Synthesis of C-Analogues of β-Glucogallin and Aldose Reductase Inhibition Studies

Article abstract of DOI:10.1002/ejoc.201701468

β-Glucogallin 1 (BGG), a major component isolated from the Indian gooseberry (Emblica officinalis) medicinal plant, is a potent and selective inhibitor of aldose reductase (AKR1B1). Structurally, BGG is a glucosyl-1-ester, wherein gallic acid is linked to

Full text of DOI:10.1002/ejoc.201701468

A Journal of
Accepted Article
Title: Synthesis of C-Analogues of β‑Glucogallin and Aldose
Reductase Inhibition Studies
Authors: Indrapal Singh Aidhen, Mannem Rajeswara Reddy, Shruthi
Karnam, and Geereddy Bhanuprakash Reddy
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701468
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10.1002/ejoc.201701468
European Journal of Organic Chemistry
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Synthesis of C-Analogues of β‑Glucogallin and Aldose
Reductase Inhibition Studies.
Mannem Rajeswara Reddy,a Indrapal Singh Aidhen,*[a] Karnam Shruthi,b Geereddy Bhanuprakash
Reddy*[b]
Abstract: -Glucogallin 1 (BGG), a major component isolated from
the Indian gooseberry (Emblica officinalis) medicinal plant, is a potent
and selective inhibitor of aldose reductase (AKR1B1). Structurally,
BGG is a glucosyl-1-ester, wherein gallic acid is linked to the β-D-
glucose ring through ester functionality. Susceptibility of the easily
hydrolysable ester functional group in aqueous solution has been the
cause of concern. Isosteric replacement of glucosyl-O- with -NH- has
offered the more stable and potent analogue 2, the C-analogue 3,
wherein a –CH2- unit replaces the glucosyl-O however remains
unexplored. Synthesis of C-analogues 3 and 4 and their aldose
reductase inhibition (ARI) constitutes the work presented herein.
Introduction
The number of people with diabetes rose to 422 million in 2014
from 108 million in 1980.1a Diabetes can lead to macrovascular
complications like stroke and cardiovascular diseases and
microvascular complications like retinopathy, nephropathy,
cataract and neuropathy. The plant Emblica officinalis
(gooseberry) has been used for thousands of years as traditional
Indian Ayurvedic medicine for the treatment of diabetes in human.
Extracts from this plant have been shown to be efficacious against
the progression of cataract in a diabetic rat model.1b Aldose
reductase (ALR2 or AKR1B1) is implicated in the development of
secondary complications of diabetics including cataract. The
enzyme, ALR2 has been a major drug target for the development
of therapies to treat diabetic complications.2 The compound 1-O-
galloyl--glucose (-glucogallin) (BGG) 1 extracted as a major
component from the fruit of the gooseberry displays selective as
well as relatively potent inhibition of AKR1B1.3 Structurally BGG 1
is a D-glucosyl-1-ester and therefore susceptible to easy
hydrolysis in aqueous solution. LaBarbera 4 has synthesized and
explored hydrolytically more stable, N-analogue of BGG,
Figure 1. Isosteric replacement D-glucosyl-O-of -glucogallin.
isosteric replacement of glucosyl-O atom in BGG with a -CH2 - unit.
The findings of these studies are reported herein.
The synthesis of the targeted compounds 3 and 4 through the
disconnection depicted in figure 1 banked on the use of Weinreb
amide (WA) functionality.5 The WA based building block 5, would
afford not just the desired targets 3 and 4, but also enable access
to several other analogues through variation in the nature of the
aryl residue. Same disconnection and a similar building block 6 is
capable of bringing variation in the glycosyl part. With the use of
6, as an illustration, the corresponding D-galacto configured aryl
ketones can be obtained with the same ease.
compound
2 for aldose reductase inhibition activity. The
promising results obtained therein, inspired us to undertake
synthesis of C-analogues 3 and 4 towards the same objective.
The envisaged compounds are essentially ketones, resulting from
[a]
Department of Chemistry, Indian institute of Technology Madras,
Chennai 600036, India.
Results and Discussion
E-mail: isingh@iitm.ac.in
http://chem.iitm.ac.in/faculty/indrapalsinghaidhen/
Biochemistry Division, National Institute of Nutrition, Hyderabad-
500007, India.
[b]
The synthesis of building blocks 5 and 6 required convenient
access to the corresponding acids 7 and 8 respectively. Literature
known method for the synthesis of 7 6 which involves addition of
lithiumethylacetate 7 on 2, 3, 4, 6-tetra-O-benzylgluconolactone 9
8 for the addition of two carbons on the anomeric position, was
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
1
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10.1002/ejoc.201701468
European Journal of Organic Chemistry
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used for the synthesis of both 7 and 8. The requisite D-galacto
configured lactone 10 required for the synthesis of acid 8 was
prepared from commercially available D-galactose using literature
reported method.9 Addition of 2, 3, 4, 6-tetra-O-benzylglucono-
lactone 9 onto a freshly prepared lithiumethylacetate followed by
reduction of resulted hemiketal with Et3SiH in presence of
For the synthesis of 3, 4, 5-trimethoxyphenyl substituted glucosyl
ketone 4, 3,4,5-trimethoxyphenylmagnesium bromide was
prepared according to the literature known procedure,10 and
added to the building block 5. The reaction afforded the benzyl
ether protected ketone 15 in good yield. Synthesis of targeted final
product 4 needed debenzylation on the glucosyl moiety alone,
whereas complete deprotection was required for the access to
target 3. The hydrogenation method for debenzylation using 10%
Pd/C as catalyst in THF on compound 15 resulted in additional
concomitant reduction of carbonyl group and such observations
have been reported at other occasions too.11 The combined
benzyl-ether and methyl-ether deprotection on compound 15, for
the synthesis of the target 3, using BBr312 in dry dichloromethane
or trimethylsilyl iodide13 in acetonitrile resulted in degradation and
formation of a complex products mixture. In order, to circumvent
these difficulties, for obtaining 4, and several of its analogues,
envisaged through variation in the aryl residue, change in the
nature of protection in the glucosyl residue was invoked. Given
the fact that O-methoxymethyl ether protection (O-MOM) group
has widespread utility in synthetic organic chemistry in general,14
and also in carbohydrate chemistry,15 we envisaged another
building block 17 as an attractive alternative. The conversion of
compound 5 to corresponding MOM protected building block 17
was accomplished in two steps. Debenzylation through
hydrogenolysis with catalytic Pd/C, and subsequent treatment of
tetrol 16 with chloro methyl methyl ether in presence of Hunigs
base in anhydrous CH2Cl2 afforded the MOM protected Weinreb
amide based building block 17 as a pale-yellow color gummy
material in good yield. Successful addition of 3, 4, 5-
trimethoxyphenylmagnesium bromide onto amide 17 afforded the
desired trimethoxyphenyl ketone 18 in good yield. The aqueous
acidic condition, enabled facile removal of MOM protection and
the formation of target molecule 4. (Scheme 2)
.
BF3 OEt2 provided known ethyl ester 11. Base hydrolysis of 11
with LiOH in presence of H2O/THF gave the carboxylic acid 7 in
good yield. Activation of acid 7 with pivaloyl chloride followed by
treatment of the mixed anhydride, formed insitu with N, O-
dimethyl hydroxylamine hydrochloride (DMHA.HCl) in anhydrous
o
CH2Cl2 at 0 C gave the amide 5 in 91% yield (Scheme 1). The
same reaction sequence on D-galacto lactone 10 afforded the
corresponding D-galacto-configured WA based building block 6.
Scheme 1. Synthesis of Building Blocks 5 and 6
Both the building blocks, 5 and 6, when subjected to reaction with
various arylmagnesium bromides afforded the corresponding
glycosyl aryl ketones 13a-e and 14a-e respectively, in good yields
(Table 1).
Table 1. Addition of various Grignard reagents on building block 5 and 6.
Entry
X=OBn,Y=H
(D-Gluco)
Yielda
Ar
Yielda
X=H,Y=OBn
(D-Galacto)
1
2
3
4
5
13a
13b
13c
13d
13e
77%
75%
76%
81%
86%
4-(Me)C6H4
4-(F)C6H4
4-(Cl)C6H4
4-(OMe)C6H4
Thiophenyl
81%
74%
79%
73%
83%
14a
14b
14c
14d
14e
[a] isolated yield.
Scheme 2. Synthesis of MOM protected Building Block 17 and target 4.
2
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10.1002/ejoc.201701468
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The  orientation of the C-residue at the anomeric position was
confirmed through the observed coupling constant for C1-proton
in the peracetylated derivative 19 and single crystal X-ray analysis
of the same (Figure 2). Several glucosyl ketones 21a-h, were
prepared by the same scheme in good yield and convenience
(Table 2). On observing the significance of MOM protection in the
synthetic scheme, we envisaged possible use of MOM protected
arylmagnesium bromide 23 for the synthesis of target compound
3. Synthesis of this Grignard reagent from the corresponding 5-
bromo-1, 2, 3-tris (methoxymethyl ether) benzene 2216 is not
reported earlier and conventional activation procedures17 (entry
1-3, Table 3) did not enable formation of the desired
arylmagnesium derivative 23.
Figure 2. ORTEP diagram of compound 19.
Table 2. Addition of various Grignard reagents on amide 17, synthesis of glycosyl aryl ketones.
Entry
Ar
20
Yielda
Ar
21
Yielda
1
2
3
4
5
6
7
8
4-(OMe)C6H4
4-(Cl)C6H4
4-(OMOM)C6H4
4-(F)C6H4
3,4-(Cl)2C6H3
3,4-(OMe)2C6H3
3,5-(F)2C6H3
3,4,5-(Cl)3C6H2
20a
20b
20c
20d
20e
20f
68%
70%
68%
61%
68%
61%
60%
66%
4-(OMe)C6H4
4-(Cl)C6H4
4-(OH)C6H4
4-(F)C6H4
3,4-(Cl)2C6H3
3,4-(OMe)2C6H3
3,5-(F)2C6H3
3,4,5-(Cl)3C6H2
21a
21b
21c
21d
21e
21f
79%
72%
62%
56%
75%
62%
72%
41%
20g
20h
21g
21h
[a] isolated yield.
With the use of 1, 2-dibromoethane for activation of magnesium
o
at 50 C, substantial amount of homo coupling product 25 was
obtained after aqueous acidic work up. The observation that
addition of 5-12 mol% of diisobutylaluminum hydride (DIBALH)
activates the magnesium metal surface18 and LiCl in conjunction
facilitates the insertion19 of the same into functionalized aryl
bromides, we ventured into use of this method for preparation of
23. Indeed, quantitative formation of 23 was realized, as
evidenced by formation of 24 in quantitative yield, after aqueous
acidic work up (Scheme 3). Although, formation of 23 was now
achieved, it failed to add onto WA functionality in the MOM
protected building block 17. Presuming low reactivity of WA as a
possible reason, the WA was reduced and addition of 23 was
attempted on aldehyde 26. Clean addition reaction occurred and
afforded the corresponding product 27 as a diastereomeric
mixture. Oxidation of alcohol 27 with IBX indeed afforded the
MOM protected target molecule 28 (Scheme 4). Although fully
protected compound 28 was repeatedly and conveniently
amenable by this approach, the obtainment of the target 3,
through deprotection remained elusive. The deprotection of
compound 28 with aq.6N HCl only led to extensive decomposition.
Scheme 3. Preparation of MOM protected arylmagnesium bromide 23.
3
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10.1002/ejoc.201701468
European Journal of Organic Chemistry
FULL PAPER
indicate some other parameter, such as H-bonding with amino
acid residue on the protein structure to be more relevant for good
substrate binding.
Table 3. Reaction condition for the synthesis of Grignard reagent 23.
Table 4. In vitro biological activity of synthesized glucosyl aryl ketones with
Wister male rat lens.
Entry
Condition
Ar-H 24 a
Dimer 25a
Entry
1
Compound
Concentrationa
% Inhibition
1
2
3
4
I2/ Mg/ rt or reflux
0
0
0
0
15
30
60
32
46
62
1 (BGG)
MeI/ I2/ Mg/ rt or
reflux
1,2-dibromoethane/
10%
100%
90%
0%
25
50
200
7
9
12
Mg/ 50
ͦ C
2
3
4
4
Mg/ LiCl/ DIBAL-H/ rt
10
100
200
11
12
8
[a] isolated yield.
21a
21b
25
100
250
7
8
10
15
25
150
200
21
19
22
29
5
6
7
8
9
21c
21d
21e
21f
15
25
150
11
10
8
25
100
200
6
5
6
25
100
250
7
5
17
25
100
200
5
5
2
21g
21h
Scheme 4. Addition of more functionalized Grignard reagent 23, synthesis of
desired glycosyl aryl ketone 28.
25
100
250
6
13
8
10
Biological Study:
[a] micro molar.
Crude aldose reductase (AR) was isolated from rat lens. Eyeballs
were removed from 12-week-old Wistar male rats obtained from
National Center for Laboratory Animal Services, National Institute
of Nutrition, Hyderabad. AR activity was assayed according to the
reported method 20. The synthesized ketones, 4, 21a-h, C-
analogues of β-Glucogallin derivatives were screened for aldose
reductase inhibition at different concentrations. Among these
synthesized compounds, with extensive variation of substituent’s
in the aryl ring, compound 21c alone showed partial inhibition, 
30% at 200µM concentration. The conjecture that increased
electrophilicity of the carbonyl may be an important factor in AR
inhibition, seems to be invalid, as compounds with inductively,
electron withdrawing substituents, such as chloro, fluoro
substiutents, substrates 20b and 20d, respectively did not show
any promising activity. Compounds with multiple chlorine atoms
(20e, 20h) or two fluorine atoms (20g), presumably with increased
carbonyl electrophilicity, also showed poor AR inhibition.
Apparently the observed inhibition with compound 21c seems to
Conclusions
In conclusion, synthesis of several D-glucosyl-aryl ketones, 4 and
21a-h, bridged through a methylene unit at anomeric position has
been achieved. All these compounds are new C-analogues of
BGG, a natural product known for aldose reductase inhibition.
Among the synthesized C-analogues, compound 21c indeed
showed promising aldose reductase inhibition activity.
Experimental Section
All reactions were carried out in oven dried glassware. Solvents used for
column chromatography were laboratory reagent grade. Solvents were
distilled from CaH2 (CH2Cl2, DMF), Na/Benzophenone for THF, Mg/I2
(MeOH). Reactions were performed under nitrogen atmosphere. NMR
4
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10.1002/ejoc.201701468
European Journal of Organic Chemistry
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ͦ
spectra were recorded at 293 K, unless stated otherwise Thin layer
chromatography was performed on aluminum plates coated with silica gel
60. Visualization was observed by U.V. light or by dipping into a solution
of cerium(IV) sulfate (2.5 g) and ammonium molybdate (6.25 g) in 10 %
sulfuric acid (250 mL) followed by charring on a hot plate. Melting points
were determined for compounds 4, 21a-h purified by silica gel column
chromatography using MeOH:CH2Cl2 (1:9), compound 19 was
271.3
(c 0.4, CHCl3); 1H NMR (CDCl3, 400 MHz):
2.39(s3.013.10m3.403.46m3.643.78m
3.94-3.99 (m, 1H), 4.40 (d, 1H, J = 12 HzdJ = 12.4 Hz), 4.57
(d, 1H, J = 10.8 Hz), 4.68 (d, 1H, J = 11.2 Hz), 4.81 (d, 1H, J = 10.8 Hz),
4.88-4.94 (m, 3H), 7.18-7.33 (m, 22H), 7.75 (d, 2H, J = 8 Hz). 13C NMR
(100 MHz, CDCl3) :21.6 (CH3), 40.7 (CH2), 68.7 (CH2), 73.4 (CH2),
74.9 ( 2 CH2), 75.5 (CH), 75.5 (CH2), 78.4 (CH), 79.0 (CH), 81.0 (CH), 87.5
(CH), 127.6 (CH), 127.7 (CH), 127.8 (CH), 127.9 (CH), 127.9 (CH), 128.3
(CH), 128.4 (CH), 128.5 (CH), 128.5 (CH), 128.6 (CH), 129.2 (CH), 135.0
(C), 138.2 (C), 138.3 (C), 138.3 (C), 138.7 (C), 143.8 (C), 197.4 (CO). IR
(CHCl3): 1210, 1425, 1538, 1684, 2883, 2918 cm-1 HRMS: calcd for
C43H44O6Na (M+Na)+ 679.3036, found 679.3025.
recrystallized from EtOAc: hexane. H (400 MHz and 500 MHz) and 13C
1
(100 MHz and 125 MHz) high resolution NMR experiments were recorded
on BRUKER AV 400 and 500 FT NMR spectrometer using
tetramethylsilane (TMS) as an internal standard. 1H NMR spectra were
referenced to CDCl3 ( =7.26 ppm), MeOH [D4] (  = 3.34 ppm) and central
line of DMSO [D6] ( =2.5 ppm), whereas 13C NMR spectra were
referenced to the central line of CDCl3 ( =77.16 ppm), MeOH [D4] ( =
49.15 ppm) and [D6] DMSO ( =39.5 ppm). Multiplicities are given as, s =
singlet, d = doublet, t = triplet, dd = doublet of doublet, m = multiple, and
br. s = broad singlet. IR spectra was recorded with a JASCO-FT/IR-4100
Spectrometer with a NaCl cell. Elemental analyses was determined with
Perkin–Elmer Instruments series II CHNS/O analyzer. HRMS were
recorded with a MICRO-QTOF mass spectrometer by using the ESI
technique at 10 eV.
1-(4-fluorophenyl)-2-(2′, 3 , 4′, 6′-tetra-O-benzyl--D-glucopyranosyl)
ethanone (13b); Building block 5 (0.16 g, 0.256 mmol), magnesium
turnings (0.018 g, 0.768 mmol), 1-Bromo-4-Flouro Benzene (0.084 ml,
0.768 mmol) were treated according to the general procedure A to give the
title compound 13b, after column chromatography on silica gel (EtOAc :
hexane 1:9 ) as a semi solid ( 0.032 g, 77 % ); Rf = 0.4 (EtOAc/Hexane
1:4); []25 8.3
ͦ
(c 0.8, CHCl3); 1H NMR (CDCl3, 400 MHz):
D
3.023.19m3.40-3.45 (m, 2H), 3.60-3.80 (m, 5H), 3.942 (m, 1H),
4.426 (t, 1H, J = 12.0 Hz), 4.50 (d,1H, J = 12.0 Hz), 4.57 (d, 1H, J = 10.8
Hz), 4.67 (d, 1H, J = 11.2 Hz), 4.81 (d, 1H, J = 10.8Hz), 4.88- 4.95 (m, 2H),
7.03-7.31 (m, 22H), 7.85 (m, 2H). 13C NMR (100 MHz, CDCl3):
40.8CH2, 68.7 (CH2), 73.4 (CH2), 74.9 (CH2), 74.9 (CH2), 75.5 (CH),
75.6 (CH2), 78.4 (CH), 78.9 (CH), 80.9 (CH), 87.3 (CH), 115.4 (d, CH, J 2
CH-F = 21.5 Hz) , 127.5 (CH), 127.6 (CH), 127.7 (CH), 127.7 (CH), 127.8
(CH), 127.8 (CH), 127.9 (CH), 128.2 (CH), 128.2 (CH), 128.3 (CH), 128.4
(CH), 128.4 (CH), 130.9 (d, J 3 CH-F = 9.2 Hz), 133.7 (C), 137.8 (C), 138.0
1-N-methoxy-N-methyl-2-(2′, 3′, 4′, 6′-tetra-O-benzyl--D-glucopyran-
osyl) acetamide (5): The oven dried round bottom flask was charged with
acid 7 (2.72 g, 4.68 mmol) in anhydrous CH2Cl2 followed by pivaloyl
chloride (0.744 ml, 6.08 mmol) and triethyl amine (0.98 ml, 7.49 mmol) at
ͦ
0 C for 10 min. The reaction mixture was warmed to rt and stirred for 3 h.
Then, N,O-dimethylhydroxlamine hydrochloride (0.735 g, 7.40 mmol ) and
triethylamine (0.98 ml, 7.49 mmol ) were added slowly at 0 C, and the
ͦ
1
mixture was stirred for 3h at rt. The reaction mixture was quenched with
water. The organic layer was extracted with CH2Cl2, dried over Na2SO4
and concentrated under reduced pressure to give crude product, which
was further purified by column chromatography on silica. Eluting with ethyl
acetate : hexane (1:2), gave the title compound as a light yellow color solid
(C), 138.1 (C), 138.4 (C), 165.6 (d, J C-F = 253 Hz), 196.1 (CO). IR
(CHCl3): 1063, 1231, 1396, 1600, 1665, 2909 cm-1. HRMS: calcd for
C42H42O6F (M+H)+ 661.2965, found 661.2979.
1-(4-chlorophenyl)-2-(2′, 3′, 4′, 6′-tetra-O-benzyl--D-glucopyranos-yl)
ethanone (13c); Building block 5 (0.3 g, 0.48 mmol), magnesium turnings
(0.035 g, 1.44 mmol), 1-bromo-4-chloro benzene (0.275 g, 1.44 mmol)
were treated according to the general procedure A to give the title
compound 13c, after column chromatography on silica gel (EtOAc :
hexane 1:9) as colorless gummy solid (0.081 g, 75 %); Rf = 0.4
(EtOAc/Hexane 1:4); []27D 9.2 (c 0.5, CHCl3); 1H NMR (CDCl3, 400MHz):
3.15dd, 1H, J 1 = 15.6 Hz, J 2 = 7.6), 3.38 (dd, 1H, J 1 = 15 Hz, J 2
5.2 Hz), 3.58-3.68 (m, 4H), 3.75-3.82 (m, 2H), 4.44 (d, 1H, J = 12.4 Hz),
4.49 (d, 1H, J = 10.8 Hz), 4.57 (dd, 2H, J 1 = 11.6 Hz, J 2 = 5.6 Hz), 4.66
(d, 1H, J = 11.6 Hz), 4.78-4.91 (m, 4H), 7.2-7.32 (m, 20H), 7.36 (d, 2H, J
(2.54 g, 87%); m.p. = 86-88 oC, Rf = 0.1 (EtOAc/Hexane 3:7); []27D 113
ͦ
(c 0.5, CHCl3); 1H NMR: (CDCl3, 400 MHz) 2.642.74m, 2H), 3.13 (s,
3H, NCH3), 3.48-3.38 (m, 2H), 3.60 (s, 3H, OMe), 3.75-3.65 (m, 4H), 3.87-
3.82 (m, 1H), 4.48 (d, 1H, J =12 Hz), 4.55 (d, 1H, J=10 Hz), 4.58 (d,1H, J
= 8.8 Hz), 4.67 (d,1H, J = 11.6 Hz ), 4.81 (d, 1H, J = 10.8 Hz), 4.86-4.93
(m, 3H), 7.16-7.30 (m, 20H).13C NMR (100 MHz, CDCl3) 34.2CH2),
68.8 (CH2), 73.3 (CH2), 74.8 (CH2), 74.9 (CH2), 75.5 (CH2), 75.7 (CH), 78.4
(CH), 78.7 (CH), 81.4 (CH), 87.3 (CH), 127.6 (CH), 127.7 (CH), 127.7 (CH),
127.9 (CH), 127.9 (CH), 128.3 (CH), 128.4 (CH), 128.4 (CH), 128.5 (CH),
138.2 (C), 138.3 (C), 138.6 (C), 171.7 (CO). IR (CHCl3): 1214, 1428, 1640,
2926, 3021, cm-1. HRMS: calcd for C38H44O7N 6263118found
626.3120.
ͦ
=
=
8
Hz), 7.76 (d, 2H, J=
8
Hz). 13C NMR (100 MHz,
CDCl3):35.8CH268.8CH271.3 (CH), 72.9 (CH), 73.4 (CH2), 73.5
(CH2), 74.9 (CH2), 75.2 (CH2), 77.6 (CH), 79.3 (CH), 82.0 (CH), 127.9 (CH),
128.0 (CH), 128.0 (CH), 28.1 (CH), 128.2 (CH), 128.2 (CH), 128.5 (CH),
128.6 (CH), 129.1 (CH), 129.8 (CH), 135.6 (C), 138.1 (C), 138.2 (C), 138.4
(C), 138.8 (C), 139.7 (C), 196.0 (CO). IR (CHCl3) 1082, 1274, 1362, 1472,
1588, 1673, 2860, 2907 cm-1. HRMS: calcd for C42H41O6ClNa (M+Na)+
699.2489, found 699.2500.
General procedure A for the addition of arylmagnesium bromide onto
the Weinreb amide building blocks 5, 6 and 17: The oven dried two
necked round bottom flask was charged with magnesium turnings (3 eq)
and a catalytic amount of molecular iodine was added under nitrogen
atmosphere. The reaction flask was pre-heated under vacuum to activate
the magnesium. Substituted aryl bromide (3 eq) in anhydrous THF was
added under stirring into the activated magnesium. After complete
consumption of magnesium, the requisite amide (1 eq) in anhydrous THF
1-(4-methoxyphenyl)-2-(2′, 3′, 4′, 6′-tetra-O-benzyl--D-glucopyrano-
syl) ethanone (13d). Building block 5 (0.1 g, 0.16 mmol), magnesium
turning (0.012 g, 0.048 mmol) and 1-bromo-4- methoxy benzene (0.06 g,
0.48 mmol) were treated according to the general procedure A to give the
title compound 13d, after column chromatography on silica gel (1:4) as
colorless solid (0.80 mg, 75 %), m.p. = 81-83 oC; Rf = 0.3 (EtOAc/Hexane
ͦ
was added to the reaction mixture at 0 C. After 3h, saturated NH4Cl
solution was added and the aqueous layer was extracted with EtOAc. The
organic layer was dried over Na2SO4 and concentrated in vacuum. The
product obtained was purified by silica-gel column chromatography to yield
the corresponding ketones.
1:4); []27D -18.2 (c 0.8, CHCl3); 1H NMR (CDCl3, 400 MHz):  = 3.0-3.11
ͦ
(m, 2H), 3.41-3.46 (m, 2H), 3.62-3.78 (m,4H), 3.84 (s, 3H, OMe), 3.94-3.99
(m, 1H), 4.41 (d, 1H, J = 12.4 Hz), 4.51 (d, 1H, J = 12.4 Hz), 4.58 (d, 1H,
J =10.8 Hz) 4.69 (d, 1H, J = 11.2 Hz), 4.81 (d, 1H, J = 10.4 Hz), 4.88-4.95
1-(4-methylphenyl)-2-(2′, 3′, 4′, 6′-tetra-O-benzyl--D-glucopyranosyl)
ethanone (13a): Same procedure as described above is adopted.
Magnesium turnings (0.035 g, 1.44 mmol), 4-bromotoluene (0.18 ml, 1.44
mmol) was converted to the corresponding ArMgBr and amide 5 (0.3 g,
0.48 mmol) was added, to give the compound 13a after column
chromatography on silica gel (EtOAc : hexane 1:9) yielded a white solid
(m, 3H), 6.87 (d, 2H, J = 8 Hz), 7.16-7.32 (m, 20H), 7.83-7.85 (m,2H). 13
C
NMR (100MHz, CDCl3): 40.5CH255.4 OCH368.7 (CH2), 73.4
(CH2), 74.9 (2xCH2), 75.5 (CH2), 75.6 (CH), 78.4 (CH), 79.2 (CH), 81.1
(CH), 87.4 (CH), 113.7 (CH), 127.6 (CH), 127.7 (CH), 127.8 (CH), 127.9
(CH), 127.9 (CH), 127.9 (CH), 128.3 (CH), 128.4 (CH), 128.5 (CH), 128.5
( 0.078 mg, 76 % ); m.p. = 72-74 oC; Rf = 0.5 (EtOAc/Hexane 1:4); []25
D
5
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701468
European Journal of Organic Chemistry
FULL PAPER
(CH), 130.7 (CH), 138.2 (C), 138.3 (C), 138.7 (C), 163.5 (C), 196.3 (C). IR
(CHCl3): 1296, 1426, 1517, 1591, 1653, 2927 cm-1 HRMS: calcd for
C43H44O7Na (M+Na)+ 695.2985 found 695.2975.
the title compound 14b, after column chromatography on silica gel
(EtOAc : hexane 1:9 ) as a semi solid ( 0.068 g, 81 % ); Rf = 0.4
ͦ
(EtOAc/Hexane 1:4); ]27 15.3 (c 0.8, CHCl3); 1H NMR (CDCl3, 400
D
MHz): 3.08-3.09 (m, 2H), 3.45-3.53 (m, 2H), 3.61 (t, 1H, J = 6.4 Hz),
3.67 (dt, 1H, J 1 = 9.2 Hz, J 2 = 1.2 Hz), 3.79 (t, 1H, J= 9.2 Hz), 3.92-4.02
(m, 2H), 4.35 (d, 1H, J = 11.6 Hz), 4.41 (d, 1H, J = 12 Hz), 4.62 (d, 1H, J
= 11.2 Hz), 4.67 (dd, 2H, J 1 = 11.6 Hz , J 2 = 4 Hz), 4.76 (d, 1H, J = 11.6
Hz), 4.96 (dd, 2H, J 1 = 22 Hz, J 2 = 11.6 Hz), 7.01-7.06 (m, 2H), 7.21-7.37
(m, 20H), 7.82-7.85 (m,2H). 13C NMR (100 MHz, CDCl3): 41.3 (CH2),
68.7 (CH2), 72.2 (CH2), 73.4 (CH2), 73.9 (CH), 74.6 (CH2), 75.0 (CH2),
75.7 (CH), 77.1 (CH), 77.8 (CH), 84.9 (CH), 115.4 (d, CH, J 2CH-F = 21.6
Hz), 127.6 (CH), 127.73 (CH), 127.8 (CH), 128. 1 (CH), 128.2 (CH), 128.39
(CH), 128.4 (CH), 128.4 (CH), 130.1 (d, CH, J 3 CH-F = 9.3 Hz), 133.8 (C),
1-(thiophenyl)-2-(2′, 3′, 4′, 6′-tetra-O-benzyl--D-glucopyranosyl) eth-
anone (13e): building block 5 (0.3 g, 0.48 mmol), magnesium turnings
(0.035 g, 1.44 mmol) and 2-bromothiophene (0.140 ml, 1.44 mmol) were
treated according to the general procedure A to give the title compound
13e, after column chromatography on silica gel (EtOAc : hexane 1:9 ) as
light yellow color solid (0.130 g, 83 %), m.p. = 95-97 oC; Rf = 0.4
ͦ
(EtOAc/Hexane 1:4); []27D 15.3 (c 0.3, CHCl3); 1H NMR (CDCl3, 400MHz):
2.93dd, 1H, J 1 = 15.2 Hz, J 2 = 8 Hz), 3.03 (dd, 1H, J 1 = 15.2 Hz, J 2
= 2 Hz), 3.33-3.38 (m, 2H), 3.57-3.70 (m, 4H), 3.85-3.89 (m, 1H), 4.33 (d,
1H, J = 12.4 Hz), 4.43 (d,1H, J = 12 Hz), 4.50 (d, 1H, J = 10.8 Hz), 4.61 (d,
1H, J = 11.2 Hz), 4.74 (d 1H, J = 10.8Hz), 4.80-4.87(m, 3H), 7.00 (t, 1H, J
= 4.4 Hz), 7.09-7.25 (m, 20H),7.52 (d, 2H, J = 4.4 Hz). 13C NMR (100 MHz,
CDCl3):  = 41.7 (CH2), 68.8 (CH2), 73.4 (CH2), 74.9 (CH2), 74.9 (CH2),
75.5 (CH2), 75.6 (CH), 78.4 (CH), 79.0 (CH), 80.9 (CH), 87.3 (CH), 127.5
(CH), 127.6 (CH), 127.7 (CH), 127.7 (CH), 127.8 (CH), 127.9 (CH), 128.1
(CH), 128.2 (CH), 128.3 (CH), 128.4 (CH), 132.3 (CH), 133.6 (CH), 138.2
(C), 138.3 (C), 138.7 (C), 145.0 (C), 190.5 (CO). IR (CDCl3): 1095, 1311,
1451, 1540, 1653, 2843, 2928, 3031 cm-1. HRMS: calcd for C40H40O6SNa
(M+Na)+ 671.2443 found 671.2454.
1
C-F
138.1(C), 138.3 (C), 138.4 (C), 138.8 (C), 165.7 (d, C, J
= 253 Hz),
196.2 (CO). IR (CHCl3): 1232, 1320, 1581, 1675, 2909 cm-1. HRMS: calcd
for C42H42O6F (M+H)+ 661.2965, found 661.2956.
1-(4-chlorophenyl)-2-(2′, 3′, 4′, 6′-tetra-O-benzyl--D-galactopyranos-
yl) ethanone (14c): Building block 6 (0.128 g, 0.204 m.mol), magnesium
turning (0.015 g, 0.614 mmol) and 1-bromo-4-chloro benzene (0.117 g,
0.614 mmol) were treated according to the general procedure A to give the
title compound 14c, after column chromatography on silica gel (EtOAc :
hexane 1:9) as a colorless gum (0.110 g, 79%); Rf = 0.4 (EtOAc/Hexane
ͦ
1:4); []26D 233.4 (c 0.5, CHCl3); 1H NMR (CDCl3, 400MHz):  = 3.06-3.08
(m, 2H), 3.44-3.53 (m, 2H), 3.60 (t, 1H, J = 6.8 Hz), 3.66 (dd, 1H, J 1 = 9.2
Hz, J 2 = 2.8 Hz), 3.78 (t, 1H, J = 9.6 Hz), 3.90-3.95 (m, 1H), 4.01 (d, 1H,
J = 2 Hz), 4.35 (d, 1H, J = 11.6 Hz), 4.40 (d, 1H, J = 12 Hz), 4.61 (d, 1H, J
= 11.6 Hz), 4.66 (dd, 2H, J 1 = 11.6 Hz, J 2 = 6.0 Hz), 4.75 (d, 1H, J = 11.6
Hz), 4.92 (d, 1H, J = 11.6 Hz), 4.98 (d, 1H, J = 11.2 Hz), 7.21—7.35 (m,
22H), 7.74 (d, 2H, J = 8.8 Hz). 13C NMR (100 MHz, CDCl3): 41.5 (CH2),
68.6 (CH2), 72.2 (CH2), 73.4 (CH2), 73.9 (CH), 74.6 (CH2), 75.0 (CH2),
75.7 (CH), 77.1 (CH), 77.8 (CH), 84.9 (CH),127.8 (CH), 127.9 (CH), 128.1
(CH), 128.3 (CH),128.4 (CH),128.6 (CH), 128.7 (CH), 128.9 (CH), 129.9
(CH), 135.9 (CH), 138.2 (C), 138.4 (C), 138.5 (C), 138.9 (C), 139.5 (CH),
196.7 (CO). IR (CHCl3): 1095, 1216, 1590, 1679, 2923, 3021 cm-1. HRMS:
calcd for C42H41O6ClNa (M+Na)+ 700.2568, found 700.2581.
1-N-methoxy-N-methyl-2-(2′, 3′, 4′, 6′-tetra-O-benzyl--D-galactopy-
ranosyl) acetamide (6). Acid 8 (0.6 g, 1.03 mmol), pivolyl chloride (0.15
ml, 1.23 mmol), N,O dimethylhydroxyl amine hydrochloride (0.15 g, 1.54
mmol) and triethylamine (0.21 ml, 1.54 mmol) were reacted according to
the one step procedure 5. Purification by column chromatograph on silica,
eluting with EtOAc / Hexane (1:3), gave the title compound as a light yellow
ͦ
gum (0.593 g, 92 %). Rf = 0.1 (EtOAc/Hexane 3:7); []25 189.3 (c 0.3,
D
1
CHCl3); H NMR (CDCl3, 400 MHz):  = 2.64-2.67 (m, 2H), 3.021 (s, 3H,
NMe), 3.46-3.47 (m, 2H), 3.49 (s, 3H, OMe), 3.54 (d, 1H, J = 6.4 Hz), 3.58
(dd, 1H, J 1 = 9.2 Hz, J 2 = 2.8 Hz ), 3.66 (t, 1H, J = 9.2 Hz), 3.75-3.80 (m,
1H), 3.94 (d,1H, J = 2.8 Hz), 4.32 (d, 1H, J = 12 Hz), 4.37 (d, 1H, J = 12
Hz), 4.52-4.60 (m, 3H), 4.66 (d,1H, J = 12 Hz), 4.86 (d,1H, J = 11.6 Hz),
4.90 (d, 1H, J = 11.2 Hz), 7.16-7.28 (m,20H). 13C NMR (100 MHz, CDCl3):
34.8 (CH2), 61.3 (CH2), 68.6 (CH2), 72.22 (CH2), 73.4 (CH2), 74.0 (CH),
74.6 (CH2), 74.9 (CH2), 76.0 (CH), 76.8 (CH), 78.2 (CH), 84.8 (CH), 127.5
(CH),127.5 (CH), 127.6 (CH), 127.7 (CH), 127.9 (CH), 128.0 (CH), 128.2
(CH), 128.3 (CH), 128.4 (CH), 128.4 (CH), 138.1 (C), 138.4 (C), 138.6 (C),
139.0 (C). IR (CHCl3): 1101, 1370, 1452, 1589, 1649, 2882, 2926 cm-1.
HRMS: Calcd for C38H44O7N MH626.3118found 626.3107.
1-(4-methoxyphenyl)-2-(2′, 3′, 4′, 6′-tetra-O-benzyl--D-galactopyrano-
syl) ethanone (14d): Building block 6 (0.070 g, 0.112 mmol), magnesium
turnings (0.008 g, 0.336 mmol) and 1-bromo-4- methoxy benzene (0.043
ml, 0.336 mmol) were treated according to the general procedure A to give
the title compound 14d, after column chromatography on silica gel (1:4 )
ͦ
as a colorless gum ( 0.034 g, 79 % ); []25D 294.7 (c 0.4, CHCl3); 1H NMR
(CDCl3, 400 MHz): 3.08-3.10 (m, 2H), 3.47-3.53 (m, 2H), 3.61 (t, 1H, J
= 6.8 Hz), 3.68 (dd, 1H, J 1 = 9.2 Hz, J 2 = 2.8 Hz), 3.79 (d, 1H, J = 2.4 Hz),
3.84 (s, 3H, OMe), 3.95-3.98 (m, 1H), 4.03 (d, 1H, J = 2.0 Hz), 4.34 (d, 1H,
J = 11.6 Hz), 4.40 (d, 1H, J = 11.6 Hz), 4.63 (d, 1H, J = 11.6 Hz), 4.67 (d,
2H, J = 11.6), 4.76 (d, 1H, J = 11.6 Hz), 4.93 (d, 1H, J = 11.6 Hz), 4.98 (d,
1H, J = 11.2), 6.86 (d,2H, J = 8.8 Hz), 7.23-7.36 (m, 20H), 7.82 (d, 2H, J =
9.2 Hz). 13C NMR (100 MHz, CDCl3): 41.0 (CH2), 55.5 (OMe), 68.7
(CH2), 72.2 (CH2), 73.4 (CH2), 73.8 (CH), 74.6 (CH2), 75.0 (CH2), 75.8
(CH), 77.0 (CH), 77.9 (CH), 84.9 (CH),113.5 (CH), 127.7 (CH), 127.8 (CH),
128.0 (CH),128.3 (CH), 128.3 (CH), 128.5 (CH),128.5 (CH), 130.7 (CH),
138.1 (C), 138.4 (C), 138.4 (C), 138.8 (C), 163.4 (C), 196.3 (CO). IR
(CHCl3): 1248, 1458, 1509, 1599, 1653, 2922 cm-1. HRMS: calcd for
C43H44O7Na (M+Na)+ 695.2985 found 69.2961.
1-(4-methylphenyl)-2-(2′, 3′, 4′, 6′-tetra-O-benzyl--D-galactopyranos-
yl) ethanone (14a): Building block 6 (0.08 g, 0.128 mmol), magnesium
turnings (0.010 g, 0.384 mmol) and parabromotoluene (0.048 ml, 0.384
mmol) were treated according to the general procedure A to give the title
compound 14a, after column chromatography on silica gel ( EtOAc :
hexane 1:9 ) as a colorless gum ( 0.061 g, 73 % ); Rf = 0.4 (EtOAc/Hexane
ͦ
1:4); []27 7.6 (c 0.3, CHCl3); 1H NMR (CDCl3, 400 MHz): 2.37 (S,
D
3H), 3.10-3.12 (m, 2H), 3.46-3.54 (m,2H, 3.61 (t, 1H, J = 6.8 Hz), 3.6 (dd,
1H, J 1 =9.2Hz, J 2 = 2.8 Hz), 3.79 (t, 1H, J = 9.2 Hz), 3.94-4.02 (m, 2H),
4.34 (d, 1H, J = 12 Hz), 4.40 (d, 1H, J = 12 Hz), 4.62 (d, 1H, J = 11.6 Hz),
4.67 (d, 2H, J = 11.2 Hz), 4.75 (d, 1H, J = 11.6 Hz), 4.95 (dd, 2H, J 1 = 18.8
Hz, J 2 = 11.6 Hz), 7.18 (d, 2H, J = 8 Hz), 7.21-7.37 (m, 20H), 7.73 (d, 2H,
J= 8 Hz). 13C NMR (100 MHz, CDCl3): 21.7 (CH3), 41.2 (CH2), 68.6
(CH2), 72.2 (CH2), 73.4 (CH2), 73.9 (CH), 74.6 (CH2), 75,0 (CH2), 75.8 (CH),
77.0 (CH), 77.9 (CH), 84.9 (CH), 127.7 (CH),127.7 (CH), 128.0 (CH), 128.3
(CH), 128.3 (CH) ,128.5 (CH), 128.5 (CH), 128.5 (CH), 129.2 (CH), 134.9
(C), 138.1 (C) ,138.4 (C), 138.5 (C), 138.9 (C), 143.7 (C), 197.4 (CO). IR
(CHCl3): 1113, 1405, 1588, 1644, 2881, 2928 cm-1. HRMS: calcd for
C43H44O6Na (M+Na)+ 679.3036, found 679.3032 .
1-(thiophenyl)-2-(2′, 3′, 4′, 6′-tetra-O-benzyl--D- galactopyranosyl) et-
hanone (14e): Building block 6 (0.3 g, 0.48 mmol), magnesium turnings
(0.035 g, 1.44 mmol) and 2-bromothiophene (0.140 ml, 1.44 mmol) were
treated according to the general procedure A to give the title compound
14e, after column chromatography on silica gel to provide the title
compound as a light yellow color gum (0.130 g, 83 %). Rf = 0.4 (EtOAc/
ͦ
hexane 1:4); []25 18.4 (c 0.5, CHCl3); 1H NMR (CDCl3, 400 MHz):
D
3.05dd, 1H, J 1 = 16.0 Hz, J 2 = 8 Hz), 3.12 (dd, 1H, J 1 = 12.0 Hz, J
2 = 2.8 Hz), 3.46-3.54 (m, 2H), 3.59-3.62 (m, 1H), 3.67 (dd, 1H, J 1 = 9.2
Hz, J 2 = 2.8 Hz), 3.78 (t, 1H, J = 9.2 Hz), 3.93-3.98 (m, 1H), 4.01-4.02 (m,
1H), 4.60-4.77 (m, 4H), 4.75 (d, 1H, J = 11.6 Hz), 4.92 (d,H, J = 11.6 Hz),
1-(4-fluorophenyl)-2-(2′, 3′, 4′, 6′-tetra-O-benzyl--D-galactopyranos-
yl) ethanone (14b): Building block 6 (0.08 g, 0.128 m. mol), magnesium
turnings (0.010 g, 0.384 m. mol) and 1-bromo-4-flouro benzene (0.042 ml,
0.384 m.mol) were treated according to the general procedure A to give
6
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701468
European Journal of Organic Chemistry
FULL PAPER
4.98 (d, 1H, J = 11.2 Hz), 7.05 (dd, 1H, J 1 = 4.8 Hz, J 2 = 4.0 Hz), 7.22-
7.37 (m, 20H),7.56-7.59 (m, 2H). 13C NMR (100 MHz, CDCl3):  = 42.0
(CH2), 68.6 (CH2), 72.2 (CH2), 73.4 (CH2), 73.9 (CH2), 74.6 (CH2), 75.0
(CH), 75.9 (CH), 77.1 (CH), 77.8 (CH), 84.9 (CH), 127.6 (CH), 127.7 (CH),
127.9 (CH), 128.1 (CH), 128.2 (CH), 128.3 (CH), 128.4 (CH), 132.3 (2xCH),
133.6 (CH), 138.0 (C), 138.2 (C), 138.3 (C), 138.7 (C), 144.8 (C), 190.4
(CO). IR (CHCl3): 1342, 1400, 1588, 1648, 2921 cm-1. HRMS: calcd for
C40H40O6SNa (M+Na)+ 671.2443 found 671.2454.
(CH), 84.5 (CH), 96.8 (CH2), 98.5 (CH2), 98.8 (2xCH2): IR (CHCl3): 1053,
1134, 1248, 1458, 1653, 2919 cm-1. HRMS: calcd for C18H35NO11Na
(M+Na)+ 464.2108 found 464.2114.
1-(3, 4, 5-trimethoxyphenyl)-2-(2′, 3′, 4′, 6′-tetra-O- methoxy methyl--
D-glucopyranosyl) ethanone (18): Building block 17 (0.850 g, 1.9 mmol),
magnesium turnings (0.191g, 7.962 mmol), 1-bromo-3, 4, 5-
trimethoxybenzene (1.96 g, 7.962 mmol) were treated according to the
procedure mentioned for compound 15. The crude residue was purified by
column chromatography on silica gel to yield the title compound 18 (0.65
1-(3, 4, 5-trimethoxyphenyl)-2-(2′, 3′, 4′, 6′-tetra-O-benzyl--D-gluco-
pyranosyl) ethanone (15): A oven dried two necked round bottom flask
was charged with magnesium turnings (0.063 g, 2.6 mmol), catalytic
amount of molecular iodine under nitrogen atmosphere. 1-bromo-3, 4, 5-
trimethoxybenzene (0.7 g, 2.6 mmol) in anhydrous THF was added into
the activated magnesium. To that solution catalytic amount of MeI was
added at 50 ºC, and heating was continued until the colour change of the
reaction mixture. After complete consumption of magnesium, building
block 5 (0.4 g, 0.71 mmol) in anhydrous THF was added to reaction
mixture. After 3h saturated NH4Cl solution was added and the aqueous
layer was extracted with EtOAc, the organic layer was dried over Na2SO4
and concentrated in vacuum. The crude residue was purified by column
chromatography on silica gel to yield the title compound 15 (0.37g, 75%)
ͦ
g, 59.6%) as a colorless gum. Rf = 0.5 (EtOAc/hexane 1:1); []26D 19.5 (c
1.0, CHCl3); 1H NMR (CDCl3, 500 MHz) = 3.22-3.29 (m, 4H), 3.31- 3.35
(m, 4H), 3.37-3.41 (m, 4H), 3.43-3.45 (m, 4H), 3.53 (t, 1H, J = 12.0 Hz),
3.61-3.68 (m, 2H), 3.76 (dd, 1H, J 1 = 14.0 Hz, J 2 = 2.5 Hz), 3.91 (s, 9H),
3.95-4.02 (m, 1H), 4.57 (dd, 2H, J 1 = 14.0 Hz, J 2 = 8.0 Hz), 4.71-4.74 (m,
2H), 4.83-4.87 (m, 3H), 4.92 (d, 1H, J = 8.5 Hz), 7.24 (s, 2H). 13C NMR
(125 MHz, CDCl3):40.8 (CH2), 55.2 (OMe), 56.2 (OMe), 56.3 (2 x
OMe), 56.5 (OMe), 56.5 (OMe), 60.9 (OMe), 66.4 (CH2), 74.9 (CH), 77.0
(CH), 78.2 (CH), 80.7 (CH), 84.4 (CH), 96.8 (CH2), 98.5 (CH2), 98.7 (CH2),
98.8 (CH2), 105.7(CH), 132.5 (C),142.5 (C),152.99 (C), 196.5 (CO)). IR
(CHCl3): 1076, 1143, 1206, 1406, 1509, 1573, 1603, 2879 cm-1. HRMS:
calcd for C25H40O13Na (M+Na)+ 571.2367 found 571.2347.
as color less gum. Rf = 0.3 (EtOAc:hexane 3:7); []26D 97.5 (c 1.0, CHCl3);
ͦ
1H NMR (CDCl3, 400 MHz):  = 3.04 (dd, 1H, J 1 = 16 Hz, J 2 = 8 Hz), 3.12
(dd, 1H, J 1 = 16 Hz, J 2 = 3.2 Hz), 3.41-3.46 (m, 2H), 3.65- 3.66 (m, 2H),
3.7 (d, 1H, J = 9.2 Hz), 3.76 (d, 1H, J = 8.8 Hz), 3.82 (s, 6H, 2xOMe), 3.89
(s, 3H, OMe), 3.95-4.0 (m, 1H), 4.41 (d, 1H, J = 12.0 Hz), 4.51 (d, 1H, J =
12.4 Hz), 4.58 (d, 1H, J =10.8 Hz ) 4.69 (d, 1H, J = 11.2 Hz), 4.81 (d, 1H,
J = 10.8 Hz), 4.88-4.95 (m, 3H), 7.13 (s, 2H), 7.15-7.18 (m ,2H), 7.23-7.32
(m,18H). 13C NMR (100 MHz, CDCl3): 40.7 (CH2), 56.3 (2xOCH3), 60.9
(OMe), 68.9 (CH2), 73.4 (CH2), 74.8 (2xCH2), 74.9 (CH2), 75.5 (CH2), 75.5
(CH), 78.5 (CH), 79.0 (CH), 81.0 (CH), 87.4 (CH), 106. (CH), 127.6 (CH),
127.7 (CH), 127.7 (CH), 127.8 (CH), 127.9 (CH), 128.2 (CH), 128.3 (CH),
128.4 (CH), 128.5 (CH), 128.6 (CH), 132.6 (C), 138.1 (C), 138.1 (C), 138.2
(C), 138.5 (C), 142.6 (C), 153.0 (C), 196.5 (C). IR (CHCl3): 1217, 1342
1460, 1510, 1568, 1653, 2922 cm-1. HRMS: calcd for C45H49O9 (M+H)+
733.3377 found 733.3385.
1-(4-methoxyphenyl)-2-(2′, 3′, 4′, 6′-tetra-O-methoxy methyl--D-gluco
pyranosyl) ethanone (20a): An oven dried flask was charged with
magnesium turnings (0.100 g, 4.172 mmol), catalytic amount of molecular
iodine under nitrogen atmosphere.
A
solution of 1-bromo-4-
methoxybenezene (0.523 g, 4.172 mmol), in anhydrous THF (8 mL) was
added under stirring. After 10 min the reaction mixture got strongly self -
heated, stirring was continued for further 1 hour, then the solution of crude
building block 17 (0.460 g, 1.043 mmol) in anhydrous THF was added to
the reaction mixture at 0 oC. After consumption of starting material
(monitored by TLC), the reaction mixture was quenched by adding NH4Cl
(20 mL). The aqueous phase was extracted with EtOAc (3x50 mL), the
organic phase was washed with brine (50 mL), dried (Na2SO4),
concentrated, and purified by silica gel column chromatography to give the
title compound 20a (0.340 g, 68%) as a colorless gum; Rf = 0.3
ͦ
(EtOAc/hexane 1:1); []27 -21.2 (c 0.5, CHCl3); 1H NMR (CDCl3, 500
D
1-N-methoxy-N-methyl-2-(2′, 3′, 4′, 6′-tetra-O-methoxy methyl--D glu-
copyranosyl) acetamide (17): To a stirred solution of building block 5 in
THF was added Pd-C (10 mol %) at rt. The reaction mixture was stirred
under an atmosphere of H2 with balloon pressure until starting material
was disappeared on TLC. The mixture was filtered through celite and the
solvent was removed in vacuo. The resultant tetrol was used for the next
step without further purification.
MHz):= 3.21-3.26 (m, 4H), 3.30-3.33 (m, 4H), 3.36-3.43 (m, 5H), 3.44
(S, 3H), 3.52 (t, 1H, J = 9.0 Hz), 3.61 (dd, 1H, J 1 =11.0 Hz, J2 = 4.5 Hz),
3.65 (t, 1H, J = 9.0 Hz), 3.74 (dd, 1H, J 1 = 11.0 Hz, J 2 = 2.0 Hz), 3.86 (S,
3H), 3.97-4.01 (m, 1H), 4.55 (dd, 2H, J 1 = 14.5 Hz, J 2 = 6.5 Hz), 4.73 (dd,
2H, J 1 = 11.5 Hz, J 2 = 6.5 Hz), 4.82-4.85 (m, 3H), 4.91 (d, 1H, J = 6.5 Hz),
6.92 (d, 2H, J = 9.0 Hz), 7.95 (d, 2H, J = 9.0 Hz). 13C NMR (125 MHz,
CDCl3): 40.7 (CH2), 55.2 (OMe), 55.5 (OMe), 56.4 (OMe), 56.5 (OMe),
56.6 (OMe), 66.5 (CH2), 75.0 (CH) 77.0 (CH), 78. 2 (CH), 80.9 (CH), 84.4
(CH), 96.7 (CH2), 98.4 (CH2), 98.7 (CH2), 98.8 (CH2), 113.6 CH), 130.5
(CH), 163.4 (C), 196.4 (CO). IR (CHCl3): 1045, 1160, 1270, 1334, 1441,
1513, 1597, 1631, 2901 cm-1. HRMS: calcd for C23H36O11Na (M+Na)+
511.2155 found 511.2134.
In a flame dried two necked round bottom flask under nitrogen atmosphere,
tetrol (0.591 g, 2.238 mmol) was combined with anhydrous
dichloromethane (10 mL), upon cooling the suspension on a ice bath (0
oC) diisopropylethylamine (2.53 ml, 18.0 mmol) was added drop wise. The
suspension was stirred at the same temperature for an additional 10 min
and then chloromethylmethylether (2.575 mL, 33.59 mmol) was added
slowly. After stirring for another 15 min at the same temperature
tetrabutylammoniumiodide (3.324 g, 8.9 mmol) was added and then
solution was allowed to attain room temperature. The reaction was stirred
in darkness for 72 hours, the solution gradually turned red in color and was
cooled to 0 oC, saturated NH4Cl (50 ml) solution was added and the
organic layer was extracted with dichloromethane (3x100 ml), dried over
Na2SO4, and concentrated to give the 17 as a yellow color oil (0.87 g, 92%
1-(4-chlorophenyl)-2-(2′, 3′, 4′, 6′-tetra-O-methoxy methyl--D-gluco
pyranosyl) ethanone (20b): Building block 17 (0.430 g, 0.995 mmol),
magnesium turnings (0.093 g, 3.90 mmol), 1-bromo-4-chlorobenzene
(0.745 g, 3.90 m. mol) were treated according to the procedure in 20a to
give the title compound 20b, after column chromatography on silica gel as
ͦ
a color less syrup (0.320g, 70%). Rf = 0.6 (EtOAc/hexane 1:1); []27D 17.7
(c 0.3, CHCl3); 1H NMR (CDCl3, 500 MHz):= 3.20-3.26 (m, 4H), 3.31-
3.34 (m, 4H), 3.36-3.42 (m, 5H), 3.34 (s, 3H), 3.51 (t, 1H, J = 9.0 Hz), 3.60
(dd, 1H, J 1 =11.0 Hz, J 2 = 4.5 Hz), 3.64 (t, 1H, J = 9.0 Hz), 3.73 (dd, 1H,
J 1 = 11.0 Hz, J 2 = 2.0 Hz), 3.94-3.98 (m, 1H), 4.55 (dd, 2H, J 1 = 13.5 Hz,
J 2 = 6.5 Hz), 4.71 (dd, 2H, J 1 = 9.0 Hz, J 2 = 6.5 Hz), 4.82-4.86 (m, 3H),
4.90 (d, 1H, J = 6.5 Hz), 7.42 (d, 2H, J = 8.5 Hz), 7.90 (d, 2H, J = 9.0 Hz).
13C NMR (125 MHz, CDCl3): 41.2 (CH2), 55.3 (OMe), 56.3 (OMe), 56.5
(OMe), 56.6 (OMe), 66.5 (CH2), 74.9 (CH), 77.0 (CH), 78.3 (CH), 80.8 (CH),
84.3 (CH), 96.7 (CH2), 98.5 (CH2), 98.7 (CH2), 98.9 (CH2), 128.8 (CH),
129.6 (CH), 135.7 (C), 139.5 (C), 196.8 (CO). IR (CHCl3): 886, 1038,
ͦ
yield). Rf = 0.2 (EtOAc/ hexane 1:1, 2,4 DNP active); []26D 233.4 (c 0.5,
CHCl3); 1H NMR (CDCl3, 500 MHz): 2.76-2.89 (m, 2H), 3.19 (s, 3H, NMe),
3.32 (s, 3H, OMe), 3.34-3.38 (m, 1H), 3.39 (s, 3H), 3,41 (s, 3H), 3.44 (s,
3H), 3.51 (t, 1H, J = 11.5 Hz), 3.60-3.64 (m, 1H), 3.66 (dd, 1H, J 1 = 10.5
Hz, J 2 = 4.5 Hz), 3.70 (s, 3H, OMe), 3.79-3.87 (m, 2H), 4.61-4.64 (m, 2H),
4.68-4.75 (m, 2H), 4.80-4.84 (m, 2H), 4.86-4.93 (m, 2H), 5.04 (ddd, 1H, J
1 = 31.5 Hz, J 2 = 7.0 Hz, J 3 = 4.0 Hz). 13C NMR (CDCl3, 125 MHz): 
32.1 (NCH3), 34.7 (CH2), 55.3 (OMe), 55.5 (OMe), 56.4 (OMe), 56.5 (OMe),
56.6 (OMe), 61.3 (OMe), 66.6 (CH2), 75.3 (CH) 77.1 (CH), 78.2 (CH), 80.6
7
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701468
European Journal of Organic Chemistry
FULL PAPER
1167,1276, 1491, 1597, 1687, 2978 cm-1. HRMS: calcd for C22H33O10ClNa
(M+Na)+ 515.1600 found 515.1638.
1189,1233, 1481, 1562, 1683, 2952 cm-1. HRMS: calcd for
C22H32O10Cl2Na (M+Na)+ 549.1270 found 549.1268.
1-(4-O-methoxymethylphenyl)-2-(2′, 3′, 4′, 6′-tetra-O-methoxy methyl-
-D glucopyranosyl) ethanone (20c): Into a dried flask heated in an oven
was charged with magnesium turnings (0.145 g, 6.009 mmol), activated by
molecular iodine and added anhydrous THF (5 mL) with syringe. During
stirring the solution of 1-bromo-4-methoxymethyl benzene (0.745 g, 6.01
1-(3, 4-dimethoxyphenyl)-2-(2′, 3′, 4′, 6′-tetra-O-methoxy methyl--D-
glucopyranosyl) ethanone (20f): An oven dried two necked flask was
charged with magnesium turnings (0.145 g, 6.009 mmol). LiCl (0.153 g in
5 ml anhydrous THF) was added and the magnesium was activated with
iBu2AlH (0.12 ml, 1 M in toluene, 0.12 mmol). After stirring for 10 min, 1-
bromo-3, 4-dimethoxybenzene (0.846 ml, 6.009 m.mol) in anhydrous THF
(7 ml) was added and stirring was continued for 1h. The suspension was
cooled to 0 oC whereupon the building block 17 (0.530 g, 1.201 mmol) was
added in anhydrous THF. The reaction mixture was allowed to warm to 25
ºC and the stirring was continued until the starting material got over (as
monitored by TLC). The reaction mixture was quenched with saturated
NH4Cl (50 ml) solution and the resulting mixture was extracted with EtOAc
(3x 100 ml). The combined organic layer was dried over Na2SO4,
concentrated in vacuo and the crude residue was purified by column
chromatography on silica gel to give the title compound 20f (0.380 g, 61%)
ͦ
mmol) in anhydrous THF was added at 50 C. Reaction flask was strongly
self-heated, stirring was continued for 2 h at same temperature, then the
solution of crude building block 17 (0.460 g, 1.043 mmol) in anhydrous
THF was added to the reaction mixture at 0 oC. After completed (monitored
by TLC), the reaction mixture was quenched by adding NH4Cl (20 ml). The
aqueous phase was extracted with EtOAc (3x50 ml), the organic phase
was washed with brine (50 mL), dried (Na2SO4), concentrated, and purified
by silica gel column chromatography to give the title compound 20c as
ͦ
colorless syrup (0.380 g, 61%). Rf = 0.5 (EtOAc/hexane 1:1); []27D 31.1
(c 0.5, CHCl3); 1 H NMR (CDCl3, 500 MHz): 3.19-3.26 (m, 4H), 3.31-
3.39 (m, 5H), 3.41-3.43 (m, 4H), 3.44 (s, 3H), 3.48 (s, 3H), 3.52 (t, 1H, J =
9.5 Hz), 3.62 (dd, 1H, J 1 = 11.5 Hz, J 2 = 4.5 hz), 3.65 (t, 1H, J = 9.0 Hz),
3.74 (dd, 1H,J 1 = 11.5 Hz, J 2 = 2.0 Hz), 3.97-4.01 (m, 1H), 4.57 (dd, 2H,
J 1 = 14.5 Hz, J 2 = 6.6 Hz),4.73 (dd, 2H, J 1 = 11.5 Hz, J 2 = 6.5 Hz) 4.82-
4.87 (m, 3H), 4.917 (d, 1H, J = 7.0 Hz), 5.23 (s, 2H), 7.06 (d, 2H, J = 9.0
Hz), 7.94 (d, 2H, J = 9.0 Hz). 13C NMR (125 MHz, CDCl3): 40.8CH2),
55.2 (OMe), 56.2 (OMe), 56.3 (OMe), 56.5 (OMe), 56.5 (OMe), 66.4 (CH2),
75.0 (CH), 77.0 (CH), 78.2 (CH), 80.8 (CH), 84.4 (CH), 94.0 (CH2), 96.7
(CH2), 98.5 (CH2), 98.7 (CH2), 98.8 (CH2), 115.7 (CH), 130.4 (CH), 131.4
(C), 161.1 (C), 196.4 (CO). IR (CHCl3): 1038, 1167, 1276, 1491, 1597,
1687, 2978 cm-1 HRMS: calcd for C24H38O12Na (M+Na)+ 541.2261 found
541.2261.
ͦ
as a colorless gum. Rf = 0.4 (EtOAc/ hexane 1:1); []27D 19.1 (c 0.5, CHCl3);
1H NMR (CDCl3, 500 MHz):= 3.1- 3.2 (m, 4H), 3.30- 3.35 (m, 4H), 3.38-
3.43 (m, 5H), 3.44 (s, 3H, OMe), 3.52 (t, 1H, J= 9.0 Hz), 3.62 (dd, 1H, J 1
= 12.5 Hz, J 2 = 5.0 Hz), 3.65 (t, 1H, 9.0 Hz), 3.73 (d, 1H, J = 11.5), 3.92-
3.93 (m, 6H), 3.9 (t, 1H, J = 9.0 Hz), 4.57 (dd, 2H, J 1 = 14.0 Hz, J 2 = 6.5
Hz), 4.7-4.7 (m, 2H), 4.82- 4.85 (m, 3H), 4.90 (d, 1H, J = 6.5 Hz), 6.8 (d,
1H, J = 8.5 Hz), 7.5 (s, 1H), 7.59 (d, 1H, J = 2.0 Hz). 13C NMR (125 MHz,
CDCl3): 40.6CH2), 55.2 (OMe), 55.9 (OMe), 56.1 (OMe), 56.3 (OMe),
56.5 (OMe), 56.5 (OMe), 66.4 (CH2), 75.0 (CH), 77.0 (CH), 78.2 (CH), 80.8
(CH), 84.4 (CH), 96.7 (CH2), 98.5 (CH2), 98.7 (CH2), 98.8 (CH2), 109.9
(CH), 110.2 (CH), 123.0 (CH), 130.6 (C),149.0 (C),153.3 (C), 196.414
(CO). IR (CHCl3): 1051, 1125, 1263, 1442, 1589, 1663, 2928 cm-1. HRMS:
calc for C24H38O12Na (M+Na)+ 541.2261 found 541.2274.
1-(4-fluorophenyl)-2-(2′, 3′, 4′, 6′-tetra-O-methoxy methyl--D-gluco-
pyranosyl) ethanone (20d): Building block 17 (0.440 g, 0.997 mmol),
magnesium turnings (0.091 g, 3.99 mmol), 1-bromo-4-fluorobenzene
(0.438 mL, 3.99 mmol) were treated according to the procedure in 20a to
give the title compound 20d as colorless syrup (0.310g, 68.43%) after
silica gel column chromatography. Rf 0.3 (EtOAc:hexane 3:7); []26
371.1 (c 0.3, CHCl3); 1 H NMR (CDCl3, 500 MHz): 3.22-3.26m, 4H),
3.33-3.366 (m, 4H), 3.38-3.40 (m, 5H), 3.44 (s, 3H), 3.51 (t, 1H, J = 9.5
Hz), 3.59-3.66 (m, 2H), 3.73 (d, 1H, J = 6.5 Hz), 3.96 (t, 1H, J = 9.0 Hz),
4.56 (dd, 2H, J 1 = 12.5 Hz, J 2 = 6.0 Hz), 4.72 (t, 2H, J = 7.5 Hz), 4.82-
4.85 (m, 3H), 4.90 (d, 1H, J = 6.0 Hz), 7.115 (t, 2H, J = 8.0 Hz), 7.99 (t, 2H,
J = 6.0 Hz). 13C NMR (125 MHz, CDCl3): 41.0CH2), 55.2 (OMe), 56.3
(OMe), 56.5 (OMe), 56.5 (OMe), 66.4 (CH2), 74.9 (CH), 77.0 (CH), 78.3
(CH), 80.8 (CH), 84.4 (CH), 96.7 (CH2), 98.5 (CH2), 98.7 (CH2), 98.9 (CH2),
115.6 (d, CH, J 2 = 21.75 Hz), 130.9 (d, CH, J 3 = 9.3 Hz), 133.8 (C), 165.7
(d, C, J 1 = 253 Hz), 196.3 (CO). IR (CHCl3): 967, 1153, 1298, 1456, 1569,
1653, 2913 cm-1. HRMS: calcd for C22H33FO10K (M+K)+ 515.1695 found
515.1683.
1-(3, 4-difluorophenyl)-2-(2′, 3′, 4′, 6′-tetra-O-methoxy methyl--D-
glucopyranosyl) ethanone (20g): Building block 17 (0.550 g, 1.247
mmol), magnesium turnings (0.119 g, 4.98 mmol) and 1-bromo-3,5-
difluorobenzene (0.574 mL, 4.172 mmol) were treated according to the
procedure 20a to give the title compound 20g, after column
chromatography on silica gel (EtOAc/hexane 3:7), as a colorless syrup
=
D
ͦ
ͦ
(0.350 g, 60%); []26D 210 (c 0.5, CHCl3); 1H NMR (CDCl3, 500 MHz):=
3.2 (dd, 1H, J 1 =16.0 Hz, J 2 = 8.0 Hz ), 3.2 (s, 3H, OMe), 3.3- 3.3 (m, 4H),
3.37- 3.43 (m, 5H), 3.44 (s, 3H, OMe), 3.52 (t, 1H, J = 9.0 Hz), 3.61 (dd,
1H, J 1 = 11.5 Hz, J 2 = 5.0 Hz), 3.64 (t, 1H, J = 9.0 Hz), 3.74 (dd, 1H, J 1
= 11.0 Hz, J 2 = 2.0 Hz), 3.91-3.95 (m, 1H), 4.58 (dd, 2H, J 1 = 14.5 Hz, J
2 = 5.5 Hz), 4.72 (t, 2H, J = 6.5 Hz), 4.81- 4.87 (m, 3H), 4.90 (d, 1H, J =
7.0 Hz), 7.005 (tt, 1H, J 1 = 8.5 Hz, J 2 = 2.0 Hz), 7.46-7.48 (m, 2H). 13C
NMR (125 MHz, CDCl3): 41.3CH2), 55.2 (OMe), 56.3 (OMe), 56.5
(2xOMe), 66.4 (CH2), 74.9 (CH), 76.9 (CH), 78.3 (CH), 80.8 (CH), 84.4
(CH), 96.7 (CH2), 98.5 (CH2), 98.7 (CH2), 98.9 (CH2), 118.2 (t, CH, J = 25
Hz), 111.2 (dd, CH, J 1 = 19.8 Hz, J 2 = 6.3 Hz), 140.3 (d, C, J = 7.2 Hz ),
1
2
162.9 (dd, C, J = 249 Hz, J = 11.8 Hz), 195.6 (CO). IR (CHCl3): 971,
1153, 1262, 1413, 1563, 1653, 2913 cm-1. HRMS: calcd for C22H32O10F2
(M+Na)+ 517.1861 found 517.1846.
1-(3, 4-dichlorophenyl)-2-(2′, 3′, 4′, 6′-tetra-O-methoxy methyl--D-
glucopyranosyl) ethanone (20e): Building block 17 (0.460 g, 1.043
mmol), magnesium turnings (0.100 g, 4.172 mmol), 1-bromo-3,4-
dichlorobenzene (0.535 g, 4.172 mmol) were treated according to the
procedure 20a to give the title compound 20e, after column
chromatography on silica gel yielded as a colorless syrup (0.350 g,
1-(3, 4, 5-trichlorophenyl)-2-(2′, 3′, 4′, 6′-tetra-O-methoxy methyl--D-
glucopyranosyl) ethanone (20h):
ͦ
67.73%). Rf = 0.4 (EtOAc:hexane 3:7); []27D 14.1 (c 0.5, CHCl3); 1H NMR
An oven dried two necked round bottom flask was charged with
magnesium turnings (0.216 g, 9.04 mmol), under nitrogen atmosphere. 1-
bromo-3,4,5-trichlorobenzene (1.18 g, 4.53 mmol) in anhydrous THF was
added into the activated magnesium. To that solution 1,2-dibromoethane
(0.390 mL, 4.53 mmol) was added at 50 ºC, heating was continued until
the complete consumption of magnesium. Building block 17 (0.5 g, 1.13
mmol) in anhydrous THF was added to reaction mixture. After 3h saturated
NH4Cl solution was added and the aqueous layer was extracted with
EtOAc, the organic layer was dried over Na2SO4 and concentrated in
vacuum. The crude residue was purified by column chromatography on
(CDCl3, 500 MHz): = 3.21 (dd, 1H, J 1 =16.0 Hz, J 2 = 8.0 Hz ), 3.27 (s,
3H, OMe), 3.32- 3.36 (m, 5H), 3.38- 3.43 (m, 4H), 3.44 (s, 3H, OMe), 3.52
(t, 1H, J = 9.0 Hz), 3.60 (dd, 1H, J 1 = 11.5 Hz, J 2 = 5.0 Hz), 3.64 (t, 1H,
9.0 Hz), 3.73 (dd, 1H, J 1 = 11.0 Hz, J 2 = 2.0 Hz), 3.91- 3.95 (m, 1H), 4.56
(dd, 2H, J 1 = 14.5 Hz, J 2 = 5.5 Hz), 4.72 (t, 2H, J = 6.5 Hz), 4.82- 4.85 (m,
3H), 4.90 (d, 1H, J = 7.0 Hz), 7.53 (d, 1H, J = 8.5 Hz), 7.78 (dd, 1H, J 1
=
8.0 Hz, J 2 = 2.0 Hz), 8.04 (d, 1H, J = 2.0 Hz). 13C NMR (125 MHz, CDCl3):
41.2CH2), 55.3 (OMe), 56.3 (OMe), 56.6 (2OMe), 66.5 (CH2), 74.9
(CH), 76.9 (CH), 78.3 (CH), 80.8 (CH), 84.2 (CH), 96.7 (CH2), 98.5 (CH2),
98.7 (CH2), 98.9 (CH2), 127.3 (CH), 130.3 (CH), 130.6 (CH), 133.2
(C),137.0 (C),137.6 (C), 195.9 (CO). IR (CHCl3): 886, 961, 1061,
silica gel to yield title compound as a color less gum. Rf
0.5
=
(EtOAc:hexane 1:1); []27 -61.5 (c 0.8, CHCl3); 1H NMR (CDCl3, 400
ͦ
D
8
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701468
European Journal of Organic Chemistry
FULL PAPER
MHz): = 3.17-3.23 (m, 1H), 3.28 (s, 3H, OMe), 3.31- 3.68 (m, 4H), 3.41(s,
3H, OMe), 3.44 (s, 3H, OMe), 3.49-3.54 (m, 1H), 3.58-3.66 (m, 2H), 3.71-
3.79 (m, 2H), 3.84-3.92 (m, 1H), 4.55-4.65 (m, 2H), 4.69-4.77 (m, 3H),
4.81-4.87 (m, 3H), 4.89-4.93 (m, 1H), 7.95 (s, 2H). 13C NMR (100 MHz,
CDCl3): CH2), 55.2 (OMe), 56.3 (OMe), 56.5 (2 x OMe), 66.4
(CH2), 74.9 (CH), 76.7 (CH), 78.2 (CH), 80.7 (CH), 84.1 (CH), 96.8 (CH2),
98.5 (CH2), 98.7 (CH2), 98.8 (CH2), 128.7 (CH), 134.7 (2xC),136.6 (C),
195.1 (CO). IR (CHCl3): 1012, 1162, 1296, 1481, 1549, 1692, 2978 cm-1.
HRMS: calcd for C22H31O10Cl3K (M+K)+ 599.0620 found 599.0620.
(CD3OD, 500 MHz): 3.17-3.22 (m, 3H), 3.30-3.40 (m, 4H, one from
solvent ), 3.61 (dd, 1H, J 1 =12.0 Hz, J 2 =5.0 Hz), 3.74 (d, 1H, J = 11.5
Hz), 3.84 (t, 1H, J = 8.5 Hz), 7.21 (t, 2H, J = 9.0 Hz) , 8.07 (dd, 2H, J 1
=
9.0 Hz, J 2 = 5.5 Hz ), 13C NMR (125 MHz, CD3OD) : 40.9 (CH2), 61.3
(CH2), 70.2 (CH), 73.6 (CH), 75.9 (CH), 78.3 (CH), 80.2 (CH), 116.5 (d,
CH, J = 21.87 Hz), 132..3 (d, CH, J = 9.25 Hz),135.1 (d, C, J = 2.87 Hz),
167.1 (d, C, J = 251.6 Hz) 140.5 (C), 198.9 (CO). IR (KBr): 1160, 1451,
1562, 1637, 2983, 3274 cm-1 HRMS: cald for C14H17O6FNa (M+Na)+
323.0907 found. 323.0927.
General procedure B for the removal of MOM protection: The methoxy
methyl ether protected compounds (18, 20a-h) dissolved in methanol (2
ml) and were stirred at room temperature for 5 minutes. Aqueous HCl was
added and stirring was continued until the starting material disappeared
on TLC. The wine-red colored solution was concentrated in vacuum and
black colored residual material was purified by silica gel column
chromatography to provide the title compounds.
1-(3, 4-dichlorophenyl)-2-(-D-glucopyranosyl) ethanone (21e). The
colorless gum 20e (0.340 g, 0.646 mmol), methanol (3 mL) and HCl (6 N,
25 mL) were treated according to the general procedure B to provide the
title compound 21e (0.171 g, 75.66%) as a colorless solid. Rf 0.4
=
ͦ
(MeOH/DCM 1:9); m.p 138-140 oC; []27 -7.9 (c 1.0, MeOH); 1H NMR
D
(CD3OD, 500 MHz): 3.17-3.23m, 4H ), 3.32-3.34 (m, 1H ), 3.36-3.38
(m, 2H), 3.60 (dd, 1H, J 1 =12.0 Hz, J 2 =5.0 Hz), 3.74 (dd, 1H, J 1 = 12.0
Hz, J 2 = 2.5 Hz ), 3.82 (td, 1H, J 1 = 9.0 Hz, J 2 = 2.5 Hz ), 7.66 (d, 2H, J
= 8.5 Hz) , 7.91 (dd, 1H, J 1 = 8.5 Hz, J 2 = 2.0 Hz ), 8.11 (d, 1H, J = 2.0
Hz). 13C NMR (125 MHz, CD3OD): 42.3 (CH2), 62.7 (CH2), 71.6 (CH),
75.0 (CH), 77.2 (CH), 79.7 (CH), 81.6 (CH), 129.0 (CH), 131.2 (C), 131.9
(CH), 133.9 (C), 138.2 (C) 138.6 (C), 198.1 (CO). IR (KBr): 962, 1090,
1219, 1523, 1660, 2991, 3293 cm-1 HRMS: calcd for C14H18O6Cl2 (M+H)+
352.0480 found. 352.0467.
1-(4-methoxyphenyl)-2-(-D-glucopyranosyl) ethanone (21a): The
color less gum 20a (0.270 g, 0.53 mmol), methanol (2 mL) and HCl (6 N,
20 mL) were treated according to the general procedure B to provide the
title compound 21a (0.105 g, 62%) as a yellow color solid. Rf 0.3
=
o
ͦ
(MeOH/DCM 1:9); m.p 150-152 C; []27 -6.4 (c 1.0, MeOH); 1H NMR
D
(CD3OD, 500 MHz): 3.14dd, 1H, J 1 = 16 Hz, J 2 = 9 Hz ), 3.19-3.22
(m, 2H ), 3.29-3.36 (m, 2H, one from solvent ), 3.35-3.38 (m, 2H ), 3.60
(dd, 1H, J 1 =12.0 Hz, J 2 =5.0 Hz), 3.73 (dd, 1H, J 1 = 11.5 Hz, J 2 = 2.5
Hz ), 3.82 (td, 1H, J 1 = 9.0 Hz, J 2 = 2.5 Hz ), 3.87 (s, 3H ), 7.0 (d, 2H, J =
9.0 Hz) , 7.99 (d, 2H, J 1 = 9.0 Hz ), 13C NMR (125 MHz, CD3OD) :42.9
(CH2), 62.7 (CH2), 71.6 (CH), 75.1 (CH), 77.5 (CH), 79.7 (CH), 81.57 (CH),
114.8 ( CH ), 131.3 (C), 131.8 (CH ), 165.3 (C), 198.9 (CO). IR (KBr): 1162,
1481, 1549, 1663, 2921, 3214 cm-1. HRMS: calcd for C15H120O7Na
(M+Na)+ 335.1107 found. 355.1125.
1-(3, 4-dimethoxyphenyl)-2-(-D-glucopyranosyl) ethanone (21f): The
color less gum 20f (0.270 g, 0.521 mmol), methanol (2 mL) and HCl (6 N,
25 mL) were treated according to the procedure B to provide the title
compound 21f (0.105 g, 62%) as a yellow colored solid. Rf 0.3
=
ͦ
1
(MeOH/DCM 1:9); m.p 142-144 oC; []27 -38.4 (c 1.0, MeOH); H NMR
D
(DMSO-D6, 400 MHz): 2.98-3.05m, 3H ), 3.07-3.10 (m, 2H ), 3.15-
3.22 (m, 2H ), 3.68 (dd, 2H, J 1 =11.6 Hz, J 2 =5.2 Hz), 3.79 (s, 3H), 3.82
(s, 3H), 7.04 (d, 1H, J =8.4 Hz), 7.43 (d, 1H, J = 2.0 Hz ), 7.62 (dd, 1H, J
1 =8.4 Hz, J 2 = 2.0 Hz) 13C NMR (100 MHz, DMSO-D6) : 40.9 (CH2),
55.7 (OMe), 55.9 (OMe), 61.3 (CH2), 70.4 (CH), 73.6 (CH), 76.2 (CH), 78.3
(CH), 80.8 (CH), 110.5 ( CH ), 111.0 (CH), 123.1 (CH ), 130.1 (C), 148.7
(C), 153.2 (C), 197.0 (CO). IR (KBr): 1063, 1296, 1403, 1523, 1662, 2986,
3219 cm-1. 1 Elemental analysis calcd (%) for C16H22O8 (342.13): C 56.14,
H 6.48; found: C 56.46, H 6.07.
1-(4-chlorophenyl)-2-(-D-glucopyranosyl) ethanone (21b): The
viscous gum 20b (0.280 g, 0.569 mmol), methanol (2 ml) and HCl (6 N, 20
mL) were treated according to the general procedure B to give the title
compound 21b (0.130 g, 72.22%) as
a
colorless solid. Rf
0.7
=
(MeOH/DCM 1:9); m.p. = 110-112 oC; []27D -29.1 (c 1.0, MeOH); 1H NMR
(CD3OD, 500 MHz): 3.17-3.23m, 3H), 3.30-3.31 (m, 2H), 3.35-3.39
(m, 2H), 3.60 (dd, 1H, J 1 =12.0 Hz, J 2 =5.0 Hz), 3.74 (dd, 1H, J 1 = 11.5
Hz, J 2 = 2.5 Hz), 3.83 (td, 1H, J 1 = 9.0 Hz, J 2 = 2.5 Hz), 7.50 (d, 2H, J =
9.0 Hz) , 7.98 (d, 2H, J = 9.0 Hz).13C NMR (125 MHz, CD3OD): 40.9
(CH2), 61.3 (CH2), 70.2 (CH), 73.6 (CH), 75.9 (CH), 78.3 (CH), 80.2 (CH),
128.5 (CH), 129. 6 (CH), 137.1 (C), 140.5 (C), 199.2 (CO). IR (KBr): 967,
1152, 1393, 1560, 1682, 2991, 3319 cm-1. Elemental analysis calcd (%)
for C14H17O6 (316.07): C 53.09, H 5.41; found: C 53.38, H 5.34.
ͦ
1-(3, 5-diflurophenyl)-2-(-D-glucopyranosyl) ethanone (21g): The
colorless gum 20g (0.280 g, 0.566 mmol), methanol (2 mL) and HCl (6 N,
25 mL) were treated according to the general procedure B to provide the
title compound 21g (0.130 g, 72.3%) as colorless solid. Rf
0.3
=
(MeOH/DCM 1:9); m.p 142-144 oC; []27 -8.1 (c 1.0, MeOH); 1H NMR
ͦ
D
(CD3OD, 500 MHz): 3.19dd, J 1 = 17.0 Hz, J 2 1H ), 3.21-3.23 (m, 3H ),
3.33-3.38 (m, 2H), 3.60 (dd, 1H, J 1 =12.0 Hz, J 2 =5.0 Hz), 3.74 (d, 1H, J
= 11.5 Hz ), 3.80 (t, 1H, J = 9.0 Hz), 7.22 (t, 1H, J = 8.5 Hz), 7.58 (d, 2H, J
= 7.5 Hz ), 13C NMR (100 MHz, CD3OD): 41.1 (CH2), 61.2 (CH2), 70.2
(CH), 73.5 (CH), 75.7 (CH), 78.2 (CH), 80.1 (CH), 107.8 (t. J = 25.7 Hz,
CH ), 110.9 (dd, CH, J 1 = 20.21 Hz, J 2 = 6.0 Hz) 140.4 (d, J = 7.4 Hz, C),
163.8 (dd, C, J 1 = 248.2 Hz, J 2 = 12.0 Hz), 198.95 (CO). IR (KBr): 1191,
1422, 1569, 1691, 2913, 3295, cm-1 Elemental analysis calcd (%) for
C14H16O6F2 (318.09): C 52.83, H 5.07; found: C 52.98, H 4.45.
1-(4-hydroxyphenyl)-2-(-D-glucopyranosyl) ethanone (21c): The
colorless gum 20c (0.280 g, 0.54 mmol), methanol (2 mL) and HCl (6 N,
20 mL) were treated according to the general procedure B to provide the
title compound 21c (0.09 g, 56%) as a yellow colored solid. Rf 0.65
=
ͦ
(MeOH/DCM 2:8); []27 -45.0 (c 0.5, MeOH); 1H NMR (DMSO-D6, 500
D
MHz): 2.9-3.0m, 3H ), 3.07-3.12 (m, 1H ), 3.14-3.36 (m, 2H ), 3.53-
3.58 (m, 2H ), 3.68 (td, 1H, J 1 =9.0 Hz, J 2 =2.0 Hz), 4.30 (t, 1H, J = 5.5
Hz ), 4.89 (d, 1H, J = 5.0 Hz ), 4.97 (d, 1H, J = 4 Hz ), 5.08 (d, 1H, J = 5.5
Hz ), 6.87 (d, 2H, J = 8.5 Hz), 7.84 (d, 2H, J 1 = 8.5 Hz ), 10.44 (s, 1H, OH),
13C NMR (125 MHz, CD3OD) : 40.6 (CH2), 61.0 (CH2), 70.1 (CH), 73.4
(CH), 75.8 (CH), 78.1 (CH), 80.6 (CH), 115.1 ( CH ), 128.6 (C), 130.5 (CH ),
162.0 (C), 196.1 (CO). IR (KBr): 1067, 1421, 1523, 1625, 2991, 3216, 3520
cm-1. HRMS: calcd for C14H18O7Na (M+Na)+ 321.0950 found. 321.0972.
1-(3, 4, 5-trimethoxy phenyl)-2-(-D-glucopyranosyl) ethanone (4):
The colorless gum 18 (0.555 g, 1.021 mmol), methanol (3 mL) and HCl (6
N, 30 mL) were treated according to the general procedure B to give the
title compound 4 (0.30 g, 62%) as light yellow colored solid. Rf 0.3
=
o
ͦ
(MeOH/DCM 1:9); m.p. 164-166 C; []27 -2.5 (c 0.3, MeOH); 1H NMR
D
(CD3OD, 500 MHz): 3.18-3.23 m, 1H ), 3.24-3.29 (m, 2H ), 3.36-3.38
(m, 1H), 3.40-3.44 (m, 1H), 3.45-3.48 (m, 1H), 3.66 (dd, 1H, J 1 =12.0 Hz,
J 2 =5.2 Hz), 3.80 (dd, 1H, J 1 = 12.0 Hz, J 2 = 2.4 Hz ), 3.85-3.90 (m, 4H),
3.94 (s, 6H), 7.36 (s, 2H) , 13C NMR (125 MHz, CD3OD): 42.2 (CH2)
56.8 ( 2x OMe), 61.2 (OMe), 62.7 (CH2), 71.6 (CH), 75.0 (CH), 77.6 (CH),
79.7 (CH), 81.6 (CH), 107.2 ( CH ), 133.9 (C), 143.8 (C ), 154.43 (2xC),
1-(4-fluorophenyl)-2-(-D-glucopyranosyl) ethanone (21d): The
colorless gum 20d (0.260 g, 0.546 mmol), methanol (2 mL) and HCl (6 N,
20 mL) were treated according to the general procedure B to provide the
title compound 21d (0.130 g, 79.7%) as a brown colored solid. Rf = 0.7
ͦ
(MeOH/DCM 1:9); m.p 134-136 oC; []27D -17.3 (c 1.0, MeOH); 1H NMR
9
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701468
European Journal of Organic Chemistry
FULL PAPER
199.5 (CO). IR (KBr): 1067, 1133, 1462, 1561, 1656, 2943, 3269 cm-1
HRMS: calcd for C17H24O9Na (M+Na)+ 395.1381 found. 395.1299.
1H, J 1 =8.5 Hz, J 2 = 2.5 Hz ), 2.87 (dd, 1H, J 1 = 3.5 Hz, J 2 = 1.5 Hz ),
3.34 (s, 3H), 3.36 (s, 3H), 3,43 (s, 3H), 3.44-3.45 (m, 4H), 3.47-3.50 (m,
2H), 3.60-3.65 (m, 2H), 3.79-3.83 (m, 2H), 4.63 (s, 2H), 4.68-4.72 (m,1H),
4.73-4.77 (m, 1H), 4.82-4.84 (m, 2H), 4.85-4.87 (m, 2H), 9.79-9.80 (m, 1H).
13C NMR (CDCl3, 125 MHz):  45.8 (CH2), 55.3 (OMe), 55.5 (2xOMe),
56.5 (OMe), 66.5 (CH2), 73.9 (CH) 77.0 (CH), 78.5 (CH), 80.0 (CH), 84.1
(CH), 96.8 (CH2), 98.5 (CH2), 98.8 (2xCH2), 200.5 (C, -CHO). IR (CHCl3):
1061, 1189, 1233, 1481, 1562, 1757, 2863, 2952 cm-1. HRMS: calcd for
C26H30O10Na (M+Na)+ 405.1737 found 405.1754.
1-(3, 4, 5-trimethoxyphenyl)-2-(2’, 3’, 4’, 6’-tetra-O-acetyl--D-gluco-
pyranosyl) ethanone (19): To the tetrol 4 (0.130 g, 0.350 mmol) in DMF
(2 mL) were added successively acetic anhydride (0.396 mL, 4.192 mmol),
N, N diisopropylethylamine (0.77 mL, 7 mmol) and 4-(dimethyl-amino)-
ͦ
pyridine (0.022 g) at 0 C, and the resultant mixture was stirred at room
temperature for 12 h. To the reaction mixture was added water and the
organic layer was extracted with EtOAc. The combined organic layer was
washed with saturated sodium hydrogen carbonate solution, dried over
Na2SO4, concentrated under reduced pressure. The residue was purified
by column chromatography on silica gel to yield title compound 19 (0.169
1-(3, 4, 5-trimethoxymethylphenyl)-2-(2′, 3′, 4′, 6′-tetra-O-methoxy
methyl--D-glucopyranosyl) ethanone (28):
ͦ
g, 89.8%), as a colorless solid. Rf = 0.5 (EtOAc:hexane 1:1); m.p. 127-129
Step 1: Aldehyde 26 (0.120 g, 0.314 mmol), magnesium turnings (0.030g,
1.256 mmol), LiCl (0.026 g, 0.628 mmol), iBu2AlH (0.031 mL, 1 M in
toluene, 0.031 mmo0l) and 1-bromo-3,4,5-trimethoxymethylbenzene 25
(0.423 g, 1.256 mmol) were treated according to the procedure 20f to give
the mixture of diastereomers, after column chromatography on silica gel
(EtOAc/hexane 3:2), as a colorless syrup (0.150 g, 71.77%).
ͦ
1
C; []27D 67 (c 1.0, CHCl3); H NMR (CDCl3, 400MHz):  = 1.97 (s, 3H),
2.0 (s, 6H), 2.03 (s, 3H), 2.9 (dd, 1H, J 1 = 16.4 Hz, J 2 = 3.6 Hz), 3.30 (dd,
1H, J 1 = 16.4 Hz, J 2 = 8.0 Hz), 3.71-3.75 (m, 1H), 3.9 (s, 9H), 3.99 (dd,
1H, J 1 = 12.4 Hz, J 2 = 2.0 Hz), 4.20-4.24 (m, 1H), 4.25-4.29 (m, 1H), 5.04
(t, 1H, J = 9.6 Hz), 5.1 (t, 1H, J =9.6 Hz) 5.25 (t, 1H, J= 9.6 Hz), 7.1 (s, 2H).
13C NMR (100 MHz, CDCl3): 20.6 (CH3), 40.3 (CH2), 56.3 ((2xOCH3),
60.9 (OMe), 62.0 (CH2), 68.4 (CH), 71.8 (CH), 74.2 (CH), 74.3 (CH), 75.8
(CH), 105. 8(CH), 132.0 (C), 143.0 (C), 153.0 (C), 169.5 (C), 170.0 (C),
170.2 (C), 170.5 (C), 195.1 (C). IR (KBr): 1033, 1118, 1263, 1409, 1571,
1619, 1637, 1697, 2990, 3216 cm-1 HRMS: calc for C25H33O13 (M+H)+
541.1921 found 541.1943.
Step 2: To the mixture of diastereomers (0.120 g, 0.184 mmol), dimethyl
sulfoxide (3 mL) and IBX (0.103 g, 0.369 mmol) were added at room
temperature and the solution was kept at 70 o C for 3h. After completed the
o
reaction (monitored by TLC), the solution was allowed to stirr at 25 C,
then diluted with H2O (5 ml) and filtered through a pad of celite. The filtrate
was extracted with EtOAc (3x50 ml), the organic layer was dried over
Na2SO4 and concentrated in vacuum. The crude residue was purified by
silica gel column chromatography to give the title compound 30 (0.095 g,
1-(3, 4, 5-trichlorophenyl)-2-(-D-glucopyranosyl) ethanone (21h):
The colorless gum 20h (0.3 g, 1.021 mmol), methanol (3 mL) and HCl (6
N, 30 mL) were treated according to the general procedure B to give the
title compound 21h (0.07 g, 41%) as a light yellow colored solid. Rf = 0.3
(MeOH/DCM 1:9); m.p. 94-96 oC; []27 -11.7 (c 0.5, MeOH); 1H NMR
(CD3OD, 400 MHz): 3.08-3.10 m, 1H ), 3.12-3.14 (m, 2H ), 3.23-3.25
(m, 2H), 3.27-3.29 (m, 1H), 3.50 (dd, 1H, J 1 = 11.6 Hz, J 2 = 7.2 Hz), 3.65
(dd, 1H, J 1 =12.0 Hz, J 2 =2.0 Hz), 3.71 (td, 1H, J 1 = 8.8.0 Hz, J 2 = 2.8
Hz ), 7.98 (s, 2H) , 13C NMR (100 MHz, CD3OD) : 40.9 (CH2), 61.2
(CH2), 70.2 (CH), 73.6 (CH), 75.8 (CH), 78.2 (CH), 80.2 (CH), 128.2 ( CH ),
134.3 (2x C), 135.3 (C ), 137.0 (C), 195.6 (CO). IR (KBr): 1067, 1163, 1238,
1444, 1523, 1678, 2991, 3216 cm-1HRMS: cald for C14H15O6 Cl3Na
(M+Na)+ 406.9832 found. 406.9829.
ͦ
79.83%) as a colorless gum. Rf = 0.4 (EtOAc:hexane 1:1); []26D 110.5 (c
1.0, CHCl3); 1H NMR (CDCl3, 500 MHz): = 3.22 (dd, 1H, J 1 =17.0 Hz, J
2 = 8.5 Hz ), 3.29-3.33 (m, 4H), 3.35- 3.39 (m, 4H), 3.41 (s, 3H), 3.43- 3.46
(m, 4H), 3.50 (s, 6H), 3.52-3.55 (m, 1H), 3.61 (s, 3H, OMe), 3.62-3.67 (m,
2H), 3.77 (dd, 1H, J 1 = 11.5 Hz, J 2 = 2.0 Hz), 3.97-4.01 (m, 1H), 4.59 (dd,
2H, J 1 = 12.5 Hz, J 2 = 6.5 Hz), 4.72 (dd, 2H, J 1 = 18.0 Hz, J 2 = 7.0 Hz),
4.83- 4.87 (m, 3H), 4.91 (d, 1H, J = 7.0 Hz), 5.21 (s, 2H), 5.24 (s, 2H),
5.24 (s, 2H), 7.438 (s, 2H). 13C NMR (125 MHz, CDCl3): CH2),
55.3 (OMe), 56.3 (OMe), 56.4 (2 x OMe), 56.5 (OMe), 56.6 (OMe), 57.3
(OMe), 66.5 (CH2), 74. (CH), 77.0 (CH), 78.2 (CH), 80.5 (CH), 84.5 (CH),
95.3(2 x CH2), 96.8 (CH2), 98.5 (2 x CH2), 98.7 (CH2), 98.7 (CH2), 110.4
(CH), 133.2 (C),140.9 (C),150.8 (C), 196.1 (CO). IR (CHCl3): 1031, 1162,
1276, 1438, 1561, 1623, 2923 cm-1 HRMS: calcd for C28H46O16 (M+Na)+
661.2684 found 661.2692.
ͦ
D
3, 3', 4, 4', 5, 5'-hexakis(methoxymethyl ether)-1, 1'-biphenyl (25): To
a two necked round bottom flask fitted with a condenser was added
magnesium( 0.094 g, 3.93 mmol), the setup was kept on oil bath at 60 C
ͦ
for five minutes. To this was added the bromo compound 22 (0.67 g, 1.96
mmol) in anhydrous THF (8 ml), and 1,2-dibromoethane (0.17 mL, 1.96
mmol), while maintaining the same temperature. Stirring was continued at
Crystal data for compound 19: Formula: C25H32O13; unit cell parameters:
a = 9.2676 (5), b = 15.6349 (12), c = 18.7223 (4), space group P21; CCDC
1588605 contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
ͦ
60 C, until the magnesium was fully consumed. After acidic workup with
saturated aq. NH4Cl, the organic layer was extracted with EtOAc, dried
over Na2SO4, concentrated under reduced pressure, the resultant crude
product was purified by silica gel column chromatography to give the title
compound as light yellow colored gummy compound 25 (0.58 g, 58%), Rf
Biological assay:
1
= 0.7 (EtOAc:hexane 1:1); H NMR (CDCl3, 400 MHz): =3.44s, 12H),
Rat lens aldose reductase: Crude aldose reductase (AR) was prepared
from rat lens. Eyeballs were removed from 12-week-old Wistar strain
(WNIN) male rats obtained from National Center for Laboratory Animal
Services, National Institute of Nutrition, Hyderabad. Animal care and
protocols were in accordance with and approved by Institutional Animal
Ethics Committee. Lenses were dissected by posterior approach and
homogenized in 9 volumes of 100 mM potassium phosphate buffer pH 6.2.
The homogenate was centrifuged at 12,000x g for 30 min at 4 °C and the
resulting supernatant was used as the source of AR.
3.55 (s, 6H), 5.1 (s, 4H), 5.2 (s, 8H), 6.9 (s, 4H). 13C NMR (CDCl3, 125
MHz): = 56.3 (CH3), 57.2 (CH3) 95.6 (CH2), 96.6 (CH2), 109.9 (CH),
136.2 (C), 137.5 (C), 151.1 (C). HRMS: calcd for C24H34O12Na (M+Na)+
537.1948 found 537.1960.
2-(2′, 3′, 4′, 6′-tetra-O-methoxy methyl--D glucopyranosyl) acetal-
dehyde 26: An oven dried round bottom flask was charged with amide 17
(0.350 g, 0.793 mmol) in anhydrous THF under a nitrogen atmosphere.
Lithium aluminum hydride (0.40 g, 1.03 mmol), was added to the reaction
ͦ
mixture at 0 C. Stirring was continued until the starting material
Aldose reductase assay: AR activity was assayed according to the
reported method.20 Briefly, the assay mixture in 1 ml contained 50 µM
potassium phosphate buffer pH 6.2, 0.2 M lithium sulfate, 5 µM 2-mercapto
ethanol, 10 µM DL-glyceraldehyde, 0.1 µM NADPH, and enzyme
preparation (rat lens). Appropriate blanks were employed for corrections.
The assay mixture was incubated for 5 min at 37 °C and initiated by the
disappeared (on TLC). To the suspension was added H2O dropwise, and
it was filtered through a pad of celite. The organic layer was extracted with
EtOAc, dried over Na2SO4, and concentrated under reduced pressure. The
crude residue was purified by column chromatography to yield the title
compound 26 as a colorless gum (0.190 g, 62.7%), Rf = 0.3 (EtOAc:hexane
ͦ
1:1); []27D 53.1 (c 0.7, CHCl3); 1H NMR (CDCl3, 500 MHz): =2.65 (dd,
10
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701468
European Journal of Organic Chemistry
FULL PAPER
addition of NADPH at 37 °C. The change in the absorbance at 340 nm due
to NADPH oxidation was followed in a Simadzu spectrophotometer.
[14] P. G. M. Wuts,In Encyclopedia of Reagents for Organic Synthesis,
John Wiley & Sons, Ltd, 2001.
[15] J. R. Walker, G. Alshafie, H. Abou-Issa, R. W. Curley, Bioorg. Med.
Chem. Lett. 2002, 12, 2447-2450.
Inhibition studies: For inhibition studies concentrated stocks of
compounds were prepared in water. Various concentrations of inhibitors
were added to the assay mixture and incubated for 5 min before initiating
the reaction by NADPH as described above. The percent of inhibition with
test compounds was calculated considering the AR activity in the absence
of inhibitor as 100%.
[16] C. Nagamani, J. Guo, S. Thayumanavan, J. Polym. Sci. Part A
Polym. Chem. 2012, 50, 1187–1196.
[17] G. Silverman, In Handbook of Grignard Reagents, CRC Press, 1996,
9-21.
[18] U. Tilstam, H. Weinmann, Org. Process Res. Dev. 2002, 6, 906–
910.
[19] F. M. Piller, A. Metzger, M. A. Schade, B. A. Haag, A. Gavryushin,
P. Knochel, Chem. Eur. J. 2009, 15, 7192-7202.
[20] P. Suryanarayana, P. A. Kumar, M. Saraswat, J. M. Petrash, G. B.
Reddy, Mol. Vis. 2004, 10, 148–54.
Results: Among the synthesized C-analogues of β-Glucogallin,
compounds 4, 21a-h, substrate 21c alone, showed partial inhibition, 30%
at 200µM concentration.
Acknowledgements
We thank the Department of Science and Technology (DST) New
Delhi for funding towards the 400 MHz NMR spectrometer to the
Department of Chemistry, IIT-Madras under the IRPHA Scheme
and the ESI-MS facility under the FIST program. The Council of
Scientific
&
Industrial Research (CSIR) New Delhi is
acknowledged for funding of the project in 2015. M. R. Reddy Is
thankful to the IIT-Madras for a Senior Research Fellowship
(SRF). KS received a research fellowship from Department of
Science and Technology under INSPIRE program. GBR is
supported by grants from Science and Engineering Research
Board and Department of Biotechnology, Government of India,
New Delhi.
Keywords: -Glucogallin • Aldose reductase • Weinreb amide •
Glycosyl ketones • C-analogues
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10.1002/ejoc.201701468
European Journal of Organic Chemistry
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Entry for the Table of Contents (Please choose
one layout)
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-Glucogallin
1
(BGG),
a
major
Key Topic*
component isolated from the Indian
Author(s), Corresponding Author(s)*
gooseberry
(Emblica
officinalis)
medicinal plant, is
a
potent and
Page No. – Page No.
selective inhibitor of aldose reductase
(AKR1B1). Synthesis of C-analogue
wherein –CH2- unit replaces the
Title
glucosyl-O
remains
unexplored.
Synthesis of C-analogue 4 in particular
and its aldose reductase inhibition
(ARI) activity studies have been
performed.
Layout 2:
FULL PAPER
Key Topic*
Author(s), Corresponding Author(s)*
((Insert TOC Graphic here; max. width: 11.5 cm; max. height: 2.5 cm; NOTE: the
final letter height should not be less than 2 mm.))
Page No. – Page No.
Title
Text for Table of Contents
*one or two words that highlight the emphasis of the paper or
the field of the study
12
This article is protected by copyright. All rights reserved.