Synthesis of 4-C-β-D-Glucosylated Isoliquiritigenin and Analogues for Aldose Reductase Inhibition Studies

A Journal of

Accepted Article

Title: Synthesis of 4-C-β-D-Glucosylated Isoliquiritigenin and

Analogues for Aldose Reductase Inhibition Studies.

Authors: Mannem Rajeswara Reddy, Indrapal Singh Aidhen, Utkarsh

A Reddy, Geereddy Bhanuprakash Reddy, Kundan Ingle, and

Sami Mukhopadhyay

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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900413

Link to VoR: http://dx.doi.org/10.1002/ejoc.201900413

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Synthesis of 4-C--D-Glucosylated Isoliquiritigenin and

Analogues for Aldose Reductase Inhibition Studies

Mannem Rajeswara Reddy,^[a]Indrapal Singh Aidhen,^[a]*Utkarsh A. Reddy,^[b]Geereddy Bhanuprakash

Reddy,^[b]Kundan Ingle,^[c]Sami Mukhopadhyay^[c]

Dedicated to Professor Richard R. Schmidt on the occasion of his 84^thBirthday

Abstract: Inspired from natural product isoliquiritine, an O-glucoside

and the corresponding aglycone chalcone, isoliquiritigenin (ISL),

several C-glucosylated chalcones and dihydrochalcones have been

synthesized and evaluated for aldose reductase (AR) inhibition

activity, for the first time. The initial inputs from molecular docking

studies were also encouraging. Claisen-Schmidt condensation

reaction between 4-C-glucosylated benzaldehyde, a key building

block developed during the synthetic efforts and acetophenones

enabled convenient access to the targeted compounds in good yields.

Excellent AR inhibition has been observed with C-glucosylated ISL

with IC₅₀value of 21 M. This is similar to the chalcone ISL, displaying

IC₅₀of 19 M. In the light of limited aqueous solubility of ISL, the

observed AR inhibition with C-glucosylated ISL, gains importance.

Additionally, the studies have revealed significance of the oxygenation

pattern on the aromatic residue and paved way for the identification

of few more new compounds with equally promising AR inhibition.

represented by structure 6, for ALR2 inhibition activity. The 4-O-

glucosylated ISL, known as isoliquiritine 7 is present in natural

sources,⁸however the well-known greater hydrolytic stability of C-

verses O-glycosides, emboldened us in favor of C-glucosylated 4

and 5 as our targets for synthesis and biostudies (Figure 1).

Introduction

Chalcones are emerging as privileged scaffold¹and have shown

promise in the management of diabetes through variety of

mechanisms.²The chalcone, isoliquiritigenin (ISL) (1)³and its

dihydrochalcone analogue, davidigenin (2)⁴isolated from

Glycyrrhizae radix and Artemisia plant respectively have shown

ALR2 inhibition activity similar to flavonoid, quercetin 3, a well-

known ALR2 inhibitor.⁵Subsequent biostudies with synthetic

chalcones⁶and molecular docking studies⁷indicate the presence

of hydroxy groups in the A-ring as an essential feature for the

optimal activity from chalcones. However, the hydroxyl-

substituted chalcones have inadequate water solubility and

bioavailability. Given the fact that glucosylation of low molecular

weights compounds is a promising approach for enhancing water

solubility, improved stability and bioavailability, we proposed to

synthesize and evaluate, 4-C-glucosylated isoliquiritigenin (4), it’s

dihydro derivative 5 in particular and several analogues, thereof,

Figure 1. Proposed D-glucosylated chalcones 4 and dihydrochalcones 5.

Before undertaking synthesis and biostudies, docking studies

(see infra) were performed for understanding the promising

features, if any, with the proposed C-glucosylated targets 4 and 5.

Although ISL 1, and the proposed C-glucosylated targets 4 and 5

had favourable docking scores in arbitrary units of -70.37, -53.47

and -72.38 respectively, the key stabilizing and favourable binding

interactions at the active site were significantly more with the

proposed new targets 4 and 5, compared to ISL. These

observations further inspired us to undertake synthesis of

proposed new targets and evaluate their ALR inhibition.

Presented herein are the results of these findings.

[a]*

Rajeswara Reddy, Prof. Indrapal Singh Aidhen. Department of

Chemistry, Indian Institute of Technology Madras, Chennai 600036,

India 1

E-mail:isingh@iitm.ac.in

Results and Discussion

Homepage: http://chem.iitm.ac.in/faculty/indrapal/

Dr. Utkarsh A. Reddy, Dr. Geereddy Bhanuprakash Reddy

Biochemistry Division, National Institute of Nutrition, Hyderabad

500007, India

Kundan Ingle, Dr. Sami Mukhopadhyay. NovaLead Pharma Pvt.

Ltd., 2^ndFloor, Plot No-05, Ram Indu Park, Baner Road, Pune

411045, Maharashtra, India

[b]

[c]

1. Molecular Docking Studies.

1.1 Selection and Preparation of Protein Structure

The X-ray structure of human Aldose Reductase (PDB ID 1PWM

X-Ray resolution of 0.92 Å) in complex with NADP and the

inhibitor fidarestat was obtained from the RCSB Protein Bank

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(RCSB pdb). Crystallographic protein structure downloaded from

protein data bank contains various potential problems which must

be resolved. These issues involved removal of water and other

co-crystal ligands, addition of hydrogen atoms and assigning

correct charges to protein structures.

Preparation of protein structures for docking purpose were

performed using VLife Molecular Design Suite (VLifeMDS®).⁹

1.2 Preparation of the Ligands

The structures of compounds isoliquiritigenin 1, glucosylated

isoliquiritigenin 4 and the reduced (C=C double bond reduced)

glucosylated isoliquiritigenin 5 were generated using the 2D Draw

tool of the VLifeMDS®.The 2D structures were prepared for

docking by adding hydrogen atoms and energy minimized using

force field MMFF with RMSD gradient of 0.01 kcal/mol Å.

Conformations of the molecules were generated using a Monte

Carlo method with an RMSD cutoff of 0.7. All these steps were

carried out using VLifeMDS®.⁹

results was based on both the docking score (PLP) as well as the

binding interactions with active site residues.^10,11

1.4 Docking Results and Analysis

The favourable stabilizing key binding interactions are

significantly more in both C-glucosylated targets 4 (Glc-ISL) and

5 (Glc-DH-ISL) as compared to natural product isoliquiritigenin 1

(ISL). While ISL has favourable binding interactions: H-bond

interaction with LEU300A and Pi Stacking with TRP20A, and

TRP219A, the molecule

4

captures favourable binding

interactions: H-bond interactions with HIS110A, CYS298A and Pi

stacking interaction with TRP20A and TRP219A as well as

hydrophobic interactions with VAL47A, TRP111A, CYS298A

whereas molecule 5 (Glc-DH-ISL) captures favourable binding

interactions: H-bond interactions with GLN183A, CYS298A and

Pi stacking interactions with TRP20A, TYR209A, TRP219A,

HIS110A as well as hydrophobic interactions with CYS298A. This

clearly shows that both the proposed targets 4 and 5 are able to

capture more favourable binding interactions in the active site of

aldose reductase, compared to natural product ISL 1. This

understanding motivated us to synthesize compounds 4 and 5 for

evaluating their aldose reductase inhibition activity. The best

docked poses presenting key binding interactions as discussed

above are depicted in Figures 2-4. In case of the 3D images, the

active site surface of aldose reductase (1pwm) is shown in picture

(c), whereas the other picture (b) is without the surface, for clarity

of visualising the binding interactions. Different binding

interactions of the ligands in the active site are shown in different

colours together with the colour code for ease of understanding.

1.3 Docking Study

The following molecular docking study was carried out with an aim

to rationalise the background for synthesizing the different G

glucosylated isoliquiritigenin molecules with respect to their

inhibitory activity towards aldose reductase in the light of

designing novel promising anti-diabetic agents.

The active site used for docking was determined by the key active

site residues as cited in published literature.^10,11The software

VLife Molecular Design Suite (VLifeMDS®)⁹has been utilized for

carrying out the molecular docking. Piecewise Linear Pairwise

Potential (PLP)¹²was used as the dock scoring function. The PLP

empirical score is in arbitrary units.

All the three ligands 1, 4, and 5 were docked in to the binding site

of the PDB (Aldose Reductase (1pwm)). Analysis of the docking

Figure 2. Molecular docking images of ISL 1, (a) 2D, (b) 3D and (c) 3D Pocket & Interactions.

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Figure 3. Molecular docking images for 4, (a) 2D, (b) 3D and (c) 3D Pocket & Interactions.

Figure 4. Molecular docking images for 5, (a) 2D, (b) 3D and (c) 3D Pocket & Interactions.

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In all the 2D images the aromatic interactions mean Pi-stacking

interactions. It is interesting to note that while the resorcinol unit,

aromatic ring A, in natural product, ISL 1 captures favourable key

binding interactions with the active site of aldose reductase

(Figure 2), surprisingly with the Glc-ISL, 4, the best docked pose

has glucosyl residue capturing the favourable binding interactions

with the active site (Figure 3) and the resorcinol aromatic ring A

of Glc-ISL, 4 is out of the active site pocket. In case of Glc-DH-

ISL, compound 5, the best docked pose (Figure 4) once again has

favourable binding with the resorcinol unit, aromatic ring A, similar

to that observed for the natural product 1. Compound 5 being a

dihydrochalcone, the apparent contrast between 4 and 5 may be

because of the additional conformational freedom available in 5

from free C-C rotation along the ,  carbon atoms. The observed

interactions compensate towards overall favourable binding and

these are reflected in the fact that both the structures 4 and 5 have

favourable docking scores (in arbitrary units) of -53.47 and -72.38

respectively.

To rationalize the surprise element between compound 1 and 4

and with the understanding that the interactions between a

molecule and its receptor need not necessarily correspond to

minimum energy, guided docking of compound 4 was carried out

forcing the resorcinolic aromatic ring A inside the aldose

reductase active site. The results of this guided docking studies

afforded poor docking scores indicating that these docked poses

of Glc-ISL, 4 are unfavorable for binding in the active site pocket

of aldose reductase. The docked poses, in fact showed severe

steric clashes of the glucosyl group with the surrounding aldose

reductase residues. In this context, the analogues of substrate 4

with varying substituents in ring A, apparently, should have

identical bioactivity, until and unless the electronic effects of the

substituents get transmitted via the π-conjugated framework and

alter the primary interactions of the portion of the moleccule inside

the pocket. The synthesis of compound 4, 5 and their analogues,

along with the results of biostudies are presented below.

2. Chemistry

Synthesis of hitherto unknown building blocks 8a and 8b was

readily achieved as described in synthetic scheme 1. It involved

formation of functionalized aryl magnesium bromide from ethyl-4-

iodobenzoate 10 using well known and elegant procedure

developed by Knochel’s group¹³and addition onto protected D-

gluconolactone 12¹⁴for the desired C-C bond formation. A metal-

halogen exchange reaction was performed between the

isopropylmagnesium bromide (prepared in situ) and ethyl-4-

iodobenzoate 10 for the formation of arylmagnesium bromide 11.

To the formed Grignard reagent, was added D-gluconolactone 12.

The reaction afforded after work-up and purification the -anomer

product 13 in 82%. Reductive anomeric deoxygenation in lactol

.

13 was carried out using triisopropylsilane and BF₃OEt₂. The

reduction was clean and afforded the desired compound 14 in

66% yield with exclusive selectivity. It merits to mention that the

use of more commonly used, triethylsilane, showed low selectivity

and this has been also observed in the literature.¹⁵Reduction with

LiAlH₄, followed by oxidation of the benzylic alcohol 15 with PCC

afforded the desired aldehyde 8a in 86% yield, over two steps. A

single step reduction of ester 14 with DIBAL-H afforded a mixture

of desired aldehyde 8a and over reduced product 15. Reductive

hydrogenolysis of compound 14 with Pd-C (10 mol%), and

subsequent treatment of the resultant tetrol with chloromethyl

methyl ether in presence of Hunig‘s base in anhydrous CH₂Cl₂

generated the O-MOM protected compound 16 in 75% yield, over

two steps. Subsequent reduction with lithium aluminum hydride

and oxidation of benzylic alcohol with IBX in presence of DMSO

furnished the O-MOM protected 4-C-glucosylated benzaldehyde

8b as a pale-yellow color gum in good yields (Scheme 1).

The synthesis of targeted compounds 4, 5 and analogues

essentially banked on the classical Claisen Schmidt condensation

reaction

between

suitably

protected

4-C-glucosylated

benzaldehyde and acetophenones and subsequent deprotections.

To begin with and to provide some degree of orthogonality among

protections on the glucosyl and aromatic residue part from

acetophenones, we envisaged 8a and 8b as the key building

block for the synthetic scheme (Figure 5).

Scheme 1. Synthesis of key building blocks 8a and 8b.

Figure 5: Retrosynthetic scheme for glucosylated target 4 and 5.

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Both the building blocks 8a and 8b underwent the expected

condensation with requisite 2, 4-disubstituted acetophenone 9a¹⁶

in presence of alcoholic (ethanol) 10% NaOH, at room

temperature affording the corresponding chalcone 17a and 18a

respectively in good yields (Scheme 2). However, the simple and

final removal of ether protections in 17a and 18a was not trouble

free. The use of BBr₃for deprotection resulted in formation of a

complex mixture of products as observed from NMR spectrum (¹H,

Table 1. Synthesis of methoxy substituted chalcones 21a-g.

Entry

9

21

Yield ^[a]

o

¹³C). Even with the use of TMSOTf at low temperature (-40 C),

1

2

3

4

5

6

9a: R = 2, 4-(OMe)₂

9b: R = 2, 4-(OBn)₂

9d: R = 2-OH-4,6-(OMe)₂

9e: R = 3,4-(OMe)₂

9f: R = 4-(OMe)

21a: R = 2, 4-(OMe)₂

21b: R = 2, 4-(OBn)₂

21d: R = 2-OH-4,6-(OMe)₂

21e: R = 3,4-(OMe)₂

21f: R = 4-(OMe)

73%

65%

57%

69%

62%

63%

the deprotection attempt was not successful. The reaction lead to

decomposition of the starting material. The chalcone 17b

prepared from benzyl ether protected acetophenone 9b¹⁷also

presented similar difficulties in final deprotection.

9g: R = 2, 4, 6-(OBn)₃

21g: R = 2, 4, 6-(OBn)₃

[a] Isolated Yield

The aldehyde 19 in fact underwent trouble free Claisen-Schmidt

reaction with 9c, as a representative acetophenone furnishing the

corresponding chalcone 21c in 67% yield. The obtainment of the

1

chalcone 21c was confirmed by H NMR spectrum. The doublet

present at 4.19 ppm represents the anomeric proton (Ha), the

coupling constant 9.5 Hz confirmed the -orientation, whereas

two doublets present at 6.98 and 7.34 ppm represent the two

olefinic protons of chalcone and the coupling constant 16.0 Hz

confirms the trans-geometry of the enone functionality. Even the

peracetylated aldehyde 20 condensed with acetophenone 9c,

with equal ease (Scheme 3). Basic conditions during

condensation assured the facile and convenient removal of the

acetyl group protections in the same pot. The generality of the

scheme was demonstrated with several other acetophenones

(Table 1).

Our earlier experience of facing difficulties in removal of the ether

protections on the glucosyl and aromatic part, we first chose the

acetyl or benzoyl protected, 2,4-dihydroxy acetophenone 9h or 9i

respectively for condensation with the peracetylated aldehyde 20

towards the synthesis of targeted compound 4. This was with the

premise that the basic conditions will not only enable

condensation but would also ensure, de-acylation on glucosyl and

aromatic ring together. To our surprise, no condensation occurred

and only mere recovery of de-acetylated building block 19 was

seen. This could be presumably due to faster rates for the

deacylation reaction compared to condensation reaction. In order

to circumvent this failure, the MOM ether protected 2, 4-dihydroxy

acetophenone 9j was explored for condensation with aldehyde 20.

To our satisfaction, condensation occurred affording the

corresponding targeted 4-C-glucosylated isoliquiritigenin 4 in 67%

isolated yield, after acidic work-up, which affected the removal of

MOM protection (Scheme 4). The developed protocol was

generalized with two other MOM protected acetophenones 9k

and 9l. The corresponding products 21h and 21i, containing

hydroxyl functionality like isoliquiritigenin on the aromatic ring

were obtained in similar yields.

Scheme 2. Synthesis of protected chalcones 17a-b and 18a.

The frustration of deprotection on the D-glucosyl residue at the

final stages, emboldened us to investigate the formation of

chalcone with protection free aldehyde 19, which will obviate the

aforesaid need of deprotection at the final stages. The protection-

free aldehyde 19 was easily prepared from the corresponding

benzyl ether protected aldehyde 8a in two steps. The benzyl ether

protections in aldehyde 8a were removed using TMSOTf (1.5 eq.)

in presence of acetic anhydride as solvent. The reaction afforded

the corresponding peracetylated product 20 in 77% yield.

Subsequent deacetylation with NaOMe in presence of MeOH

gave the desired protection free aldehyde 19 as a colorless solid

in good yield (Scheme 3).

Scheme 3. Synthesis of protection free building block 19 from 8a.

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chalcones 4/21b, 21c, and 21g afforded the corresponding

dihydrochalcones 5, 22b and 22e respectively in good yields. In

case of other chalcones, 21a, 21e-f and 21h-i unwanted partial or

complete reduction of the carbonyl group was also observed.

Such an observation of aromatic carbonyl group reduction to

methylene compounds via the intermediacy of benzylic alcohol

under Pd/C-catalyzed hydrogenation condition is well reported.¹⁸

The addition of

a

sulfur containing additive such as

diphenylsulfide (Ph₂S) prevents the reduction of carbonyl group in

chalcones during hydrogenation¹⁹and this was used for the

chemoselective hydrogenation of the olefin functionality alone.

Addition of 0.1 equivalent of Ph₂S into the reaction mixture, during

the hydrogenation of 21a and 21e-i afforded the corresponding

desired dihydro chalcones 22a-g in good yields as shown in the

table 2. The synthesized D-glucosylated chalcones and

dihydrochalcones were subjected to biological studies.

Scheme 4. Synthesis of target compound 4 and it’s analogues 21h-i.

The synthesis of dihydrochalcones involved simple hydrogenation,

using, Pd-C (10 mol%) under H₂balloon pressure (1 atm). The

Table 2. Synthesis of dihydrochalcones 5 and 22a-g from appropriate chalcones

Entry

21

Condition/t

22

Yield ^[a]

Entry

21

Condition/t

22

Yield ^[a]

1

2

21a

21b

B/18 h

A/10 h

22a: R = 2, 4-(OMe)₂

5: R = 2,4-(OH)₂

73%

77%

5

6

21f

B / 24 h

A / 12 h

22d: R = 4-(OMe)

76%

78%

21g

22e: R = 2, 4, 6-(OH)₃

3

4

21c

21e

A/10 h

B/24 h

22b: R = 2, 4, 6-(OMe)₃

22c: R = 3, 4-(OMe)₂

68%

64%

7

8

21h

21i

B / 24 h

B / 18 h

22f: R = 3,4-(OH)₂

22g: R = 4-(OH)

67%

61%

[a] Isolated yield

Biological Studies

methyl ether derivative 21f showed extremely good activity with

100% inhibition at 200M.

As expected, to our delight, both C-glucosylated ISL 4 and C-

glucosylated davidigenin 5 have exhibited the promising AR

inhibitory activity. The natural product, ISL (1), showed 91%

inhibition at 100 M concentration, whereas C-glucosylated ISL,

4, exhibited 100% inhibition at 120 M concentration. The loss in

activity with compound 21a (8% inhibition at 200 M), the methyl

ether derivative of 4 corroborates the importance of phenolic

hydroxyls and their positioning. The oxygenation pattern and the

number of phenolic hydroxyls in aromatic ring A seems to be

crucial for activity. Chalcones containing tri-oxygenated aromatic

ring A with oxygenation pattern being 2,4,6 essentially showed no

activity (compound 21c, 21d). The chalcone 21h, di-oxygenated

and positional isomer of C-glucosylated ISL, had 61% inhibition at

120 M and the corresponding methyl ether derivative compound

21e, exhibited 100% inhibition at 200M. The chalcone 21i with

mono-oxygenated ring A, had no activity, even at 250M while it’s

Compare to chalcones, all the corresponding dihydrochalcones

were relatively less active. The C-glucosylated davidigenin 5,

exhibited AR inhibitory activity of 57% and 73% at 120 M and

Table 3. IC₅₀values for the important chalcones and dihydrochalcones

comparing with ISL.

Entry

Compound

IC₅₀(M)

19.00

Entry

Compound

21e

IC₅₀(M)

145.0

1

2

3

4

ISL^[a]

4

5

6

7

21.00

22f

245.0

21h

5

55.00

22e

336.0

72.00

[a] Natural product

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Figure 6. IC₅₀Graphs (a) ISL, (b) Compound 4, (c) Compound 21h, and (d) Compound 5.

corresponding dihydrochalcones 5 and 22a-g, without any

reduction or over reduction of the carbonyl group. The synthetic

work and biostudies have enabled identification of a three new

chalcones 21h, 21e and 21f with equally promising activity. While

21h displays 61% inhibition at 120 M, the other two chalcones

21e and 21f showed 100% inhibition at 200M. The variation in

the experimentally observed bio-activity of chalcones

(compounds 21a, 21c-f, 21h, 21i), analogues of Glc-ISL,

compound 4, with varying substituents on the resorcinolic

aromatic ring A, reflects, probable transmission of electronic

effects of the substituents via the π conjugated framework

comprising of carbonyl group and double bond. The relayed

electronic effects of the substituents, being different, due to the

nature and position of the substituents, alters the binding efficacy

of the portion inside the pocket, differently, and this is reflected in

the observed bioactivity.

240 M respectively. The compounds 22e and 22f showed

moderate activity with 38% and 48% at 240 M respectively, while

other dihydro chalcones 22a, 22b, 22c, 22d, and 22g were not

active (≤15%) even at higher concentration (250 M). The IC₅₀

values of the six promising compounds are presented in Table 3

and the data of three most promising compounds among them

are graphically represented in Figure 6.

Conclusions

The synthesized 4-C-glucosylated chalcones in general and C--

D-glucosylated isoliquiritigenin 4 in particular are indeed showing

good AR inhibition. These synthetic compounds are easily

accessible through the Claisen-Schmidt condensation reaction

between 4-C-glucosylated benazaldehyde 20, a key building

block developed in the scheme and appropriate acetophenones

9a-l. Chemoselective reduction of the double bond in the

chalcones under hydrogenation conditions, using diphenyl sulfide

(Ph₂S) as additive, afforded convenient access to the

Our research findings will be of relevance and importance, given

the fact that search of aldose reductase inhibitors (ARIs) for the

prevention and/or arrest of long-term diabetic complications

resulting from hyperglycemia remains unabated and focus clearly

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shifting towards small sized organic molecules from natural

sources in the recent times.²⁰

To

a solution of lactol 13 (2.8 g, 4.06 mmol) in a mixture of

acetonitrile:dichloromethane (1:1, 30 mL) was added triisopropylsilane

(2.25 g, 5.90 mmol) at room temperature under nitrogen atmosphere.

Subsequently, BF₃OEt₂was added to the reaction mixture at -30 ^oC for 5

.

min then the reaction was stirred at room temperature for 3 h. After

completion, the reaction mixture was diluted with sat. NaHCO₃solution.

The aqueous layer was extracted with dichloromethane (3x100 mL),

resultant organic layer was washed with brine, dried over Na₂SO₄, and

concentrated in vacuo. The resultant residue was purified by column

chromatography on silica gel (EtOAc/hexanes, 85:15) affording compound

14 (1.8 g, 66%) as a colorless solid. R_f= 0.6 (EtOAc/hexanes, 1:4); m.p. =

82-84 ^oC; ²³_D= 43.3 (c = 0.5, CHCl₃); ¹H NMR (400 MHz, CDCl₃):  =

1.41 (t, J = 7.2 Hz, 3 H), 3.4 (t, J = 9.2 Hz, 1 H), 3.61 (d, J = 8.0 Hz, 1 H),

3.77-3.81 (m, 5 H), 4.30 (d, J = 11.6 Hz, 1 H), 4.36-4.42 (m, 3 H), 4.56 (d,

J = 12.4, 1 H), 4.62-4.65 (m, 2 H), 4.86 ( d, J = 11.2 Hz, 1 H), 4.91-4.95

(m, 2 H), 6.91-6.93 (m, 2 H), 7.19-7.25 (m, 5 H). 7.28-7.34 (m, 13 H). 7.53

(d, J = 8.4 Hz, 2 H), 8.04 (d, J = 8.8 Hz, 2 H), ¹³C NMR (100 MHz, CDCl₃):

= 14.4 (CH₃), 61.0 (CH₂), 69.0 (CH₂), 73.4 (CH₂), 75.0 (CH₂), 75.1 (CH₂),

75.7 (CH₂), 78.2 (CH), 79.3 (CH), 81.1 (CH), 84.0 (CH), 86.0 (CH), 127.5

(CH), 127.6 (CH), 127.7 (CH), 127.7 (CH), 127.8 (CH), 127.8 (CH), 128.0

(CH), 128.2 (CH), 128.3 (CH), 128.4 (CH), 128.5 (CH), 129.5 (CH), 130.2

(C), 137.9 (C), 138.1 (C), 138.2 (C), 138.5 (C), 144.2 (C), 166.5 (C). IR

(CHCl₃): ν˜ = 1185, 1417, 1543, 1691, 2891, 2967 cm–¹. HRMS: Calcd for

C₄₃H₄₄O₇Na [M+Na]⁺695.2984, found 695.2992.

Experimental Section

All reactions were carried out in an oven dried glassware. Solvents used

for column chromatography were laboratory reagent grade. Solvents were

distilled from CaH₂(CH₂Cl_2,DMF), Na/Benzophenone for THF and Mg/I₂

(MeOH). Reactions were performed under nitrogen atmosphere. NMR

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 in capillaries. All compounds were purified by silica gel

column chromatography (100-200 mesh), using respective solvent system.

¹H (400 MHz and 500 MHz) and ¹³C (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 DMSO [D₆] ( =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. HRMS were

recorded with a Agilent technologies 6545-QTOF mass spectrometer by

using the ESI technique at 10 eV.

4-(2,3,4,6-tetra-O-benzylglucopyranosyl)benzylic alcohol 15:

To a solution of 14 (5.8 g, 8.6 mmol) in anhydrous THF (60 mL) was added

LiAlH₄(0.7 g, 17.24 mmol) at 0 ^oC under nitrogen atmosphere. The

reaction mixture was stirred at the same temperature for 2 h. After

completion, the reaction mixture was diluted with slow addition of H₂O and

filtered. The filtrate was extracted with EtOAc, the organic layer was

washed with brine, dried over Na₂SO₄and concentrated under reduced

pressure. The resulting residue was purified by column chromatography

on silica gel (EtOAc/hexanes, 2:3) to give the title compound 15 as a

colorless gum (5.1 g, 94%). R_f= 0.3 (EtOAc/hexanes, 2:3); ]²³_D= -119.1

(c = 7.0, CHCl₃); ¹H NMR (400 MHz, CDCl₃):  = 3.49-3.53 (m, 1 H), 3.59-

3.60 (m, 1 H), 3.74-3.81 (m, 5 H), 4.25 (d, J = 9.6 Hz, 1 H), 4.36 (d, J =

10.0 Hz, 1 H), 4.54 (d, J = 12.4, 1 H), 4.63-4.65 (m, 2 H), 4.69 (s, 2 H),

4.85-4.95 (m, 3 H), 6.92-6.93 (m, 2 H), 7.18-7.23 (m, 5 H). 7.28-7.37 (m,

15 H). 7.46 (d, J = 8.0 Hz, 2 H), ¹³C NMR (100 MHz, CDCl₃): = 65.1 (CH₂),

69.1 (CH₂), 73.5 (CH₂), 74.9 (CH₂), 75.1 (CH₂), 75.7 (CH₂), 78.3 (CH), 79.3

(CH), 81.4 (CH), 84.3 (CH), 86.7 (CH), 126.8 (CH), 127.6 (CH), 127.6 (CH),

127.7 (CH), 127.8 (CH), 127.9 (CH), 128.0 (CH), 128.2 (CH), 128.3 (CH),

128.4 (CH), 128.5 (CH), 137.7 (C), 138.2 (C), 138.3 (C), 138.7 (C), 138.7

(C), 140.9 (C). IR (CHCl₃): ν˜ = 1178, 1396, 1519, 2901, 2987, 3412 cm–

¹. HRMS: Calcd for C₄₁H₄₂O₆Na [M+Na]⁺653.2879, found 653.2865.

ethyl 4-(2,3,4,6-tetra-O-benzyl-1-hydroxy--D-glucopyranos)benzoate

13:

An oven dried two necked round bottom flask was charged with

magnesium turnings (0.71 g, 29.6 mmol) and catalytic amount of I₂was

added. The flask was pre-heated under vacuum to activate the magnesium

and anhydrous THF (25 mL) was added. At stirring isopropylbromide (1.26

mL, 16.7 mmol) was added slowly, after 5 min the mixture was strongly

self heated. As the magnesium turnings were finished, ethyl-4-

iodobenzoate 10 (4.05 g, 14.8 mmol) in anhydrous THF was added to the

reaction mixture at -15 ^oC slowly and stirring was continued for 2 h at the

same temperature. To the resulting yellow color solution was added

lactone 12 (4.0 g, 7.4 mmol) in anhydrous THF for 15 min at -15 ^oC, and

the solution was warmed to 0 ^oC, allowed to stir for 3 h at same

temperature. The solution was diluted with cold aq. NH₄Cl solution,

aqueous phase was extracted with EtOAc (3 x 100 mL) and the combined

organic layer was washed with brine solution, dried over Na₂SO₄, and

concentrated under reduced pressure. The crude product was purified by

column chromatography on silica gel (EtOAc/hexanes, 1:3) affording the

lactol 13 (4.2 g, 82%) as a light yellow color gum; R_f= 0.4 (EtOAc/hexanes,

1:4); []²³_D= -9.8 (c = 1.0, CHCl₃); ¹H NMR (400 MHz, CDCl₃): = 1.41 (t,

J = 7.2 Hz, 3 H), 3.3 (s, 1 H), 3.54 (d, J = 9.2 Hz, 2 H), 3.72 (dd, J = 10.8,

2.0 Hz, 1 H), 3.80-3.85 (m, 3 H), 4.05-4.09 (m, 1 H), 4.10-4.12 (m, 1H),

4.16-4.19 (m, 1 H), 4.39 (q, J = 7.2., 2 H), 4.43 (d, J = 8.0 Hz, 1 H), 4.54

( d, J = 12.4 Hz, 1 H), 4.61-4.66 (m, 2H), 4.87 (d, J = 10.8 Hz, 1 H), 4.90

(s, 1 H), 6.93-6.96 (m, 2 H), 7.14-7.23 (m, 4 H). 7.25-7.33 (m, 14 H). 7.69

(d, J = 8.8 Hz, 2 H), 8.03 (d, J = 8.8 Hz, 2 H), ¹³C NMR (100 MHz, CDCl₃):

 = 14.4 (CH₃), 62.7 (CH₂), 68.9 (CH₂), 72.2 (CH), 73.3 (CH₂), 75.1 (CH₂),

75.5 (CH₂), 75.7 (CH₂), 78.2 (CH), 83.5 (CH), 84.6 (CH), 97.8 (C), 126.3

(CH), 127.6 (CH), 127.7 (CH), 127.8 (CH), 127.9 (CH), 128.2 (CH), 128.3

(CH), 128.4 (CH), 128.4 (CH), 129.4 (CH), 130.6 (C), 137.9 (C), 138.1 (C),

138.3 (C), 138.5 (C), 146.9 (C), 166.4 (C). IR (CHCl₃): ν˜ = 1103, 1370,

1532, 1701, 2873, 3226 cm–¹. HRMS: Calcd for C₄₃H₄₄O₈Na [M+Na]⁺

711.2933, found 711.2941.

4-(2,3,4,6-tetra-O-benzylglucopyranosyl)benzaldehyde 8a:

To a solution of 15 (5.5 g, 8.7 mmol) in anhydrous dichloromethane (60

mL) was added PCC (3.7 g, 17.46 mmol) and molecular sieves powder (4

A^◦, 3 g) at room temperature under nitrogen atmosphere. The reaction

mixture was stirred at the same temperature for 4 h. After completion, the

reaction mixture was filtered, the filtrate was washed with sat. NaHCO₃

solution. The aqueous layer was extracted with DCM, the combined

organic layer was washed with brine, dried over Na₂SO₄and concentrated

under reduced pressure. The resulting residue was purified by column

chromatography on silica gel (EtOAc/hexanes, 1:4) to give the title

compound 8a as a colorless solid (4.7 g, 86%). R_f= 0.3 (EtOAc/hexanes,

1:4); m.p. = 127-129 ^oC; ²³_D= 67.5 (c = 1.0, CHCl₃); ¹H NMR (500 MHz,

CDCl₃): = 3.47 (t, J = 7.2 Hz, 1 H), 3.60-3.63 (m, 1 H), 3.77-3.84 (m, 5

H), 4.32 (d, J = 9.5 Hz, 1 H), 4.44 (d, J = 10.5, 1 H), 4.55-4.63 (m, 2 H),

4.64-4.65 (m, 1 H), 4.87 (d, J = 10.5 Hz, 1 H), 4.90-4.95 (m, 2 H), 6.91-

6.93 (m, 2 H), 7.17-7.21 (m, 4 H). 7.27-7.32 (m, 14 H). 7.61 (d, J = 8.0 Hz,

2 H), 7.86 (d, J = 8.5 Hz, 2 H), 10.02 (s, 1H) ppm. ¹³C NMR (125 MHz,

CDCl₃): = 69.0 (CH₂), 73.4 (CH₂), 75.0 (CH₂), 75.2 (CH₂), 75.7 (CH₂),

Ethyl-4-(2,3,4,6-tetra-O-benzylglucopyranosyl)benzoate 14:

10.1002/ejoc.201900413

European Journal of Organic Chemistry

FULL PAPER

78.2 (CH), 79.4 (CH), 81.0 (CH), 84.0 (CH), 86.8 (CH), 127.5 (CH), 127.6

(CH), 127.7 (CH), 127.7 (CH), 127.8 (CH), 127.8 (CH), 128.0 (CH), 128.1

(CH), 128.2 (CH), 128.3 (CH), 128.4 (CH), 128.5 (CH), 129.6 (CH), 136.2

(C), 137.3 (C), 138.1 (C), 138.2 (C), 138.5 (C), 146.2 (C), 192.0 (C). IR

(CHCl₃): ν˜ = 1156, 1419, 1558, 1777, 2871, 2992, cm–¹. HRMS: Calcd

for C₄₁H₄₀O₆Na [M+Na]⁺651.2722, found 651.2704.

4.8 Hz, 2 H), 3.92 (dd, J = 11.2, 2.0 Hz, 1 H), 4.03 (d, J = 6.4 Hz, 1 H),

4.17 (d, J = 9.6 Hz, 1 H), 4.40 (d, J = 6.4 Hz, 1 H), 4.65 (s, 4 H), 4.78 (d, J

= 6.4 Hz, 1 H), 4.86–4.93 (m, 3 H), 7.32 (d, J = 8.4 Hz, 2 H), 7.37 (d, J =

8.4 Hz, 2 H), ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 55.2 (OMe), 55.8

(OMe), 56.5 (2xOMe), 64.8 (CH₂), 66.8 (CH₂), 77.1 (CH) 78.7 (CH), 80.2

(CH), 81.5 (CH), 83.7 (CH), 96.7 (CH₂), 97.4 (CH₂), 98.6 (CH₂), 98.7 (CH₂)

126.7 (CH), 128.1 (CH), 138.1 (C), 141.1 (C) ppm. IR (CHCl₃): ν˜ = 1217,

1558, 2871, 2992, 3510 cm– ¹. HRMS: Calcd for C₂₁H₃₄O₁₀K [M+K]⁺

485.1789, found 485.1790.

Ethyl-4-(2,3,4,6-tetra-O-methoxymethyl--D-

glucopyranosyl)benzoate 16:

Step 2: To a solution of above resultant compound (3.6 g, 8.1 mmol) in

DMSO (40 mL) was added IBX (3.4 g, 12.16 mmol) at room temperature

under nitrogen atmosphere. The reaction mixture was stirred at the same

temperature for 4 h. After completion, the reaction mixture was diluted with

H₂O, then filtered, the filtrate was extracted with EtOAc, the combined

organic layer was washed with brine, dried over Na₂SO₄and concentrated

under reduced pressure. The resulting residue was purified by column

chromatography on silica gel (EtOAc/hexanes, 1:4) to give the title

compound 8b as a colorless gum. (2.97 g, 83%). R_f= 0.6 (EtOAc/hexanes,

2:3); []²³_D= 23.4 (c = 0.5, CHCl₃); ¹H NMR (400 MHz, CDCl₃): δ = 2.6 (s,

3 H), 3.32 (s, 3 H), 3.38 (s, 6 H), 3.55 (t, J = 9.2 Hz, 1 H), 3.54-3.63 (m, 2

H), 3.66-3.67 (m, 1 H), 3.71 (t, J = 8.4 Hz, 1 H), 3.87 (d, J = 11.2 Hz, 1 H),

4.02 (d, J = 6.8 Hz, 1 H), 4.21 (d, J = 9.6 Hz, 1 H), 4.42 (d, J = 6.8 Hz, 1

H), 4.60 (s, 2 H), 4.70 (d, J = 6.8 Hz, 1 H), 4.80 (s, 2 H), 4.84–4.85 (m, 1

H), 7.51 (d, J = 8.0 Hz, 2 H), 7.79 (d, J = 8.4 Hz, 2 H), 9.93 (s, 1 H) ppm.

¹³C NMR (100 MHz, CDCl₃): δ = 55.32 (OMe), 55.9 (OMe), 56.6 (2xOMe),

66.8 (CH₂), 77.1 (CH) 78.9 (CH), 80.0 (CH), 81.1 (CH), 83.8 (CH), 96.7

(CH₂), 97.6 (CH₂), 98.7 (CH₂), 98.8 (CH₂) 128.7 (CH), 129.7 (CH), 136.3

(C), 145.6 (C), 192.0 (C) ppm. IR (CHCl₃): ν˜ = 1189, 1283, 1514, 1784,

2886, 2992 cm–¹. HRMS: Calcd for C₂₁H₃₂O₁₀Na [M+Na]⁺467.1893, found

467.1887.

Step 1: To a stirred solution of compound 14 (1.7 g, 2.52 mmol) in

anhydrous THF (20 mL) was added Pd-C (10 mol %) (0.268 g, 0.252

mmol) at room temperature. The reaction mixture was stirred under an

atmosphere of H₂with balloon pressure until starting material was

disappeared on TLC. The mixture was filtered through celite and the

solvent was removed in vacuo. The resultant residue was further purified

by silica gel column chromatography (MeOH/CH₂Cl_2,1:9) to give the tetrol

(0.720 g, 91%) as a colorless foam. R_f= 0.5 (MeOH/CH₂Cl₂, 1:9); ²³

=

D

93.5 (c = 0.3, MeOH); ¹H NMR (400 MHz, CD₃OD): = 1.28 (t, J = 7.2 Hz,

3 H), 3.19-3.2 (m, 1 H), 3.21-3.24 (m, 1 H), 3.32-3.33 (m, 1 H), 3.36-3.41

(m, 1 H), 3.62 (dd, J = 12.0, 5.2 Hz, 1 H), 3.77-3.81 (m, 1 H), 4.11 (d, J =

9.6 Hz, 1 H), 4.25 (q, J = 7.2 Hz, 2 H), 7.44 (d, J = 8.4 Hz, 2 H), 7.88 (d, J

= 8.4 Hz, 2 H), ¹³C NMR (100 MHz, CD₃OD):  = 13.2 (CH₃), 60.7 (CH₂),

61.7 (CH₂), 70.4 (CH), 75.1 (CH), 78.3 (CH), 80.8 (CH), 81.5 (CH), 127.5

(CH), 128.7 (CH), 129.6 (C), 145.0 (C), 166.6 (C). IR (KBr): ν˜ = 1136,

1558, 1693, 2871, 2992, 3430 cm – ¹. HRMS: Calcd for C₁₅H₂₀O₇Na

[M+Na]⁺335.1106, found 335.1100

Step2: In a flame-dried two-necked round-bottomed flask was charged

with above resulted tetrol (0.8 g, 2.56 mmol) in anhydrous dichloromethane

(10 mL), upon cooling the suspension in an ice bath (0 °C),

diisopropylethylamine (3.53 mL, 20.51 mmol) was added dropwise. The

suspension was stirred at the same temperature for an additional 10 min

and then chloromethylmethylether (1.55 mL, 20.51 mmol) was added

slowly. After stirring for another 15 min at the same temperature

tetrabutylammoniumiodide (3.8 g, 10.24 mmol) was added and then

solution was allowed to attain room temperature. The reaction was stirred

in darkness for 24 h, the solution gradually turned into red in color and was

cooled to 0 °C, saturated NH₄Cl (10 mL) solution was added and the

organic layer was extracted with dichloromethane (3 × 70 mL), dried over

Na₂SO₄, and concentrated to give the title compound 16 as a colorless

gum (1.03 g, 82%), after column chromatography on silica gel

(EtOAc/hexanes, 2:3). R_f= 0.3 (EtOAc/hexanes, 1:4); ²³_D= -181.4 (c =

0.3, CHCl₃); ¹H NMR (400 MHz, CDCl₃): δ = 1.39 (t, J = 7.2 Hz,3 H), 2.76

(s, 3 H), 3.34 (s, 3 H, OMe), 3.38 (s, 6 H), 3.55 (t, J = 9.2 Hz, 1 H), 3.61-

3.65 (m, 2 H), 3.72 (dd, J = 11.6, 4.8 Hz, 1 H), 3.78 (t, J = 8.8 Hz, 1 H),

3.92 (d, J = 10.8 Hz, 1 H), 4.05 (d, J = 6.4 Hz, 1 H), 4.25 (d, J = 6.4 Hz, 1

H), 4.36 (q, J = 7.2 Hz, 2 H), 4.45 (d, J = 6.4 Hz, 1 H), 4.66 (s, 2 H), 4.78

(d, J = 6.4 Hz, 1 H), 4.86–4.93 (m, 3 H), 7.47 (d, J = 8.0 Hz, 2 H), 8.0 (d, J

= 8.0 Hz, 2 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 14.3 (CH₃), 55.3

(OMe), 55.9 (OMe), 56.4 (2xOMe), 61.0 (CH₂), 66.7 (CH₂), 75.3 (CH) 77.1

(CH), 78.8 (CH), 80.0 (CH), 81.2 (CH), 83.7 (CH), 96.6 (CH₂), 97.5 (CH₂),

General procedure for the preparation of chalcones:

To a solution of substituted acetophenone (2 equiv.) in 10% ethanolic

NaOH (1

g NaOH in 10 mL EtOH) was added 4-C-glucosylated

benzaldehyde building block 20 or 8a or 8b (1 equiv.) in EtOH at room

temperature. The reaction mixture was stirred at same temperature for 3

h, then diluted by adding aq. HCl (10%). The solution was concentrated

under reduced pressure, the resultant residue was purified by column

chromatography on silica gel using appropriate solvent system as eluent.

(E)-1-(2’,4’-dimethoxyphenyl)-3-(4-(2,3,4,6-tetra-O-benzyl-D-

glucopyranosyl)phenyl)chalcone 17a:

Building block 8a (0.28 g, 0.445 mmol), acetophenone 9a (0.16 g, 0.89

mmol), 10% alcoholic NaOH (3 mL) and EtOH (2 mL) were treated

according to the general procedure, to give the title compound 17a as a

colorless gum (0.27 g, 77%). R_f= 0.3 (EtOAc/hexanes, 1:4); [²³_D= 79.4

(c = 0.5, CHCl₃); ¹H NMR (400 MHz, CDCl₃); δ = 3.50 (t, J = 8.8 Hz, 1 H),

3.60-3.61 (m, 1 H), 3.77-3.78 (m, 1 H), 3.79-3.80 (m, 1 H), 3.81-3.82 (m,2

H), 3.85-3.86 (m,1 H), 3.87 (s, 3 H), 3.91 (s, 3 H), 4.26 (d, J = 9.6 Hz, 1 H),

4.42 (d, J = 10.4 Hz, 1 H), 4.54-4.63 (m, 1 H), 4.63-4.66 (m, 2 H), 4.86-

4.89 (m, 1 H), 4.92-4.97 (m, 2 H), 6.50 (d, J = 2.0 Hz, 1 H), 6.57 (dd, J =

8.8 Hz, 2.4 Hz, 1 H), 6.90-6.93 (m, 2 H), 7.17-721 (m, 5 H), 7.28-7.30 (m,

4 H), 7.32-7.34 (m, 9 H), 7.47 (d, J = 8.0 Hz, 2 H), 7.54 (d, J = 15.6 Hz, 1

H) 7.59 (d, J = 8.0 Hz, 2 H), 7.70 (d, J = 15.6 Hz, 1 H), 7.77 (d, J = 8.8 Hz,

1 H). ¹³C NMR (100 MHz, CDCl₃); δ = 55.6 (OMe), 55.8 (OMe), 69.1 (CH₂),

73.4 (CH₂), 75.0 (CH₂), 75.2 (CH₂), 75.7 (CH₂), 78.3 (CH), 79.3 (CH), 81.3

(CH), 84.1 (CH), 86.7 (CH), 98.7 (CH), 105.2 (CH), 122.2 (C), 127.3 (CH),

127.6 (CH), 127.7 (CH), 127.8 (CH), 128.0 (CH), 128.1 (CH), 128.2 (CH),

128.3 (CH), 128.4 (CH), 128.5 (CH), 132.9 (CH), 135.4 (C), 137.5 (C),

138.1 (C), 138.3 (C), 138.6 (C), 141.2 (CH), 141.7 (CH), 160.4 (C), 164.2

(C), 190.5 (CO). IR (CHCl₃): ν˜ = 1216, 1439, 1561, 1689, 2881, 3018,

cm–¹. HRMS: Calcd for C₅₁H₅₁O₈[M+H]⁺791.3583, found 791.3577.

98.6 (CH₂), 98.7 (CH₂) 127.5 (CH), 128.7 (CH), 130.3 (C), 143.7 (C), 166.4

(C) ppm. IR (CHCl₃): ν˜ = 1136, 1558, 1693, 2871, 2992, 3430 cm^–

HRMS: Calcd for C₂₃H₃₆O₁₁Na [M+Na]⁺511.2155, found 511.2155.

.

1

4-(2,3,4,6-tetra-O-methoxymethyl--D-glucopyranosyl)benzaldehyde

8b:

Step 1: The ester 16 (3.9 g, 7.99 mmol), LiAlH₄(0.455 g, 11.98 mmol) and

anhydrous THF (40 mL) were treated according to the procedure used for

the synthesis of compound 15, to give the resultant alcohol, after column

chromatography on silica gel as a colorless gum (2.97 g, 84%). R_f= 0.3

(EtOAc/hexanes, 2:3); []²³_D= -96.4 (c = 0.3, CHCl₃); ¹H NMR (400 MHz,

CDCl₃): δ = 2.8 (s, 3 H), 3.33 (s, 3 H), 3.45 (s, 6 H), 3.55 (t, J = 9.2 Hz, 1

H), 3.57-3.59 (m, 1 H), 3.62 (t, J = 9.6 Hz, 1 H), 3.69-3.78 (dd, J = 11.6,

10.1002/ejoc.201900413

European Journal of Organic Chemistry

FULL PAPER

(E)-1-(2’,4’-dibenzyloxyphenyl)-3-(4-(2,3,4,6-tetra-O-benzyl--D-

(CH₂), 68.4 (CH), 72.5 (CH), 74.0 (CH), 76.2 (CH), 79.5 (CH), 127.7 (CH),

129.7 (CH), 136.6 (C), 142.8 (C), 168.7 (CO), 169.4 (CO), 170.3 (CO),

170.6 (CO), 191.7 (CHO). IR (CHCl₃): ν˜ = 1576, 1697, 1783, 2896, 2982

cm–¹. HRMS: Calcd for C₂₁H₂₅O₁₀[M+H]⁺437.1447, found 437.1459.

glucopyranosyl)phenyl)chalcone 17b:

Building block 8a (0.3 g, 0.48 mmol), acetophenone 9b (0.23 g, 0.71 mmol),

10% alcoholic NaOH (4 mL) and EtOH (3 mL) were treated according to

the general procedure, to give the title compound 17b as a colorless solid

(0.348 g, 78%). R_f= 0.4 (EtOAc/hexanes, 1:4); m.p. = 78-80 ^oC; []²³

4-(-D-glucopyranosyl)benzaldehyde 19:

=

D

117.7 (c = 1.0, CHCl₃); ¹H NMR (500 MHz, CDCl₃); δ = 3.46-3.50 (m, 1 H),

3.59-3.61 (m, 1 H), 3.78-3.82 (m, 5 H), 4.24 (d, J = 9.5 Hz, 1 H), 4.40 (d, J

= 10.5 Hz, 1 H), 4.57 (d, J = 12.0 Hz, 1 H), 4.65-4.67 (m, 2 H), 4.87-4.96

(m, 3 H), 5.11-5.12 (m, 4 H), 6.66-6.68 (m, 2 H), 6.89-6.91 (m, 2 H), 7.15-

7.22 (m, 5 H), 7.24-7.39 (m, 21 H), 7.40-7.44 (m, 6 H), 7.64 (d, J = 15.5

Hz, 1 H), 7.69 (d, J = 15.5 Hz, 1 H), 7.88 (d, J = 9.0 Hz, 1 H). ¹³C NMR

(125 MHz, CDCl₃); δ = 69.1 (CH₂), 70.3 (CH₂), 70.9 (CH₂), 73.5 (CH₂), 74.9

(CH₂), 75.1 (CH₂), 75.7 (CH₂), 78.3 (CH), 79.4 (CH), 81.3 (CH), 84.2 (CH),

86.7 (CH), 100.5 (CH), 106.6 (CH), 122.3 (C), 127.4 (CH), 127.5 (CH),

127.6 (CH), 127.6 (CH), 127.7 (CH), 127.7 (CH), 127.8 (CH), 127.8 (CH),

127.9 (CH), 128.0 (CH), 128.1 (CH), 128.2 (CH), 128.3 (CH), 128.3 (CH),

128.4 (CH), 128.4 (CH), 128.7 (CH), 133.4 (CH), 135.3 (C), 135.8 (C),

136.2 (C), 137.5 (C), 138.1 (C), 138.3 (C), 138.6 (C), 141.0 (CH), 141.6

(CH), 159.7 (C), 163.4 (C), 189.7 (CO). IR (CHCl₃): ν˜ = 1189, 1491, 1568,

1691, 2917, 3087, cm–¹. HRMS: Calcd for C₆₃H₅₉O₈[M+H]⁺943.4209,

found 943.4208.

A round bottom flask was charged with Compound 20 (1.1 g, 2.52 mmol)

in MeOH (15 mL) at room temperature. To that solution, NaOMe (0.068

mg, 1.26 mmol) was added and stirred the reaction mixture for 2 h at same

temperature. Then the reaction mixture was neutralized with 10% HCl (1

mL) and concentrated under reduced pressure. The resultant crude

product was purified by column chromatography on silica gel

(MeOH/CH₂Cl₂, 1:9) to afford the title compound 19 (0.51 g, 75%) as a

colorless solid. R_f= 0.3 (MeOH/CH₂Cl_2,1:2); m.p = 126-128 C; []²⁷_D= -

164.3 (c 0.3, MeOH); ¹H NMR (400 MHz, CD₃OD); δ = 3.35 (m, 1 H), 3.46

(m, 2 H), 3.53 (m, 1 H), 3.75 (d, J = 10.8 Hz, 1 H), 3.92 (d, J = 11.6 Hz, 1

H), 4.27 (d, J = 9.2 Hz, 1 H), 7.67 (d, J = 8.0 Hz, 2 H), 7.90 (d, J = 8.0 Hz,

2 H). 10.00 (s, 1 H) ppm. ¹³C NMR (100 MHz, CD₃OD); δ = 61.6 (CH₂),

70.3 (CH), 75.1(CH), 78.3 (CH), 80.8 (CH), 81.5 (CH), 128.1 (CH), 128.9

(CH), 136.1 (C), 146.6 (C), 192.6 (CHO). IR (CHCl₃): ν˜ = 1567, 1769,

2896, 3101, 3402 cm–¹. HRMS: Calcd for C₁₃H₁₆O₆Na [M+Na]⁺291.0844,

found 291.0835.

(E)-1-(2’,4’-dimethoxyphenyl)-3-(4-(2,3,4,6-tetra-O-methoxymethyl-

D-glucopyranosyl)phenyl)chalcone 18a:

(E)-1-(2’,4’-dimethoxyphenyl)-3-(4-(D-

glucopyranosyl)phenyl)chalcone 21a:

Building block 8b (0.18 g, 0.40 mmol), acetophenone 9a (0.088 g, 0.48

mmol), 10% alcoholic NaOH (2 mL) and EtOH (2 mL) were treated

according the general procedure, to give the title compound 18a as a

Aldehyde 20 (0.25 g, 0.57 mmol), 2’, 4’-dimethoxyacetophenone 9a (0.15

g, 0.916 mmol), 10% ethanolic NaOH (2.5 mL), EtOH (4 mL) were treated

as described in the general procedure for 2 h to give the title compound

21a, after column chromatography on silica gel (MeOH/CH₂Cl_2,1:9) as a

light yellow color solid (0.18 g, 73%); R_f= 0.4, (MeOH/CH₂Cl₂, 1:9); m.p =

92-94 ^oC. []²³_D= -141.6 (c 0.5, MeOH). ¹H NMR (500 MHz, CD₃OD):  =

3.39 (d, J = 9.0 Hz, 1 H), 3.17-3.21 (m, 1 H), 3.47 (d, J = 9.5 Hz, 1 H), 3.53

(d, J = 8.5 Hz, 1 H), 3.75 (dd, J = 12.0, 5.0 Hz, 1 H), 3.86 (s, 3 H), 3.89-

3.93 (m, 4 H), 4.20 (d, J = 9.0 Hz, 1 H), 6.59-6.61 (m, 2 H), 7.50 (d, J = 8.0

Hz, 2 H), 7.56-7.58 (m, 2 H), 7.61 (d, J = 8.5 Hz, 2 H), 7.67-7.68 (m, 1 H),

¹³C NMR (125 MHz, CD₃OD): = 54.8 (CH₃), 54.9 (CH₃), 61.7 (CH₂), 70.5

(CH), 75.1 (CH), 78.4 (CH), 80.7 (CH), 81.7 (CH), 98.1 (CH), 105.5 (CH),

121.3 (C), 126.7 (CH), 127.7 (CH), 128.1 (CH), 132.3 (C), 134.7 (CH),

141.8 (C), 141.9 (C),160.8 (C), 164.9 (C), 191.2 (C). IR (KBr): ν˜ = 1137,

1596, 1656, 2912, 2982 cm–¹. HRMS: Calcd for C₂₃H₂₆O₈Na [M + Na]⁺

453.1525, found 453.1526.

colorless gum (0.108 g, 44%). R_f= 0.5 (EtOAc/hexanes, 1:1); []²³= -

D

114.4 (c = 0.3, CHCl₃); ¹H NMR (400 MHz, CDCl₃): δ = 2.77 (s, 3 H), 3.34

(s, 3 H), 3.45 (s, 3 H), 3.46 (s, 3 H), 3.52-3.65 (m, 3 H), 3.70-3.74 (m, 1 H),

3.77 (t, J = 8.8 Hz, 1 H), 3.89 (s, 3 H), 3.91-3.94 (m, 4 H), 4.10 (d, J = 6.4

Hz, 1 H), 4.21 (d, J = 9.2 Hz, 1 H), 4.48 (d, J = 6.4 Hz, 1 H), 4.66 (s, 2 H),

4.78 (d, J = 6.8 Hz, 1 H), 4.86–4.91 (m, 2 H), 4.92 (d, J = 6.4 Hz, 1 H), 6.50

(d, J = 2.4 Hz, 1 H), 6.56 (dd, J = 8.4, 2.0 Hz, 1 H), 7.42 (d, J = 8.0 Hz, 2

H), 7.51 (d, J = 16.0 Hz, 1 H), 7.57 (d, J = 8.4 Hz, 2 H), 7.65 (d, J = 15.6

Hz, 1 H), 7.76 (d, J = 8.8 Hz, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ =

55.3 (OMe), 55.5 (OMe), 55.7 (OMe), 56.8 (OMe), 56.5 (2xOMe), 66.8

(CH₂), 77.1 (CH) 78.8 (CH), 79.9 (CH), 81.3 (CH), 83.8 (CH), 96.7 (CH₂),

97.5 (CH₂), 98.6 (CH₂), 98.7 (CH₂), 105.2 (CH), 122.1 (CH), 127.3 (CH),

128.2 (CH), 128.4 (CH), 132.9 (CH), 135.5 (C), 140.0 (C), 141.5 (C), 160.4

(C), 164.2 (C), 190.4 (C) ppm. IR (CHCl₃): ν˜ = 1168, 1296, 1498, 1658,

2896, 2982 cm–¹. HRMS: Calcd for C₃₁H₄₃O₁₂[M+H]⁺607.2754, found

607.2766.

(E)-1-(2’,4’-dibenzyloxyphenyl)-3-(4-(D-

glucopyranosyl)phenyl)chalcone 21b:

4-(2,3,4,6-tetra-O-acetyl--D-glucopyranosyl)benzaldehyde 20:

Aldehyde 20 (0.1 g, 0.37 mmol), 2’, 4’-dibenzyloxyacetophenone 9b (0.327

g, 0.746 mmol), 10% ethanolic NaOH (3 mL), EtOH (3 mL) were treated

as described in the general procedure for 2 h to give the title compound

21b, after column chromatography on silica gel (MeOH/CH₂Cl_2,1:9) as a

light yellow color solid (0.188 g, 65%); R_f= 0.5, (MeOH/CH₂Cl₂, 1:9); m.p

= 118-120 ^oC. []²³_D= -141.6 (c 0.5, MeOH). ¹H NMR (500 MHz, DMSO-

d₆):  = 3.12-3.16 (m, 1 H), 3.20-3.22 (m, 1 H), 3.24-3.26 (m, 1 H), 3.27-

3.31 (m, 1 H), 3.46-3.51 (m, 1 H), 3.71-3.74 (m, 1 H), 4.06 (d, J = 9.5 Mz,

1 H), 4.88 (d, J = 6.0 Hz, 1 H), 4.98-5.00 (m, 2 H), 5.24-5.25 (m, 4 H), 6.67

(dd, J = 8.5 Hz, 2.0 Hz, 2 H), 6.95 (d, J = 2.5 Hz, 1 H), 7.38-7.44 (m, 10

H), 7.49-7.54 (m, 5 H), 7.62 (d, J = 16.0 Hz, 1 H), 7.69 (d, J = 16.0 Hz, 1

H). ¹³C NMR (125 MHz, DMSO-d₆): = 61.8 (CH₂), 70.1 (CH₂), 70.7 (CH₂),

70.8 (CH), 75.2 (CH), 78.8 (CH), 81.4 (CH), 81.7 (CH), 100.9 (CH), 107.5

(CH), 121.9 (C), 127.2 (CH), 128.1 (CH), 128.3 (CH), 128.5 (CH), 128.6

(CH), 128.9 (CH), 129. 0 (CH), 132.8 (C), 134.3 (CH), 136.7 (C), 136.9 (C),

141.6 (CH), 143.9 (C), 159.8 (C), 163.5 (C), 189.1 (C). IR (KBr): ν˜ = 1198,

1596, 1663, 2912, 2982 cm – 1. HRMS: Calcd for C₃₅H₃₅O₈[M+H]⁺

583.2331, found 583.2331.

An oven dried round bottom flask was charged with compound 8a (4.4 g,

6.99 mmol) in acetic anhydride (50 mL) at room temperature. To that

solution, trimethylsilyl trifluoromethanesulfonate (1.8 mL, 10.49 mmol) was

added at 0 ^oC, slowly. Then the reaction mixture was allowed to stirr at

room temperature for 5 h. The reaction mixture was diluted with H₂O,

dropwise, and extracted with EtOAc (3x100 mL). The combined organic

layer was washed with sat. NaHCO₃solution (100 mL), dried over Na₂SO₄

and concentrated under reduced pressure. The resultant crude product

was purified by column chromatography on silica gel (EtOAc/hexanes, 2:3)

to afford the peracetylated compound 20 (2.38 g, 77%) as a colorless solid.

R_f= 0.3 (EtOAc/hexanes 1:2); m.p = 90-92 C; []²⁷_D= -78.3 (c 0.3, CHCl₃);

¹H NMR (500 MHz, CDCl₃); δ = 1.83 (s, 3H), 2.00 (s, 3H), 2.07 (s, 3H),

2.10 (s, 3 H), 3.87 (ddd, J = 7.0 Hz, 4.5 Hz, 2.0, 1 H), 4.18 (dd, J = 12.5

Hz, 2.0 Hz, 1 H), 4.31 (dd, J = 12.5 Hz, 5.0 Hz, 1 H), 4.49 (d, J = 9.5 Hz, 1

H), 5.10 (t, J = 10.5 Hz, 1 H), 5.24 (t, J = 10.0 Hz, 1 H), 5.36 (t, J = 9.5 Hz,

1 H), 7.53 (d, J = 8.0 Hz, 2 H), 7.87 (d, J = 8.0 Hz, 2 H), 10.01 (s, 1 H). ¹³

NMR (125 MHz, CDCl₃); δ = 20.3 (CH₃), 20.6 (2 X CH₃), 20.7 (CH₃), 62.2

C

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(E)-1-(2’,4’,6’-trimethoxyphenyl)-3-(4-(D-

after column chromatography on silica gel (MeOH/CH₂Cl_2,1:9) as light

brown color solid (0.198 g, 62%); R_f= 0.5, (MeOH/CH₂Cl₂, 1:9); m.p = 172-

174 ^oC. []²³_D= -141.9 (c 0.5, MeOH)_.¹H NMR (400 MHz, DMSO-d₆):  =

3.13-3.16 (m, 1 H), 3.17-3.21 (m, 1 H), 3.22-3.25 (m, 1 H), 3.27-3.30 (m, 1

H), 3.45-3.51 (m, 1 H), 3.72 (dd, J = 11.2, 5.2 Hz, 1 H), 3.88 (s, 3 H), 4.08

(d, J = 9.6 Hz, 1 H), 4.50 (t, J = 5.6 Hz, 1 H), 4.89 (d, J = 6.0 Hz, 1 H), 4.98-

5.01 (m, 2 H), 7.10 (d, J = 8.8 Hz, 2 H), 7.43 (d, J = 8.0 Hz, 2 H), 7.72 (d,

J = 15.6 Hz, 1 H), 7.83 (d, J = 8.0 Hz, 2 H), 7.94 (d, J = 15.2 Hz, 1 H), 8.23

(d, J = 8.8 Hz, 2 H), ¹³C NMR (100 MHz, DMSO-d₆):  = 56.0 (CH₃), 61.8

(CH₂), 70.7 (CH), 75.2 (CH), 78.8 (CH), 81.4 (CH), 81.7 (CH), 114.5 (CH),

122.0 (CH), 128.6 (CH), 128.7 (CH), 130.9 (C), 131.4 (CH), 134.3 (C),

143.4 (C),143.6 (C), 163.6 (C), 187.8 (C). IR (KBr): ν˜ = 1146, 1286, 1596,

1656, 2912, 2982 cm–¹. HRMS: Calcd for C₂₂H₂₅O₇[M+H]⁺401.1600,

found 401.1592.

glucopyranosyl)phenyl)chalcone 21c:

Aldehyde 20 (0.20 g, 0.74 mmol), 2’, 4’, 6’-trimethoxyacetophenone 9c

(0.313 g, 1.49 mmol), 10% ethanolic NaOH (2.0 mL), EtOH (3 mL) were

treated as described in the general procedure for 2 h to give the title

compound 21c, after column chromatography on silica gel (MeOH/CH₂Cl_2,

1:9) as a light green color solid (0.24 g, 68%); R_f= 0.3, (MeOH/CH₂Cl₂,

1:9); m.p = 98-100 ^oC; [²³_D= -229.96 (c 0.5, MeOH)_.¹H NMR (500 MHz,

CD₃OD):  = 3.33-3.35 (m, 1 H), 3.41-3.45 (m, 2 H), 3.47-3.53 (m, 1 H),

3.74 (dd, J = 12.0, 5.0 Hz, 1 H), 3.79 (s, 6 H), 3.90 (s, 3 H), 3.91 (d, J =

12.5 Hz, 1 H), 4.20 (d, J = 9.5 Hz, 1 H), 6.32 (s, 2 H), 6.97 (d, J = 16.0 Hz,

1 H), 7.34 (d, J = 16.0 Hz, 1 H), 7.50 (d, J = 8.0 Hz, 2 H), 7.57 (d, J = 8.0

Hz, 2 H), ¹³C NMR (125 MHz, CD₃OD):  = 54.6 (CH₃), 54.9 (2xCH₃), 61.7

(CH₂), 70.4 (CH), 75.1 (CH), 78.4 (CH), 80.7 (CH), 81.7 (CH), 90.5 (CH),

110.7 (CH), 127.7 (CH), 128.1 (CH), 128.4 (CH), 134.2 (C), 142.3 (C),

144.8 (CH), 158.8 (C), 163.1 (C), 195.7 (C). IR (KBr): ν˜ = 1212, 1496,

1642, 2844, 2992 cm–¹. HRMS: Calcd for C₂₄H₂₉O₉[M+H]⁺461.1811,

found 461.11814.

(E)-1-(2’,4’,6’-tribenzyloxyphenyl)-3-(4-(D-

glucopyranosyl)phenyl)chalcone 21g:

Aldehyde 20 (0.27 g, 0.1 mmol), 2’, 4’, 6’-tribenzyloxyacetophenone 9g

(0.67 g, 2.0 mmol), 10% ethanolic NaOH (4 mL), EtOH (4 mL) were treated

as described in the general procedure for 2 h to give the title compound

21g, after column chromatography on silica gel (MeOH/CH₂Cl_2,1:9) as a

light yellow color solid (0.23 g, 64%); R_f= 0.5, (MeOH/CH₂Cl₂, 1:9); m.p =

(E)-1-(2’-hydroxy-4’,6’-dimethoxyphenyl)-3-(4-(D-

glucopyranosyl)phenyl)chalcone 21d:

126-128 ^oC. []²³

=

-141.6 (c 0.5, MeOH). ¹H NMR (400 MHz,

D

Aldehyde 20 (0.18 g, 0.74 mmol), 2’-hydroxy, 4’, 6’-

dimethoxyacetophenone 9d (0.121 g, 1.49 mmol), 10% ethanolic NaOH

(2.0 mL), EtOH (3 mL) were treated as described in the general procedure

for 2 h to give the title compound 21d, after column chromatography on

silica gel (MeOH/CH₂Cl_2,1:9) as yellow color solid (0.105 g, 57%); R_f= 0.3,

CDCl₃:CD₃OD 1:1):  = 3.36-3.42 (m, 2 H), 3.44-3.47 (m, 2 H), 3.78-3.81

(m, 2 H), 3.92 (d, J = 12.0 Hz, 1 H), 5.04-5.05 (m, 4 H), 5.09-5.13 (m, 2 H),

6.67 (s, 2 H), 7.00 (d, J = 16.0 Hz, 1 H), 7.09 (d, J = 7.6 Hz, 2 H), 7.25-

7.28 (m, 8 H), 7.37-7.42 (m, 3 H), 7.43-7.46 (m, 3 H), 7.49-7.51 (m, 2 H),

7.67 (d, J = 15.2 Hz, 1 H), 7.89 (d, J = 16.0 Hz, 1 H). ¹³C NMR (100 MHz,

CDCl₃:CD₃OD): = 62.0 (CH₂), 70.1 (2xCH₂), 70.7 (CH₂), 71.3 (CH), 74.6

(CH), 78.1 (CH), 79.9 (CH), 81.4 (CH), 93.3 (CH), 126.7 (CH), 127.3 (C),

127.4 (CH), 127.6 (CH), 127.7 (CH), 127.9 (CH), 128.0 (CH), 128.1 (CH),

128.2 (CH), 128.4 (CH), 128.5 (CH), 128.7 (CH), 134.4 (C), 134.9 (C),

135.1 (C), 136.2 (CH), 141.3 (C), 142.2 (CH), 157.5 (2xC), 161.6 (C),

195.2 (C). IR (KBr): ν˜ = 1862, 1568, 1674, 2896, 2986 cm–¹. HRMS:

Calcd for C₄₂H₄₁O₉[M+H]⁺689.2750, found 689.2744.

(MeOH/CH₂Cl₂, 1:9); m.p = 100-102 ^oC; []²³= -171 (c 0.5, MeOH)_.¹H

D

NMR (400 MHz, CD₃OD):  = 3.37 (t, J = 9.2 Hz, 1 H), 3.44-3.48 (m, 2 H),

3.52 (t, J = 9.2 Hz, 1 H), 3.74 (dd, J = 12.0, 5.2 Hz, 1 H), 3.86 (s, 3 H), 3.91

(d, J = 12.4 Hz, 1 H), 3.96 (s, 3 H) 4.20 (d, J = 9.6 Hz, 1 H), 6.12 (s, 2 H),

7.52 (d, J = 8.0 Hz, 2 H), 7.65 (d, J = 8.0 Hz, 2 H), 7.73 (d, J = 16.4 Hz, 1

H), 7.57 (d, J = 16.0 Hz, 1 H), ¹³C NMR (100 MHz, CD₃OD):  = 54.7 (CH₃),

55.1 (CH₃), 61.7 (CH₂), 70.4 (CH), 75.1 (CH), 78.4 (CH), 80.8 (CH), 81.7

(CH), 90.7 (CH), 93.4 (CH) 105.9 (CH), 127.2 (CH), 127.6 (CH), 128.1

(CH), 134.9 (C), 141.6 (CH), 141.9 (C), 162.7 (C), 166.6 (C), 167.4 (C),

192.7 (C). IR (KBr): ν˜ = 1186, 1498, 1648, 2896, 2996 cm–¹. HRMS:

Calcd for C₂₃H₂₇O₉[M+H]⁺447.1655, found 447.1648.

(E)-1-(2’,4’-dihydroxyphenyl)-3-(4-D-

glucopyranosyl)phenyl)chalcone 4:

(E)-1-(3’,4’-dimethoxyphenyl)-3-(4-(D-

glucopyranosyl)phenyl)chalcone 21e:

Aldehyde 20 (0.290 g, 0.664 mmol), 2’, 4’-(bismethoxymethoxy)

acetophenone 9j (0.245 g, 1.33 mmol), 10% ethanolic NaOH (4.0 mL),

EtOH (5 mL) were treated as described in the general procedure for 3 h to

give the title compound 4, after column chromatography on silica gel

(MeOH/CH₂Cl_2,1:4) as yellow color solid (0.18 g, 67%); R_f= 0.5,

(MeOH/CH₂Cl₂, 1:4); m.p = 192-194 ^oC. []²³_D= -148.9 (c = 0.2, MeOH)_.¹H

NMR (500 MHz, CD₃OD):  = 3.26-3.28 (m, 1 H), 3.34-3.37 (m, 2 H), 3.40-

3.41 (m, 1 H), 3.63 (d, J = 11.0, 1 H), 3.81 (m, 1 H), 4.10 (d, J = 9.5 Hz, 1

H), 6.20 (s, 1 H), 6.34 (d, J = 7.0 Hz, 1 H), 7.41-7.43 (m, 2 H), 7.64 (m, 2

H), 7.72 (s, 2 H), 7.90 (d, J = 7.5 Hz, 1 H), ¹³C NMR (125 MHz, CD₃OD):

= 61.7 (CH₂), 70.4 (CH), 75.1 (CH), 78.3 (CH), 80.8 (CH), 81.7 (CH),

102.4 (CH), 107.9 (CH), 113.2 (C), 120.4 (CH), 128.1 (CH), 128.2 (CH),

132.2 (CH), 134.5 (C), 142.3 (C), 143.5 (CH), 165.2 (C), 166.2 (C), 195.7

(C). IR (KBr): ν˜ = 1176, 1506, 1648, 2888, 2996 cm–¹. HRMS: Calcd for

C₂₁H₂₃O₈[M+H]⁺403.1392, found 403.1385.

Aldehyde 20 (0.2 g, 0.45 mmol), 3’, 4’-dimethoxyacetophenone 9e (0.123

g, 0.687 mmol), 10% ethanolic NaOH (2.0 mL), EtOH (3 mL) were treated

as described in the general procedure for 2 h to give the title compound

21e, after column chromatography on silica gel (MeOH/CH₂Cl_2,1:9) as

dark yellow color solid (0.135 g, 69%); R_f= 0.3, (MeOH/CH₂Cl₂, 1:9); m.p

= 104-106 ^oC. []²³_D= -223.9 (c 0.5, MeOH). ¹H NMR (500 MHz, CD₃OD):

 = 3.38 (d, J = 9.5 Hz, 1 H), 3.42-3.48 (m, 2 H), 3.52 (t, J = 8.5 Hz, 1 H),

3.74 (dd, J = 12.0, 5.5 Hz, 1 H), 3.91-3.92 (m, 4 H), 3.94 (s, 3 H), 4.21 (d,

J = 9.5, Hz, 1 H), 7.10 (d, J = 8.5 Hz, 1 H), 7.53 (d, J = 8.0 Hz, 2 H), 7.65

(d, J = 2.0 Hz, 1 H), 7.75 (dd, J = 8.0 Hz, 2 H), 7.79-7.80 (m, 2 H), 7.73-

7.75 (dd, J = 8.5, 2.0 Hz, 1 H), ¹³C NMR (125 MHz, CD₃OD): = 55.1 (CH₃),

55.1 (CH₃), 61.7 (CH₂), 70.5 (CH), 75.1 (CH), 78.4 (CH), 80.8 (CH), 81.7

(CH), 110.3 (CH), 110.7 (CH), 121.1 (CH), 123.5 (CH), 127.9 (CH), 128.1

(CH), 130.1 (C), 134.5 (C), 142.1 (C), 143.5 (CH), 149.3 (C), 153.8 (C),

189.2 (C). IR (KBr): ν˜ = 1196, 1507, 1644, 2891, 2987 cm–¹. HRMS:

Calcd for C₂₃H₂₇O₈[M+H]⁺431.1705, found 431.1703.

(E)-1-(3’,4’-dihydroxyphenyl)-3-(4-(D-

glucopyranosyl)phenyl)chalcone 21h:

Aldehyde 20 (0.33 g, 0.756 mmol), 3’, 4’-(bismethoxymethoxy)

acetophenone 9k (0.363 g, 1.512 mmol), 10% ethanolic NaOH (4.0 mL),

EtOH (6 mL) were treated as described in the general procedure for 3 h to

give the title compound 21h, after column chromatography on silica gel

(MeOH/CH₂Cl_2,1:4) as yellow color solid (0.21 g, 69%); R_f= 0.5,

(MeOH/CH₂Cl₂, 1:4); m.p = 140-142 ^oC: []²³_D= -156.7 (c 0.5, MeOH). ¹H

NMR (500 MHz, CD₃OD): = 3.39 (d, J = 9.5 Hz, 1 H), 3.44-3.48 (m, 2 H),

(E)-1-(4’-methoxyphenyl)-3-(4-(D-glucopyranosyl)phenyl)chalcone

21f:

Aldehyde 20 (0.35 g, 0.45 mmol), 4’-methoxyacetophenone 9f (0.24 g,

0.916 mmol), 10% ethanolic NaOH (3 mL), EtOH (4 mL) were treated as

described in the general procedure for 3 h to give the title compound 21f,

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3.52 (t, J = 9.0 Hz, 1 H), 3.74 (dd, J = 12.0, 5.5 Hz, 1 H), 3.92 (dd, J = 12.0,

2.0 Hz, 1 H), 4.21 (d, J = 9.5 Hz, 1 H), 6.91 (d, J = 8.5 Hz, 1 H), 7.52 (d, J

= 8.5 Hz, 2 H), 7.55 (d, J = 2.0 Hz, 1 H), 7.61 (dd, J = 8.5, 2.5 Hz, 1 H),

7.71 (s, 1 H), 7.73-7.75 (m, 3 H), ¹³C NMR (125 MHz, CD₃OD):= 61.7

(CH₂), 70.5 (CH), 75.1 (CH), 78.4 (CH), 80.8 (CH), 81.7 (CH), 114.5 (CH),

115.0 (CH), 121.4 (CH), 122.3 (CH), 127.8 (CH), 128.1 (CH), 130.1 (C),

134.6 (C), 142.1 (C), 143.5 (CH), 145.3 (C), 151.0 (C), 189.4 (C). IR (KBr):

ν˜ = 1186, 1496, 1652, 2912, 2996 cm–¹. HRMS: Calcd for C₂₁H₂₃O₈

[M+H]⁺403.1392, found 403.1385.

gel (MeOH/CH₂Cl_2,1:9) as a colorless solid (0.108 g, 77%); m.p = 123-125

1

^oC; []²³_D= -146.3 (c 0.3, MeOH). H NMR (400 MHz, CD₃OD): = 2.95

(m, 2 H), 3.29 (m, 2 H), 3.40-3.44 (m, 3 H), 3.51 (d, J = 9.5 Hz, 1 H), 3.72-

3.75 (m, 1 H), 3.90-3.94 (m, 1 H), 4.14-4.16 (m, 1 H), 6.58 (s, 1 H), 6.29

(s, 1 H), 6.401 (d, J = 8.4 Hz, 1 H), 7.28-7.30 (m, 2 H), 7.38-7.40 (m, 2 H),

7.76 (d, J = 8.8 Hz, 1 H). ¹³C NMR (100 MHz, CD₃OD):  = 33.7 (CH₂),

42.8 (CH₂), 65.7 (CH₂), 74.5 (CH), 78.9 (CH), 82.3 (CH), 84.7 (CH), 86.0

(CH), 106.2 (CH), 111.6 (CH), 116.6 (C), 131.6 (CH), 131.7 (CH), 136.1

(C), 141.1 (C), 144.8 (C), 168.8 (C), 168.9 (C), 207.6 (C). HRMS: Calcd

for C₂₁H₂₅O₈[M+H]⁺405.1549, found 405.1544.

(E)-1-(4’-hydroxyphenyl)-3-(4-(D-glucopyranosyl)phenyl)chalcone

21i:

1-(2’,4’,6’-trimethoxyphenyl)-3-(4-D-

glucopyranosyl)phenyl)dihydrochalcone 22b:

Aldehyde 20 (0.20 g, 0.458 mmol), 4’-(methoxymethoxy)-acetophenone 9l

(0.165 g, 0.916 mmol), 10% ethanolic NaOH (3.0 mL), EtOH (3 mL) were

treated as described in the general procedure for 2 h to give the title

compound 21i, after column chromatography on silica gel (MeOH/CH₂Cl_2,

1:9) as light brown color solid (0.12 g, 68%); R_f= 0.4, (MeOH/CH₂Cl₂, 1:9);

Chalcone 21c (0.160, 0.347 mmol), Pd/C (0.037 g, 0.034) and MeOH (3

mL) were treated as described in the general procedure, condition A, for

10 h to give the title compound 22b, after column chromatography on silica

gel (MeOH/CH₂Cl_2,1:9) as colorless solid (0.109 g, 68%); R_f= 0.4,

1

m.p = 192-194 ^oC; ]²³= -219.08 (c 0.5, MeOH)_.¹H NMR (400 MHz,

(MeOH/CH₂Cl₂, 1:9); m.p =72-74 ^oC; []²³_D= -112.3 (c = 0.3, MeOH). H

D

CD₃OD):  = 3.35-3.40 (m, 1 H), 3.44-3.46 (m, 2 H), 3.50-3.54 (m, 1 H),

3.75 (dd, J = 12.0, 4.8 Hz, 1 H), 3.92 (d, J = 11.2 Hz, 1 H), 4.21 (d, J = 9.2

Hz, 1 H), 6.92 (d, J = 8.8 Hz, 2 H), 7.53 (d, J = 8.4 Hz, 2 H), 7.74 (d, J =

8.0 Hz, 2 H), 7.78-7.79 (m, 2 H), 8.05 (d, J = 8.8 Hz, 2 H), ¹³C NMR (100

MHz, CD₃OD): = 61.7 (CH₂), 70.4 (CH), 75.1 (CH), 78.4 (CH), 80.8 (CH),

81.7 (CH), 115.1 (CH), 121.3 (CH), 127.9 (CH), 128.1 (CH), 129.5 (C),

131.0 (CH), 134.6 (C), 142.2 (C), 143.5 (CH), 163.1 (C), 195.7 (C). IR

(KBr): ν˜ = 1182, 1517, 1656, 2896, 2968 cm–1. HRMS: Calcd for

C₂₁H₂₃O₇[M+H]⁺387.1443, found 387.1434.

NMR (500 MHz, CD₃OD): = 3.29 (t, J = 7.5 Hz, 2 H), 3.03 (t, J = 7.5 Hz,

2 H), 3.36-3.45 (m, 3 H), 3.49 (t, J = 8.5 Hz, 1 H), 3.71 (dd, J = 12.0, 5.5

Hz, 1 H), 3.76 (s, 6 H), 3.83 (s, 3 H), 3.88 (dd, J = 12.0, 2.0 Hz, 1 H), 4.11

(d, J = 9.5 Hz, 1 H), 6.22 (s, 2 H), 7.18 (d, J = 8.5 Hz, 2 H), 7.34 (d, J = 8.0

Hz, 2 H), ¹³C NMR (125 MHz, CD₃OD):  = 29.4 (CH₂), 45.8 (CH₂), 54.6

(CH₃), 54.9 (2xCH₃), 61.7 (CH₂), 70.6 (CH), 74.9 (CH), 78.4 (CH), 80.7

(CH), 82.0 (CH), 90.3 (CH), 112.7 (CH), 127.6 (CH), 127.7 (CH), 137.0

(CH), 141.0 (C), 158.3 (2xC), 163.0 (C), 204.7 (C). IR (KBr): ν˜ = 1212,

1522, 1648, 2882, 2998 cm – ¹. HRMS: Calcd for C₂₄H₃₁O₉[M+H]⁺

463.1968, found 463.1966.

General procedure for the hydrogenations of chalcones:

1-(3’,4’-dimethoxyphenyl)-3-(4-(D-

glucopyranosyl)phenyl)dihydrochalcone 22c:

To the solution of chalcone (1 equiv.) in methanol was added Pd/C (0.1

equiv., condition A) or Pd/C and Ph₂S as additive (0.1 equiv. of each,

condition B) at room temperature. To remove the air inside the reaction

flask, two vacuum cycles with hydrogen gas was purged. The reaction

mixture was vigorously stirred at room temperature under hydrogen

atmosphere (H_2,balloon pressure) until the complete consumption of

chalcone. The reaction mixture was filtered using a pad of celite, the filtrate

was concentrated, and resultant residue was purified by column

chromatography on silica gel to provide the dihydrochalcones.

Chalcone 21e (0.110, 0.258 mmol), Pd/C (0.027 g, 0.025), Ph₂S (0.01 mL,

0.025 mmol) and MeOH (3 mL) were treated as described in the general

procedure, condition B, for 24 h to give the title compound 22c, after

column chromatography on silica gel (MeOH/CH₂Cl_2,1:9) as colorless

solid (0.07 g, 64%); R_f= 0.4, (MeOH/CH₂Cl₂, 1:9); m.p =114-116 ^oC; ]²³

D

1

= -149.8 (c 0.5, MeOH). H NMR (400 MHz, CD₃OD):  = 3.02 (t, J = 7.6

Hz, 2 H), 3.29 (t, J = 7.2 Hz, 2 H), 3.44-3.48 (m, 2 H), 3.43 (t, J = 9.2 Hz,

1 H), 3.49 (t, J = 8.0 Hz, 1 H), 3.70 (dd, J = 12.0, 4.8 Hz, 1 H), 3.87-3.90

(m, 7 H), 4.11 (d, J = 9.6 Hz, 1 H), 7.02 (d, J = 8.4 Hz, 1 H), 7.25 (d, J =

7.6 Hz, 2 H), 7.35 (d, J = 8.0 Hz, 2 H), 7.61 (s, 1 H), 7.66 (d, J = 8.4 Hz, 1

H). ¹³C NMR (100 MHz, CD₃OD): = 29.8 (CH₂), 39.3 (CH₂), 54.9 (CH₃),

55.1 (CH₃), 61.7 (CH₂), 70.5 (CH), 74.9 (CH), 78.4 (CH), 80.7 (CH), 82.1

(CH), 110.1 (CH), 110.3 (CH), 122.8 (CH), 127.7 (CH), 127.8 (CH), 129.8

(C), 137.2 (C), 141.1 (C), 149.0 (CH), 153.6 (C), 198.9 (C). IR (KBr): ν˜ =

1198, 1510, 1686, 2896, 2960 cm–¹. HRMS: Calcd for C₂₃H₂₉O₈[M+H]⁺

433.1862, found 433.1862.

1-(2’,4’-dimethoxyphenyl)-3-(4-(D-

glucopyranosyl)phenyl)dihydrochalcone 22a:

Chalcone 21a (0.120, 0.278 mmol), Pd/C (0.030 g, 0.028), Ph₂S (0.01 mL,

0.028 mmol) and MeOH (3 mL) were treated as described in the general

procedure, condition B, for 18 h to give the title compound 22a, after

column chromatography on silica gel (MeOH/CH₂Cl_2,1:9) as colorless

solid (0.088 g, 73%); R_f= 0.4, (MeOH/CH₂Cl₂, 1:9); m.p = 75-77 ^oC; []²³

= -229.3 (c 0.5, MeOH). H NMR (400 MHz, CD₃OD):  = 2.95 (t, J = 7.6

D

1

1-(4’-methoxyphenyl)-3-(4-(D-

glucopyranosyl)phenyl)dihydrochalcone 22d:

Hz, 2 H), 3.25 (t, J = 7.6 Hz, 2 H), 3.37-3.46 (m, 3 H), 3.47-3.51 (m, 1 H),

3.71 (dd, J = 12.0, 4.8 Hz, 1 H), 3.88-3.91 (m, 7 H), 4.12 (d, J = 9.2 Hz, 1

H), 6.58-6.61 (m, 2 H), 7.21 (d, J = 8.0 Hz, 2 H), 7.35 (d, J = 8.0 Hz, 2 H),

7.72 (d, J = 8.4 Hz, 1 H). ¹³C NMR (100 MHz, CD₃OD):  = 30.1 (CH₂),

45.0 (CH₂), 54.7 (CH₃), 61.8 (CH₂), 70.6 (CH), 74.9 (CH), 78.4 (CH), 80.7

(CH), 82.1 (CH), 97.8 (CH), 105.5 (CH), 120.3 (C), 127.7 (CH), 127.7 (CH),

132.1 (C), 137.0 (CH), 141.4 (C),161.1 (C), 165.1 (C), 200.3 (C). IR (KBr):

ν˜ = 1146, 1512, 1678, 2978, 3010 cm–¹. HRMS: Calcd for C₂₃H₂₉O₈

[M+H]⁺433.1862, found 433.1862.

Chalcone 21f (0.155, 0.387 mmol), Pd/C (0.041 g, 0.039), Ph₂S (0.01 mL,

0.039 mmol) and MeOH (3 mL) were treated as described in the general

procedure, condition B, for 24 h to give the title compound 22d, after

column chromatography on silica gel (MeOH/CH₂Cl_2,1:9) as colorless

solid (0.119 g, 76%); R_f= 0.5, (MeOH/CH₂Cl₂, 1:9); m.p = 134-136 ^oC;

[]²³_D= -232.1 (c 0.5, MeOH). ¹H NMR (400 MHz, CD₃OD): = 3.00 (t, J

= 7.2 Hz, 2 H), 3.27 (t, J = 7.2 Hz, 2 H ), 3.36-3.41 (m, 2 H), 3.42-3.43 (m,

1 H), 3.46-3.52 (m, 1 H), 3.71 (dd, J = 12.0, 5.2 Hz, 1 H), 3.87-3.90 (m, 4

H), 4.11 (d, J = 9.2 Hz, 1 H), 7.00 (d, J = 8.8 Hz, 2 H), 7.25 (d, J = 8.0 Hz,

2 H), 7.35 (d, J = 8.0 Hz, 2 H), 7.96 (d, J = 8.8 Hz, 2 H), ¹³C NMR (100

MHz, CD₃OD):  = 29.7 (CH₂), 39.4 (CH₂), 54.6 (CH₃), 61.8 (CH₂), 70.5

(CH), 74.9 (CH), 78.3 (CH), 80.7 (CH), 82.1 (CH), 113.5 (CH), 127.7 (CH),

127.8 (CH), 129.7 (C), 130.9 (CH), 137.2 (C), 141.4 (C),163.8 (C), 198.8

1-(2’,4’-dihydroxyphenyl)-3-(4-(D-

glucopyranosyl)phenyl)dihydrochalcone 5:

Chalcone 21b (0.240, 0.348 mmol), Pd/C (0.037 g, 0.034) and MeOH (3

mL) were treated as described in the general procedure, condition A, for

10 h to give the title compound 5, after column chromatography on silica

10.1002/ejoc.201900413

European Journal of Organic Chemistry

FULL PAPER

(C). IR (KBr): ν˜ = 1186, 1526, 1696, 2996, 3080 cm–1. HRMS: Calcd for

4 °C and the resulting supernatant was used as the source of AR. For

inhibition studies concentrated stocks of compounds were prepared in

water/DMSO mixture. Various concentrations of inhibitors were added to

the assay mixture and incubated for 5 min before initiating the reaction by

NADPH. The percent of inhibition with test compounds was calculated

considering the AR activity in the absence of inhibitor as 100%.²¹

C₂₂H₂₆O_7Na [M+Na]⁺425.1576, found 425.1568.

1-(2’,4’,6’-trihydroxyphenyl)-3-(4-(D-

glucopyranosyl)phenyl)dihydrochalcone 22e:

Chalcone 21g (0.10, 0.171 mmol), Pd/C (0.02 g, 0.017) and MeOH (2 mL)

were treated as described in the general procedure, condition A, for 12 h

to give the title compound 22e, after column chromatography on silica gel

(MeOH/CH₂Cl_2,1:9) as colorless solid (0.056 g, 78%); m.p = 138-140 ^oC.

[]²³_D= -194.1 (c 0.6, MeOH). ¹H NMR (500 MHz, CD₃OD): = 2.92 (t, J

= 7.5 Hz, 2 H), 3.02-3.05 (m, 2 H), 3.36-3.42 (m, 3 H), 3.43-3.45 (m, 1 H),

3.49 (t, J = 8 5, 1 H), 3.70 (dd, J = 12.0, 5.5 Hz, 1 H), 3.88 (dd, J = 12.0,

2.0 Hz, 1 H), 4.12 (d, J = 9.5 Hz, 1 H), 6.22 (s, 1 H), 7.18 (d, J = 8.0 Hz, 2

H), 7.33 (d, J = 8.0 Hz, 2 H), ¹³C NMR (125 MHz, CD₃OD): = 29.4 (CH₂),

45.8 (CH₂), 54.6 (OMe), 54.9 (2xOMe), 61.8 (CH₂), 70.6 (CH), 74.9 (CH),

78.4 (CH), 80.7 (CH), 82.1 (CH), 90.3 (CH), 112.4 (CH), 127.6 (CH), 127.7

(CH), 137.0 (CH), 141.0 (C), 158.3 (C), 163.0 (C), 204.7 (C). HRMS: Calcd

for C₂₁H₂₅O₉[M+H]⁺421.1498, found 421.1492.

Acknowledgments

We thank 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

[02(0228)/15/EMR-II]. M. R. Reddy Is thankful to the IIT-Madras

for a Senior Research Fellowship (SRF). Utkarsh received a

postdoctoral fellowship from Science and Engineering Research

Board (PDF/2017/000611). GBR acknowledges the financial

assistance from Science and Engineering Research Board,

SERB (EMR/2016/001984) and Department of Health Research,

Government of India (V.25011/287-HRD/2016-HR).Funding from

IITM, through ERP proposal, CHY/17-18/850/RFER/INDR, is also

acknowledged

1-(3’,4’-dihydroxyphenyl)-3-(4-(D-

glucopyranosyl)phenyl)dihydrochalcone 22f:

Chalcone 21h (0.120, 0.298 mmol), Pd/C (0.031 g, 0.029), Ph₂S (0.005

mL, 0.029) and MeOH (2 mL) were treated as described in the general

procedure, condition B, for 24 h to give the title compound 22f, after

column chromatography on silica gel (MeOH/CH₂Cl_2,1:9) as colorless

solid (0.08 g, 67%); m.p = 134-136 ^oC: []²³_D= -146.1 (c 0.6, MeOH). ¹H

NMR (400 MHz, CD₃OD): = 2.99 (t, J = 7.6 Hz, 2 H), 3.22 (t, J = 7.6 Hz,

2 H), 3.39-3.46 (m, 3 H), 3.47-3.51 (m, 1 H), 3.70 (dd, J = 12.0, 5.2 Hz, 1

H), 3.87-3.90 (m, 1 H), 4.11 (d, J = 9.2 Hz, 1 H), 6.83 (d, J = 8.0 Hz, 1 H),

Keywords: Aldose Reductase inhibition • Chalcones •

Isoliquiritigenin • C-glucosylation

7.24 (d, J = 8.4 Hz, 2 H), 7.34 (d, J = 8.0 Hz, 2 H), 7.42-7.44 (m, 2 H). ¹³

C

NMR (100 MHz, CD₃OD): = 29.9 (CH₂), 39.3 (CH₂), 61.7 (CH₂), 70.5

(CH), 74.9 (CH), 78.4 (CH), 80.7 (CH), 82.0 (CH), 114.4 (CH), 114.5 (CH),

121.6 (CH), 127.7 (CH), 127.8 (CH), 129.8 (C), 137.1 (C), 141.1 (C), 145.0

(CH), 150.7 (C), 199.1 (C). HRMS: Calcd for C₂₁H₂₄O₈Na [M+Na]⁺

427.1368, found 427.1366.

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Hz, 2 H), 3.26 (t, J = 7.2 Hz, 2 H ), 3.38-3.41 (m, 2 H), 3.43-3.45 (m, 1 H),

3.47-3.49 (m, 1 H), 3.68-3.73 (m, 1 H), 3.89 (d, J = 12.4 Hz, 1 H), 4.12 (d,

J = 9.2 Hz, 1 H), 6.84 (d, J = 8.4 Hz, 2 H), 7.25 (d, J = 8.0 Hz, 2 H), 7.35

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 = 29.8 (CH₂), 39.3 (CH₂), 61.8 (CH₂), 70.5 (CH), 74.9 (CH), 78.4 (CH),

80.7 (CH), 82.1 (CH), 114.8 (CH), 127.7 (CH), 127.8 (CH), 128.1 (C),

130.4 (CH), 137.1 (C), 141.1 (C),162.3 (C), 198.9 (C). IR (KBr): ν˜ = 1573,

1693, 2996, 3417 cm–¹. HRMS: Calcd for C₂₁H₂₅O₇[M+H]⁺389.1600,

found 389.1592.

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Entry for the Table of Contents (Please choose one layout)

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characters)

Key Topic*

Author(s), Corresponding Author(s)*

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Title

((Insert TOC Graphic here: max.

width: 5.5 cm; max. height: 5.0 cm;

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not be less than 2 mm.))

*one or two words that highlight the emphasis of the paper or the field of the study

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Key Topic* C-Glucosylated

Chalcones

Mannem Rajeswara Reddy,^[a]Indrapal

Singh Aidhen,^[a]*Utkarsh A. Reddy,^[b]

Geereddy Bhanuprakash Reddy,^[b]

Kundan Ingle,^[c]Sami Mukhopadhyay^[c]

Inspired from natural product isoliquiritigenin (ISL), to enhance the bioavailability of

ISL, 4-C-glucosylated isoliquiritigenin and several C-glucosylated chalcones have

been synthesized and evaluated for aldose reductase (AR) inhibition activity.

Excellent AR inhibition has been observed with C-glucosylated ISL with IC₅₀value

of 21 M which is similar to the chalcone ISL (IC₅₀of 19 M). The studies have

revealed few new analogues with promising activity.

Page No. – Page No.

Synthesis of 4-C--D-Glucosylated

Isoliquiritigenin and Analogues for

Aldose Reductase Inhibition Studies

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Article Doi

Synthesis of 4-C-β-D-Glucosylated Isoliquiritigenin and Analogues for Aldose Reductase Inhibition Studies

DOI: 10.1002/ejoc.201900413

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Article abstract of DOI:10.1002/ejoc.201900413

Full text of DOI:10.1002/ejoc.201900413

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