1,2-di-O-isopropylidene-3-O-
[3%-[{1-(2-pyridyl)-piperazin-4-yl}]-2%-hydroxy-
propan-1%-yl]-h-
D
-glucofuranose (20)
propan-1%-yl-h-D-glucofuranose (30)
Colourless oil, yield 75%; [h]D (−) 22.12 (c, 0.014,
CHCl3); FABMS: m/z: 440 [M+1]+; IR (neat): 3400
(OH), 3000, 2980, 2800 (CꢀH stretching); 1H-NMR
(CDCl3): l=8.20 (dd, J=8 Hz, J=1.5 Hz, 1H, pyridyl
protons), 7.50 (dd, J=8 Hz, J=1.5 Hz, 1H, pyridyl
protons), 6.63 (m, 2H, pyridyl protons), 5.93 (d, J=4.5
Hz, 1H, H-1), 4.59 (d, J=4.5 Hz, 1H, H-2), 4.15 (m,
2H, H-3 and H-4), 4.00 (m, 2H, H-1), 3.89 (m, 1H,
H-2%), 3.70 (m, 3H, H-5 and H-6), 3.58 (m, 4H, H-3% and
piperazin ring protons), 2.67 (bs, OH), 2.55 and 2.38
(each m, each 2H, piperazin ring protons), 1.50 and 1.32
(each s, each 3H, ꢀC(CH3)2); Anal. C21H33N3O7 (C, H,
N).
Colourless oil, yield 75%; [h]D (−) 20.12 (c, 0.016,
CHCl3); FABMS; m/z: 440 [M+1]+; FTIR: 3392 (ꢀOH),
3016, 2848 (CH3 and CH2 stretching); 1H-NMR
(CDCl3): l=8.20 (d, J=5 Hz, 1H, pyridyl proton),
7.50 (dd, J=8 Hz, J=1.5 Hz, 1H, pyridyl proton), 6.80
(m, 2H, pyridyl proton), 5.94 (d, J=4.5 Hz, 1H, H-1),
4.56 (d, J=4.5 Hz, 1H, H-2), 4.18 (m, 1H, H-4), 4.12
(dd, J=12 Hz, J=4 Hz, 1H, H-3), 4.05–3.99 (m, 3H,
H-5, H-1%), 3.90 (two dd, J=12 Hz, J=4.5 Hz, 1H,
H-2%), 3.85 (dd, J=14 Hz, J=3.5 Hz, 1H, H-2%), 3.72–
3.64 (m, 4H, H-3%, H-6), 2.89–2.84 (m, 2H, piperazin
ring protons), 2.79–2.62 (m, 6H, piperazin ring pro-
tons), 1.50, 1.34 (each s, each 3H, C(CH3)2); Anal.
C21H33N3O7 (C, H, N).
6.1.3.10. (2%R/S)-1,2-O-isopropylidene-3-O-
[3%-{1-(2-pyridyl)-piperazin-4-yl}-2%-hydroxy-
6.1.3.13. (2%S)-1,2-O-isopropylidene-3-O-
[3%-{1-(2-pyridyl)-piperazin-4-yl}-2%-hydroxy-
propan-1%-yl]-h- -allofuranose (24)
D
Colourless oil, yield 60%; [h]D (−) 21.26 (c, 0.02,
CHCl3); EIMS; 439 [M+]; FTIR: 3388 (OH), 2989, 2933,
2893 and 2835 (CH3 and CH2 stretching); 1H-NMR
(CDCl3): l=8.20 (d, J=8 Hz, 1H, pyridyl proton),
7.50 (dd, J=8 Hz, J=4 Hz, 1H, pyridyl proton), 6.66
(m, 2H, pyridyl proton), 5.80 (d, J=4.5 Hz, 1H, H-1),
4.68 (pseudo triplet, J=4.5 Hz, 1H, H-2), 4.38 (m, 1H,
H-4), 4.25 (m, 2H, H-3 and H-5), 4.10 and 3.97 (m, 2H,
H-1%), 3.72 (m, 1H, H-2%), 3.62 (m, 4H, H-3% and H-6),
2.82 and 2.70 (each m, 6H, piperazin ring proton), 2.50
(m, 2H, piperazin ring proton), 1.60 and 1.35 (each s,
each 3H, 2×C(CH3)2); Anal. Found: C, 57.92; H, 7.51;
N, 9.53. Calc. for C21H33N3O7: C, 57.40; H, 7.51; N,
9.56%.
propan-1%-yl-h- -allofuranose (35)
D
Colourless oil, yield 60%; [h]D (−) 19.22 (c, 0.041,
CHCl3); FABMS; m/z: 440 [M+1]+; FTIR: 3396 (ꢀOH),
1
3020, 2925, 2850 (CH3 and CH2 stretching); H-NMR
(CDCl3): l=8.20 (d, J=4.5 Hz, 1H, pyridyl proton),
7.50 (dd, J=8 Hz, J=4.5 Hz, 1H, pyridyl proton), 6.65
(dd, J=5 Hz, J=1.5 Hz, 2H, pyridyl proton), 5.80 (d,
J=4.5 Hz, 1H, H-1%), 4.69 (pseudo triplet, J=4.5 Hz,
1H, H-2), 4.14 (m, 1H, H-4), 3.98 (m, 3H, H-3, H-5 and
H-1%A), 3.74 (m, 4H, H-1%B, H-2% and H-6), 3.60 and
3.55 (m, 2H, H-3%), 2.96, 2.83 and 2.63 (m, 8H, piperazin
ring protons), 1.59, 1.36 (each s, each 3H, 2×C(CH3)2);
Anal. C21H33N3O7 (C, H, N).
6.1.3.11. (2%S)-1,2-O-isopropylidene-3-O-
[3%-[{1-(2-pyridyl)-piperazin-4-yl}]-2%-hydroxy-
6.1.3.14. (2%R)-1,2-O-isopropylidene-3-O-
[3%-{1-(2-pyridyl)-piperazin-4-yl}-2%-hydroxy-
propan-1%-yl-h-
D
-glucofuranose (29)
propan-1%-yl]-h-D-allofuranose (36)
Colourless oil, yield 75%; [h]D (−) 19.21 (c, 0.004,
CHCl3); FABMS; m/z: 440 [M+1]+; FTIR: 3384 (ꢀOH),
2935, 2900 (CH3 and CH2 stretching); 1H-NMR
(CDCl3): l=8.20 (d, J=4.5 Hz, 1H, pyridyl proton),
7.50 (dd, J=10 Hz, J=1.5 Hz, 1H, pyridyl proton),
6.67 (m, 2H, pyridyl proton), 5.94 (d, J=4.5 Hz, 1H,
H-1%), 4.55 (d, J=4.5 Hz, 1H, H-2), 4.15 (m, 1H,H-4),
4.03 (m, 2H, H-3, H-5), 3.89, 3.74 (two dd, J=12 Hz,
J=1.5 Hz, 2H, H-1%), 3.68 (m, 1H, H-2%), 2.80 (m, 2H,
piperazin ring protons), 2.58, 2.40 (m, 6H, piperazin
ring proton), 1.48, 1.32 (each s, each 3H, C(CH3)2);
Anal. C21H33N3O7 (C, H, N).
Colourless oil, yield 58%; [h]D (−) 15.41 (c, 0.018,
CHCl3); FABMS; 440 [M+1]+; FTIR: 3310 (ꢀOH),
3010, 2945, 2889 and 2831 (CH3 and CH2 stretching);
1H-NMR (CDCl3): l=8.20 (d, J=5 Hz, 1H, pyridyl
proton), 7.46 (dd, J=8 Hz, J=4 Hz, 1H, pyridyl
proton), 6.60 (m, 2H, pyridyl proton), 5.80 (d, J=4.5
Hz, 1H, H-1%), 4.67 (pseudo triplet, 1H, H-2), 4.32 (m,
1H, H-4), 4.08–4.00 (m, 4H, H-3, H-5 and H-1%A), 3.87
(m, 1H, H-2%), 3.60–3.42 (m, 4H, H-3%, H-6), 2.78, 2.64
and 2.45 (three m, 8H, piperazin ring protons), 1.48,
1.32 (each s, each 3H, 2×C(CH3)2)); Anal. C24H37N3O7
(C, H, N).

A.R. Khan et al. / European Journal of Medicinal Chemistry 36 (2001) 435–445
445
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Acknowledgements
[6] D.L. Cahall, R. Conklin, in 20th Intersci. Conf. Antimicrobial
Agents Chemother., New Orelans, LA, 22–24 September 1980,
Abstr. 81.
The authors thank Dr D.K. Dixit for fruitful discus-
sions, and the Director of CDRI for his generous help in
carrying out this work. A.R.K. is thankful to CSIR for
financial assistance. Technical assistance provided by
Mr V.K. Maurya is also acknowledged.
[7] Srivastava A.K., Tripathi R.P., Khan A.R., Bhaduri A.P.,
Singh S.N., Chatterjee R.K., Helminthologia 32 (1995) 25–29.
[8] Tripathi R.P., Srivastava A.K., Bhatnagar S., Khan A.R.,
Singh V., Bhaduri A.P., in: Soni P.L. (Ed.), Trends in Carbohy-
drate Chemistry, Surya International, Dehradun, 1995, pp.
1–4.
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