Regioselective facile synthesis of novel isoxazole-linked glycoconjugates

Article abstract of DOI:10.1039/c5ra05905d

A concise and efficacious protocol for the regioselective synthesis of novel 3,5-disubstituted isoxazole-linked glycoconjugates (4, 7 and 9) via a 1,3-dipolar cycloaddition reaction between in situ generated glycosyl-β-nitrile oxide (derived from glycosyl

Full text of DOI:10.1039/c5ra05905d

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Regioselective facile synthesis of novel isoxazole-
linked glycoconjugates†
Cite this: RSC Adv., 2015, 5, 41520
Amrita Mishra, Bhuwan B. Mishra and Vinod K. Tiwari*
A concise and efficacious protocol for the regioselective synthesis of novel 3,5-disubstituted isoxazole-
linked glycoconjugates (4, 7 and 9) via a 1,3-dipolar cycloaddition reaction between in situ generated
glycosyl-b-nitrile oxide (derived from glycosyl-b-nitromethane ester 3 and 6) and various terminal
alkynes bearing sugar, alkyl and aryl substituents (2a–n), has been devised. The formation of nitrile oxide
during the reaction course has been supported by DFT calculations, which gave the optimized structure
of the glycosyl-b-nitrile oxide ester. This one-pot methodology offers a way for utilizing D-glucose
derived nitrile oxide, as a new variant in click chemistry for the synthesis of novel isoxazole-linked
Received 2nd April 2015
Accepted 22nd April 2015
DOI: 10.1039/c5ra05905d
glycoconjugates, paving
a new route for the construction of carbohydrate based scaffolds of
www.rsc.org/advances
multifaceted biological profiles.
2
0
conveniently by ‘click chemistry’ is widely utilized for
conjugating two different entities to form new conjugates.
Introduction
1
9
Isoxazoles constitute an important class of ve-membered In the similar way, the isoxazole ring may also be used as a
heterocycles employed in a wide range of pharmaceutical linker for bioconjugation.
1
,2
3
4
activities including, antitumor, anticancer, antitubercular,
The nitroalkanes are sufficiently stable and can easily be
5
6
21
antibactericidal and antifungicidal. They are important transformed to stable nitrile oxide by various methods. Due to
constituents of various drugs such as COX-2 selective inhibitor the signicant role of carbohydrates in cycloaddition reac-
7
8
22
Valdecoxib (I), anti-rheumatic Leunomide (II), b-lactamase- tions, we envisaged to employ the isoxazole moiety in the
9
10
resistant Cloxacillin (III), androgenic steroid Danazol (IV)
aforementioned sense. Herein, we report a highly regioselective
Fig. 1). The immense bio-activity of the isoxazole ring may be facile synthesis of novel 3,5-disubstituted isoxazole-linked gly-
(
attributed to the facile cleavage of the N–O bond, which leads to coconjugates utilizing [3 + 2] cycloaddition between glycosyl-b-
the formation of other more reactive species. Because of their nitrile oxide ester and various substituted terminal alkynes. The
versatility towards chemical transformations to useful inter- methodology is advantageous as it provides an expeditious and
mediates involved in various natural product syntheses, simple route for the introduction of isoxazole-ring at different
substituted isoxazoles are considered to be important positions of sugar derivatives, with apparent ease. Hence, it may
1
1
synthons.
Considering the pivotal role of carbohydrates in various chemistry for the targeted synthesis of complex isoxazole-linked
prove as a promising strategy in the eld of carbohydrate
1
2
physiological and pathological important processes, there glycoconjugates.
has been a rapid growth of interest in the synthesis of novel
glycoconjugates. In this context ‘bioconjugation’ has
emerged as a simple and fast growing strategy for the
formation of novel conjugates possessing the combined
1
3–15
properties of parent components.
Due to cooperative
action of both the entirely distinct entities in the new
conjugate, they are known to exhibit unusual pharmacolog-
1
6–19
ical activities.
The 1,2,3-triazole linker formed
Department of Chemistry, Centre of Advanced Study, Faculty of Science, Banaras
Hindu University, Varanasi-221005, India. E-mail: Tiwari_chem@yahoo.co.in
1
13
†
Electronic supplementary information (ESI) available: Copies of H and
C
NMR for all the new compounds, single crystal X-ray data of 9a and
computational data has been provided. CCDC 1042109. For ESI and
crystallographic data in CIF or other electronic format see DOI:
Fig. 1 Structure of some isoxazole based drugs.
1
0.1039/c5ra05905d
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Results and discussion
Towards our target molecule isoxazole-linked glycoconjugate 4,
a retrosynthetic analysis was carried out by taking into account
the ready access to alkyne 2, and glycosyl-b-nitromethane ester 3
prepared from corresponding glycosyl-b-olenic ester
Scheme 1).
The synthetic phase of our investigation started from cheap
1
Scheme 2 Synthesis of glycosyl-b-nitromethane ester 3.
(
and readily available D-glucose, which aer processing through isoxazole-linked glycoconjugates in 32–42% yield aer puri-
a number of high-yielding steps, such as isopropylidene cation by column chromatography over silica gel (Scheme 4).
protection, 3-O-benzyl protection, selective 5,6-isopropylidene
deprotection, followed by NaIO oxidation and nally urea, and CO as side product under this condition. More-
HEW-Wittig olenation afforded glycosyl olenic ester over, the Mukaiyama method states for such reactions to occur
The low yield might be due to the formation of furoxane,
21a
4
2
(
1R,2R,3S,4R)-ethyl-[3-O-benzyl-5,6-dideoxy-1,2-O-isopropylidene- via the generation of nitrile oxide, therefore, a substantial
23
a-D-gluco]-heptfuran-5-enuronate 1.
Further reaction of increase in nitrile oxide generated during the course of reaction
compound 1 (1.0 equiv) with nitromethane (2.2 equiv) in pres- would led to an enhanced yield of products. Thus, in order to
ence of K CO (2.73 equiv) at reuxing temperature for 6 h in access the yield further, we investigated the one-pot reaction of
2
3
anhydrous ethanol furnished (1R,2R,3S,4R,5R)-ethyl-[3-O- compound 3 with alkynes 2 using tosyl chloride, 18-crown-6
21c
benzyl-5,6-dideoxy-1,2-O-isopropylidene-5-nitromethyl]-b-L-ido- ether system, and organic/inorganic bases in dry toluene at
ꢀ
heptofuranurnate 3 (ref. 24) in 85% yield (Scheme 2).
80 C to afford 3,5-disubstituted isoxazoles 4 in good yields.
Aer this, we focused our attention towards the generation This methodology also performed well under MW irradiation at
ꢀ
of substituted isoxazole ring at the C-5 position of glycosyl 100 W and 110 C for 15–20 minutes. The short reaction time
olenic ester 1. For this purpose, corresponding nitrile oxide with enhanced yield, simple work-up procedure, and easy
from compound 3 has to be generated which can undergo separation of isoxazoles (soluble in toluene) from solid by-
[
3 + 2] dipolar cycloaddition with diverse alkynes (Scheme 3). products (water soluble) makes this strategy more advanta-
The synthesis of various sugar alkynes is required for this geous (Scheme 5).
step, which was done by utilizing a variety of readily available
We briey investigated the effect of diverse bases, results
monosaccharides (D-glucose, D-mannose, D-ribose, D-galac- summarized in Table 1. The reactions carried out using
tose and D-fructose). All these monosaccharides aer pro- 2.0 equiv of either bicarbonate or carbonate bases demon-
2
5,26
cessing through suitable protection strategies
were strated a greater yield of products (entry 1–3). In case of amine
converted to their respective sugar alcohols, which on NaH bases, low yield of product was obtained (entry 4–9, Table 1).
mediated reaction of propargyl bromide in anhydrous DMF Using K CO as base the reaction was accomplished in signi-
2
3
afforded corresponding O-propargyl ethers 2a–i in good to cantly less time with higher yield of product (entry 2, Table 1).
27,28
excellent yield.
Hence, the treatment of methyl-2,3-O-iso-
Next, the reaction was screened for a variety of organic
propylidene-b-D-ribofuranoside with NaH and propargyl solvents in presence of 18-crown-6 (10 mol%), K CO (2.0 equiv)
2
3
ꢀ
ꢀ
bromide in dry DMF at 0 C for 12 h led to the formation of and TsCl (1.3 equiv) at 80 C. The results clearly illustrated that
methyl-2,3-O-isopropylidene-5-O-propargyl-b-D-ribofuranoside 2a the reaction proceeded best in nonpolar solvents such as
in 84% yield (see, ESI Table S1†).
toluene and benzene and the product was isolated in good yield
The developed alkynes 2a–i were further treated with and short reaction period. When methanol was used as solvent,
glycosyl-b-nitromethane ester 3 in presence of phenyl isocya- the product was obtained only in trace amount even aer stir-
nate and triethylamine in dry toluene at room temperature ring the reaction for 20 hours. The reaction showed poor
21a
under Mukaiyama's condition. The reaction proceeded with performance in tetrahydrofuran, acetone, 1,4-dioxane, diethyl
complete regioselectivity affording the 3,5-disubstituted ether, acetonitrile, dichloromethane and chloroform in terms of
yield and reaction time. The yield could not improve even when
the reaction was stirred for longer durations (see, ESI Table S2†).
The nal optimization study was done by observing the effect
of crown ethers as catalyst for the reaction. The reaction was
screened under the above conditions with 18-crown-6 ether and
monaza-15-crown-5 anellated to methyl-4,6-O-benzylidene-a-D-
Scheme 1 Retrosynthetic analysis.
Scheme 3 Formation of isoxazole ring at C-5 position of compound 1.
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crown catalyst might be catalyzing the reaction by enhancing
the rate of formation of O-tosylnitronate (refer mechanism;
Fig. 6), by weakening the interaction between potassium ion
and glycosyl-b-nitronate moiety and hence facilitating the
attack of tosyl group (Fig. 2).
Thus, under the above optimized reaction conditions, the
model reaction between glycosyl-b-nitromethane ester 3 and
methyl-2,3-O-isopropylidene-5-O-propargyl-b-D-ribofuranoside
Scheme
Mukaiyama's method.
4 Synthesis of isoxazole-linked glycoconjugates by
0 0 0
2
a gave regioselectively the desired 3-[ethyl-(3 -O-benzyl-5 ,6 -
0
0
0
dideoxy -1 ,2 -O-isopropylidene)-b-L-ido-heptofuranurnate-5 -yl]-
5
ide-5 -yl)-isoxazole 4a (70% yield). The regioisomeric nature of
compound 4a was established based on its spectroscopic data.
00 00 00
-(methyl-2 ,3 -O-isopropylidene-5 -O-methyl-b-D-ribofuranos-
0
0
1
In H NMR spectrum of 4a, the appearance of characteristic
singlet at d 6.26 for the proton of the isoxazole ring conrms the
formation of cycloadduct. Other signals such as a multiplet
integrated to ve protons at d 7.33 and the two anomeric
Scheme 5 Synthesis of isoxazole-linked glycoconjugates.
0
0
protons appeared at d 5.91 (J ¼ 3.6 Hz) as a doublet (1-H ), d 4.94
0
as singlet (1-H ) and the remaining signals are in accordance
Table 1 Base optimization using TsCl (1.3 equiv) and 18-crown-6
with the assigned structure of glycoconjugated isoxazole. In the
C NMR, the signals at d 167.9, 163.8 and 104.1 ppm were
(
10 mol%) in anhydrous toluene with alkyne 2a (1.2 equiv) and 3 (1.0
1
3
equiv)
attributed for the carbon of isoxazole ring. The carbonyl carbon
appeared at d 170.9 and the two anomeric carbons appeared at
d 109.1 and 104.7, which lent further support to the assigned
structure of desired cycloadduct. The IR spectrum showed
ꢁ1
absorption bands corresponding to –C–O–N– (1212 cm ) and
ꢁ1
C]N (1608 cm ) functional groups respectively. A molecular
+
a
b
ion peak at m/z 634 [M + H] in mass spectrum nally conrmed
Entry
Base
Time
Yield (%)
the unambiguous structure of compound 4a.
1
2
3
4
5
6
7
8
9
Na
2
CO
3
8
8
8
18
18
18
14
14
18
65
70
64
12
10
10
5
The stereochemical outcome of the regioselective cycload-
dition and the conguration of the synthesized isoxazole ring
can be well predicted on the basis of the conguration of
glycosyl-b-nitromethane ester 3. Based on Felkin-Anh and
Cram's transition state it can be well predicted, that the major
attack of nitromethane at C-5 in olenic ester would take place
from the side of the least bulky group (hydrogen attached to C-4
of the furanose ring, the “Si” diastereoface), and hence the
major reaction product has “R” conguration at C-5, while that
K
2
CO
3
NaHCO
DMAP
DIPEA
DBU
3
DABCO
Et
3
N
20
10
Pyridine
a
b
Reaction time in hours. Isolated yield of product 4a.
23a,b
of the minor one is ‘S’.
conjugate addition of nitromethane on glycosyl-b-olenic ester
gave almost exclusively the b-L-ido isomer having ‘R’ cong-
According to literature precedent, the
1
29,30
24
gluco pyranoside.
The obtained results suggested that uration at C-5. So, the synthesized glycoconjugates with the
1
8-crown-6 ether was better in terms of yield as compared to isoxazole ring at the C-5 carbon, would also be the b-L-ido
uncatalyzed reaction and monaza-15-crown-5 ether. This might isomer i.e. the isoxazole ring would be below the plane with
be due to the cavity size of 18-crown-6 ether which is most respect to glycosyl-b-olenic ester (Scheme 6).
suitable for potassium ions, having a binding constant of
Having established the reaction conditions for the regiose-
0 M in methanol for K ions. In case of 15-crown-5 ethers, lective formation of 3,5-disubstituted isoxazole-linked glyco-
the cavity size is decreased and is not so appropriate for binding conjugate 4a by reaction of O-propargyl ether of sugar 2a and
6
ꢁ1
+
31
1
32
large ions like potassium (Table 2).
glycosyl-b-nitromethane ester 3, we further explored the scope
Finally, the catalyst amount was optimized and it was of other alkynes in this reaction and developed a library of
observed that 10 mol% of 18-crown-6 gave the best yield of isoxazole-linked glycoconjugate 4a–n in good yields (Table 4).
product. However, the yield did not improved with temperature Reaction yield was comparatively better in case of O-propargyl
rise in presence of same amount of catalyst (10 mol%) ethers of sugar (entry 1–9, Table 4). The methodology displays
(entry 2–3, Table 3). No enhancement in yield was noticed on good compatibility with a variety of terminal alkynes having
increasing the mol% of catalyst (entry 4–10, Table 3). Hence, it sugar, alkyl and aryl functionalities.
ꢀ
can be concluded that 10 mol% of 18-crown-6 at 80 C gave the
The methodology was further explored with glycosyl-b-
maximum product yield. These observations suggested that the olenic ester derivative having 3-O-ethyl substituent at the C-3
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Table 2 Catalyst optimization with compound 3 and 2a using TsCl (1.3 equiv) and K
CO
2 3
(2.0 equiv) in dry toluene
a
ꢀ
b
c
Entry
Catalyst
Mol%
Temp. ( C)
Time t
1
(h)/t
2
(min)
Yield (%) y
1
/y
2
1
30
80
8/15
68/70
2
30
100
80
10/20
8/20
42/45
3
No catalyst
—
42/45
a
ꢀ
b
ꢀ
c
Reaction temperature 80–100 C. Time: t
1
¼ reaction under heating, t
2
¼ reaction under MW at 110 C with a stirring rate 200 rpm. Isolated
yield of glycoconjugate 4a: y
1
¼ yield under heating condition, y ¼ yield under MW condition.
2
Table 3 Catalyst (18-crown-6) amount optimization study using TsCl
1.3 molar equiv) and K CO (2.0 molar equiv) in dry toluene with
alkyne 2a (1.2 equiv) and compound 3 (1.0 equiv)
(
2
3
a
ꢀ
b
c
Entry
Mol% Temp ( C) Time t
1
(h)/t
2
(min) Yield (%) y
1
/y
2
1
2
3
4
5
6
7
8
9
5
100
80
100
80
100
80
80
80
100
80
8/15
8/15
8/15
10/20
8/15
8/15
8/15
10/20
10/20
10/20
65/66
69/70
69/70
68/69
67/68
66/66
68/70
65/66
63/65
65/66
10
10
15
20
25
30
35
40
50
1
0
a
b
Mol% of 18-crown-6 catalyst. Reaction time: t
1
¼ reaction under
ꢀ
heating, t
2
4
2
¼ reaction under microwave at 110 C with a stirring rate
c
00 rpm. Isolated yield of product isoxazole-linked glycoconjugates
a: y ¼ yield under microwave
¼ yield under heating condition, y
1
2
condition.
Scheme 6 Formation of L-ido isomer of isoxazole-linked glyco-
conjugate from Si face attack.
Aer successfully synthesizing various novel isoxazole-linked
glycoconjugate 4a–n and 7a–c, we turned our attention towards
the introduction of isoxazole ring at different positions of sugar
derivatives. We know modication of carbohydrates at any
specic position has always remained a great challenge for
synthetic organic chemists. In this continuation, due to
immense biological signicance, carbohydrate moiety when
integrated with any heterocyclic motifs at specic position
Fig.
2 Showing the probable role of 18-crown-6 ether in the
formation of isoxazole-linked glycoconjugates.
33
of furanose ring of D-glucose. The ethyl-[3-O-ethyl-5,6-dideoxy- alters their physiochemical behavior to a great extent. With
,2-O-isopropylidene-5-nitromethyl]-b-L-ido-heptofuranurnate 6 this in view, we have utilized our above established reaction
1
has been prepared from corresponding olenic ester 5 using the conditions for introducing isoxazole ring at different positions
similar protocol as described for compound 3 to afford of sugar derivatives and prepared a library of novel isoxazole
compound 6 in 87% yield. Utilizing the above established bearing sugar derivatives. Hence, the reaction of nitroethane
reaction conditions for the formation of isoxazole-linked gly- (1.2 equiv) with various O-propargyl ethers of sugar 2b–i
coconjugates, the reaction of compound 6 and different sugar (1.0 equiv) in dry toluene (10.0 mL) with TsCl (1.3 equiv), K
2
CO
3
ꢀ
alkynes (2c, 2g, 2i) afforded 7a–c in good yields (Scheme 7).
(2.0 equiv) and 18-crown-6 ether (10 mol%) as catalyst at 80 C
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Table 4 Synthesis of library of isoxazole-linked glycoconjugates 4a–n
a
b
c
d
Entry
Alkyne
Cycloadduct
Time t
1
(h)/t
2
(min)
Yield (%) y
1
Yield (%) y
2
1
8/15
69
70
2
3
4
8/20
9/15
9/20
65
66
65
68
68
66
5
6
7
8/15
9/20
8/20
62
68
66
63
70
68
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Table 4 (Contd.)
8
9
9/20
8/20
66
65
66
67
1
1
0
1
9/20
8/20
63
56
65
58
1
1
2
3
4
8/20
9/20
8/20
65
55
68
66
58
70
1
a
Molar ratios: glycosyl-b-nitromethane ester 3, terminal alkynes having sugar, alkyl and aryl substituents 2a–n, TsCl, K
2
CO
3
(1 : 1.2 : 1.3 : 2
b
ꢀ
ꢀ
equivalent) and 18-crown-6 (10 mol%). Reaction time: t
stirring rate 200 rpm. Isolated yield: y
1
¼ reaction under heating at 80 C, t
2
¼ reaction under microwave at 110 C with a
c
d
1
¼ under heating condition. Isolated yield: y
2
¼ yield under MW condition.
for 8–10 hours as well as under microwave irradiation at 100 W (2.2 equiv) in anhydrous toluene (10 mL) with TsCl (2.6 equiv),
ꢀ
and 110 C for 15–20 minutes afforded compounds 9a–h in
K
2
CO
3
(4.0 equiv) and 18-crown-6 ether (20 mol%) as catalyst at
ꢀ
good yields (Scheme 8).
80 C for 10 hours as well as under MW irradiation at 100 W and
ꢀ
0
All the developed compounds of this library have been 110 C for 20 min afforded 1,4:3,6-dianhydro-2,5-bis-O-[5 -
characterized using extensive spectral studies (IR, H, and
1
13
0
0
C
(methyl)-3 -methyl-isoxazole-5 -yl]-D-mannitol compound 9i in
NMR). Also single-crystal X-ray analysis of compound 9a clearly good yield (Scheme 9).
showed the presence of isoxazole ring and conrms its unam-
biguous structure (Fig. 3 and 4; see, ESI for details Fig. D1 and
Table D1–D3†).
Mechanistic considerations
Similar reaction conditions when applied on 2,5-di-O-prop- The proposed mechanism consists of initial formation of
argyl-1,4:3,6-dianhydro-D-mannitol (1.0 equiv) and nitroethane glycosyl-b-nitronate A which reacts with tosylchloride to give
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Scheme 7 Synthesis of novel isoxazole-linked glycoconjugates (7a–c) from glycosyl olefinic ester.
Scheme 8 Developed library of novel isoxazole-linked glycoconjugates having the isoxazole ring at different positions of sugar derivatives.
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The reaction follows the proposed mechanism has been
further supported by Density Functional Theory (DFT) wherein
the geometry of both the intermediates i.e. glycosyl-b-nitrile
oxide ester C and the adduct D formed via path I and II
respectively, along with glycosyl-b-nitromethane ester 3 and
O-tosylnitronate B were optimized at B3LYP/6-31G (d,p) level of
34
theory in gas phase using Gaussian 09 package. Gauss view
.09 was used to visualize the optimized molecular geometry,
3
bond length, and bond angles. For each set of calculations,
vibrational analysis was done using the same basis set
employed in the corresponding geometry optimization. DFT
calculations supported the view that glycosyl-b-nitrile oxide
ester C and adduct D formed during the reaction path I and II
Fig. 3 Molecular structure of 9a. Thermal ellipsoids of C, N, and O are are intermediates, not transition states because no negative
set at 40% probability.
frequencies are obtained in the DFT based frequency calcula-
tion of compound C and D (Fig. 7 and 8) (see, ESI for details;
Fig. D2–D4 and Table D4–D7†).
Secondly, taking a closer look at the transition state involved
in the formation of adduct D via path II, we observed that steric
factor governs the formation of adduct D to a great extent. The
transition state of adduct D includes alkyne and O-toluenesul-
phonyl group. The O-toluenesulphonyl group is very bulky in
nature hence it destabilizes the transition state to a consider-
able extent. As a result the possibility of formation of adduct D
is minimized, hence disfavouring the reaction to follow path II.
On the other hand, the transition state involved in the forma-
tion of isoxazole-linked glycoconjugates via path I includes the
alkyne and intermediate glycosyl-b-nitrile oxide ester. So no
Fig. 4 Showing two types of interaction in 9a, N.H interaction
between N-atom of isoxazole ring and the hydrogen of methylene
group attached to phenyl ring; C.H interaction between the hydrogen
atom of methyl group and the p-electron density of phenyl ring.
Scheme 9 Synthesis of bis-isoxazole linked D-mannitol derivative.
O-tosylnitronate B that can follow two plausible pathways to
yield the desired 3,5 disubstituted isoxazoles. Following path I,
the O-tosylnitronate B reacts with second mole of K CO to
2
3
furnish glycosyl-b-nitrileoxide ester C, which further undergoes
3 + 2] cycloaddition with substituted alkynes to furnish product
. However, when the reaction follows path II, the O-tosylnitr-
onate B rst reacts with substituted alkynes to yield a new
[
4
adduct D. The adduct D then reacts with second mole of K
to give product 4 (Fig. 5).
2 3
CO
Fig. 5 Proposed mechanism for the formation of isoxazole-linked
glycoconjugates.
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transition states involved in both pathways as discussed earlier,
suggests that the reaction would possibly follow path I of the
proposed mechanism (Fig. 6–8).
Conclusions
A
versatile and readily adaptable regioselective one-pot
approach has been devised for an easy access to diverse range
of novel 3,5-disubstituted isoxazole-linked glycoconjugates via
[3 + 2] cycloaddition of glycosyl-b-nitrileoxide ester and alkyne.
Fig. 6 Proposed transition state for path I and II respectively.
The high regioselectivity, efficiency, less by-product formation,
good yield and broad substrate scope are the key features of this
methodology. The introduction of isoxazole ring at any specic
position of sugar derivative is a salient feature of this reaction
strategy. The protocol demonstrates signicant compatibility
under microwave conditions and thus enhancing its signi-
cance from green chemistry perspective. In addition, the wide
accessibility to the starting materials is also appealing. Further
investigations towards the related reaction of glycosyl-b-nitro-
methane and their applications are currently underway in our
laboratory.
Experimental section
General remarks
Fig. 7 Optimized geometry of glycosyl-b-nitromethane ester 3 and
glycosyl-b-nitrileoxide ester C at B3LYP/6-31G (d,p) level of theory in All the reactions were carried out in anhydrous solvents under
the gas phase. The bond lengths shown are in angstrom ( A˚ ); point
an argon atmosphere in one hour oven dried glassware at
group: C1; total energy E: ꢁ1434.87162955 and ꢁ1358.44006328
ꢀ
100 C. Solvents were puried by standard procedures. Yields
hartree for optimized structures 3 and C respectively.
refer to chromatographically pure material. All reagents and
solvents were of pure analytical grade. Thin layer chromatog-
raphy (TLC) was performed on 60 F254 silica gel, pre-coated on
steric hindrance is involved in this transition state, hence it will
be more favoured. This extends further support for the reaction
to follow path I of the proposed mechanism (Fig. 6). Another
probable reason, for the reaction to follow path I, might be that
in this route the O-tosylnitronate B rst reacts with K CO and
aluminium plates and revealed with either a UV lamp (lmax
54 nm) or a specic colour reagent (Draggendorff reagent or
iodine vapours) or by spraying with methanolic-H SO solution
¼
2
2
4
13
ꢀ
1
and subsequent charring by heating at 100 C. H and C NMR
were recorded at 300 and 75 MHz, respectively. Chemical shis
given in ppm downeld from internal TMS; J values in Hz. Mass
and the high resolution mass spectra (HRMS) of the developed
glycoconjugates were recorded using electro spray ionization
mass spectrometry. Infrared spectra recorded as Nujol mulls in
KBr plates. Reactions under microwave were carried out in a
single-mode microwave reactor from CEM Discover® LabMate,
2
3
this would be an ionic reaction while in path II the O-tosyl-
nitronate B reacts with an alkyne by a covalent reaction. The
probable rate of ionic reaction is faster as compared to covalent
reaction. Hence, due to fast reaction rates and stability of the
ꢀ
Wattage: 300 W, T-300 C. Single-crystal X-ray data of compound
9
a was collected on Xcalibur Eos (Oxford) CCD diffractometer
using graphite monochromated MoKa radiation (l ¼ 0.71073 A˚ ).
Procedure for the synthesis of orthogonally protected sugars
The protected sugars were prepared from readily available
carbohydrates (D-glucose, D-galactose, D-ribose, methyl-D-gluco-
pyranoside and D-xylose) using standard protection
25,26
methodologies.
Fig. 8 Optimized geometry of O-tosylnitronate B and adduct D at General procedure for the synthesis of O-propargyl ethers of
B3LYP/6-31G (d,p) level of theory in the gas phase. The bond lengths
shown are in Angstrom ( A˚ ); point group: C1; total energy E:
27,28
orthogonally protected sugars (2a–i)
To stirred solution of orthogonally protected sugars
(1.0 mmol) in dry DMF (10 mL) was added NaH (2.1 mmol)
a
ꢁ
2253.79125394 and ꢁ2541.37233681 hartree for optimized structure
B and D respectively.
41528 | RSC Adv., 2015, 5, 41520–41535
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ꢀ
fractionwise at 0 C and the reaction was allowed to stir for mixtures of n-hexane/ethyl acetate (7 : 3) as eluant afforded 3,5
0–15 minutes, then propargyl bromide (1.3 mmol) and TBAB disubstituted isoxazole-linked glycoconjugates 4a–n, 7a–c and
50 mg) were added to the reaction mixture and stirring 9a–i in good yields.
continued for 10–12 hours at rt. Completion of the reaction was For microwave assisted synthesis, the reaction mixtures were
1
(
conrmed by TLC (n-hexane/ethyl acetate (9 : 1); reaction exposed to single-mode microwave reactor CEM Discover®
mixture was extracted with ethyl acetate and dried over anhy- LabMate with a new sealed pressure regulation 10 mL pres-
drous Na
2
SO
4
. Solvent evaporated under reduced pressure surized vial with “snap-on” cap and teon-coated magnetic stir
) of crude bar. The standard temperature control system consisted non-
ꢀ
below 55 C and column chromatography (SiO
2
product using gradient mixtures of n-hexane/ethyl acetate contact calibrated infrared sensor which monitors and
afforded the desired sugar alkynes 2a–i. controls the temperature conditions of the reaction vessel
,6-Di-O-benzyl-5-O-propargyl-1,2-O-isopropylidene-a-D-glu- located in the instrument cavity. For each set of reaction with
3
cofuranose (2i). To a stirred solution of 3,6-di-O-benzyl-1,2-O- standardized molar ratios of reagents, the reaction temperature
ꢀ
isopropylidene-a-D-glucofuranose (2.0 g, 5.0 mmol) in dry DMF was maintained at 110 C and 200 rpm. Aer completion of
ꢀ
(
16 mL) was added with NaH (0.25 g, 10.49 mmol) at 0 C. The reaction (monitored by TLC; n-hexane/ethyl acetate 7 : 3), the
reaction mixture was allowed to stir for 15 minutes, then reaction mixture was in vacuo concentrated and further extrac-
propargyl bromide (0.63 mL, 6.49 mmol) and TBAB (50 mg) were tion and purication as similar to conventional heating
added and reaction continued for 12 h at room temperature to condition.
0 0 0 0 0
3-[Ethyl-(3 -O-benzyl-5 ,6 -dideoxy-1 ,2 -O-isopropylidene)-b-
afford 2i as yellow liquid (1.83 g, yield 84%). R ¼ 0.51 (12% ethyl
f
1
0
00 00
acetate/n-hexane); MS: m/z 461 [M + Na]; H NMR (300 MHz, L-ido-heptofuranurnate-5 -yl]-5-(methyl-2 ,3 -O-isopropylidene-
0
0
00
CDCl ): d 7.33 (m, 10H), 5.87 (s, 1H), 4.66 (d, J ¼ 11.7 Hz, 1H), 5 -O-methyl-b-D-ribofuranoside-5 -yl)-isoxazole (4a). To a stir-
3
4
6
1
3
1
1
2
.55 (m, 4H), 4.39 (d, J ¼ 15.9 Hz, 1H), 4.26 (m, 1H), 4.22 (d, J ¼ ring solution of glycosyl-b-nitromethane ester 3 (500 mg,
.9 Hz, 1H), 4.16–4.10 (m, 1H), 4.05-4.00 (m, 1H), 3.90 (1H, J ¼ 1.22 mmol) in dry toluene (12 mL) was added with p-toluene-
0.8 Hz, 1H), 3.65 (dd, J ¼ 5.4, 10.2 Hz, 1H), 2.33 (s, 1H), 1.46 (s, sulphonyl chloride (300 mg, 1.59 mmol), K
2 3
CO (337 mg,
1
3
3
H), 1.30 (s, 3H); C NMR (75 MHz, CDCl ): d 138.3, 137.6, 2.44 mmol), methyl-2,3-O-isopropylidene-5-O-propargyl-b-D-
28.3 (2C), 128.2 (2C), 127.7, 127.6 (2C), 127.5, 127.4 (2C), 111.7, ribofuranoside 2a (355 mg, 1.47 mmol) and 18-crown-6
05.0, 81.9, 81.5, 80.1, 78.7, 74.9, 74.1, 73.3, 72.2, 70.8, 57.7, (10 mol%). The resulting reaction mixture was reuxed with
ꢀ
6.7, 26.3 ppm.
stirring at 80 C for 8 h to afford 4a as pale yellow solid (541 mg,
ꢀ
2
,5-Di-O-propargyl-1,4:3,6-dianhydro-D-mannitol (2o). 1,4:3,6- yield 70%). mp 98–100 C; Rf ¼ 0.51 (35% ethyl acetate/
Dianhydromannitol (5.0 g, 34.2 mmol) dissolved in dry DMF n-hexane); IR (KBr) nmax: 2987, 2934, 1734 (C]O), 1608 (C]N),
ꢀ
(
15 mL) was maintained at 0 C, subsequently NaH (3.28 g, 1587, 1455, 1374, 1212 (C–O–N), 1164, 1107, 1075, 1023, 961,
ꢁ
1 1
1
3
36.8 mmol) was added to it and reaction was kept for stirring. 869, 738 cm ; H NMR (300 MHz, CDCl ): d 7.33 (m, 5H), 6.26
Aer 30 min propargyl bromide (6.7 mL, 75.2 mmol) and TBAB (s, 1H), 5.91 (d, J ¼ 3.6 Hz, 1H), 4.94 (s, 1H), 4.73 (d, J ¼ 12 Hz,
(
50 mg) were added to the reaction mixture and stirring 1H), 4.64 (d, J ¼ 4.2 Hz, 2H), 4.56 (m, 3H), 4.45 (d, J ¼ 12.0 Hz,
continued for overnight. Completion of the reaction was 1H), 4.34–4.30 (m, 2H), 4.07–4.02 (m, 2H), 3.93 (m, 1H), 3.81–
conrmed by TLC monitoring; reaction mixture was extracted 3.75 (m, 1H), 3.59–3.45 (m, 2H), 3.28 (s, 3H), 2.72 (dd, J ¼ 10.2,
with ethyl acetate and dried over Na SO . Column chromatog- 15.9 Hz, 1H), 2.39 (d, J ¼ 16.2 Hz, 1H), 1.47 (s, 3H), 1.45 (s, 3H),
2
4
1
3
raphy (SiO
2
) of crude product using hexane/ethyl acetate (9 : 1) 1.31 (s, 6H), 1.18 (t, J ¼ 7.2 Hz, 3H); C NMR (75 MHz, CDCl
3
): d
as eluant afforded the desired glycosyl alkyne 2o as white crys- 170.9, 167.9, 163.8, 136.7, 128.5 (2C), 128.1, 128.0 (2C), 112.3,
talline solid (6.2 g, 82%). MS: m/z 245 [M + Na]; H NMR (CDCl
1
3
,
111.6, 109.1, 104.7, 104.1, 85.0, 84.8, 81.4, 81.3, 80.9, 80.8, 71.8,
3
3
8
00 MHz): d 4.61 (s, 2H), 4.36–4.24 (m, 6H), 4.12–4.07 (m, 2H), 71.5, 64.0, 60.5, 54.7, 34.4, 33.3, 26.6, 26.3, 26.2, 24.9, 14.1 ppm.
1
3
+
.73 (t, J ¼ 8.7 Hz, 2H), 2.4 (s, 2H); C NMR (75 MHz, CDCl
3
): d HRMS calcd for C32H44NO12 [M + H] : 634.2864; found
0.3 (2C), 79.2, 78.7 (3C), 75.1 (2C), 70.9 (2C), 57.6 (2C) ppm.
634.2837.
0
0
0
0
0
3
-[Ethyl-(3 -O-benzyl-5 ,6 -dideoxy-1 ,2 -O-isopropylidene)-
0
00
00 00
b-l-ido-heptofuranurnate-5 -yl]-5-(5 -O-benzyl-1 ,2 -O-isopro-
General procedure for the synthesis of 3,5-disubstituted
isoxazole-linked glycoconjugates (4a–i)
00
00
pylidene-3 -O-methyl-a-D-xylofuranose-3 -yl)-isoxazole
(4b).
Compound 3 (0.5 g, 1.22 mmol) on treatment with 5-O-benzyl-
To a stirred solution of glycosyl-b-nitromethane ester 3 1,2-O-isopropylidene-3-O-propargyl-a-D-xylofuranose 2b (0.47 g,
1.0 equiv) in dry toluene (10 mL) was added K CO (2.0 equiv), 1.47 mmol) in presence of TsCl (0.3 g, 1.59 mmol), K CO (0.337
(
2
3
2
3
p-toluenesulphonyl chloride (1.3 equiv), terminal alkynes 2a–n g, 2.44 mmol) and 18-crown-6 (10 mol%) in dry toluene (12 mL)
ꢀ
(
1.2 equiv) and 18-crown-6 (10 mol%). The reaction mixture was at 80 C for 8 h and workup as described in general procedure
ꢀ
stirred under reuxing condition for 8–10 h at 80 C. Aer afforded 4b as yellow liquid (589 mg, yield 68%). R
completion of reaction (monitored by TLC; n-hexane/ethyl ethyl acetate/n-hexane); IR (KBr) nmax: 2988, 2935, 1736 (C]O),
acetate, 7 : 3), the reaction mixture was in vacuo concentrated 1615 (C]N), 1580, 1433, 1369, 1218 (C–O–N), 1169, 1071, 1028,
and extracted with ethyl acetate, washing with water and satu- 965, 864, 735 cm ; H NMR (300 MHz, CDCl
rated brine solution. The obtained organic layer was dried over 6.24 (s, 1H), 5.91 (d, J ¼ 4.5 Hz, 1H), 5.89 (d, J ¼ 4.2 Hz, 1H), 4.73
anhydrous Na SO
and concentrated under reduced pressure. (d, J ¼ 11.7 Hz, 1H), 4.64 (d, J ¼ 3.9 Hz, 1H), 4.57 (d, J ¼ 9.6 Hz,
Column chromatography (SiO
) of crude product using gradient 1H), 4.54–4.43 (m, 4H), 4.38–4.28 (m, 3H), 4.30 (d, J ¼ 9.9 Hz,
¼ 0.45 (35%
f
ꢁ
1 1
3
): d 7.33 (m, 10H),
2
4
2
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0 0 0 0 0
3-[Ethyl-(3 -O-benzyl-5 ,6 -dideoxy-1 ,2 -O-isopropylidene)-b-
1
2
H), 4.04 (d, J ¼ 6.9 Hz, 1H), 3.99 (d, J ¼ 2.7 Hz, 1H), 3.92 (d, J ¼
.4 Hz, 1H), 3.80–3.76 (m, 2H), 3.71 (d, J ¼ 6.3 Hz, 1H), 2.71 (dd, L-ido-heptofuranurnate-5 -yl]-5-(1 ,2 :5 6 -di-O-isopropylidene-
0
00 00 00 00
00
0
0
J ¼ 9.9, 15.9 Hz, 1H), 2.37 (d, J ¼ 12.9 Hz, 1H), 1.47 (s, 3H), 1.44 3 -O-methyl-a-D-glucofuranose-3 -yl)-isoxazole (4e). Compound
1
3
(
s, 3H), 1.30 (s, 6H), 1.17 (t, J ¼ 6.9 Hz, 3H); C NMR (75 MHz, 3 (250 mg, 0.61 mmol) on treatment with 1,2:5,6 di-O-iso-
CDCl ): d 170.9, 167.5, 163.9, 137.9, 136.7, 128.5 (2C), 128.3 (2C), propylidene-3-O-propargyl-a-D-glucofuranose 2e (218 mg,
28.1 (2C), 128.0 (2C), 127.8, 127.6, 111.7, 111.6, 105.0, 104.8, 0.73 mmol), TsCl (151 mg, 0.79 mmol), K CO (168 mg,
3
1
1
3
2
3
04.1, 82.8, 82.7, 81.3, 80.9, 78.8, 73.5, 71.5, 67.1, 63.2, 60.5, 1.22 mmol), 18-crown-6 (10 mol%) in dry toluene (10 mL) at
ꢀ
4.3, 33.3, 26.6 (2C), 26.1 (2C), 14.0 ppm; HRMS calcd for 80 C for 8 h and workup as described in general procedure
+
C
38
H
3
48NO12 [M + H] 710.3177; found 710.3174.
afforded 4e as white liquid (261 mg, yield 62%). R ¼ 0.45 (30%
f
0
0
0
0
0
-[Ethyl-(3 -O-benzyl-5 ,6 -dideoxy-1 ,2 -O-isopropylidene)- ethyl acetate/n-hexane); IR (KBr) n : 2992, 2940, 1734 (C]O),
max
0
00
00 00
b-L-ido-heptofuranurnate-5 -yl]-5-(3 -O-benzyl-1 ,2 -O-isopro- 1619 (C]N), 1589, 1466, 1374, 1215 (C–O–N), 1169, 1109, 1073,
00
00
ꢁ1
1
pylidine-5 -O-methyl-a-D-xylofuranose-4 -yl)-isoxazole
(4c). 1019, 961, 853, 731 cm ; H NMR (300 MHz, CDCl ): d 7.33 (m,
3
Compound 3 (0.35 g, 0.85 mmol) on treatment with 3-O- 5H), 6.31 (s, 1H), 5.89 (d, J ¼ 15.3 Hz, 2H), 4.73 (d, J ¼ 11.7 Hz,
benzyl-1,2-O-isopropylidene-5-O-propargyl-a-D-xylofuranose 2c 2H), 4.68 (d, J ¼ 5.1 Hz, 1H), 4.65 (d, J ¼ 3.3, 1H), 4.53 (d, J ¼
(
1
8
312 mg, 1.03 mmol), TsCl (212 mg, 1.11 mmol), K
2
CO
3
(236 mg, 3.3 Hz, 1H), 4.46 (d, J ¼ 12 Hz, 1H), 4.32 (d, J ¼ 3.9 Hz, 1H), 4.29
.71 mmol), 18-crown-6 (10 mol%) in dry toluene (12 mL) at (m, 1H), 4.08 (d, J ¼ 5.7 Hz, 1H), 4.03–3.93 (m, 7H), 3.82–3.74
ꢀ
0 C for 9 h and workup as described in general procedure (m, 1H), 2.74 (dd, J ¼ 10.2, 16.2 Hz, 1H), 2.37 (d, J ¼ 13.8 Hz,
afforded 4c as yellow oil (416 mg, yield 70%). R ¼ 0.47 (35% 1H), 1.59 (s, 3H), 1.48 (s, 3H), 1.42 (s, 3H), 1.35 (s, 3H), 1.30 (s,
f
1
3
ethyl acetate/n-hexane); IR (KBr) n : 2985, 2937, 1732 (C]O), 9H); C NMR (75 MHz, CDCl ): d 171.0, 167.7, 166.7, 136.8,
max
3
1
1
7
4
2
9
610 (C]N), 1590, 1467, 1376, 1218 (C–O–N), 1166, 1102, 1075, 129.3, 128.5 (2C), 128.0 (2C), 111.9, 111.6, 109.1, 105.1, 104.7,
015, 966, 856, 736 cm ; H NMR (300 MHz, CDCl ): d 7.32– 104.2, 82.6, 81.3, 80.9, 80.8, 79.9, 72.2, 71.6, 71.4, 64.3, 63.6,
3
ꢁ
1 1
.26 (m, 10H), 6.25 (s, 1H), 5.90 (d, J ¼ 3.9 Hz, 2H), 5.29 (s, 1H), 56.1, 33.7, 31.9, 26.8, 26.7, 26.4, 26.1, 25.3, 22.6, 14.1 ppm;
+
.73–4.66 (m, 5H), 4.61 (d, J ¼ 11.7 Hz, 2H), 4.49 (d, J ¼ 14.7 Hz, HRMS: calcd for C H NO [M + H] : 690.3126; found
3
5
48
13
H), 4.43-4.31 (m, 1H), 4.03 (d, J ¼ 6.9 Hz, 2H), 3.93 (d, J ¼ 690.3137.
0
0
0
0
0
.3 Hz, 2H), 3.78 (m, 2H), 2.71(dd, J ¼ 9.9, 15.6 Hz, 1H), 2.40 (dd,
3-[Ethyl-(3 -O-benzyl-5 ,6 -dideoxy-1 ,2 -O-isopropylidene)-b-
0
00 00 00 00
J ¼ 3, 15.9 Hz, 1H) 1.48 (s, 3H), 1.44 (s, 3H), 1.30 (s, 6H), 1.17 (t, L-ido-heptofuranurnate-5 -yl]-5-(2 ,3 :5 ,6 -di-O-isopropylidene-
1
3
00
00
J ¼ 6.9 Hz, 3H); C NMR (75 MHz, CDCl ): d 171.0, 168.1, 163.8, 1 -O-methyl-D-mannofuranose-1 -yl)-isoxazole (4f). Compound
3
1
1
7
37.4, 136.8, 129.7, 129.7, 128.4 (4C), 128.0 (2C), 127.6 (2C), 3 (0.5 g, 1.22 mmol) on treatment with 2,3:5,6 di-O-iso-
11.7, 111.6, 105.0, 105.0, 104.0, 82.3, 82.1, 81.4, 81.1, 81.0, 79.0, propylidene-1-O-propargyl-D-mannofuranose 2f (0.44 g, 1.47 mmol),
2.0, 71.5, 68.6, 64.2, 60.5, 34.5, 33.3, 26.8, 26.7, 26.2, 26.2, 14.0 TsCl (0.3 g, 1.59 mmol), K CO (0.34 g, 2.44 mmol), 18-crown-6
2
3
+
ꢀ
ppm; HRMS: calcd for C38
H
47NO12 [M + H] : 710.3177; found (10 mol%) in dry toluene (12 mL) at 80 C for 9 h and workup as
7
10.3192.
described in general procedure afforded 4f as pale yellow oil
0
0
0
0
0
0
3
-[Ethyl-(3 -O-benzyl-5 ,6 -dideoxy-1 ,2 -O-isopropylidene)-b- (589 mg, yield 68%). R ¼ 0.42 (35% ethyl acetate/n-hexane); IR
f
00 00 00 00
L-ido-heptofuranurnate-5 -yl]-5-(1 ,2 :4 5 -di-O-isopropylidene- (KBr) n : 2985, 2936, 1732 (C]O), 1610 (C]N), 1432, 1368, 1216
max
0
0
00
ꢁ1 1
3
3
-O-methyl-D-fructopyranose-1 -yl)-isoxazole (4d). Compound (C–O–N), 1168, 1072, 1025, 968, 865, 736 cm ; H NMR (300 MHz,
(0.35 g, 0.85 mmol) on treatment with 1,2:4,5-di-O-iso- CDCl ): d 7.33 (m, 5H), 6.25 (s, 1H), 5.92 (d, J ¼ 3.3 Hz, 1H), 5.06 (s,
3
propylidene-3-O-propargyl-D-fructopyranose 2d (305 mg, 1H), 4.77 (d, J ¼ 3.9 Hz, 1H), 4.72 (d, J ¼ 11.7 Hz, 1H), 4.65–4.60 (m,
1
1
8
.03 mmol), TsCl (212 mg, 1.11 mmol), K
2
CO
3
(236 mg, 3H), 4.49 (d, J ¼ 12.6 Hz, 1H), 4.44–4.38 (m, 2H), 4.33 (d, J ¼ 5.1 Hz,
.71 mmol), 18-crown-6 (10 mol%) in dry toluene (10 mL) at 1H), 4.13–3.93 (m, 6H), 3.80–3.75 (m, 1H), 2.73 (dd, J ¼ 10.2, 16.2
ꢀ
0 C for 9 h and workup as described in general procedure Hz, 1H), 2.40 (d, J ¼ 12.6 Hz, 1H), 1.45 (s, 9H), 1.38 (s, 3H), 1.31 (s,
13
afforded 4d as yellow liquid (383 mg, yield 65%). R
ethyl acetate/n-hexane); IR (KBr) nmax; 2987, 2946, 1732 (C]O), 167.3, 163.9, 136.8, 128.5 (2C), 128.1, 127.9 (2C), 112.7, 111.6, 109.2,
f
¼ 0.43 (30% 6H), 1.18 (t, J ¼ 6.9 Hz, 3H); C NMR (75 MHz, CDCl ): d 171.0,
3
1
1
616 (C]N), 1586, 1463, 1378, 1216 (C–O–N), 1164, 1106, 1076, 105.9, 104.8, 104.3, 84.9, 81.5, 81.2, 81.0, 80.7, 79.3, 72.9, 71.5, 66.8,
ꢁ
1 1
021, 965, 850, 730 cm ; H NMR (300 MHz, CDCl ): d 7.33-7.26 60.5, 59.5, 34.4, 33.3, 26.8, 26.7, 26.2, 25.8, 25.2, 24.5, 14.0 ppm;
3
+
(
m, 5H), 6.25 (s, 1H), 5.90 (d, J ¼ 3.6 Hz, 1H), 4.92 (d, J ¼ 13.5 Hz, HRMS: calcd for C H NO [M + H] : 690.3126; found 690.3140.
35
48
13
0 0 0 0 0
1
1
8
H), 4.78–4.71 (m, 2H), 4.64 (d, J ¼ 3.9 Hz, 1H), 4.45 (d, J ¼
3-[Ethyl-(3 -O-benzyl-5 ,6 -dideoxy-1 ,2 -O-isopropylidene)-b-
0
00 00 00 00
00
1.7 Hz, 1H), 4.36–4.29 (m, 1H), 4.20–4.14 (m, 2H), 4.07 (d, J ¼ L-ido-heptofuranurnate-5 -yl]-5-(1 ,2 :3 ,4 -di-O-isopropylidene-
0
0
.4 Hz, 2H), 4.02 (d, J ¼ 8.4 Hz, 2H), 3.96-3.84 (m, 4H), 3.50 (d, 6 -O-methyl-a-D-galactopyranose-6 -yl)-isoxazole (4g). Compound
J ¼ 7.5 Hz, 1H), 2.71 (dd, J ¼ 10.2, 16.2 Hz, 1H), 2.37 (d, J ¼ 3 (0.35 g, 0.85 mmol) on treatment with 1,2:3,4-di-O-iso-
1
1
5.9 Hz, 1H), 1.53 (s, 3H), 1.48 (s, 3H), 1.44 (s, 3H), 1.37 (s, 3H), propylidene-6-O-propargyl-a-D-galactopyranose 2g (0.31 g,
.30 (s, 3H), 1.25 (s, 3H), 1.18 (t, J ¼ 7.2 Hz, 3H); C NMR 1.03 mmol), (212 mg, 1.11 mmol), K CO (236 mg, 1.71 mmol),
1
3
2
3
ꢀ
75 MHz, CDCl ): d 170.9, 168.2, 163.8, 136.7, 129.2, 128.5 (2C), 18-crown-6 (10 mol%) in dry toluene (10 mL) at 80 C for 8 h and
3
(
1
8
2
28.0 (2C), 112.2, 111.6, 109.2, 104.7, 104.2, 103.9, 81.5, 81.3, workup as described in general procedure afforded 4g as pale
1.1, 80.8, 74.2, 73.7, 71.7, 71.5, 71.4, 63.7, 60.5, 34.4, 33.3, 28.1, yellow liquid (389 mg, yield 66%). R ¼ 0.45 (35% ethyl acetate/
f
6.9, 26.6, 26.2, 26.1, 25.8, 14.0 ppm; HRMS: calcd for n-hexane); IR (KBr) n : 2984, 2933, 1736 (C]O), 1612 (C]N),
max
+
C
35
H
48NO13 [M + H] : 690.3126, found 690.3159.
1589, 1459, 1369, 1218 (C–O–N), 1166, 1109, 1075, 1025, 966, 872,
41530 | RSC Adv., 2015, 5, 41520–41535
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ꢁ
1 1
7
1
1
(
1
32 cm ; H NMR (300 MHz, CDCl
3
): d 7.32–7.26 (m, 5H), 6.26 (s, (2C), 128.4 (2C), 128.2 (2C), 128.1 (2C), 127.9 (2C), 127.8 (2C),
H), 5.91 (d, J ¼ 4.8 Hz, 1H), 5.52 (d, J ¼ 5.1 Hz, 1H), 4.71 (d, J ¼ 127.7 (2C), 127.5, 111.7, 111.5, 105.2, 104.7, 103.6, 81.8, 81.7,
1.7 Hz, 1H), 4.67–4.53 (m, 4H), 4.45 (d, J ¼ 12 Hz, 1H), 4.35–4.30 81.4, 81.3, 80.9, 78.8, 73.4, 73.3, 72.1, 71.5, 64.2, 64.1, 60.4, 34.3,
m, 2H), 4.23 (d, J ¼ 4.8 Hz, 1H), 4.06–4.02 (m, 3H), 3.95 (d, J ¼ 33.3, 26.7 (2C), 26.2 (2C), 14.0 ppm; HRMS: calcd for
+
6.2 Hz, 1H), 3.80 (d, J ¼ 9.6 Hz, 1H), 3.76–3.68 (m, 1H), 3.64 (d,
46
C H56NO13 [M + H] : C35H48NO13: 830.3752; found 830.3764.
0 0 0 0 0
J ¼ 9.9 Hz, 1H), 2.72 (dd, J ¼ 9.9, 15.9 Hz, 1H), 2.40 (d, J ¼ 16.2 Hz,
3-[Ethyl-(3 -O-benzyl-5 ,6 -dideoxy-1 ,2 -O-isopropylidene)-b-
0 00 00
H), 1.53 (s, 3H), 1.45 (s, 3H), 1.44 (s, 3H), 1.32 (s, 6H), 1.30 (s, 3H), L-ido-heptofuranurnate-5 -yl]-5-(1 -uorobenzene-4 -yl)-isoxazole
1
1
1
1
6
1
3
.18 (t, J ¼ 6.9 Hz, 3H); C NMR (75 MHz, CDCl
3
): d 171.0, 168.3, (4j). Compound 3 (0.35 g, 0.85 mmol) on treatment with
63.7, 136.8, 128.5 (2C), 128.1, 127.9 (2C), 111.6, 109.2, 108.5, 1-ethynyl-4-uorobenzene 2j (123 mg, 1.03 mmol), (212 mg, 1.11
04.7, 103.8, 96.3, 81.3, 81.1, 71.5, 71.0, 70.6, 70.5, 70.4, 69.8, 66.7, mmol), K CO (236 mg, 1.71 mmol), 18-crown-6 (10 mol%) in
4.2, 60.5, 34.5, 33.3, 26.7, 26.2, 26.0, 25.9, 24.9, 24.4, 14.0 ppm; dry toluene (10 mL) at 80 C for 8 h and workup as described in
HRMS: calcd for C H NO [M + H] : C H NO : 690.3126; general procedure afforded 4j as colourless liquid (275 mg, yield
2
3
ꢀ
+
3
5
48
13
35 48
13
found 690.3139.
63%). R
f
¼ 0.48 (25% ethyl acetate/n-hexane); IR (KBr) nmax
:
0
0
0
0
0
0
3
-[Ethyl-(3 -O-benzyl-5 ,6 -dideoxy-1 ,2 -O-isopropylidene)-b- 3066, 2985, 2926, 2854, 1732 (C]O), 1615 (C]N), 1602, 1511,
00 00 00
00
ꢁ1
L-ido-heptofuranurnate-5 -yl]-5-(methyl-2 ,3 ,4 tri-O-benzyl-6 - 1456, 1375, 1235 (C–O–N), 1163, 1075, 1025, 949, 842, 813 cm
O-methyl-a-D-glucopyranoside-6 -yl)-isoxazole (4h). Compound
;
0
0
1
3
H NMR (300 MHz, CDCl ): d 7.73–7.68 (m, 2H), 7.33 (m, 5H),
3
(0.25 g, 0.61 mmol) on treatment with methyl-2,3,4-tri-O- 7.13–7.07 (m, 2H), 6.48 (s, 1H), 5.94 (d, J ¼ 3.9 Hz, 1H), 4.75 (d,
benzyl-6-O-propargyl-a-D-glucopyranoside 2h (0.39 g, 0.73 J ¼ 11.4 Hz, 1H), 4.66 (d, J ¼ 3.9 Hz, 1H), 4.47 (d, J ¼ 11.4 Hz,
mmol), TsCl (151 mg, 0.79 mmol), K CO (168 mg, 1.22 mmol) 1H), 4.38 (dd, J ¼ 3, 9.9 Hz, 1H), 4.10–4.04 (m, 2H), 3.95 (d, J ¼
2
3
ꢀ
and 18-crown-6 (10 mol%) in dry toluene (10 mL) at 80 C for 9 h 2.4 Hz, 1H), 3.86–3.79 (m, 1H), 2.78 (dd, J ¼ 10.5, 16.2, 1H), 2.41
and workup as described in general procedure afforded 4h as (dd, J ¼ 3.6, 15.9 Hz, 1H), 1.46 (s, 3H), 1.31 (s, 3H), 1.19 (t, J ¼
1
3
pale yellow liquid (372 mg, yield 66%). R
f
¼ 0.49 (35% ethyl 6.9 Hz, 3H); C NMR (75 MHz, CDCl
3
): d 171.1, 168.2, 164.6,
acetate/n-hexane); IR (KBr) nmax: 2987, 2929, 1733 (C]O), 1615 136.8, 128.5 (2C), 128.1, 128.0 (2C), 127.8, 127.7, 124.0, 116.0,
(
C]N), 1594, 1455, 1371, 1216 (C–O–N), 1168, 1112, 1074, 1015, 115.7, 111.6, 104.9, 104.7, 100.4, 81.5, 81.3, 80.9, 71.5, 60.5, 34.4,
ꢁ
1 1
9
2
1
9
63, 875, 739 cm ; H NMR (300 MHz, CDCl
0H), 6.24 (s, 1H), 5.89 (d, J ¼ 3.6 Hz, 1H), 4.97 (d, J ¼ 10.8 Hz,
H), 4.83 (t, J ¼ 10.2 Hz, 1H), 4.74 (d, J ¼ 9 Hz, 1H), 4.69–4.32 (m, L-ido-heptofuranurnate-5 -yl)-5-(toluene-4 -yl)-isoxazole
H), 4.31 (d, J ¼ 9.6 Hz, 1H), 4.01 (d, J ¼ 6.9 Hz, 1H), 3.97–3.94 Compound 3 (0.35 g, 0.85 mmol) on treatment with 4-ethynyl
3
): d 7.33–7.24 (m, 33.4, 26.6, 26.1, 14.0 ppm.
0
0
0
0
0
00
3-(Ethyl-[3 -O-benzyl-5 ,6 -dideoxy-1 ,2 -O-isopropylidene]-b-
0
(4k).
(
(
2
m, 2H), 3.91 (d, J ¼ 2.7 Hz, 1H), 3.77 (d, J ¼ 9.6 Hz, 1H), 3.74 toluene 2k (0.13 mL, 1.026 mmol), TsCl (212 mg, 1.11 mmol),
dd, J ¼ 9.6, 16.8 Hz, 1H), 3.62 (d, J ¼ 9.6 Hz, 1H), 3.58–3.55 (m,
K
2
CO
3
(236 mg, 1.71 mmol), 18-crown-6 (10 mol%) in dry
ꢀ
H), 3.51 (d, J ¼ 3.3 Hz, 1H), 3.35 (s, 3H), 2.69 (m, 1H), 2.37 (d, toluene (10 mL) at 80 C for 9 h and workup as described in
J ¼ 12.9 Hz, 1H), 1.42 (s, 3H), 1.29 (s, 3H), 1.15 (t, J ¼ 6.9 Hz, 3H); general procedure afforded 4k as pale yellow liquid (242 mg,
1
3
C NMR (75 MHz, CDCl
3
): d 170.9, 168.0, 163.8, 138.7, 138.19, yield 56%). R
f
¼ 0.54 (30% ethyl acetate/n-hexane); IR (KBr) nmax
:
1
1
9
6
38.10, 136.8, 128.4 (4C), 128.3 (2C), 128.2 (4C), 128.0 (2C), 3032, 2984, 2926, 1732 (C]O), 1615 (C]N), 1599, 1455, 1352,
27.9 (2C), 127.8 (2C), 127.6 (2C), 127.4 (2C), 111.5, 104.7, 104.0, 1258 (C–O–N), 1164, 1075, 1025, 820, 699 cm
ꢁ
1
1
; H NMR
8.0, 81.9, 81.4, 81.3, 81.0, 80.9, 79.7, 75.6, 74.9, 73.3, 71.5, 69.9, (300 MHz, CDCl ): d 7.61 (d, J ¼ 7.8 Hz, 2H), 7.33 (m, 5H), 7.21
3
9.4, 64.3, 60.4, 55.1, 34.4, 33.37, 33.31, 26.6, 26.1, 14.0 ppm.
(d, J ¼ 8.1 Hz, 2H), 6.48 (s, 1H), 5.95 (d, J ¼ 3.6 Hz, 1H), 4.75 (d, J
0
0
0
0
0
3
-[Ethyl-(3 -O-benzyl-5 ,6 -dideoxy-1 ,2 -O-isopropylidene)-b- ¼ 11.7 Hz, 1H), 4.66 (d, J ¼ 3.9 Hz, 1H), 4.45 (d, J ¼ 11.7 Hz, 1H),
0
00 00
00
L-ido-heptofuranurnate-5 -yl]-5-(3 ,6 -di-O-benzyl-5 -O-methyl- 4.40 (d, J ¼ 7.2 Hz, 1H), 4.12–4.03 (m, 2H), 3.95 (d, J ¼ 2.4 Hz,
00
00
00
1
,2 -O-isopropylidene-a-D-glucofuranose-5 -yl)-isoxazole (4i). 1H), 3.83 (td, J ¼ 3.9, 10.2 Hz, 1H), 2.78 (dd, J ¼ 10.2, 16.2 Hz,
Compound 3 (0.35 g, 0.85 mmol) on treatment with 3,6-di-O- 1H), 2.47–2.40 (m, 1H), 2.37 (s, 3H), 1.46 (s, 3H), 1.31 (s, 3H),
1
3
benzyl-5-O-propargyl-1,2-O-isopropylidene-a-D-glucofuranose 2i 1.18 (t, J ¼ 7.5 Hz, 3H); C NMR (75 MHz, CDCl ): d 171.1, 169.3,
3
(
500 mg, 1.03 mmol), TsCl (212 mg, 1.11 mmol), K CO (236 mg, 164.4, 139.9, 136.8, 129.4 (2C), 128.5 (2C), 128.1, 128.0 (2C),
2 3
1
8
.71 mmol), 18-crown-6 (10 mol%) in dry toluene (10 mL) at 125.7 (2C), 125.0, 111.6, 104.8, 99.8, 81.5, 81.4, 81.0, 71.5, 60.5,
ꢀ
0 C for 9 h and workup as described in general procedure 34.5, 33.5, 26.7, 26.2, 21.4, 14.0 ppm; HRMS: calcd for
+
afforded 4i as pale yellow liquid (460 mg, yield 65%); R
f
¼
C
29
H34NO
7
[M + H] : 508.2335; found 508.2346.
0 0 0 0 0
0
1
1
.43 (35% ethyl acetate/n-hexane). IR (KBr) nmax: 2994, 2934,
3-[Ethyl-(3 -O-benzyl-5 ,6 -dideoxy-1 ,2 -O-isopropylidene)-b-
0
00
734 (C]O), 1618 (C]N), 1588, 1459, 1368, 1215 (C–O–N), L-ido-heptofuranurnate-5 -yl]-5-(pyridine-3 -yl)-isoxazole
(4l).
170, 1102, 1073, 1014, 969, 874, 732 cm ; H NMR (300 MHz, Compound 3 (0.5 g, 1.22 mmol) on treatment with 3-ethynyl
ꢁ1 1
CDCl ): d 7.32–7.29 (m, 15H), 6.18 (s, 1H), 5.88 (d, J ¼ 4.2 Hz, pyridine 2l (151 mg, 1.47 mmol), TsCl (0.3 g, 1.59 mmol), K CO3
3
2
2
H), 4.84 (d, J ¼ 12.9 Hz, 1H), 4.72 (d, J ¼ 11.7 Hz, 1H), 4.66–4.63 (0.34 g, 2.44 mmol), 18-crown-6 (10 mol%) in dry toluene
ꢀ
(
(
3
2
3
m, 6H), 4.56 (d, J ¼ 11.1 Hz, 1H), 4.45 (d, J ¼ 12.3 Hz, 1H), 4.31 (10 mL) at 80 C for 8 h and workup as described in general
d, J ¼ 9.6 Hz, 1H), 4.21 (d, J ¼ 6.9 Hz, 1H), 4.16–3.92 (m, 5H), procedure afforded 4l as pale yellow solid (403 mg, yield 65%).
ꢀ
.86 (d, J ¼ 10.5 Hz, 1H), 3.80–3.74 (m, 1H), 3.67–3.62 (m, 1H), mp 113–115 C; R
f
¼ 0.51 (30% ethyl acetate/n-hexane); IR (KBr)
.71 (dd, J ¼ 10.2, 16.2 Hz, 1H), 2.36 (d, J ¼ 15.9 Hz, 1H), 1.47 (s,
nmax: 3127, 2987, 2929, 1735 (C]O), 1620 (C]N), 1581, 1496,
1
3
ꢁ1
1
H), 1.44 (s, 3H), 1.30 (s, 6H), 1.16 (t, J ¼ 6.9 Hz, 3H); C NMR 1228 (C–O–N), 1196, 1073, 1041, 812, 706 cm
; H NMR
(75 MHz, CDCl
3
): d 170.9, 168.6, 163.7, 138.2, 137.5, 136.8, 128.5 (300 MHz, CDCl
3
): d 8.96 (s, 1H), 8.62 (s, 1H), 8.01 (d, J ¼ 7.8 Hz,
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H), 7.33 (m, 6H), 6.64 (s, 1H), 5.95 (d, J ¼ 3.6 Hz, 1H), 4.76 (d, (Yield 80%); R
Paper
1
1
f
¼ 0.45 (10% ethyl acetate/n-hexane); H NMR
J ¼ 12 Hz, 1H), 4.68 (d, J ¼ 3.6 Hz, 1H), 4.47 (d, J ¼ 11.7 Hz, 1H), (300 MHz, CDCl ): d 6.95 (dd, J ¼ 5.1, 15.9 Hz, 1H), 6.16 (d, J ¼
3
4
3
2
6
1
1
2
4
.37 (d, J ¼ 6.6 Hz, 1H), 4.07 (dd, J ¼ 1.5, 7.2 Hz, 1H), 3.96 (d, J ¼ 15.6 Hz, 1H), 5.96 (d, J ¼ 3.3 Hz, 1H), 4.78 (s, 1H), 4.59 (d, J ¼
Hz, 1H), 3.89–3.81 (m, 2H), 2.79 (dd, J ¼ 10.5, 16.2 Hz, 1H), 3.3 Hz, 1H), 4.19 (q, J ¼ 7.2 Hz, 2H), 3.88 (d, J ¼ 2.7 Hz, 1H),
.41 (d, J ¼ 15.9 Hz, 1H), 1.46 (s, 3H), 1.31 (s, 3H), 1.19 (t, J ¼ 3.66–3.56 (m, 1H), 3.52–3.44 (m, 1H), 1.50 (s, 3H), 1.33 (s, 3H),
1
3
13
.9 Hz, 3H); C NMR (75 MHz, CDCl
3
): d 170.9, 166.2, 164.7, 1.28 (t, J ¼ 7.2 Hz, 3H), 1.15 (t, J ¼ 7.2 Hz, 3H); C NMR
3
50.5, 146.8, 136.7, 132.8, 132.7, 128.5 (2C), 128.1, 128.0 (2C), (75 MHz, CDCl ): d 165.7, 141.2, 122.9, 111.5, 104.8, 83.6, 82.8,
23.5, 111.6, 104.9, 101.8, 81.3, 80.8, 80.7, 71.5, 60.5, 34.3, 33.4, 79.2, 66.0, 60.1, 26.5, 25.9, 14.8, 13.9 ppm.
+
6.7, 26.2, 14.1 ppm; HRMS: calcd for C27
95.2131; found 495.2139.
H
31
N
2
O
7
[M + H] :
Ethyl-[3-O-ethyl-5,6-dideoxy-1,2-O-isopropylidene-5-nitro-
methyl]-b-L-ido-heptofuranurnate (6). A stirred solution of
0 0 0 0 0
3
-[Ethyl-(3 -O-benzyl-5 ,6 -dideoxy-1 ,2 -O-isopropylidene)-b- compound 5 (2.0 g, 6.99 mmol) and nitromethane (0.823 mL,
0
00
00
L-ido-heptofuranurnate-5 -yl]-5-(2 -phenylmethan-1 -yl)-isoxazole 0.015 mol) in presence of K CO (1.93 mg, 0.013 mol) at
2
3
(
4m). Compound 3 (0.35 g, 0.85 mmol) on treatment with reuxing temperature for 6 h in anhydrous ethanol (20 mL)
3
1
-phenyl-1-propyne 2m (0.127 mL, 1.03 mmol), TsCl (212 mg, afforded 6 which was puried by ash column chromatography
.11 mmol), K
2
CO
3
(236 mg, 1.71 mmol), 18-crown-6 (10 mol%) using gradient mixtures of n-hexane and EtOAc (8 : 2). Colour-
ꢀ
in dry toluene (10 mL) at 80 C for 9 h and workup as described less liquid, 2.11 g, yield 87%; R
in general procedure afforded 4m as yellow liquid (238 mg, yield n-hexane), H NMR (300 MHz, CDCl
5
3
f
¼ 0.51 (15% ethyl acetate/
1
3
): d 5.82 (s, 1H), 4.79 (d, J ¼
5%). R ¼ 0.51 (25% ethyl acetate/n-hexane); IR (KBr) nmax: 13.2 Hz, 1H), 4.61–4.51 (m, 2H), 4.15–4.10 (m, 3H), 3.75–3.67
f
039, 2983, 2932, 1732 (C]O), 1611 (C]N), 1580, 1458, 1240 (m, 2H), 3.41 (s, 1H), 3.01 (m, 1H), 2.45 (d, J ¼ 4.5 Hz, 2H), 1.42
ꢁ
1
1
13
(C–O–N), 1163, 1074, 1030, 860, 723 cm ; H NMR (300 MHz, (s, 3H), 1.27 (s, 3H), 1.25–1.15 (m, 6H); C NMR (75 MHz,
CDCl
3
): d 7.30–7.21 (m, 10H), 5.91 (s, 1H), 5.90 (d, J ¼ 3.6 Hz, CDCl
3
): d 170.9, 111.7, 104.6, 82.0, 81.7, 78.9, 75.5, 65.5, 60.8,
1
1
4
H), 4.69 (d, J ¼ 11.7 Hz, 1H), 4.64 (d, J ¼ 3.6 Hz, 1H), 4.42 (d, J ¼ 33.4, 33.0, 26.6, 26.2, 15.0, 14.0 ppm.
0 0 0 0 0
3-[Ethyl-(3 -O-ethyl-5 ,6 -dideoxy-1 ,2 -O-isopropylidene)-b-
1.7 Hz, 1H), 4.33 (d, J ¼ 6.6 Hz, 1H), 4.34–4.31 (m, 1H), 4.05–
.00 (m, 3H), 3.90 (d, J ¼ 2.7 Hz, 1H), 3.77–3.70 (m, 1H), 2.69 L-ido-heptofuranurnate-5 -yl]-5-(3 -O-benzyl-1 ,2 -O-isopropyl-
0
00
00 00
0
0
00
(dd, J ¼ 9.9, 16.2 Hz, 1H), 2.38 (dd, J ¼ 3.6, 15.9 Hz, 1H), 1.43 (s, idene-4 -O-methyl-a-D-xylofuranose-4 -yl)-isoxazole
(7a).
1
3
3H), 1.30 (s, 3H), 1.14 (t, J ¼ 7.2 Hz, 3H); C NMR (75 MHz, Compound 6 (450 mg, 1.29 mmol) on treatment with 3-O-
CDCl ): d 171.1, 165.5, 163.8, 136.8, 136.0, 129.8, 128.8 (2C), benzyl-1,2-O-isopropylidene-4-O-propargyl-a-D-xylofuranose 2c
3
1
8
28.6 (2C), 128.4 (2C), 128.1, 127.9, 126.9, 111.6, 104.7, 102.8, (494 mg, 1.55 mmol), TsCl (320 mg, 1.68 mmol), K CO (355 mg,
2 3
1.5, 81.3, 81.1, 71.5, 60.4, 34.5, 33.7, 33.2, 26.6, 26.2, 14.0 ppm; 2.59 mmol), 18-crown-6 (10 mol%) in dry toluene (10 mL) at
+
ꢀ
HRMS: calcd for C29
H
34NO
7
[M + H] : 508.2335; found 508.2341. 80 C for 9 h and workup as described in general procedure
0
0
0
0
0
3
-(Ethyl-[3 -O-benzyl-5 ,6 -dideoxy-1 ,2 -O-isopropylidene]-b- afforded 7a as pale yellow liquid (562 mg, yield 67%). R
f
¼ 0.32
0
00
00
L-ido-heptofuranurnate-5 -yl)-5-(3 cyanopropan-1 -yl)-isoxazole (30% ethyl acetate/n-hexane); IR (KBr) nmax: 2986, 2937, 1732
(
1
4n). Compound 3 (0.5 g, 1.22 mmol) on treatment with 5-cyano- (C]O), 1610 (C]N), 1590, 1467, 1376, 1217 (C–O–N), 1166,
-pentyne 2n (0.153 mL, 1.47 mmol), TsCl (300 mg, 1.59 mmol), 1101, 1075, 1015, 964, 856, 735 cm ; H NMR (300 MHz,
ꢁ
1
1
K CO (337 mg, 2.44 mmol), 18-crown-6 (10 mol%) in dry CDCl ): d 7.34–7.30 (m, 5H), 6.22 (s, 1H), 5.92 (d, J ¼ 3.3 Hz, 1H),
2
3
3
ꢀ
toluene (10 mL) at 80 C for 9 h and workup as described in 5.89 (d, J ¼ 3.9 Hz, 1H), 5.87–4.47 (m, 6H), 4.25–4.29 (m, 2H),
general procedure afforded 4n as pale yellow liquid (589 mg, 4.18–3.95 (m, 3H), 3.86–3.61 (m, 5H), 3.51–3.40 (m, 1H), 2.83–
yield 68%). R
f
¼ 0.47 (30% ethyl acetate/n-hexane); IR (KBr) nmax
:
2.78 (m, 1H), 2.70 (d, J ¼ 3.9 Hz, 1H), 1.45 (s, 6H), 1.31 (s, 6H),
13
2
927, 2247, 1732 (C]O), 1604 (C]N), 1455, 1375, 1260 (C–O– 1.21–1.15 (m, 6H); C NMR (75 MHz, CDCl
3
) d 171.2, 168.1,
H NMR 163.9, 137.3, 128.4 (2C), 127.9, 127.6 (2C), 111.7, 111.5, 105.0,
): d 7.33–7.26 (m, 5H), 6.06 (s, 1H), 5.92 (d, J ¼ 104.8, 103.8, 82.2, 82.1, 81.6, 81.3, 81.1, 79.0, 72.0, 68.5, 65.5,
.3 Hz, 1H), 4.73 (d, J ¼ 11.7 Hz, 1H), 4.65 (d, J ¼ 3.9 Hz, 1H), 64.2, 60.5, 34.6, 33.5, 26.7 (2C), 26.2 (2C), 15.0, 14.0 ppm.
ꢁ
1
1
N), 1165, 1075, 1024, 857, 806, 700, 740 cm
300 MHz, CDCl
;
(
3
3
4
7
2
7
1
1
1
2
4
0 0 0 0 0
3-[Ethyl-(3 -O-ethyl-5 ,6 -dideoxy-1 ,2 -O-isopropylidene)-b-
.45 (d, J ¼ 11.7 Hz, 1H), 4.32 (d, J ¼ 6.9 Hz, 1H), 4.06 (d, J ¼
.2 Hz, 2H), 3.93 (m, 1H), 3.79–3.72 (m, 1H), 2.88–2.83 (m, 2H), L-ido-heptofuranurnate-5 -yl]-5-(3 ,6 -di-O-benzyl-5 -O-methyl-
0
00 00
00
0
0
00
00
.70 (dd, J ¼ 7.2, 16.2 Hz, 1H), 2.40–2.35 (m, 3H), 2.03 (d, J ¼ 1 ,2 -O-isopropylidene-a-D-glucofuranose-5 -yl)-isoxazole (7b).
.2 Hz, 1H), 1.99 (d, J ¼ 6.9 Hz, 1H), 1.46 (s, 3H), 1.31 (s, 3H), Compound 6 (450 mg, 1.29 mmol) on treatment with 3,6-di-O-
1
3
.19 (t, J ¼ 6.9 Hz, 3H); C NMR (75 MHz, CDCl
3
): d 170.9, 169.7, benzyl-5-O-propargyl-1,2-O-isopropylidene-a-D-glucofuranose 2i
64.0, 136.7, 128.4 (2C), 128.1, 127.9 (2C), 118.7, 111.6, 104.7, (680 mg, 1.55 mmol), TsCl (320 mg, 1.68 mmol), K
02.7, 81.4, 81.2, 80.9, 71.5, 60.5, 34.5, 33.3, 26.6, 26.1, 25.4, 2.59 mmol), 18-crown-6 (10 mol%) in dry toluene (10 mL) at
3.2, 16.4, 14.0 ppm; HRMS: calcd for C H N O [M + H] : 80 C for 9 h and workup as described in general procedure
85.2288; found 485.2296.
2 3
CO (355 mg,
+
ꢀ
2
6
33 2 7
afforded 7b as yellow liquid (646 mg, yield 65%). R ¼ 0.47 (35%
f
Ethyl-[3-O-ethyl-5,6-dideoxy-1,2-O-isopropylidene-a-D-gluco]- ethyl acetate/n-hexane); IR (KBr) n : 2994, 2934, 1734 (C]O),
max
heptfuran-5-en-uronate (5). D-Glucose aer processing through 1618 (C]N), 1588, 1459, 1366, 1214 (C–O–N), 1170, 1102, 1075,
ꢁ
1 1
a number of high-yielding steps such as isopropylidene 1014, 968, 874, 732 cm ; H NMR (300 MHz, CDCl
protection, 3-O-ethyl protection, selective 5,6-isopropylidene 7.30 (m, 10H), 6.20 (s, 1H), 5.89 (s, 2H), 4.85 (d, J ¼ 12.9 Hz, 1H),
deprotection, NaIO
oxidation, and nally the HEW modica- 4.63–4.45 (m, 6H), 4.35 (d, J ¼ 9.3 Hz, 1H), 4.19–4.05 (m, 6H),
tion afforded the glycosyl olenic ester 5 as colourless liquid 3.89–3.43 (m, 6H), 2.81 (d, J ¼ 9.3 Hz, 1H), 2.65 (dd, J ¼ 3.3,
3
): d 7.40–
4
23
41532 | RSC Adv., 2015, 5, 41520–41535
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1
6
1
5.9 Hz, 1H), 1.47 (s, 3H), 1.44 (s, 3H), 1.30 (s, 6H), 1.20–1.16 (m, 1H), 4.68–4.46 (m, 5H), 4.36 (m, 1H), 3.95 (m, 1H), 3.77 (m, 2H),
1
3
13
H); C NMR (75 MHz, CDCl ): d 171.2, 168.6, 163.8, 137.5 (2C), 2.26 (s, 3H), 1.47 (s, 3H), 1.31 (s, 3H); C NMR (75 MHz, CDCl3):
3
29.7, 129.5, 128.4 (2C), 128.3 (2C), 127.7 (2C), 127.5 (2C), 111.7 d 168.6, 159.5, 137.2, 128.3 (2C), 127.8, 127.5 (2C), 111.6, 105.0,
(
7
1
2C), 105.1, 104.8, 103.6, 84.2, 82.0, 81.8, 81.6, 81.2, 78.8, 73.3, 103.5, 82.9, 81.6, 79.0, 71.8, 68.4, 64.0, 26.6, 26.1, 11.2 ppm.
0
0
0
0
0
2.2, 71.6, 71.5, 65.5, 63.7, 60.5, 37.3, 33.5, 26.7 (2C), 26.2 (2C),
3-Methyl-5-(1 ,2 :4 ,5 -di-O-isopropylidene-3 -O-methyl-D-fructo-
+
00
5.1, 14.0 ppm; HRMS: calcd for C41
H
54NO13 [M + H] : 768.3595; pyranose-3 -yl) isoxazole (9c). Nitroethane
8
(0.10 mL,
found 768.3588.
1.40 mmol) on treatment with 1,2:4,5-di-O-isopropylidene-3-O-
0
0
0
0
0
0
3
-[Ethyl-(3 -O-ethyl-5 ,6 -dideoxy-1 ,2 -O-isopropylidene)-b-L- propargyl-D-fructopyranose 2d (350 mg, 1.17 mmol), TsCl
00 00 00 00
ido-heptofuranurnate-5 -yl]-5-(1 ,2 :3 ,4 -di-O-isopropylidene- (291 mg, 1.52 mmol), K
2
CO
3
(324 mg, 2.34 mmol), and
0
0
00
ꢀ
6
-O-methyl-a-D-galactopyranose-6 -yl) isoxazole (7c). Compound 18-crown-6 (10 mol%) in dry toluene (10 mL) at 80 C for 8 h and
(300 mg, 0.86 mmol) on treatment with 1,2:3,4-di-O-iso- workup as described in general procedure afforded 9c as yellow
6
propylidene-6-O-propargyl-a-D-galactopyranose 2g (309 mg, liquid (271 mg, yield 65%). R ¼ 0.49 (25% ethyl acetate/
f
1
1
8
.03 mmol), TsCl (214 mg, 1.12 mmol), K
2 3
CO (238 mg, n-hexane); IR (KBr) nmax: 2939, 2855, 1753 (C]O), 1614 (C]N),
.72 mmol), and 18-crown-6 (10 mol%) in dry toluene (10 mL) at 1607, 1460, 1358, 1263 (C–O–N), 1160 1132, 1075, 1020, 954,
ꢀ
ꢁ1
1
0 C for 8 h and workup as described in general procedure 873, 869, 632 cm ; H NMR (300 MHz, CDCl
¼ 0.30 (30% 5.30 (s, 1H), 4.95 (d, J ¼ 13.5 Hz, 1H), 4.78 (d, J ¼ 13.5 Hz, 1H),
ethyl acetate/n-hexane); IR (KBr) nmax: 2984, 2933, 1736 (C]O), 4.37–4.33 (m, 1H), 4.22–4.15 (m, 1H), 4.11–3.98 (m, 2H), 3.89 (d,
3
): d 6.07 (s, 1H),
afforded 7c as yellow liquid (368 mg, yield 68%). R
f
1
1
1
612 (C]N), 1589, 1457, 1369, 1218 (C–O–N), 1166, 1109, 1075, J ¼ 8.7 Hz, 1H), 3.52 (d, J ¼ 7.5 Hz, 1H), 2.29 (s, 3H), 1.54 (s, 3H),
ꢁ
1
1
1
3
024, 966, 873, 731 cm ; H NMR (300 MHz, CDCl ): d 6.28 (s, 1.48 (s, 3H), 1.39 (s, 3H), 1.32 (s, 3H); C NMR (75 MHz, CDCl ):
3
3
H), 5.90 (s, 1H), 5.53 (d, J ¼ 4.8 Hz, 1H), 4.68–4.59 (m, 3H), 4.55 d 168.8, 159.5, 112.2, 109.1, 103.9, 103.6, 77.4 (2C), 73.7, 71.6,
(
d, J ¼ 3.3 Hz, 1H), 4.38 (d, J ¼ 9 Hz, 1H), 4.31 (m, 1H), 4.24 (d, 63.6, 60.0, 28.0, 26.7, 26.1, 25.8, 11.3 ppm.
0
0
0
0
0
J ¼ 7.8 Hz, 1H), 4.09 (d, J ¼ 6.9 Hz, 2H), 4.05–3.98 (m, 2H), 3.82–
3-Methyl-5-(1 ,2 :5 ,6 -di-O-isopropylidene-3 -O-methyl-a-D-
0
3
.62 (m, 4H), 3.45 (d, J ¼ 6.9 Hz, 1H), 2.90–2.81 (m, 1H), 2.69 (d, glucofuranose-3 -yl)-isoxazole (9d). Nitroethane 8 (0.14 mL,
J ¼ 15.9 Hz, 1H), 1.54 (s, 3H), 1.44 (s, 3H), 1.33 (s, 6H), 1.30–1.17 2.01 mmol) on treatment with 1,2:5,6-di-O-isopropylidene-3-O-
1
3
(m, 12H); C NMR (75 MHz, CDCl
3
): d 171.2, 168.4, 163.8, 111.5, propargyl-a-D-glucofuranose 2e (500 mg, 1.67 mmol), TsCl
1
6
2
09.2, 108.5, 104.8, 103.8, 96.2, 82.1, 81.6, 81.1, 71.0, 70.6, 70.4, (415 mg, 2.18 mmol), K CO (463 mg, 3.35 mmol), 18-crown-6
9.8, 66.8, 65.5, 64.2, 60.5, 34.6, 33.6, 26.7, 26.2, 26.0, 25.9, 24.8, (10 mol%) in dry toluene (10 mL) at 80 C for 10 h and
2
3
ꢀ
4.3, 15.1, 14.0 ppm.
workup as described in general procedure afforded 9d as yellow
¼ 0.59 (30% ethyl acetate/
0
0
0
0
3
-Methyl-5-(5 -O-benzyl-1 ,2 -O-isopropylidene-3 -O-methyl- liquid (405 mg, yield 68%). R
f
0
a-D-xylofuranose-3 -yl)-isoxazole (9a). Nitroethane 8 (0.07 mL, n-hexane); IR (KBr) nmax: 2929, 2858, 1756 (C]O), 1611 (C]N),
1
3
.32 mmol) on treatment with 5-O-benzyl-1,2-O-isopropylidene- 1604, 1453, 1358, 1265 (C–O–N), 1158, 1132, 1073, 1025, 958,
ꢁ
1 1
-O-propargyl-a-D-xylofuranose 2b (350 mg, 1.10 mmol), TsCl 872, 638 cm ; H NMR (300 MHz, CDCl
3
): d 6.17 (s, 1H), 5.88 (d,
(
272 mg, 1.43 mmol), K
2
CO
3
(304 mg, 2.20 mmol), 18-crown-6 J ¼ 3.6 Hz, 1H), 4.72 (m, 2H), 4.43 (d, J ¼ 3.6 HZ, 1H), 4.29 (dd,
ꢀ
(10 mol%) in dry toluene (10 mL) at 80 C for 8 h and workup J ¼ 5.7, 13.8 Hz, 1H), 4.13–4.08 (m, 2H), 4.03–3.96 (m, 2H), 2.30
13
as described in general procedure afforded 9a as white crystal- (s, 3H), 1.49 (s, 3H), 1.42 (s, 3H), 1.35 (s, 3H), 1.31 (s, 3H);
C
line solid (268 mg, yield 65%). R ¼ 0.58 (30% ethyl acetate/ NMR (75 MHz, CDCl ): d 168.2, 159.6, 111.8, 109.0, 105.2, 103.6,
f
3
n-hexane); IR (KBr) nmax: 2924, 2854, 1785 (C]O), 1613 (C]N), 82.7, 82.2, 81.0, 72.1, 67.3, 63.3, 26.8, 26.7, 26.0, 25.3, 11.2 ppm.
0
0
0
0
0
1
6
1
6
4
3
1
8
454, 1374, 1215 (C–O–N), 1165, 1076, 1018, 890, 858, 745,
3-Methyl-5-(2 ,3 :5 ,6 -di-O-isopropylidene-1 -O-methyl-D-
ꢁ1
1
0
99 cm ; H NMR (300 MHz, CDCl
3
): d 7.32 (m, 5H), 6.04 (s, mannofuranose-1 -yl) isoxazole (9e). Nitroethane 8 (0.14 mL,
H), 5.90 (d, J ¼ 3.3 Hz, 1H), 4.66 (d, J ¼ 13.8 Hz, 2H), 4.60 (d, J ¼ 2.01 mmol) on treatment with 2,3:5,6-di-O-isopropylidene-1-O-
.9 Hz, 1H), 4.56 (d, J ¼ 2.1 HZ, 1H), 4.54 (d, J ¼ 5.1, 1H), 4.49– propargyl-D-mannofuranose 2f (500 mg, 1.67 mmol), TsCl
.39 (m, 1H), 4.00 (d, J ¼ 2.4 Hz, 1H), 3.77–3.72 (m, 2H), 2.24 (s, (415 mg, 2.18 mmol), K CO (168 mg, 1.221 mmol), 18-crown-6
2
3
1
3
ꢀ
H), 1.48 (s, 3H), 1.30 (s, 3H); C NMR (75 MHz, CDCl ): d 167.9, (10 mol%) in dry toluene (10 mL) at 80 C for 8 h and workup as
3
59.6, 137.7, 128.3 (2C), 127.7, 127.6 (2C), 111.7, 104.8, 103.7, described in general procedure afforded 9e as yellow liquid
2.2 (2C), 78.6, 73.4, 66.8, 62.8, 26.6, 26.1, 11.2 ppm; HRMS: (393 mg, yield 66%). R
f
¼ 0.56 (30% ethyl acetate/n-hexane); IR
+
calcd for C20
H
26NO
6
: [M + H] : 376.1760; found 376.1769.
(KBr) nmax: 2932, 2860, 1754 (C]O), 1612 (C]N), 1606, 1455,
-Methyl-5-(3 -O-benzyl-1 ,2 -O-isopropylidene-5 -O-methyl- 1356, 1266 (C–O–N), 1158 1133, 1072, 1024, 956, 875, 636 cm
0
0
0
0
ꢁ1
3
;
0
1
a-D-xylofuranose-5 -yl)-isoxazole (9b). Nitroethane 8 (0.19 mL,
H NMR (300 MHz, CDCl
3
): d 6.09 (s, 1H), 5.07 (s, 1H), 4.80–4.77
2
5
.70 mmol) on treatment with 3-O-benzyl-1,2-O-isopropylidene- (m, 1H), 4.65 (d, J ¼ 7.5 Hz, 1H), 4.60 (d, J ¼ 9.9 Hz, 1H), 4.54 (m,
-O-propargyl-a-D-xylofuranose 2c (500 mg, 1.57 mmol), TsCl 1H), 4.41–4.37 (m, 1H), 4.12–4.07 (m, 1H), 4.00 (d, J ¼ 4.5 Hz,
(
(
150 mg, 2.04 mmol), K CO (434 mg, 3.14 mmol), 18-crown-6 1H), 3.96 (dd, J ¼ 3.9, 7.5 Hz, 1H), 2.29 (s, 3H), 1.45 (s, 3H), 1.38
13
2
3
ꢀ
10 mol%) in dry toluene (10 mL) at 80 C for 8 h and workup (s, 3H), 1.32 (s, 3H), 1.29 (s, 3H); C NMR (75 MHz, CDCl ): d
3
as described in general procedure afforded 9b as yellow liquid 167.9, 159.7, 112.7, 109.1, 105.8, 103.9, 84.8, 80.6, 79.3, 72.9,
(
383 mg, yield 65%). R
f
¼ 0.45 (25% ethyl acetate/n-hexane); IR 66.6, 59.4, 26.8, 25.7, 25.1, 24.4, 11.1 ppm.
0
0
0
0
0
(KBr) nmax: 2938, 2864, 1770 (C]O), 1613 (C]N), 1585, 1448,
3-Methyl-5-(1 ,2 :3 ,4 -di-O-isopropylidene-6 -O-methyl-a-D-
ꢁ1
0
1
370, 1219 (C–O–N), 1170, 1108, 1074, 1020, 963, 876, 732 cm
H NMR (300 MHz, CDCl ): d 7.29 (m, 5H), 6.07 (s, 1H), 5.92 (s, 1.40 mmol) on treatment with 1,2:3,4-di-O-isopropylidene-6-O-
3
;
galactopyranose-6 -yl) isoxazole (9f). Nitroethane 8 (0.105 mL,
1
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propargyl-a-D-galactopyranose 2g (350 mg, 1.17 mmol), TsCl 1611 (C]N), 1592, 1455, 1356, 1212 (C–O–N), 1170, 1112, 1074,
ꢁ
1 1
(
(
291 mg, 1.52 mmol), K CO (324 mg, 2.34 mmol), 18-crown-6 1032, 964, 865, 720 cm ; H NMR (300 MHz, CDCl ): d 6.14 (s,
2 3 3
ꢀ
10 mol%) in dry toluene (10 mL) at 80 C for 8 h and workup 2H), 4.76 (d, J ¼ 13.8 Hz, 1H), 4.65 (s, 1H), 4.55 (d, J ¼ 2.4 Hz,
as described in general procedure afforded 9f as yellow liquid 2H), 4.44–4.27 (m, 2H), 4.23 (d, J ¼ 2.4 Hz, 1H), 4.12 (d, J ¼
(
(
1
271 mg, yield 65%). R
KBr) nmax: 2954, 2864, 1753 (C]O), 1628 (C]N), 1518, 1462, 3.65 (m, 2H), 2.29 (s, 6H); C NMR (75 MHz, CDCl
357, 1262 (C–O–N), 1158, 1135, 1072, 1025, 953, 876, 880, 698 (2C), 159.7 (2C), 103.9, 103.8, 80.2, 79.7, 79.0, 78.4, 75.1, 71.0,
f
¼ 0.51 (30% ethyl acetate/n-hexane); IR 4.5 Hz, 1H), 4.08 (d, J ¼ 7.2 HZ, 1H), 4.02–3.97 (m, 1H), 3.76–
13
3
): d 168.3
ꢁ
1 1
cm ; H NMR (300 MHz, CDCl
4
3
): d 6.04 (s, 1H), 5.47 (d, J ¼ 62.9, 57.5, 11.2, 11.2 ppm.
.8 Hz, 1H), 4.56 (d, J ¼ 9.9 Hz, 1H), 4.51 (d, J ¼ 7.2 Hz, 2H), 4.24
(
1
1
d, J ¼ 3.0 Hz, 1H), 4.17 (d, J ¼ 7.5 Hz, 1H), 3.90 (d, J ¼ 5.7 Hz,
Acknowledgements
H), 3.69–3.56 (m, 2H), 2.22 (s, 3H), 1.47 (s, 3H), 1.37 (s, 3H),
.26 (s, 6H) ppm.
3
The Authors thank Dr B. Maity and Shubhendu Ghosh for their
-Methyl-5-(1 -O-methyl-2 ,3 ,4 -tri-O-benzyl-6 -O-methyl-a-D- useful suggestions and help in performing D.F.T. based study
glucopyranoside-6 -yl) isoxazole (9g). Nitroethane 8 (0.035 mL, and CISC, Banaras Hindu University, IIT Delhi, and CDRI
0
0
0
0
0
0
0.478 mmol) on treatment with methyl-2,3,4-tri-O-benzyl-6-O- Lucknow for spectroscopic studies. VKT gratefully acknowledge
propargyl-a-D-glucopyranoside 2h (200 mg, 0.478 mmol), TsCl Council of Scientic & Industrial Research, New Delhi (Grant
(
(
98 mg, 0.517 mmol), K
10 mol%) in dry toluene (10 mL) at 80 C for 10 h and
2
CO
3
(110 mg, 0.79 mmol), 18-crown-6 no. 02(0173)/13/EMRII) for the funding.
ꢀ
workup as described in general procedure afforded 9g as yellow
References
liquid (156 mg, yield 70%). R ¼ 0.53 (30% ethyl acetate/
f
n-hexane); IR (KBr) nmax: 2925, 1730 (C]O), 1606 (C]N), 1496,
1 K. A. Kumar and P. Jayaroopa, Int. J. Pharm., Chem. Biol. Sci.,
2013, 3, 294.
1
6
453, 1360, 1277 (C–O–N), 1136, 1109, 1096, 1070, 913, 806, 742,
ꢁ1 1
98 cm ; H NMR (300 MHz, CDCl
3
): d 7.26–7.13 (m, 15H), 5.95
2 P. Diana, A. Carbone, P. Barraja, G. Kelter, H. H. Fiebig and
G. Cirrincione, Bioorg. Med. Chem., 2010, 18, 4524.
3 A. Kamal, E. V. Bharathi, J. S. Reddy, M. J. Ramaiah,
D. Dastagiri, M. K. Reddy, A. Viswanath, T. L. Reddy,
T. B. Shaik, S. N. C. V. L. Pushpavalli and M. P. Bhadra,
Eur. J. Med. Chem., 2011, 46, 691.
4 S. Velaparthi, M. Brunsteiner, R. Uddin, B. Wan,
S. G. Franzblau and P. A. Petukhov, J. Med. Chem., 2008,
51, 1999.
(
(
(
s, 1H), 4.90 (d, J ¼ 10.8 Hz, 1H), 4.80–4.69 (m, 3H), 4.59–4.38
m, 4H), 3.97–3.84 (m, 2H), 3.66 (d, J ¼ 14.7 Hz, 1H), 3.60–3.43
1
3
m, 4H), 3.29 (s, 3H), 2.15 (s, 3H); C NMR (75 MHz, CDCl ): d
3
1
1
7
68.5, 159.6, 138.6, 138.1 (2C), 128.4 (4C), 128.3 (2C), 128.0 (2C),
27.9 (2C), 127.7 (2C), 127.6 (2C), 127.5, 103.7, 98.1, 81.9, 79.7,
6.5, 75.7, 74.9, 73.3, 69.8, 69.2, 64.0, 55.1, 11.2 ppm.
0
0
0
0
0
3
-Methyl-5-(3 ,6 -di-O-benzyl-5 -O-methyl-1 ,2 -O-isopropyl-
0
idene-a-D-glucofuranose-5 -yl) isoxazole (9h). Nitroethane 8
(
0.05 mL, 0.821 mmol) on treatment with 3,6-di-O-benzyl-5-O-
5 Y. K. Kang, K. J. Shin, K. H. Yoo, K. J. Seo, C. Y. Hong,
C. S. Lee, S. Y. Park, D. J. Kim and S. W. Park, Bioorg. Med.
Chem. Lett., 2000, 10, 95.
6 M. M. M. Santos, N. Faria, J. Iley, S. J. Coles,
M. B. Hursthouse, M. L. Martins and R. Moreira, Bioorg.
Med. Chem. Lett., 2010, 20, 193.
7 A. Balsamo, I. Coletta, A. Guglielmotti, C. Landol,
F. Mancini, A. Martinelli, C. Milanese, F. Minutolo,
S. Nencetti, E. Orlandini, M. Pinza, S. Rapposelli and
A. Rossello, Eur. J. Org. Chem., 2003, 38, 157.
8 M. L. Herrmann, R. Schleyerbach and B. J. Kirschbaum,
Immunopharmacology, 2000, 47, 273.
propargyl-1,2-O-isopropylidene-a-D-glucofuranose 2i (300 mg,
0
1
8
.68 mmol), TsCl (169 mg, 0.89 mmol), K CO (189 mg,
2 3
.36 mmol), 18-crown-6 (10 mol%) in dry toluene (10 mL) at
ꢀ
0 C for 10 h and workup as described in general procedure
afforded 9h as yellow liquid (220 mg, yield 63%). R
ethyl acetate/n-hexane); IR (KBr) nmax: 2988, 2932, 2862, 1728
f
¼ 0.52 (30%
(C]O), 1613 (C]N), 1497, 1454, 1374, 1216 (C–O–N), 1165,
ꢁ
1
1
1
138, 1075, 1026, 890, 739, 699 cm
): d 7.32–7.27 (m, 10H), 5.93 (s, 1H), 5.88 (d, J ¼ 3.6 Hz,
H), 4.82 (d, J ¼ 12.9 Hz, 1H), 4.69 (d, J ¼ 11.1 Hz, 1H), 4.63–4.58
m, 1H), 4.54–4.45 (m, 4H), 4.21 (dd, J ¼ 3.0, 9.0 Hz, 1H), 4.09 (d,
J ¼ 2.7 Hz, 1H), 4.06–4.01 (m, 1H), 3.89 (d, J ¼ 10.5 Hz, 1H), 3.66
; H NMR (300 MHz,
CDCl
1
(
3
9 D. M. Livermore, Clin. Microbiol. Rev., 1995, 8, 557.
(
dd, J ¼ 6.3, 10.5 Hz, 1H), 2.19 (s, 3H), 1.47 (s, 3H), 1.30 (s, 3H); 10 W. P. Dmowski, H. F. Scholer, V. B. Mahesh and
1
3
C NMR (75 MHz, CDCl
3
): d 168.9, 159.4, 138.1, 137.3, 128.3
R. B. Greenblatt, Fertil. Steril., 1971, 22, 9.
(2C), 128.1 (2C), 127.7, 127.4, 127.4, 127.2 (3C), 111.6, 105.0, 11 (a) S. Batra, T. Srinivasan, S. K. Rastogi, B. Kundu, A. Patra,
1
1
03.3, 81.57, 81.50, 78.6, 75.9, 73.3, 71.8, 71.4, 63.5, 26.6, 26.1,
1.1 ppm.
A. P. Bhaduri and M. Dixit, Bioorg. Med. Chem. Lett., 2002, 12,
1905; (b) P. G. Baraldi, A. Basco, S. Benetti, G. P. Pollini and
D. Simoni, Synthesis, 1987, 857; (c) A. P. Kozikowski, Acc.
Chem. Res., 1984, 17, 410.
0
0
1,4:3,6-Dianhydro-2,5-bis-O-[5 -(methyl)-3 -methyl-isoxazole-
0
5
-yl]-D-mannitol (9i). Nitroethane 8 (0.40 mL, 5.40 mmol) on
treatment with 2,5-di-O-propargyl-1,4:3,6-dianhydro-D-mannitol 12 (a) A. Varki, Glycobiology, 1993, 3, 97; (b) C. R. Bertozzi and
2
9
8
o (500 mg, 2.25 mmol), TsCl (1.11 g, 5.84 mmol), K
2
CO
3
(1.24 g,
L. L. Kiessling, Science, 2001, 291, 2357; (c) V. K. Tiwari,
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.0 mmol), and 18-crown-6 (10 mol%) in dry toluene (10 mL) at
ꢀ
0 C for 10 h and workup as described in general procedure
afforded 9i as yellow liquid (469 mg, yield 62%). R
ethyl acetate/n-hexane); IR (KBr) nmax: 2990, 2929, 1756 (C]O),
f
¼ 0.51 (35% 13 Y. Singh, N. Spinelli, E. DeFrancq and P. Dumy, Org. Biomol.
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