Facile synthesis of novel glycosyl carboxamide with sugar in furanose and pyranose form using benzotriazole methodology

Article abstract of DOI:10.2174/157017810790796363

There is an increased demand for significant amounts of carbohydrate based molecules for complete biological, medicinal, and pharmacological investigations where tremendous efforts have been made to develop novel and facile procedure for the synthesis of glycoconjugates and diverse carboxamides. Limitations with the common approaches for amide bond formation, including use of hazardous chemicals, long reaction times, low reaction yields, frequently require strong basic catalysts, strictly anhydrous conditions, harsh reaction conditions, expensive and limited availability of coupling materials, and moreover the less stability of activated acids warrant the search of a simple, short, and high yielding amide bond synthetic methodology. Herein, a facile and high yielding synthesis of novel glycosyl carboxamide with both furanose and pyranose sugar using benzotriazole methodology has been developed under mild conditions.

Full text of DOI:10.2174/157017810790796363

136
Letters in Organic Chemistry, 2010, 7, 136-143
Facile Synthesis of Novel Glycosyl Carboxamide with Sugar in Furanose
and Pyranose form Using Benzotriazole Methodology
Raju R. Kale, Virendra Prasad and Vinod K. Tiwari*
Department of Chemistry, Faculty of Science, Banaras Hindu University, Varanasi-5, India
Received October 06, 2009: Revised November 27, 2009: Accepted December 23, 2009
Abstract: There is an increased demand for significant amounts of carbohydrate based molecules for complete biological,
medicinal, and pharmacological investigations where tremendous efforts have been made to develop novel and facile
procedure for the synthesis of glycoconjugates and diverse carboxamides. Limitations with the common approaches for
amide bond formation, including use of hazardous chemicals, long reaction times, low reaction yields, frequently require
strong basic catalysts, strictly anhydrous conditions, harsh reaction conditions, expensive and limited availability of
coupling materials, and moreover the less stability of activated acids warrant the search of a simple, short, and high
yielding amide bond synthetic methodology. Herein, a facile and high yielding synthesis of novel glycosyl carboxamide
with both furanose and pyranose sugar using benzotriazole methodology has been developed under mild conditions.
Keywords: Acylbenzotriazole, carboxamides, glycoconjugate, amines, benzotriazole.
Amide bond formation, a common basic reaction in
organic synthesis is typically mediated by one of the myriad
of so-called coupling reagents [1-5]. Amide bond represents
the main chemical bonds that link amino acid building
blocks together to give proteins where this functionality
plays a major role in the elaboration and composition of
biological systems. Recently, amide is known for a common
functionality found in numerous drugs in therapeutic areas
including Atorvastatin, the top selling drug worldwide since
2003 which blocks the production of cholesterol [6a],
Lisinopril (a well-known inhibitor of angiotensin converting
enzyme) [6b], Valsartan (blocker of angiotensin-II receptors)
[6c], Diltiazem (calcium channel blocker used in the
treatment of angina or hypertension) [6d] and is indeed
present in hundreds of biologically active molecules (Fig. 1).
pharmaceutical potential for the development of novel
mechanism based drug [8]. Very recently, Pandey et al.
reported the solution-phase synthesis and in silico screening
of a combinatorial library of carbapeptides using glycosyl
amino acid scaffolds, where reverse docking calculations
involving over 841 protein drug targets have identified two
potential targets for these carboxamides which may open a
new paradigm basis towards development of second-
generation antimicrobial agents [9].
A common approach for amide bond formation usually
involves in the treatment of activated derivatives of acids,
especially halides, acid anhydrides, or esters with
corresponding amines, where the reaction of ammonia or
amines with acyl halides is known to be highly exothermic.
Reactions of carboxylic acids with ammonia or amines are
seldom of preparative value [10]. Acylations of ammonia,
primary or secondary amines using esters frequently requires
strong basic catalysts and/or high pressure [11]. Synthesis of
amides or esters through in situ activation of acids using
carbodiimide (EDC or DCC or DIC/HOBt) [12], under
Mitsunobu conditions (PPh3/DEAD) [13], several coupling
reagents, including HOSu, HONB, HODhbt, CBMIT,
DTPC, DPP, HODT, TOTT, TODT, TOTU, CPMA,
phosphorous based reagents or CDI mediated coupling
reaction are well documented in the literature [1-5]. For mild
synthesis of amides, enzymatic catalysis is also investigated
where in few cases the method has been introduced as useful
alternative as compared to traditional one [14]. Medicinal
chemists often generate a library of amides using broad
range of substrates with varying reactivities, such as
aromatic, aliphatic, heterocyclic, chiral, bulky, sugar based
amines etc. and therefore a coupling reagent is needed to be
cope with maximum portfolio of reactivity. Although the
above described common protocols have successfully
employed for the amide bond formation, yet most of them
have been associated with one or more limitations, including
use of hazardous chemicals, long reaction times, low
Carbohydrate represents an attractive source of readily
available, stereochemically defined, highly functionalized
moiety, which offers a valuable scaffold in drug discovery
research. There is an increased demand for significant
amounts of carbohydrate based molecules for complete
biological, medicinal, and pharmacological investigations
where tremendous efforts have been made to develop novel
and facile procedure for the synthesis of diverse
carboxamides and glycoconjugates [7]. In general,
glycosylations of peptide not only affect their
pharmacological parameters e.g. the rate of circulation,
solubility, immunogenicity etc, but also influence the wide
range of biological functions through modulating their
folding, stability and serving as a recognition signal in cell-
cell, cell matrix, cell-pathogen interactions and biomarkers in
intra- & intercellular communication events. Natural and
unnatural glycosylated peptide are known for their important
role in these processes and underlies
a significant
*Address correspondence to this author at the Department of Chemistry,
Faculty of Science, Banaras Hindu University, Varanasi-5, India; Fax: 91-
542-2368174; E-mail: tiwari_chem@yahoo.co.in
1570-1786/10 $55.00+.00
© 2010 Bentham Science Publishers Ltd.

Facile Synthesis of Novel Glycosyl Carboxamide
Letters in Organic Chemistry, 2010, Vol. 7, No. 2 137
HO
O
COOH
COOH
H3CO
N
O
OH
NH2
N
COOH
O
H
O
HOOC
H
F
NH
H
O
N
S
N
N
N
H
N
N
HN
O
N
Diltiazem
Valsartan
Lisinopril
Aorvastatin
Fig. (1). Amide group containing some representative known drugs.
reaction yields, harsh reaction conditions as few methods are
highly exothermic and/or high pressure, frequently require
strong basic catalysts, required strictly anhydrous conditions,
expensive and limited availability of coupling materials, and
moreover the less stability of activated acids obtained
through in situ activation of acids warrants to search a
simple, short, and high yielding amide bond methodology.
two steps from D-galactose via well known isopropylidene
protection followed by oxidation in basic condition, on one-
pot reaction with thionyl chloride and subsequent in situ
coupling with benzotriazole in anhydrous dichloromethane
gave a good yield of 1,2;3,4-di-O-isopropylidene-ꢀ-D-
galactopyranuronosyl benzotriazole (2a, 94%) as a white
crystalline solid. The chiral acylbenzotriazole 2a was
purified by column chromatography (SiO2, n-hexane-EtOAc)
and characterized by spectral data and elemental analysis.
Treatment of compound 2a with cyclopropyl amine in
anhydrous dichloromethane afforded N-cyclopropyl-1,2;3,4-
di-O-isopropylidene-ꢀ-D-galactopyranuronamide (4a, 90%)
(Scheme 1). The crude product was washed with Na2CO3
solution (3-4 times) to remove benzotraizole from the
reaction mixture. Thus, the obtained compound was found
RESULTS AND DISCUSSION
Our ongoing research on benzotriazole mediated novel
synthetic methodology [15] and experience in the
development of carbohydrate based new chemical entities
(NCE’s) against some frontline diseases [9, 16] encouraged
us to search a simple, facile and high yielding alternate
protocol for the synthesis of a variety of carboxamides using
N-acylbenzotriazole as the stable alternatives of
corresponding acid chlorides under mild reaction condition.
Because of sufficient stability associated with benzotriazole
containing intermediates, the chemistry offers an effective
replacement of the corresponding acid chlorides which often
found to be unstable and thus benzotriazole methodology has
received great interest in organic synthesis, including
peptides, heterocycles and other biologically active class of
compounds [17]. Katritzky group has enormously explored
the N-acylbenzotriazole as a stable intermediate in various
1
almost pure on TLC and was also evidenced from the H
NMR spectrum of crude product 4a (Fig. 2). Similar reaction
of 2a with furfuryl amine gave desired carboxamide 4b in
92% yield.
In a similar fashion, acylbenzotriazole (2b and 2c) with
sugar in furanose form was obtained in good yield starting
from readily available D-glucose in six steps. 1,2;5,6-Di-O-
isopropylidene glucofuranose on sequential reactions, inclu-
ding 3-O-alkylation, selective isopyopylidene deprotection
and NaIO4 oxidation afforded good yield of 3-O-benzyl (or
ethyl)-1,2-O-isopropylidene-5-uloses, which was separately
subjected to the treatment with freshly prepared
AgNO3/KOH, afforded 3-O-benzyl (or ethyl)-1,2-O-
isopropylidene-ꢀ-D-xylo-furanuronic acid (1b, 1c). Further
reaction with thionyl chloride followed by in situ coupling
with benzotriazole furnished white crystalline solid of 3-O-
benzyl (or ethyl)-1,2-O-isopropylidene-ꢀ-D-xylo-furanur-
onyl benzotriazole (2b and 2c respectively). The one-pot
benzotriazole coupling reaction proceeded smoothly
(monitored on TLC) to afford the acylbenzotriazole (2a and
2b) in an excellent yield (90 and 92% yield respectively).
Pure acylbenzotriazole (2a and 2b) on coupling with variety
of amines (3a-o), including cyclopropyl amine, cyclohexyl
amine, n-octyl amine, n-hexadecylamine, furfuryl amine,
phenylethylamine, aniline, m-chloro aniline, m-nitro aniline,
piperidine, morpholine, N-methyl piperazine, N-phenyl
piperazine, 4-phenyl-thiazol-2-ylamine, and 5-phenyl-
synthetic
methods
[18],
where
appropriate
N-
acylbenzotriazoles have successfully affected formylation
[19], triflouacylation [20], regiospecific C-acylation of
pyrrole or indoles [21] and have also been found to be useful
for the synthesis of oxamides [22], 1,3-diketones [23],
polycyclic heteroaromatics [24] and Weinreb amides [25].
Despite the many efficient methods and coupling reagents
available for the amide bond formation, a simple, convenient
and high yielding novel protocol is yet to be developed
through intensive research. In a relevant context our main
objective was to use the benzotriazole as a coupling reagent
for the preparation of amide linkage by activating the
carboxylic acids directly to obtain the carbohydrate based
novel amide derivatives with both furanose as well as
pyranose sugars.
The synthetic strategy begins with commercially
available D-(+) galactose and D- glucose. Thus, 1,2;3,4-di-
O-isopropylidene-ꢀ-D-galacturonic acid (1a), obtained in

138 Letters in Organic Chemistry, 2010, Vol. 7, No. 2
Kale et al.
O
O
O
R3
O
O
HNR3R4 (3), CH2Cl2 / Et3N
O
SOCl2 / BtH, RT
R1
HO
N
N
N
R1
R1
R2
R2
2(a-c)
( )n
1(a-c)
N
( )n
R4
R2
4(a-q)
( )n
n= 1, 2; R1, R2 = Sugar protection
Entry
RCOBt (2a-c)
Amine (3a-o)
Glycosyl Amide (4a-q)
Time (hrs)
Yield (%) M. P. (°C)
O
O
Bt
N
H
O
O
O
O
1
NH2
3
90
180- 81
O
O
O
O
O
O
2a
O
HN
O
O
O
2
2a
3
92
122- 123
O
NH2
O
O
O
O
OEt
O
O
OEt
O
O
Bt
O
N
3
4
NH2
3
3
88
95
--
H
O
O
2b
O
OBn
O
O
OBn
O
O
Bt
O
N
H
NH2
172-173
O
O
2c
O
OBn
O
O
N
5
6
7
8
2c
3
3
3
3
94
93
93
96
165-166
155-156
137-138
149-150
H
NH2
O
O
O
O
O
O
OBn
O
*
NH2
O
N
H
2c
2c
2c
6
6
OBn
O
*
O
NH2
N
H
14
14
OBn
O
Ph
Ph
O
N
NH2
H
O

Facile Synthesis of Novel Glycosyl Carboxamide
Letters in Organic Chemistry, 2010, Vol. 7, No. 2 139
(Scheme 1). Contd…..
Entry
RCOBt (2a-c)
Amine (3a-o)
Glycosyl Amide (4a-q)
Time (hrs)
Yield (%) M. P. (°C)
O
OBn
O
O
O
O
N
9
2c
3
90
93
169-170
145-146
H
NH2
O
O
O
Cl
Cl
O
OBn
O
10
11
2c
2c
4
N
NH2
H
NO2
O2N
O
OBn
O
3.5
91
150-151
N
H
NH2
O
OBn
O
O
N
12
13
14
15
2c
2c
2c
2c
HN
3
3
3
3
91
90
92
92
--
--
--
--
O
O
OBn
O
O
N
HN
O
O
O
O
OBn
O
O
N
Me
N
NH
NH
N
Me
O
O
OBn
O
O
N
Ph
N
N
Ph
O
OBn
O
N
O
16
17
2c
2c
3
3
94
90
168-169
160-162
N
S
O
N
H
H2N
S
O
N
N
O
OBn
O
N
N
S
O
N
H
H2N
S
O
Scheme 1. Synthesis of glycosyl carboxamide in furanose and pyranose sugar.
1
[1,3,4]thiadiazol-2-ylamine in the presence of triethyl amine
at room temperature formed the desired corboxamides (4c-q)
in high yields (Scheme 1). All the developed carboxamides
(4a-q) were purified by SiO2 column chromatography and
characterized by using spectroscopic technique (IR, MS, H
NMR, and 13C NMR) and CHN elemental analysis.
We tried different solvents eg. toluene, dichloromethane,
chloroform, DMF, acetonitrile, where dichloromethane was

140 Letters in Organic Chemistry, 2010, Vol. 7, No. 2
Kale et al.
3-O-benzyl-1,2-O-isopropylidene-ꢀ-D-xylo-furanuronyl
benzotriazole (2c)
SOCl2 (2.98 mmol) was added drop-wise to the stirring
solution of 3-O-benzyl-1,2-O-isopropylidene-ꢀ-D-xylo-
furanuronic acid (1c, 2.38 mmol) and benzotriazole (7.74
mmol) in anhydrous CH2Cl2 (15 ml). A white solid
precipitated within 5 min., the reaction mixture was further
stirred for 2 hrs, white solid was filtered off and solvent was
removed under vacuum. Thus the crude product obtained
was subjected to column chromatography (20% EtOAc in n-
hexane) to give white solid. Yield: 92 %; m.p. = 160-162 °C;
IR (KBr): ꢀmax cm-1 1677.6, 1269.5, 2923.9; MS: m/z = 418
(M+Na); 1H NMR (CDCl3, 300 MHz): ꢁ 1.40 and 1.57 [each
s, each 3H, 2 x >C(CH3)], 4.16 (d, J = 12 Hz, 1H, OCHAPh ),
4.52 (d, J = 12 Hz, 1H, OCHBPh ), 4.72 (d, J = 3.3 Hz, 1H,
H-3), 4.78 (d, J = 3.6 Hz, 1H, H-2), 6.06 (d, J = 3.6 Hz, 1H,
H-1), 6.26 (d, J = 2.7 Hz, 1H, H-4), 6.71–7.02 (m, 5H, Ar-
H), 7.55 (t, J = 7.5 Hz, 1H), 7.69 (t, J = 7.8 Hz, 1H), 8.08 (d,
J = 8.1 Hz, 1H), 8.29 (d, J = 8.4 Hz, 1H); 13C NMR (CDCl3,
75 MHz): ꢁ 26.47, 27.20, 71.95, 81.19, 82.34, 83.14, 105.90,
112.95, 114.23, 120.15, 125.80, 126.39, 127.48, 127.78,
128.02, 128.46, 130.67, 130.90, 135.91, 145.70, and 165.82
ppm.
Fig. (2). 1H NMR of crude compound 4a (washed with Na2CO3
solution to remove BtH).
found to be the most suited one. The method is short, high
yielding, feasible at room temperature, simple in handling
and easy to remove cleaved benzotriazole successfully from
reaction mixture through washing with Na2CO3 solution.
1,2;3,4-di-O-isopropylidene-ꢀ-D-galactopyranuronosyl
benzotriazole (2a, prepared in good yield from compound 1a
1
using similar procedure). Yield: 94 %, m.p. 174-175 °C, H
NMR (CDCl3, 300 MHz): ꢁ 1.26, 1.39, 1.50, and 1.62 [each
s, each 3H, 4 x >C(CH3)2], 4.52 (dd, J = 4.8 Hz and 2.7 Hz,
1H), 4.76 (d, J = 7.5 Hz, 1H), 5.06 (d, J = 7.2 Hz, 1H), 5.79
(d, J = 6.3 Hz, 1H), 5.83 (d, J = 5.4 Hz, 1H), 7.54 (t, J = 7.8
Hz, 1H), 7.67 (t, J = 7.8 Hz, 1H), 8.13 (d, J = 8.7 Hz, 1H),
8.35 (d, J = 8.1 Hz, 1H); 13C NMR (CDCl3, 75 MHz): ꢁ
24.78, 24.90, 25.88, 26.05, 70.06, 70.29, 71.30, 72.61, 96.65,
109.52, 110.77, 114.62, 120.14, 126.47, 130.70, 131.19,
145.82, and 165.78 ppm.
CONCLUSION
In conclusion, a simple and efficient method for the
preparation of secondary and tertiary glycosyl amides has
been developed by the treatment of sugar based N-
acylbenzotriazoles with primary and secondary amines,
respectively. Advantages of this procedure are as follows (a)
mild reaction condition with activation of carboxylic acid
with benzotriazole; (b) the use of acyl chlorides is avoided,
(c) N-acylbenzotriazoles can be recrystallized and stored for
a longer period of time as they are sufficiently stable, and (d)
workup procedure is very simple; (e) secondary and tertiary
amides were generally obtained in good to excellent yields.
The method is useful for the high yielding access of already
known carboxamides in a simple way and could further be
extended for the development of carbohydrate based novel
scaffolds and natural and/or unnatural glycopeptides.
General Experimental Procedure for Sugar Based
Carboxamides (4a-q)
To the stirring solution of amine (3, 1.33 mmol) and Et3N
(2.53 mmol) in anhydrous dichloromethane (15ml), 1,2;3,4-
di-O-isopropylidene-ꢀ-D-galactopyranuronosyl benzotria-
zole (2a, 1.26 mmol) or compound 2b (1.26 mmol) was
added slowly and reaction mixture was stirred for 3-4 hrs at
room temperature. Progress of reaction was monitored
through TLC (20% EtOAc in n-hexane). On completion of
reaction, the reaction mixture was diluted with
dichloromethane (20 ml), extracted, washed successively
with water (2ꢂ10 ml) and 10% Na2CO3 (3x10 ml), dried over
anhydrous Na2SO4 and concentrated under vacuum. Crude
product thus obtained on column chromatography (SiO2)
furnished carboxamide (4) in good yields (88-96%).
EXPERIMENTAL
General
Thin layer chromatography (TLC) was performed by
using silica gel 60 F-254 plates with I2 vapors as detecting
agents followed by spraying with ethanolic H2SO4 solution
and with Draggendorff reagent for carboxamides (4a-q).
Solvents were evaporated under reduced pressure at
0
N-Cyclopropyl-1,2;3,4-di-O-isopropylidene-ꢀ-D-galacto-
pyranuronamide (4a)
temperature <55 C. Silica gel (230-400 mesh) was used for
column chromatography. TMS (0.0 ppm) was used as an
internal standard in H NMR and CDCl3 (77.0 ppm) in 13C
1
Yield 90 %, Colourless solid, m.p.= 180-181 °C; IR
(KBr): ꢀmax cm-1 1678.1, 2924.9; MS: m/z = ; 1H NMR
(CDCl3, 300 MHz): ꢁ 0.54 and 0.78 (each m, each 2H,
Cyclopropyl CH2), 1.32, 1.39, 1.51, and 1.58 [each s, each
3H, 2 ꢂ >C(CH3)2], 2.77 (m, 1H, Cyclopropyl CH), 4.25 and
4.34 (each s, each 1H), 4.61 (d, J = 7.8 Hz, 1H), 4.66 (d, J =
NMR. Infrared spectra were recorded as KBr pelletes by a
Perkin Elemer RX-1 spectrometer. Melting points were
determined on a Buchi 535 melting point apparatus.
Elemental analyses were performed on a Perkin-Elmer 2400
C, H, N analyzer and values were found to be within ±0.5%
of the calculated values.

Facile Synthesis of Novel Glycosyl Carboxamide
Letters in Organic Chemistry, 2010, Vol. 7, No. 2 141
9.6 Hz, 1H), 5.54 (d, J = 4.8 Hz, 1H, H-1), 6.53 (bs, 1H, D2O
exchangeable NH); 13C NMR (CDCl3, 75 MHz): ꢀ 6.26,
6.43, 22.01, 24.18, 24.81, 25.86, 25.96, 68.72, 70.36, 70.75,
71.55, 96.19, 109.22, 109.34, and 169.67 ppm.
N-n-hexadecyl-O-benzyl-1,2-O-isopropylidene-ꢀ-D-xylo-
furanuronamide (4g)
Yield 93 %, m.p. = 137-138 °C; IR (KBr): ꢁmax cm-1
1
1671.3, 2918.4; MS: m/z = 554 (M+Na); H NMR (CDCl3,
N-Furfuryl-1,2;3,4-di-O-isopropylidene-ꢀ-D-galacto-
300 MHz): ꢀ 0.87 (t, J = 6.6 Hz, 3H), 1.25 (m, 28H), 1.31 (s,
3H, -CH3), 1.47 (s, 3H, -CH3), 3.29 (dt, J = 6 Hz and 6.6 Hz,
2H, CH2) 4.34 (d, J = 2.7 Hz, 1H, H-3), 4.56 (d, J = 3.3 Hz,
1H, H-2), 4.58 (d, J = 12.0 Hz, 1H, OCHAPh), 4.60 (d, J =
12.0 Hz, 1H, OCHBPh), 4.74 (d, J = 2.7 Hz, 1H, H-4), 5.99
(d, J = 3.3 Hz, 1H, H-1), 6.59 (bs, 1H, NH), 7.29 (m, 5H, Ar-
H); 13C NMR (DMSO-D6, 75 MHz): ꢀ 14.10, 22.65, 26.34,
26.83, 26.92, 29.25, 29.33, 29.489, 29.57, 29.66, 31.88,
39.03, 73.17, 81.09, 82.38, 82.58, 105.40, 112.63, 127.69,
127.88, 128.36, 137.25, and 167.41 ppm.
pyranuronamide (4b)
Yield 92 %, Colourless solid, m.p.= 122-123 °C, IR
(KBr): ꢁmax cm-1 1676.5, 2926.8; MS: m/z = 376 (M+Na); 1H
NMR (CDCl3, 300 MHz): ꢀ 1.33, 1.38 [ each s (two s
merged), each 3H, 4 x >C(CH3)2], 12H), 4.33 (t, J = 7.8 Hz,
1H, C4-H), 4.454 (d, J = 5.1 Hz, 1H, C3-H), 4.52 (d, J = 6
Hz, 1H, C2-H), 4.76 (d, J = 5.1 Hz, 1H, C5-H), 5.56 (d, J =
4.5 Hz, 1H, C1-H), 6.25-6.30 (d, J = 16.2 Hz, 2H, furfuryl),
6.84 (bs, 1H, NH), 7.34 (d, 1H, J = 7.2 Hz, Furfuryl); 13C
NMR (CDCl3, 75 MHz): ꢀ 24.19, 24.78, 25.80, 25.93, 35.93,
68.82, 70.39, 70.72, 71.56, 96.21, 107.26, 109.22, 109.42,
110.31, 142.07, 151.06, and 168.18 ppm.
N-Phenylethyl-3-O-benzyl-1,2-O-isopropylidene-ꢀ-D-xylo-
furanuronamide (4h)
Yield 96 %, m.p. = 149-150 °C; IR (KBr): ꢁmax cm-1
1
N-Cyclopropyl-3-O-benzyl-1,2-O-isopropylidene-ꢀ-D-xylo-
furanuronamide (4d)
1672.9, 2932.5; MS: m/z = 398 (M+H); H NMR (CDCl3,
300 MHz): ꢀ 1.31 and 1.47 [each s, each 3H, 2 x >C(CH3)],
2.76 (t, J = 6.6, 2H, CH2), 3.54 (m, 2H), 4.35 (d, J = 3.3 Hz,
1H, H-3), 4.56 (d, J = 10.8 Hz, 1H, OCHAPh), 4.58 (d, J =
10.8 Hz, 1H, OCHBPh), 4.60 (d, J = 3.6 Hz, 1H, H-2), 4.74 (
d, J = 3.0 Hz, 1H, H-4), 5.95 (d, J = 3.6 Hz, 1H, H-1), 6.61
(bs, 1H, NH), 7.14-7.29 (m, 10H, Ar-H); 13C NMR (CDCl3,
75 MHz): ꢀ 26.33, 26.93, 35.81, 40.15, 73.19, 81.11, 82.49,
82.51, 105.45, 112.64, 126.41, 127.76, 127.86, 127.95,
128.40, 128.51, 128.62, 128.69, 137.25, 138.68, and 167.56
ppm.
Yield: 95%; m.p.= 172-173 °C; IR (KBr): ꢁmax cm-1
1
1673.6, 2921.1; MS: m/z = 356 (M+Na); H NMR (CDCl3,
300 MHz): ꢀ 0.51 and 0.79 (each m, each 2H, Cyclopropyl
CH2), 1.19 and 1.46 [each s, each 3H, 2 x >C(CH3)2], 2.74
(m, 1H, cyclopropyl CH), 4.35 (d, J = 3.0 Hz, 1H, H-3), 4.57
(two d merged, J = 12.0 Hz, 1H, OCHAPh and J = 3.6 Hz
merged, 1H, H-2), 4.61 (d, J = 12.0 Hz, 1H, OCHBPh),), 4.71
(d, J = 3.3 Hz, 1H, H-4), 5.96 (d, J = 3.3 Hz, 1H, H-1), 6.63
(bs, 1H, NH), 7.31 (m, 5H, Ar-H); 13C NMR (CDCl3, 75
MHz): ꢀ 6.32, 6.38, 22.12, 26.26, 26.86, 73.04, 80.94, 82.29,
82.41, 105.44, 112.75, 114.82, 126.09, 127.87, 128.29,
136.95, 138.39, and 169.86 ppm.
N-Phenyl-O-benzyl-1,2-O-isopropylidene-ꢀ-D-xylo-furan-
uronamide (4i)
Yield 90 %, m.p. = 169-170 °C; IR (KBr): ꢁmax cm-1
N-Cyclohexyl-3-O-benzyl-1,2-O-isopropylidene-ꢀ-D-xylo-
furanuronamide (4e)
1
1668.7, 2930.9; H NMR (CDCl3, 300 MHz): ꢀ 1.34 and
1.51 [each s, each 3H, 2 x >C(CH3)2], 4.42 (d, J = 2.7 Hz,
1H, H-3), 4.56 (d, J = 3.3 Hz, 1H, H-2), 4.60 (d, J = 12.0 Hz,
1H, OCHAPh), 4.62 (d, J = 12.0 Hz, 1H, OCHBPh), 4.85 (d, J
= 3.0 Hz, 1H, H-4), 6.08 (d, J = 3.3 Hz, 1H, H-1), 7.14-7.58
(m, 10H, Ar-H), 8.28 (bs, 1H, NH); 13C NMR (CDCl3, 75
MHz): ꢀ 26.38, 27.01, 73.39, 81.35, 82.59, 82.62, 105.69,
112.95, 119.99, 124.59, 127.80, 127.97, 128.39, 128.98,
136.98, 137.02, and 162.83 ppm.
Yield: 94 %; m.p.= 165-166 °C; IR (KBr): ꢁmax cm-1
1
1677.5, 2943.3; MS: m/z = 376 (M+Na); H NMR (CDCl3,
300 MHz): ꢀ 1.14-1.87 [m, 16H, Cyclohexyl CH2 and 2 x
>C(CH3)2 merged], 3.81 (m, 1H), 4.34 (d, J = 3.0 MHz, 1H,
H-3), 4.58 (d, J = 8.1 Hz, 1H, OCHAPh), 4.63-4.61 (two d
merged, J = 12.0 Hz, 1H, OCHBPh and J = 3.3 Hz, 1H, H-2),
4.71 (d, J = 2.7 Hz, 1H, H-4), 5.99 (d, J = 3.3 Hz, 1H, H-1),
6.48 (bs, 1H, NH); 13C NMR (CDCl3, 75 MHz): ꢀ 24.72,
24.76, 25.44, 26.35, 26.92, 32.77, 32.99, 47.79, 73.16, 81.02,
82.41, 82.60, 105.39, 112.63, 127.71, 127.85, 128.31,
137.28, and 166.51 ppm.
N-m-Chlorophenyl-O-benzyl-1,2-O-isopropylidene-ꢀ-D-
xylo-furanuronamide (4j)
Yield 93 %, m.p. = 145-146 °C; IR (KBr): ꢁmax cm-1
1674.4, 1271.5, 2924.9; 1H NMR (CDCl3, 300 MHz): ꢀ 1.26
and 1.51 [each s, each 3H, 2 x >C(CH3)2], 4.35 (d, J = 3.0
Hz, 1H, H-3), 4.57 (d, J = 3.6 Hz, 1H, H-2), 4.57 (d, J = 11.1
Hz, 1H, OCHAPh), 4.60 (d, J = 11.7 Hz, 1H, O-CHBPh), 4.72
(d, J = 2.7 Hz, 1H, H-4), 5.9 (d, J = 3.3 Hz, 1H, H-1), 8.28
(bs, 1H, NH), 7.22-7.56 (m, 9H, Ar-H); 13C NMR (CDCl3,
75 MHz): ꢀ 26.39, 27.02, 73.41, 81.37, 82.62, 82.64, 105.71,
112.96, 120.01, 124.60, 127.67, 127.81, 127.97, 128.39,
128.99, 136.99, 137.03, and 165.85 ppm.
N-n-octyl-3-O-benzyl-1,2-O-isopropylidene-ꢀ-D-xylo-
furanuronamide (4f)
Yield 93 %, m.p.= 155-156 °C; IR (KBr): ꢁmax cm-1
1
1679.3, 2912.1; H NMR (CDCl3, 300 MHz): ꢀ 0.85 (d, J =
6.6 Hz, 3H, CH3), 1.24 (m, 12H, aliphatic), 1.31 (s, 3H, -CH3
), 1.47 (s, 3H, -CH3), 3.29 (t, J = 6.6 Hz, 2H, CH2-NH), 4.34
(d, J = 3.0 Hz, 1H, H-3), 4.57 (d, J = 3.6 Hz, 1H, H-2), 4.57
(d, J = 11.7 Hz, 1H, OCHAPh), 4.62 (d, J = 11.7 Hz, 1H,
OCHBPh), 4.74 (d,J = 3.0 Hz, 1H, H-4), 5.98 (d, J = 3.6 Hz,
1H, H-1), 6.58 (bs, 1H, NH), 7.30 (m, 5H, Ar-H); 13C NMR
(CDCl3, 75 MHz): ꢀ 14.05, 22.59, 26.35, 26.82, 26.93,
29.12, 29.19, 29.49, 31.76, 39.03, 73.18, 81.11, 82.41, 82.61,
105.42, 112.63, 127.68, 127.88, 128.36, 137.28, and 167.39
ppm.
N-m-Nitrophenyl-O-benzyl-1,2-O-isopropylidene-ꢀ-D-xylo-
furanuronamide (4k)
Yield 91 %, m.p. = 150-151 °C; IR (KBr): ꢁmax cm-1
1675.2, 1271.5, 2924.9; 1H NMR (CDCl3, 300 MHz): ꢀ 1.25

142 Letters in Organic Chemistry, 2010, Vol. 7, No. 2
Kale et al.
120.37, 121.14, 125.38, 127.65, 128.12, 128.17, 128.49,
129.11, 129.23, 136.70, and 165.66 ppm.
and 1.51 [each s, each 3H, 2 x >C(CH3)2], 4.43 (d, J = 2.7
Hz, 1H, H-3), 4.57 (d, J = 3.3 Hz, 1H, H-2), 4.59 (d, J = 11.7
Hz, 1H, OCHAPh), 4.64 (d, J = 11.7 Hz, 1H, OCHBPh), 4.85
(d, J = 3.0 Hz, 1H, H-4), 6.07 (d, J = 3.0 Hz, 1H, H-1), 7.11-
7.57 (m, 9H, Ar-H), 8.28 (bs, 1H, NH); 13C NMR (CDCl3,
75 MHz): ꢀ 26.38, 27.86, 73.40, 81.39, 82.71, 82.86, 105.91,
112.89, 120.01, 124.60, 124.97, 126.67, 127.67, 127.81,
127.97, 128.39, 128.99, 136.99, 137.03, and 165.85 ppm.
N-2-(4-Phenyl-thiazol-2-yl)-3-O-benzyl-1,2-O-isopropylid-
ene-ꢀ-D-xylo-furanuronamide (4p)
Yield: 94 %, m.p. = 168-169 °C; IR (KBr): ꢁmax cm-1
1
1676.6, 2945.1; H NMR (CDCl3, 300 MHz): ꢀ 1.39 and
1.60 [each s, each 3H, 2 x >C(CH3)2], 4.42 (d, J = 3.0 Hz,
1H, H-3), 4.56 (d J = 12.0 Hz, 1H, OCHAPh), 4.58 (d J =
12.0 Hz, 1H, OCHBPh), 4.63 (d, J = 2.7 Hz, 1H, H-4), 4.96
(d, J = 3.3 Hz, 1H, H-2), 6.10 (d, J = 3.0 Hz, 1H, H-1),
7.172-7.843 (m, 11H, Aromatic-H), 9.71 (bs, 1H, NH); 13C
3-O-Benzyl-1,2-O-isopropylidene aldotetrose-4-[piperidin-
1’-yl]-methanone (4l)
Yield 91 %, IR (KBr): ꢁmax cm-1 1673.8, 1271.5, 2924.9;
MS: m/z = 384 (M+Na); 1H NMR (CDCl3, 300 MHz): ꢀ1.13
(m, J = 10.5 Hz, 2H) 1.31 and 1.47 [(each s, each 3H, 2 x
>C(CH3)2], 1.58 (m, 6H), 1.78 (m, J = 14.4 Hz, 2H), 4.35 (d,
J = 3.0 Hz, 1H, H-3), 4.57 (d, J = 3.6 Hz, 1H, H-2), 4.58 (d,
J = 11.1 Hz, 1H, OCHAPh), 4.60 (d, J = 11.1 Hz, 1H,
OCHBPh), 4.71 (d, J = 2.7 Hz, 1H, H-4), 5.98 (d, J = 3.6 Hz,
1H, H-1), 7.31 (m, 5H, Ar-H); 13C NMR (CDCl3, 75 MHz):
ꢀ 24.67, 25.39, 26.33, 26.92, 32.73, 32.92, 45.71, 47.97,
73.11, 81.01, 82.41, 82.50, 105.42, 112.70, 115.02, 125.50,
127.69, 127.88, 128.31, 137.17, 139.17, and 166.88 ppm.
1
NMR (CDCl3, 75 MHz): H NMR (CDCl3, 75 MHz): ꢀ
26.35, 27.05, 73.14, 80.95, 82.41, 82.58, 105.94, 107.75,
113.09, 126.04, 127.65, 128.00, 128.39, 128.69, 134.27,
136.67, 150.17, 156.31, and 166.11 ppm.
N-(5-Phenyl-[1,34]thiadiazol-2-yl)-3-O-benzyl-1,2-O-iso-
propylidene-ꢀ-D-xylo-furanuronamide (4q)
Yield 90 %, m.p. = 160-162 °C; IR (KBr): ꢁmax cm-1
1
1673.9, 2934.2; H NMR (CDCl3, 300 MHz): ꢀ 1.35 and
1.52 [each s, each 3H, 2 x >C(CH3)2], 4.43 (d, J = 3.3 Hz,
1H, H-3), 4.52 (d, J = 11.7 Hz, 1H, OCHAPh), 4.60 (d, J =
12.0 Hz, 1H, OCHBPh), 4.65 (d, J = 3.3 Hz, 1H, H-2), 5.00
(d, J = 3.3 Hz, 1H, H-4), 6.14 (d, J = 3.3 Hz, 1H, H-1), 7.16-
7.96 (m, 10H, Ar-H); 13C NMR (CDCl3, 75 MHz): ꢀ 26.35,
27.07, 73.06, 80.99, 82.28, 82.60, 106.07, 113.24, 127.04,
127.36, 127.59, 128.12, 128.39, 128.48, 128.96, 129.15,
130.33, 130.73, 136.53, and 166.26 ppm.
3-O-Benzyl-1,2-O-isopropylidene aldotetrose-4-[morpholin-
1’-yl]-methanone (4m)
Yield 90%, IR (KBr): ꢁmax cm-1 1669.2, 2928.8; MS: m/z
1
= 386 (M+Na); H NMR (CDCl3, 300 MHz): 1.34 and 1.49
[each s, each 3H, 2 x >C(CH3)2], 3.46 (m, 4H, morpholine),
3.94 (m, 4H, morpholine), 4.26 (d, J = 3.6 Hz, 1H, H-3),
4.50 (d, J =11.4, Hz, 1H, OCHAPh), 4.65 (d, J = 3.6Hz, 1H,
H-2), 4.68 (d, J = 12.0 Hz, 1H, OCHBPh), 4.99 (d, J = 3.9
Hz, 1H, H-2), 6.10 (d, J = 3.9 Hz, 1H, H-1), 7.32 (m, 5H, Ar-
H); 13C NMR (CDCl3, 75 MHz): ꢀ 26.17, 26.74, 42.76,
45.57, 63.52, 66.47, 72.07, 80.37, 81.63, 82.60, 105.07,
112.24, 125.20, 127.52, 127.71, 128.13, 128.43, 136.68, and
165.69 ppm.
ACKNOWLEDGEMENTS
We thank CISC, BHU and RSIC, CDRI for providing
spectroscopic and analytical data of synthesized compounds
and Dr. R P Tripathi, Scientist F, Central Drug Research
Institute,
Lucknow
for
useful
suggestions
and
encouragements. Funding from UGC, New Delhi and DST,
India is gratefully acknowledged.
3-O-Benzyl-1,2-O-isopropylidene aldotetrose-4-[ N-methyl
piperazin-1-yl]-methanone (4n)
Yield 92%, IR (KBr): ꢁmax cm-1 1675.2, 2912.8; 1H NMR
(CDCl3, 300 MHz): ꢀ 1.27 and 1.42 [each s, each 3H, 2 x
>C(CH3)2], 2.14 (s, 3H, CH3), 2.25 (m, 4H, CH2), 3.50 (m,
4H, CH2), 4.19 (d, J = 3.0 Hz, 1H, H-3), 4.46 (d, J = 11.4
Hz, 1H, OCHAPh), 4.60 (d, J = 11.7 Hz, 1H, OCHBPh), 4.58
(d, J =3.3Hz, 1H, H-2), 4.94 (d, J = 3.0 Hz, 1H, H-4), 6.05
(d, J = 3.3 Hz, 1H, H-1), 7.23 (m, 5H, Ar-H); 13C NMR
(CDCl3, 75 MHz): ꢀ 26.13, 26.69, 41.91, 44.37, 45.28, 54.11,
72.03, 80.22, 81.63, 82.78, 104.98, 112.13, 114.90, 125.01,
127.94, 127.97, 128.33, 136.67, 138.00, and 165.31 ppm.
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