Synthesis and anti-inflammatory activity of isoquebecol

Bioorganic & Medicinal Chemistry xxx (2017) xxx–xxx

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Bioorganic & Medicinal Chemistry

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Synthesis and anti-inﬂammatory activity of isoquebecol

Sébastien Cardinal ^a, Pierre-Alexandre Paquet-Côté ^a, Jabrane Azelmat ^b, Corinne Bouchard ^a,

Daniel Grenier ^b, Normand Voyer ^a,

⇑

^aDépartement de Chimie and PROTEO, Université Laval, 1045 Avenue de la Médecine, Québec G1V 0A6, Canada

^bGroupe de Recherche en Écologie Buccale, Faculté de Médecine Dentaire, Université Laval, 2420 Rue de la Terrasse, Québec G1V 0A6, Canada

a r t i c l e i n f o

a b s t r a c t

Article history:

We report here the synthesis of isoquebecol, an unprecedented constitutional isomer of quebecol, a

polyphenolic compound discovered in maple syrup. The methodology used to prepare isoquebecol

Received 13 October 2016

Revised 17 January 2017

Accepted 21 January 2017

Available online xxxx

involves, as key steps, the formation of a dibromoalkene from an

a-ketoester precursor, followed by a

double Suzuki-Miyaura reaction. The anti-inﬂammatory activity of isoquebecol was studied on macro-

phage cells by monitoring its ability to inhibit LPS-induced IL-6 secretion. Results show that this new

compound has an improved bioactivity over that of its natural isomer. Precursors and derivatives of que-

becol, isoquebecol and model analog 2,3,3-triphenylpropanol were also prepared and tested in this study.

Comparison between the three series of compounds led to establishing new SARs concerning the aryl ring

substitution pattern on the triarylpropanol scaffold and substructure functionalization.

Keywords:

Isoquebecol

Quebecol

Anti-inﬂammatory activity

SAR studies

Inhibition of IL-6 secretion

1. Introduction

to play a major role in the overall inﬂammatory response and

are also major contributors to pathologies involving chronic

Chronic inﬂammatory disorders are a major contemporary con-

cern in public health.^1–3Although inﬂammation is a normal phys-

iological response to injury, tissue ischemia, infectious agents, or

an imbalance of the pro- and anti-inﬂammatory signals can lead

to inappropriate and deleterious perpetuation of the inﬂammatory

response.^4,5Deregulation of inﬂammatory processes leads to speci-

ﬁc pathologies including psoriasis, rheumatoid arthritis, periodon-

tal disease, asthma and atherosclerosis. It has also been shown to

be a fundamental contributor to other degenerative conditions,

such as diabetes, cancer and cardiovascular diseases.^5–7Further-

more, the inﬂammatory response can be identiﬁed as the major

cause of damage related to autoimmune diseases.⁶

inﬂammatory disorders.^9–11Macrophages act on the inﬂamma-

tion process of surrounding cells by secreting various chemical

agents, including cytokines, that can amplify or reduce the

inﬂammatory response. Inhibition of the production of those bio-

logical mediators, involved in various steps of the inﬂammatory

processes, is a promising approach to modulate inﬂammation.¹²

It has been previously shown that the production of pro-inﬂam-

matory mediators can be stimulated upon simulating an infec-

tion event by treating cells with bacterial lipopolysaccharides

(LPS).^13,14The activity of bacterial LPS on macrophage cells orig-

inates from their interaction with the Toll-like receptor-4 (TLR4),

which results in the activation of nuclear factor-kappaB (NF-jB).

Consequently, the regulation of inﬂammatory processes is an

essential avenue in the treatment of various pathologies. Even if

many efforts have been made in this direction in past years, the

search for new anti-inﬂammatory compounds is still an important

area of research, as traditional therapies involving steroidal or non-

steroidal agents are often associated with a lack of efﬁciency and

undesirable side effects.⁸

The anti-inﬂammatory activity of a new compound can be

studied by evaluating its effect on the inﬂammatory response

of human macrophages, a type of leukocyte cells. These leuko-

cytes, key members of the innate immune system, are known

This latter event then leads to increased gene expression of var-

ious cytokines.^13–15

Plants have been used for centuries in the traditional medicine

of many cultures to alleviate pain associated with inﬂammatory

diseases.^8,16More recently, society’s interest in functional foods

and nutraceuticals has driven efforts, by both academia and the

food industry, to discover new bioactive molecular agents in

foods.^17–22Many familiar and traditionally used plant-sourced

foodstuffs have been revisited with a molecular approach in the

search for new phytochemical compounds.^23–27As a part of this

effort, the Seeram group has extensively studied Canadian maple

syrup.^28–33In 2011, they reported the isolation of a new polyphe-

nolic compound named quebecol 1 (Fig. 1). This compound showed

activity against breast and colon cancer cell lines in preliminary

⇑

Corresponding author.

E-mail address: normand.voyer@chm.ulaval.ca (N. Voyer).

http://dx.doi.org/10.1016/j.bmc.2017.01.050

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S. Cardinal et al. / Bioorganic & Medicinal Chemistry xxx (2017) xxx–xxx

and tested analogs and substructures of this new compound to

compare their activities with the corresponding isomers related

to quebecol.³⁷We also prepared 2,3,3-triphenylpropan-1-ol 3

(Fig. 1) and its precursors to include in our bioassays as unfunc-

tionalized models.

2. Compounds of interest

An overview of the molecules used in this study is shown in

Fig. 3. Those compounds can be classiﬁed in three different series.

Series 1 is based on quebecol 1 and related compounds. Series 2

includes isoquebecol 2, its precursors and substructures. Series 3

represents the model system and contains 2,3,3-triphenylpropanol

3 and analogs with unfunctionalized aryl rings. Table 1 presents

the complete list of all 21 compounds that we evaluated for anti-

inﬂammatory properties. The compounds are presented in Table 1

according to the above-mentioned Series 1, 2, or 3, and are also

classiﬁed according to their general scaffold (Class A to D).

Firstly, in addition of quebecol 1, isoquebecol 2 and 2,3,3-tri-

arylpropanol 3, we included, in our biological assays, two precur-

sors for each Series: a triarylpropanoate ethyl ester (Class C

compounds 4–6) and a triarylacrylic acid ethyl ester (Class D com-

pounds 7–9). This allowed us to evaluate the effects of an ester or

Fig. 1. Structures of quebecol (1), isoquebecol (2) and the 2,3,3-triphenylpropanol

model system (3).

in vitro biological assays.^33–35The study of this compound has as

yet been limited by its low abundance in its primary source.

To facilitate further research on this compound by solving its

availability problem, we developed a way to synthesize quebecol

1.³⁶Our synthetic approach to quebecol 1 and to the 2,3,3-triaryl-

propanol moiety in general is illustrated in Fig. 2. It involves, as

ﬁrst key step, a Wittig-like C-1 homologation to prepare a gem-

dibromoalkene synthon from the corresponding a-ketoester com-

pound. The second key step is the installation of the two other aryl

rings, using a double Suzuki-Miyaura cross-coupling (SMC) to pre-

pare a 2,3,3-triphenylacrylic acid ester. This key precursor scaffold

then gives direct access to 2,3,3-triarylpropanol compounds by

an

a,b-unsaturated ester on the activities.

Secondly, as an attempt to identify an active region on the que-

becol/isoquebecol scaffold, we divided, in our previous study, the

structure of quebecol 1 into two substructures, denoted ‘‘South”

and ‘‘North” (Fig. 3). The same approach was used in the present

study for isoquebecol 2.

both hydrogenation and reduction of the a,b-unsaturated system.

Encouraged by the promising properties of quebecol 1 reported

by Seeram,^33–35we decided to evaluate its anti-inﬂammatory

activity. In a previous study, we demonstrated that quebecol 1

(Fig. 1) inhibits the secretion of two pro-inﬂammatory cytokines

A variety of compounds 10–19 associated with the South sub-

structures (Class B) and bearing different functional groups were

prepared and included in Series 1 and Series 2 (Table 1). Even if

compounds 10, 12, and 14 showed no signiﬁcant anti-inﬂamma-

tory properties in our previous work,³⁷we were interested in

positively enhancing the activity of this substructure. To do so,

isomers 11, 13 and 15, and new compounds 16–19 were pre-

pared and tested to evaluate the impact of a different aryl ring

substitution (Series 1 vs 2) and of new functionalities on this

substructure.

(IL-6 and TNF-a) and reduces the NF-jB activation of LPS-stimu-

lated macrophage cells, resulting in anti-inﬂammatory activity.³⁷

Precursors and compounds corresponding to substructures of 1

were also synthesized and tested. The results obtained in this pre-

vious work with those compounds allowed us to deﬁne some

structure-activity relationships (SARs) and identify the most active

region of 1.

In this study, our intent was to extend the SAR studies regarding

the anti-inﬂammatory activity of quebecol 1, by studying the

effects that structural changes in the aryl rings have on the IL-6

secretion of LPS-stimulated macrophages. More speciﬁcally, we

were interested in evaluating the impact of 1) the presence of oxy-

genated groups and 2) the relative position of those functionalities

in regard to the propanol scaffold. Novel compounds with related

structures were prepared for these studies.

Diarylmethanes 20 and 21, corresponding to the exact North

substructure (Class A) of quebecol 1 and isoquebecol 2 respectively,

Herein, we report on the synthesis and evaluation of the anti-

inﬂammatory properties of an unprecedented isomer of quebecol,

which we have named isoquebecol 2 (Fig. 1). We synthesized

Fig. 2. Synthetic strategy designed to access the 2,3,3-triarylpropanol moiety used

in the total synthesis of quebecol.

Fig. 3. Overview of the scope of compounds studied.

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S. Cardinal et al. / Bioorganic & Medicinal Chemistry xxx (2017) xxx–xxx

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Table 1

Complete list of compounds included in bioassays classiﬁed by substitution pattern on the aromatic ring (Series 1–3) and molecular scaffold (Class A–D).

Class A

Class B

Class C

Class D

Series 1

10 (R₃= CH₂COOH)

12 (R₃= CH₂COOEt)

14 (R₃= CH₂CH₂OH)

16 (R₃= CH(OH)CH₂OH)

18 (R₃= COCH₂OH)

R

₁= OH,

₂= OMe

22

23

7

8

9

1 (R₃= CH₂OH)

4 (R₃= COOEt)

Series 2

11 (R₃= CH₂COOH)

13 (R₃= CH₂COOEt)

15 (R₃= CH₂CH₂OH)

17 (R₃= CH(OH)CH₂OH)

19 (R₃= COCH₂OH)

2 (R₃= CH₂OH)

5 (R₃= COOEt)

R

₁= OMe,

₂= OMe

Series 3

₁= R₂= H

3 (R₃= CH₂OH)

6 (R₃= COOEt)

R

complete the list of the evaluated compounds. As compound 20

showed an anti-inﬂammatory activity similar to quebecol 1 in

our previous study,³⁷we were particularly interested in evaluating

the effect of the positions of the functional groups for this particu-

lar scaffold (Series 1 vs. 2).

3.2. Preparation of the South substructures of quebecol and

isoquebecol (Class B)

The preparation of the South substructure compounds (Class B)

for Series 1 and 2 is presented in Scheme 2. Compounds 10, 11, 12

and 31 (Table 1) were all commercially available. We have previ-

ously reported the preparation of 14, 30 and 32.^36,37

The exact substructure of isoquebecol 15 was prepared by the

reduction of the corresponding ester 13, which had been prepared

from its carboxylic acid precursor 11.

3. Synthesis

3.1. Preparation of North substructure of isoquebecol (Class A)

Other Class B compounds used in this study were prepared from

compounds 30 and 31. As previously mentioned, we were inter-

ested in furthering our previous studies on this moiety by extend-

ing the variety of functionalities explored. Compounds 32 and 33

were reduced to the corresponding diols 34 and 35. Deprotection

of the benzyl group on those two compounds gave phenolic com-

pounds 16 and 17, which were included in the bioassays. Further

transformations were performed on 34 and 35 to access 18 and

19 with an oxidized benzylic position. First, the use of a DMAP/

TBDMS protocol³⁸was used for a chemoselective protection of

We previously reported the preparation of the North substruc-

ture of quebecol 20 by the condensation of an arylbromine with an

aryldehyde followed by the reduction of the obtained benzhydrol

and the deprotection of the phenol.³⁷We used the same strategy

to prepare the North substructure of isoquebecol and obtained

the desired product 21 with good yields (Scheme 1). In this case,

the needed arylbromine 24 was not commercially available. Conse-

quently, it was prepared from guaïacol 22 by an acetylation/bromi-

nation/hydrolysis sequence.

Scheme 1. Synthesis of 21: North substructure of isoquebecol.

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S. Cardinal et al. / Bioorganic & Medicinal Chemistry xxx (2017) xxx–xxx

Scheme 2. Preparation of Class B compounds: South substructures of quebecol (Series 1) and isoquebecol (Series 2).

the primary alcohol to give 36 and 37. Secondly, those products

were oxidized with the Dess Martin periodinane, yielding 38 and

39. Sequential removal of the two protecting groups led to pheno-

lic compounds 18 and 19.

3.3. Preparation of triarylethene precursor of isoquebecol (Class C)

3.3.1. Preparation of cross-coupling partners

As previously mentioned, the strategy presented in Fig. 2 was

used to prepare isoquebecol.³⁶

The gem-dibromoalkene precursor of isoquebecol 41 was pre-

pared in two steps from 33 (Scheme 3). First, the benzylic position

Scheme 4. Preparation of the boronic acid synthon 42 for the synthesis of

isoquebecol.

was oxidized using Dess-Martin periodinane to give the

a-ketoe-

3.3.2. Double Suzuki-Miyaura cross-coupling

ster 40. The gem-dibromoalkene functionality was then installed

by a Wittig-like C-1 homologation reaction. The CBr₄/PPh₃protocol

used in our previous work^36,39led us to prepare 41 in a 72% yield.

We accessed the arylboronic acid partner 42, corresponding to

the isoquebecol aryl ring substitution pattern, from the aryl-

bromine compound 25. This latter compound was previously used

in the synthesis of the North substructure 21 (Scheme 1). The boro-

nic acid functionality was installed on 25, using a lithiation/trans-

metallation/hydrolysis sequence. The desired compound 42 was

obtained in a 80% yield (Scheme 4).

As a way to give a more sustainable character to our previously

reported synthesis of quebecol,³⁶we were interested, while work-

ing on the synthesis of isoquebecol, to develop alternative condi-

tions to perform the double Suzuki-Miyaura coupling (SMC)

reaction in water. Additionally, having recently developed a syn-

thetic strategy to access various 1,2,2-triarylethene compounds

using SMCs on a gem-dibromoalkene template,⁴⁰we were particu-

larly interested to explore the behavior of this substrate in aqueous

conditions.

Scheme 3. Preparation of gem-dibromoalkene precursor of isoquebecol 41.

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S. Cardinal et al. / Bioorganic & Medicinal Chemistry xxx (2017) xxx–xxx

5

Interestingly, the SMC reaction is fully compatible with an

aqueous system from a theoretical/mechanistic point of view.^41,42

In fact, many cases of SMCs have been shown to be promoted by

the presence of water.^43,44However, the solubility of organic spe-

cies remains a major limitation to efﬁcient coupling in aqueous

media.^42,43To overcome this obstacle, we explored the use of

TPGS-750-M, a commercially available surfactant developed by

Lipshutz.⁴⁵When used as an additive, this environmentally benign

amphiphile has shown to form aqueous micellar nanoparticles that

can enable many metal-catalyzed cross-couplings (including

SMCs) in water at ambient temperatures.^45–47

aryl rings (Series 3), using ethyl benzoylformate and phenylboronic

acid as starting materials.⁴⁰

3.4. Preparation of isoquebecol, 2,3,3-triphenylpropanol and

precursors (Class D)

The preparation of isoquebecol 2 from precursor 43 requires the

reduction of the

tection of the phenolic functionalities. We have previously demon-

strated, during the total synthesis of quebecol, that

a,b-usaturated ester functionality and the depro-

a

Due to their availability in our lab from other ongoing projects,

cross-coupling partners 44 and 45 (Scheme 5), associated with the

synthesis of quebecol 1, were used to investigate the extension of

this double SMC reaction to aqueous solvent systems. Due to its

efﬁciency (shown in our previous work^36,40) for double coupling

in toluene, we were interested in exploring the reactivity of the

Pd₂(dba)₃/SPhos ligand combination in water. Many experiments,

using different loading of this catalytic system, various tempera-

tures, along with different concentrations of TPGS-750-M and

Et₃N (most common base use for SMC with this surfactant), led

us to establish the optimized conditions presented in Scheme 5

for the coupling of 44 and 45 (see Supplementary data for com-

plete coupling results).

hydrogenation reaction performed at high pressure can be used

to reduce this type of double bond, in addition to removing the

benzyl groups.³⁶The same set of conditions was used on 43 to pre-

pare isoquebecol 2 via 5, also used in our bioassays (Scheme 7). Tri-

arylethane compound 6 (Series 3) was also prepared from its

triarylethene precursor 9 using this reaction.

As illustrated in Scheme 5, we used those conditions to prepare

46 (the 1,2,2-triarylethene precursor of quebecol) at a gram scale

with a 75% yield. Afterwards, we apply them to the coupling of

41 and 42 to give 43, the key precursor towards the synthesis of

isoquebecol 2. It is worth noting that, in addition to the substitu-

tion of organic solvents, ligand and catalyst loadings were reduced

by half (compared with our original conditions in toluene) in these

conditions, without affecting coupling yields. To the best of our

knowledge, these reactions are the ﬁrst reported examples of SMCs

on a gem-dibromoalkene in water.

Scheme 6. Deprotection of 43 to prepare compound 8 (Class C).

3.3.3. Deprotection

The protecting groups on the phenol functionalities of 43 had to

be removed to obtain the triarylethene precursor of isoquebecol 8

(Class C). To prepare this derivative, we submitted 43 to the same

mild hydrogenation conditions that we previously used to access

7 (Table 1) from 46 (Scheme 5).³⁷Scheme 6 shows that those con-

ditions led to the preparation of polyphenolic compound 8 in a 61%

yield.

It is noteworthy that our group has already produced the model

1,2,2-triarylethene compound 9 (Table 1) with unfunctionalized

Scheme 5. Synthesis of 1,2,2-triarylethene precursors of isoquebecol and quebecol

(43 and 46, respectively) in a TPGS-750-M (5 wt.% in H₂O) solvent system.

Scheme 7. Preparation of isoquebecol 2 and 2,3,3-triphenylpropanol 3 from

usaturated esters 45 and 9.

a,b-

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S. Cardinal et al. / Bioorganic & Medicinal Chemistry xxx (2017) xxx–xxx

The ﬁnal step in the preparation of isoquebecol 2 was the reduc-

macrophage cells was evaluated by an MTT [3-(4,5-diethylthia-

zol-2-yl)-2,5-diphenyltetrazolium bromide] assay.

The effect of each compound on the secretion of the pro-inﬂam-

matory cytokine IL-6 was evaluated by treating the macrophage

cells with different concentrations of 1–21 for 2 h, prior to a 24 h

stimulation with bacterial LPS. Concentrations ranging from 125

tion of the ester functionality of 5 to the corresponding alcohol. We

successfully performed this transformation with a large excess of a

reducing agent (12 equiv) and reﬂux heating, to complete the total

synthesis of isoquebecol 2. Due to the limited quantity of precursor

5 at hand, we were only able to do this reaction once. Therefore,

the low yield observed for this transformation (31%, Scheme 7)

could not be optimized.

to 500

l

M were evaluated for compounds of Classes A and B. A

M) was considered

wider range of concentrations (31.25–500

l

The structure of isoquebecol 2 was conﬁrmed by mass spec-

trometry as well as by ¹H and ¹³C NMR. Slight differences were

observed between the spectral signatures of quebecol 1 and iso-

quebecol 2, mainly in ¹H NMR. Three singlets on the spectrum of

isoquebecol clearly show the presence of the three methoxy groups

(d = 3.66, 3.72 and 3.78 ppm). The doublet centered at 4.18 ppm

can be attributed to one of the CH groups (b from CH₂). Signals cor-

for Class C and Class D compounds, due to their general higher cyto-

toxicity according to the MTT assay. The quantiﬁcation of IL-6 was

performed with Enzyme-linked immunosorbent assay (ELISA) kits,

according to the manufacturer’s protocol.

4.2. Anti-inﬂammatory activity of isoquebecol

responding to the other CH group (a from CH₂) and to the methy-

A primary objective of this study was to evaluate the anti-

inﬂammatory activity of isoquebecol 2 and compare it with que-

becol 1. First, those two compounds showed some similarities

regarding their biological activity. Indeed, Table 2 shows that que-

becol 1 and isoquebecol 2 have a comparable activity at their high-

est non-cytotoxic concentration. Furthermore, results obtained for

quebecol 1 and isoquebecol 2 at different concentration showed

the dose-dependent character of that inhibition. A major activity

lene group are poorly resolved on the ¹H NMR spectrum of 2 and

form the broad multiplet found between 3.47 and 3.63 ppm. All

those assignments were conﬁrmed by the COSY and HSQC spectra

(see Supplementary data for 2D NMR).

The preparation of 2,3,3-triphenylpropanol 3 was also com-

pleted by the reduction of the corresponding ester. Milder reduc-

tive conditions were used for the reduction of non-phenolic

compound 6 (Conditions 2, Scheme 7) and led us to obtain 2,3,3-

triphenylpropanol 3 as unfunctionalized analog (Series 3) of que-

becol 1 and isoquebecol 2.

drop was also observed between 250 and 125 lM in both cases.

However, the results presented in Table 2 clearly show that iso-

quebecol 2, even if showing more toxicity than quebecol 1, has a

better activity proﬁle. Indeed, isoquebecol 2 kept signiﬁcant activ-

ity at all the lower concentrations evaluated, while the activity of

4. Biological evaluation

quebecol 1 became negligible below 125

lM. In fact, isoquebecol

2 represents the most active species at 62.5

all the compounds tested at those concentrations.

l

M and below, among

4.1. General remarks

The results of all bioassays for the studied compounds of Classes

A (20 and 21), B (10–19), C (7–9) and D (1–6) are summarized in

Table 2 (see Supplementary data for complete detailed results).

Those assays were performed according to previously reported

procedures.^37,48Before the evaluation of their anti-inﬂammatory

activity, the cytotoxicity of all compounds towards the

4.3. Aryl ring functionalization and anti-inﬂammatory activity

To evaluate the impact of the aryl ring functionalization on the

anti-inﬂammatory activity of quebecol 1 and related structures,

two general aspects were investigated.

Table 2

Highest non-cytotoxic concentration and inhibition of IL-6 secretion for all tested compounds (1–21).

Compound

Highest non-cytotoxic conc. (mM)

% Inhibition of IL-6 secretion at different concentrations^a,b,c

250 mM

125 mM

62.5 mM

31.25 mM

Class A

Class B

Series 1

Series 2

20

21

500 mM

90.5 2.4

92.5 0.9

27.5 10.1

50.7 7.3

n/d^d

n/d

Series 1

10

12

14

16

18

11

13

15

17

19

>1000 mM

500 mM

0.2 0.2

0.4 0.1

0.9 0.7

8.0 1.4

64.4 2.0

2.1 0.1

3.2 0.2

2.7 0.4

20.9 0.7

24.1 2.6

0.3 0.1

0.2 0.2

1.1 0.1

2.1 0.2

4.9 1.4

0.5 0.5

0.8 0.1

0.9 0.1

1.4 0.2

0.8 0.5

n/d

500 mM

Series 2

>1000 mM

500 mM

Class C

Class D

Series 1

Series 2

Series 3

7

8

9

62.50 mM

<15.62 mM

100 0.0

99.5 0.1

97.8 1.1

11.0 0.7

11.2 7.2

31.2 3.5

0.5 0.3

2.5 0.1

0.8 0.2

0.5 0.2

Series 1

Series 2

Series 3

4

250

l

M

91.9 0.7

84.7 0.3

96.8 0.2

96.9 0.2

85.3 3.4

100 0.0

34.6 1.5

55.3 6.2

41.3 0.5

48.3 0.5

2.0 0.4

9.4 0.3

4.7 3.4

5.9 0.3

43.3 3.3

0.4 0.2

15.6 2.6

4.0 0.1

3.7 0.1

3.0 0.8

34.5 3.8

0.2 0.1

1.4 0.9

1 [quebecol]

5

2 [isoquebecol]

6

500 mM

62.50 mM

250 mM

62.50 mM

31.25 mM

3 [2.3.3-triphenylpropanol]

100 0.0

a

b

c

PMA-differentiated U937 macrophages.

The means standard deviations of triplicate assays were calculated; statistically different from control at p < 0.01.

See Supplementary data for % inhibition evaluated at 500

n/d: not determined.

lM.

d

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S. Cardinal et al. / Bioorganic & Medicinal Chemistry xxx (2017) xxx–xxx

7

4.3.1. Presence of oxygenated functions [Series 1 and 2 vs. Series 3]

Comparison between compounds of Series 3 with their corre-

sponding analogs belonging to Series 1 and 2 established that an

increase of toxicity could generally be associated with the absence

of the functional groups on the aryl rings of Class C and Class D

compounds (Table 2). Indeed, 2,3,3-triphenylpropanol 3 shows a

far greater toxicity in the MTT assay than quebecol 1 and isoque-

becol 2. Same thing could be observed with 9 when compared to

its functionalized analogs 7 and 8. Finally, compound 6 also

showed a greater toxicity than it’s analog from Series 1 (4).

Similar results were obtained for Series 2 when comparing iso-

quebecol 2 and its analogs 5 and 8, except that a more drastic rise

of toxicity was observed between 2 and 5 compared with the one

between 1 and 4 (Table 2). Also, we observed in the case of Series 2

that the ester 5 (Class D) and the a,b-unsaturated ester 8 (Class C)

have equivalent toxicities.

4.5. Anti-inﬂammatory activity of quebecol and isoquebecol

substructures (Class a and B)

We were demonstrated in our previous work that the North

substructure 20 of quebecol had an anti-inﬂammatory activity,

while the South substructures studied were inactive.³⁷Along the

same line, substructures 10, 12, 14 and 20 of Series 1 were tested

again in this study and compared with 11, 13, 15 and 21, their cor-

responding isomers of Series 2. Results presented in Table 2 illus-

trate that structures related to isoquebecol (Series 2) showed the

same behavior as the substructures of quebecol (Series 1), concern-

ing the relation between the North and South substructures.

Firstly, compound 15 corresponding to the exact South sub-

structure of isoquebecol (Class B) showed no toxicity, as well as

no inhibition of the secretion of IL-6 by macrophages. The same

behavior was observed with analogs 11 and 13, which bear differ-

ent functionalities.

4.3.2. Position of oxygenated functions [Series 1 vs. Series 2]

As expected, the impact on the biological activity of the position

of the oxygenated functions on the aryl ring (Series 1 vs. Series 2).

As discussed earlier, inverting the hydroxy and the methoxy

group from quebecol 1 (Series 1) to isoquebecol 2 (Series 2) is

accompanied by an increase in toxicity and an improvement of

the anti-inﬂammatory activity, particularly at lower concentra-

tions. Similar behavior concerning toxicity was observed when

comparing compounds 4 and 5, the other pair of isomers of Class D.

Results obtained for compounds 7 and 8 (Class C) showed that

the functional groups position does not affect toxicity in the case

of this a,b-unsaturated ester scaffold. On the other hand, a slightly

better anti-inﬂammatory activity was observed at 62.5 mM for 8

(Series 2).

Secondly, as observed with Series 1, the diarylmethane com-

pound 21 corresponding to the North substructure (Class A) of 2

(Series 2) showed an anti-inﬂammatory activity comparable to

the complete structure (2) at the studied concentrations (125–

Comparison between compounds of Series 1 and Series 2 for

quebecol and isoquebecol substructures (Class A and B respec-

tively) shows that all pairs of isomers share the same cytotoxicity.

No particular tendency regarding biological activity while was

observed. The only pairs of isomers of Class B (South substructure)

for which a meaningful difference in anti-inﬂammatory activity

was noted were 16–17 and 18–19. In the ﬁrst case, compound 17

with the substitution pattern of isoquebecol (Series 2) demon-

strated a better inhibition of IL-6 secretion than 16. In the latter

case, 18 (belonging to Series 1) was three times more active than

19. Concerning the Class A compounds (North substructures), 21

(Series 2) was about twice as active as its isomer 20 (Series 1) at

500 lM), suggesting that the anti-inﬂammatory activity of 2 comes

also from this structural subunit. This result is even more interest-

ing in the case of Series 2 (vs. Series 1), considering the drop of tox-

icity observed between the North substructure 21 and the full

structure 2. Furthermore, compound 21 (Series 2) showed a better

anti-inﬂammatory activity than its isomer 20 (Series 1) at 125 lM,

the lowest studied concentration (50.7% for 21 vs. 27.5% for 20).

We were also interested in evaluating the biological activity of

new compounds associated with the South substructure of que-

becol 1 (Class B), even if this moiety had been so far mostly inactive

in our previous study.³⁷Hence, compounds 16 and 18 (Series 1), as

well as 17 and 19 (Series 2), were included as new analogs of the

quebecol and isoquebecol South substructures. Interestingly, 16–

19 showed an improved anti-inﬂammatory activity over the other

Class B compounds tested for both Series 1 and Series 2, while main-

taining a low toxicity (Table 2). First, 16 and 17 with an ethanediol

moiety showed a low but higher inhibition of IL-6 secretion than

the one observed in our previous study for compounds 10, 12

and 14.³⁷The introduction of the carbonyl function at the benzylic

position gave a similar result for 19 in Series 2, but led to an impor-

tant increase in activity for 18 (Series 1). While moderate, the

observed activity of 18 illustrates that simple modiﬁcations on

the South substructure can have an impact on its inhibition poten-

tial. This shows that anti-inﬂammatory activity can be tuned on

this moiety and eventually on more complex analogs bearing the

quebecol/isoquebecol scaffold.

the lowest tested concentration (125 lM).

Overall, no dominant trend could be identiﬁed from our biolog-

ical results regarding the substitution pattern of the oxygenated

functions on the aryl ring. In many cases, pair of isomers showed

the same toxicity and similar anti-inﬂammatory activity, when

comparing between Series 1 and Series 2. However, compounds

with the aryl ring substitution pattern of isoquebecol (Series 2)

were generally better inhibitors when a difference was observed

between the two isomers.

4.4. Anti-inﬂammatory activity of quebecol and isoquebecol precursors

(Class C and D)

We demonstrated in our previous study that the alcohol func-

tionality on the propanol core of quebecol 1 could be modiﬁed to

an ester or to

a,b-unsaturated ester without altering the anti-

inﬂammatory activity.³⁷However, this introduction of an elec-

trophilic function considerably increased the toxicity of the scaf-

fold of interest.³⁷Similar trends were observed in the present

study for both Series 1 and Series 2 (Table 2).

5. Conclusion

Indeed, as shown in Table 2 for Series 1, the anti-inﬂammatory

activity of 1 and 4 were comparable at 250

l

M, while the activity

In summary, we synthesized an unprecedented constitutional

isomer of quebecol, which we named isoquebecol 2. We also devel-

oped aqueous conditions to efﬁciently perform the key step of the

double Suzuki-Miyaura cross-coupling in our synthetic strategy

towards quebecol 1 and isoquebecol 2.

proﬁle shown by 7 was mostly attributable to toxicity. Further-

more, comparison between the Class D compounds 1 and 4 (Series

1) showed that the ester precursor 4 was twice more toxic than

quebecol 1. The introduction of a conjugated a,b-unsaturated sys-

tem between structures 4 (Class D) and 7 (Class C) resulted in

another increase in toxicity, 7 being the most toxic of all Series 1

compounds tested.

Isoquebecol 2 showed an overall improved biological activity

over quebecol 1 in the present study. Indeed, 2 presented a

slightly higher toxicity than quebecol 1, but a better activity

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8

S. Cardinal et al. / Bioorganic & Medicinal Chemistry xxx (2017) xxx–xxx

proﬁle on the LPS-induced IL-6 secretion at low concentrations,

making it a potential anti-inﬂammatory compound to be investi-

gated further.

6.1.2. Preparation of Class A compounds (North substructures)

Our group has already reported on the preparation and com-

plete characterization of 20 (the North substructure of quebecol).³⁷

A series of isoquebecol analogs and substructures (Series 2)

were prepared and tested in our bioassays, along with their cor-

responding isomers derived from quebecol (Series 1). 2,3,3-triph-

enylpropanol 3 and two of its precursors (Series 3) were also

included in our biological assays to serve as a model for the que-

becol/isoquebecol scaffold. The cytotoxicity and inhibition of IL-6

secretion were studied for a total of 21 compounds, allowing us

to establish some structure-activity relationships (SARs). Compar-

ison between phenolic compounds (Series 1 and 2) and unfunc-

tionalized systems (Series 3) showed that the oxygenated

substituents are essential for anti-inﬂammatory activity and cell

viability, considering the important toxicity evaluated for all com-

pounds lacking those functionalities (Series 3). On the other hand,

no deﬁnitive trends could be underlined regarding the substitu-

tion pattern on the aryl rings and biological activity (Series 1 vs.

2), even if compounds associated with isoquebecol (Series 2)

showed in general more activity where a difference was observed

between two isomers.

The studies of isoquebecol substructures clearly demonstrated

that, as previously observed with quebecol,³⁷the anti-inﬂamma-

tory activity of this compound originates from its North portion

21 (Class A). We established, in our precedent study, that the

diarylmethane scaffold 20 related to quebecol is a promising moi-

ety to investigate in the search for new anti-inﬂammatory com-

pounds, considering its structural simplicity and easy synthetic

access.³⁷Interestingly, the present study showed that compound

21 has an anti-inﬂammatory activity twice as high as its isomer

6.1.2.1. (2-Methoxy)phenyl acetate (23). Guaiacol 22 (40.3 mmol,

5.00 g) was dissolved in dried CH₂Cl₂(50 mL) in a round-bottom

ﬂask. Triethylamine (60.42 mmol, 8.42 mL) and 4-dimethy-

laminopyridine (4.03 mmol, 0.49 g) were added to the mixture.

The temperature was cooled to 0 °C and acetic anhydride

(44.3 mmol, 4.19 mL) was added dropwise. The mixture was stir-

red at room temperature for 24 h and then washed several times

using the following sequence: saturated NaHCO₃, water, HCl 2 N,

water and brine. The remaining organic layer was dried with

MgSO₄and concentrated in vacuo, giving 23 without the need for

further puriﬁcation in a 85% yield (34.2 mmol, 5.66 g). Transparent

oil. ¹H NMR (400 MHz, CDCl₃): d_H7.21 (1H, ddd, J = 8.2, 7.4, 1.7),

7.06–7.02 (1H, m), 7.00–6.92 (2H, m), 3.84 (3H, s), 2.32 (3H, s).

¹³C NMR (101 MHz, CDCl₃): d_C169.3, 151.3, 140.0, 127.1, 123.0,

121.0, 112.6, 56.0, 20.9. IR (ATR, ZnSe): m_max1759, 1498, 1367,

1254, 1192, 1168, 1108, 903, 745 cm^ꢀ1. HRMS (ESI-TOF, m/z): calcd

for C₉H₁₁O₃(M+H)⁺= 167.0703, found 167.0707. This compound

has been also previously reported.⁴⁹

6.1.2.2. 5-Bromo-2-methoxyphenol (24). (2-Methoxy)phenyl acet-

ate 23 (62.92 mmol, 10.46 g) was dissolved in anhydrous acetoni-

trile (110 mL) in an oven-dried three-neck ﬂask under nitrogen.

N-Bromosuccinimide (94.39 mmol, 16.80 g) was added to the

mixture and stirred at 60 °C for 24 h or until completion was

observed by TLC (60:40 hexanes/CH₂Cl₂). The solution was then

diluted with EtOAc (150 mL) and water (150 mL). The aqueous

layer was extracted three times with EtOAc. The organic layers

were combined and washed with saturated Na₂SO₃, water and

brine. The solution was dried with MgSO₄and concentrated in

vacuo. The resulting crude product [(5-bromo-2-methoxy)phenyl

acetate] was used further puriﬁcation and dissolved in dried MeOH

(50 mL) in a three-neck ﬂask under argon. A solution of KOH

(134.37 mmol, 7.52 g) in 100 mL of MeOH was added to the mix-

ture and stirred for 5 h at reﬂux or until completion was observed

by TLC (80:20 hexanes/EtOAc). The solution was then diluted with

EtOAc (150 mL) and 150 mL of water. HCl (6 N, 60 mL) was added

to the reaction mixture and the aqueous layer was extracted three

times with CH₂Cl₂. The organic layers were combined, washed

with water and brine, dried with MgSO₄and concentrated in vacuo,

giving 24 as a brownish solid in a 81% yield (50.95 mmol, 10.34 g).

mp = 62–66 °C. ¹H NMR (400 MHz, CDCl₃): d_H7.07 (1H, d, J = 2.4),

6.97 (1H, dd, J = 8.6, 2.4), 6.71 (1H, d, J = 8.6), 3.87 (1H, s). ¹³C

NMR (101 MHz, CDCl₃): d_C146.7, 146.1, 123.0, 118.0, 113.5,

112.0, 56.3. IR (ATR, ZnSe): m_max3386, 2930, 2840, 1589, 1494,

1433, 1213, 1124, 1022, 854, 796 cm^ꢀ1. This compound has been

also previously reported.⁴⁹

20 (at 125 lM), making 21 a better candidate as a leading moiety

to a new class of anti-inﬂammatory compounds inspired from que-

becol 1.

Finally, analogs of the South substructure (Class B) bearing

previously unstudied functionalities were prepared (16–19)

and showed enhanced activity towards the inhibition of IL-6

secretion, thus demonstrating that the South region of the que-

becol/isoquebecol scaffold could be used as a ﬁne-tuning tool to

modulate and enhance the activity of future analogs. Based on

those results we are currently exploring the preparation of

new quebecol analogs, as well as additional diarylmethane

derivatives. The investigation of the activity of quebecol 1 and

isoquebecol 2 on other biological processes is also currently

underway.

6. Experimental section

6.1. Chemical synthesis

6.1.1. General information

Unless otherwise indicated, all starting materials were pur-

chased from commercial sources (Sigma-Aldrich) and used with-

out further puriﬁcation. Solvents were dried and puriﬁed by

distillation under inert atmosphere before use. All reagents and

solvents were assembled under an inert atmosphere. ¹H and ¹³C

NMR spectra were recorded on a Varian 400 MHz or an Agilent

DD2 500 MHz spectrometer. The coupling constants are reported

in hertz (Hz) and the splitting patterns are designated as: s (sin-

glet), d (doublet), dd (doublet of doublets), t (triplet), q (quartet),

br (broad singlet) and m (multiplet). All melting points were taken

using a Standford Research Systems OptiMelt MPA 100 instrument.

Mass spectra were obtained on an Agilent 6210 LC Time of Flight

Mass Spectrometer in direct injection mode. IR spectra were taken

on a Bomem MB-Series Arid-Zone spectrometer (NaCl windows) or

a Thermo Nicolet 380 (ATR, ZnSe).

6.1.2.3. 1-Benzyloxy-5-bromo-2-methoxybenzene (25). 5-Bromo-2-

methoxyphenol 24 (14.84 mmol, 3.01 g) was dissolved in anhy-

drous acetone (50 mL) in an oven-dried three-neck ﬂask under

argon. K₂CO₃(29.69 mmol, 4.10 g) was then added and the mixture

was stirred for 5 min before the addition of benzyl bromide

(17.81 mmol, 2.12 mL). The reaction was reﬂuxed for 5 h or until

completion was shown by TLC (20:80 EtOAc/hexanes) (up to

24 h). The reaction mixture was cooled down to room temperature.

Water (15 mL) was added to the reaction mixture which was

extracted three times with EtOAc (3 ꢁ 30 mL). The organic layers

were combined, washed with saturated K₂CO₃, water and brine,

dried with MgSO₄, concentrated in vacuo and puriﬁed by silica

gel column chromatography (100% hexanes), giving 25 as a white

solid in a 96% yield. mp = 106–108 °C. ¹H NMR (400 MHz, CDCl₃):

d_H7.47–7.29 (5H, m), 7.07–7.01 (2H, m), 6.77 (1H, d, J = 8.3), 5.12

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S. Cardinal et al. / Bioorganic & Medicinal Chemistry xxx (2017) xxx–xxx

9

(1H, s), 3.86 (1H, s). ¹³C NMR (101 MHz, CDCl₃): d_C149.2, 136.6,

128.9, 128.3, 127.6, 124.2, 117.4, 113.3, 112.8, 71.4, 56.4. IR (ATR,

ZnSe): m_max1455, 1246, 1213, 1185, 1159, 1128, 1000, 919, 838,

773, 698 cm^ꢀ1. HRMS (ESI-TOF, m/z): calcd for C₁₄H₁₇BrNO₂(M

+NH₄)⁺= 310.0437, found 310.0440. This compound has been also

previously reported.⁵⁰

(100 MHz, CDCl₃): d_C148.2, 137.4, 134.1, 128.8, 128.7, 128.0,

127.7, 127.6, 121.5, 115.1, 112.1, 71.1, 56.4, 41.0. IR (ATR, ZnSe):

m_max2931, 1585, 1509, 1379, 1229, 1129, 1008, 838, 795,

696 cm^ꢀ1

.

HRMS (ESI-TOF, m/z): calcd for C₂₉H₃₂NO₄(M

+NH₄)⁺= 458.2326, found 458.2346.

6.1.2.7. Bis(3-hydroxy-4-methoxyphenyl)methane (21). Bis(3-benzy-

loxy-4-methoxyphenyl)methane 29 (0.340 mmol, 0.150 g) was

dissolved in EtOAc (7 mL) in a high-pressure hydrogenation vessel.

Pd/C 10% (0.04 g) was then added. The vessel was installed in the

reactor and, after 4 purges, the H₂pressure was set to 50 psi. After

3 h, the reaction was stopped. After cooling, the mixture was ﬁl-

tered on a Celite^Òpad. The ﬁltrate was concentrated in vacuo and

the crude product was puriﬁed by silica gel column chromatogra-

phy (50:50 EtOAc/hexanes) giving 21 as a white solid in a 96% yield

(0.326 mmol, 0.085 g). mp = 138–143 °C. ¹H NMR (500 MHz, CD₃-

OD): d_H6.79 (2H, d, J = 8.1), 6.63–6.57 (4H, m), 4.89 (2H, s), 3.79

(6H, s), 3.69 (2H, s). ¹³C NMR (125 MHz, CD₃OD): d_C145.9, 145.9,

134.7, 119.6, 115.5, 111.3, 55.0, 40.1. IR(NaCl): m_max3412, 3031,

2962, 2836, 1587, 1511, 1435, 1356, 1268, 1127, 1029, 964,

6.1.2.4. 3-Benzyloxy-4-methoxybenzaldehyde (27). Isovanillin 26

(46 mmol, 7.00 g) was dissolved in anhydrous acetone (50 mL) in

an oven-dried three-neck ﬂask under argon. K₂CO₃(78.2 mmol,

10.81 g) was then added and the mixture was stirred for 5 min

before the addition of benzyl bromide (78.2 mmol, 9.30 mL). The

reaction was reﬂuxed for 24 h or until completion was shown by

TLC (EtOAc/hexanes 30:70). The reaction mixture was allowed to

warm to room temperature, poured into saturated K₂CO₃and

extracted three times with EtOAc. The organic layers were com-

bined, washed with brine, dried with MgSO₄, concentrated in vacuo

and puriﬁed by silica gel column chromatography (30:70 EtOAc/

hexanes), giving 27 as a white solid in a 92% yield (41.2 mmol,

10.17 g). mp = 61–63 °C. ¹H NMR (400 MHz, CDCl₃): d_H9.82 (1H,

s), 7.49–7.45 (4H, m), 7.41–7.30 (3H, m), 7.01–6.98 (1H, m), 5.19

(2H, s), 3.96 (3H, s). ¹³C NMR (100 MHz, CDCl₃): d_C191.1, 155.3,

149.0, 136.5, 130.2, 128.9, 128.4, 127.8, 127.7, 127.1, 111.6,

111.0, 71.1, 56.4. IR (NaCl): m_max2839, 1685, 1596, 1584, 1510,

1434, 1268, 1283, 1134, 1018, 738 cm^ꢀ1. HRMS (ESI-TOF, m/z):

calcd for C₁₅H₁₅O₃(M+H)⁺= 243.1016, found 243.1027. This com-

pound has been also previously reported.⁵¹

791 cm^ꢀ1

.

HRMS (ESI-TOF, m/z): calcd for C₁₅H₂₀O₄(M

+NH₄)⁺= 278.1387, found 278.1374.

6.1.3. Preparation and/or characterization of Class B compounds

(South substructures)

Compounds 10 and 12 were purchased from Sigma-Aldrich

[products 71639 and 197971]. Characterization of those commer-

cial products was made prior to the biological assays and have

been previously reported by our group.³⁷We have previously

reported the synthesis and complete characterization of compound

14,³⁷as well as 30 and 32.³⁶

6.1.2.5. Bis(3-benzyloxy-4-methoxyphenyl)methanol (28). At room

temperature,

1-benzyloxy-3-bromo-2-methoxybenzene

25

(21.52 mmol, 6.31 g) was dissolved in freshly distilled THF

(90 mL) in an oven-dried three-neck ﬂask under argon. The tem-

perature was cooled to ꢀ78 °C and n-BuLi (1.6 M in hexanes,

24.75 mmol, 15.5 mL) was added dropwise. The reaction mixture

was stirred for 1 h at this temperature and a solution of 27

(21.52 mmol, 5.21 g) in THF (30 mL) was added dropwise. The

reaction mixture was stirred at ꢀ78 °C for 1.5 h, allowed to warm

to room temperature and stirred for another 2 h. Water (300 mL)

was slowly added to the mixture, which was then extracted three

times with EtOAc. The organic layers were dried with MgSO₄and

concentrated in vacuo. The crude product was dissolved in a mini-

mum of EtOAc and 250 mL of hexanes were added to precipitate

the desired product. After 12 h at 0 °C, the precipitate was ﬁltered,

lightly washed with cold EtOAc and dried in vacuo, giving 28 as a

white solid in a 66% yield (14.20 mmol, 6.45 g). mp = 110–115 °C.

¹H NMR (400 MHz, CDCl₃): d_H7.42–7.25 (10H, m), 6.88–6.78

(6H, m), 5.64 (1H, s), 5.07 (4H, s), 3.88 (6H, s). ¹³C NMR

(100 MHz, CDCl₃): d_C149.2, 148.3, 137.2, 136.7, 128.7, 128.0,

127.7, 119.6, 112.6, 111.7, 75.7, 71.1, 56.3. IR (NaCl): m_max2932,

2835, 1511, 1256, 1227, 1134, 1024, 738, 697 cm^ꢀ1. HRMS (ESI-

6.1.3.1. 3-Hydroxy-4-methoxyphenyl acetic acid (11). 3-Hydroxy-4-

methoxyphenyl acetic acid 11 was purchased from Sigma-Aldrich

(product 716391). Characterization of this commercial product

was made prior to the biological assays. White powder.

mp = 129–131 °C. ¹H NMR (500 MHz, CD₃OD): d_H6.84 (1H, d,

J = 8.2), 6.75 (1H, d, J = 2.1), 6.70 (1H, dd, J = 8.2, 2.2), 3.82 (3H, s),

3.46 (2H, s). ¹³C NMR (125 MHz, CD₃OD): d_C176.0, 148.1, 147.5,

128.8, 121.6, 117.3, 112.7, 56.4, 41.3. IR (ATR, ZnSe): m_max3373,

2910, 1687, 1512, 1270, 1229, 1152, 1025, 758, 685 cm^ꢀ1. HRMS

(ESI-TOF, m/z): calcd for C₉H₁₀NaO₄(M+Na)⁺= 205.0471, found

205.0466.

6.1.3.2. Ethyl 3-hydroxy-4-methoxyphenylacetate (13). 3-Hydroxy-

4-methoxyphenyl acetic acid 11 (2.75 mmol, 0.500 g) was dis-

solved in 2.5 mL of a (10:1) MeOH/H₂O mixture and then treated

with 20% aqueous Cs₂CO₃to adjust the pH to 7. After removal of

the solvent, 5 mL of DMF was added to the dry residue. After

5 min, ethylbromide (3.02 mmol, 225 lL) was added and the mix-

TOF, m/z): calcd for

C

₂₉H₂₇O₄(M-H₂O+H)⁺= 439.1904, found

ture was stirred for 72 h. HCl 1 N was then added and the product

was extracted with 3 portions of EtOAc. The organic layers were

combined, washed with brine, dried with Na₂SO₄and concentrated

in vacuo, giving an oil which was puriﬁed by ﬂash chromatography

(50:50 EtOAc/hexanes), yielding 13 as a colorless oil in a 71% yield

(1.95 mmol, 0.408 g). ¹H NMR (500 MHz, CDCl₃): d_H6.86 (1H, d,

J = 2.1), 6.79 (1H, d, J = 8.2), 6.75 (1H, dd, J = 8.2, 2.1), 5.75 (1H, s),

4.14 (2H, q, J = 7.1), 3.85 (3H, s), 3.51 (2H, s), 1.25 (3H, t, J = 7.1).

¹³C NMR (125 MHz, CDCl₃): d_C171.9, 145.7, 145.6, 127.3, 120.8,

115.6, 110.7, 60.8, 55.9, 40.8, 14.2. IR (NaCl): m_max3437, 2981,

1731, 1592, 1513, 1442, 1274, 1212, 1029, 761 cm^ꢀ1. HRMS (ESI-

439.1938. This compound has been also previously reported.⁵²

6.1.2.6. Bis(3-benzyloxy-4-methoxyphenyl)methane (29). At room

temperature, 28 (0.438 mmol, 0.20 g) and NaBH₄(55.4 mmol,

0.917 g) were dissolved in freshly distilled Et₂O. Triﬂuoroacetic

acid (31.54 mmol, 2.43 mL) was added dropwise during a period

of 1.5 h. After the addition, the mixture was stirred for 0.5 h. A

solution of NaHCO₃10% (12 mL) was slowly added to the mixture

and after 30 min of stirring, the mixture was extracted 3 times

with Et₂O. The organic layers were combined, dried with Na₂SO₄,

concentrated in vacuo and puriﬁed by ﬂash chromatography

(50:50 EtOAc/hexanes), giving 29 as a white solid in a 86% yield

(0.377 mmol, 0.165 g). mp = 114–118 °C. ¹H NMR (400 MHz,

CDCl₃): d_H7.42–7.27 (10H, m), 6.81 (2H, d, J = 8.1), 6.70–6.66

(4H, m), 5.06 (4H, s), 3.88 (2H, s), 3.77 (2H, s). ¹³C NMR

TOF, m/z): calcd for

C

₁₁H₁₅O₄(M+H)⁺= 211.0965, found

211.0979. This compound has been also previously reported.⁵³

6.1.3.3. 2-(3-Hydroxy-4-methoxyphenyl)ethanol (15). Ethyl 3-

hydroxy-4-methoxyphenylacetate 13 (1.19 mmol, 0.250 g) was

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S. Cardinal et al. / Bioorganic & Medicinal Chemistry xxx (2017) xxx–xxx

dissolved in freshly distilled anhydrous THF (5 mL) in an oven-

dried three-neck ﬂask under argon. The temperature was cooled

to 0 °C and LiAlH₄(1 N in THF, 4.75 mmol, 4.75 mL) was added

dropwise. The mixture was allowed to warm to room temperature

and the reaction was reﬂuxed for 3 h or until completion was

shown by TLC (EtOAc/hexanes 50:50). The reaction mixture was

cooled to 0 °C and HCl 1 N was added dropwise until pH 2–3.

The mixture was extracted three times with EtOAc. The organic

layers were combined, dried with MgSO₄, concentrated in vacuo

and puriﬁed by silica gel column chromatography (EtOAc/hexanes

50:50), giving 15 as a white solid in a 70% yield (0.832 mmol,

0.140 g). mp = 79–82 °C. ¹H NMR (500 MHz, CDCl₃): d_H6.82–6.78

(2H, m), 6.70 (1H, dd, J = 8.1, 2.1), 3.86 (3H, s), 3.81 (2H, t,

J = 6.6), 2.77 (2H, t, J = 6.6). ¹³C NMR (125 MHz, CDCl₃): d_C145.7,

145.3, 131.6, 120.5, 115.2, 110.8, 63.7, 56.0, 38.5. IR (NaCl): m_max

(5H, m), 6.89 (1H, d, J = 1.9), 6.79 (1H, d, J = 8.2), 6.74 (1H, dd,

J = 8.2, 1.9), 5.05 (2H, s), 4.60 (1H, dd, J = 8.4, 3.5), 3.81 (3H, s),

3.61–3.47 (4H, m). ¹³C NMR (125 MHz, CDCl₃): d_C149.5, 147.5,

137.0, 134.2, 128.4, 127.8, 127.2, 118.4, 113.9, 109.9, 74.2, 71.0,

67.8, 55.8. IR (ATR, ZnSe): m_max3308, 2930, 2870, 1589, 1514,

1228, 1134, 1027, 847, 739, 694 cm^ꢀ1. HRMS (ESI-TOF, m/z): calcd

for C₁₆H₁₇O₃(M-H₂O+H)⁺= 257.1172, found 257.1181.

6.1.3.7. 1-(3-Benzyloxy-4-methoxyphenyl)ethane-1,2-diol (35). 1-(3-

Benzyloxy-4-methoxyphenyl)ethane-1,2-diol 35 was prepared

using the same procedure described above for 34, using 33

(15.8 mmol, 5.00 g). Product 35 was obtained as a white solid in

a

97% yield (15.3 mmol, 4.14 g). mp = 68–75 °C. ¹H NMR

(400 MHz, CDCl₃): d_H7.42–7.26 (5H, m), 6.89–6.83 (3H, m), 5.12

(2H, s), 4.66 (1H, dd, J = 3.6, 8.2), 3.85 (3H, s), 3.64–3.52 (2H, m),

2.77 (2H, br). ¹³C NMR (100 MHz, CDCl₃): d_C149.6, 148.4, 137.2,

133.3, 128.8, 128.2, 127.7, 119.2, 112.3, 111.9, 74.6, 71.3, 68.3,

56.3. IR (NaCl): m_max3319, 2934, 1516, 1262, 1233, 1159, 1137,

11061, 1025 cm^ꢀ1. HRMS (ESI-TOF, m/z): calcd for C₁₆H₁₇O₃(M-

H₂O+H)⁺= 257.1172, found 257.1190. This compound has been

also previously reported.⁵⁵

3380, 2938, 1591, 1514, 1441, 1272, 1131, 1024, 804, 761 cm^ꢀ1

.

HRMS (ESI-TOF, m/z): calcd for C₉H₁₁O₂(M-H₂O+H)⁺= 151.0754,

found 151.0760. This compound has been also previously

reported.⁵⁴

6.1.3.4. Ethyl 3-hydroxy-4-methoxymandelate (31). Ethyl 3-

hydroxy-4-methoxymandelate 31 was purchased from Sigma-

Aldrich (product 78814). Characterization of this commercial

product was made, prior to biological assays. White powder.

mp = 125–126 °C. ¹H NMR (500 MHz, CD₃OD): d_H6.92–6.85 (3H,

m), 5.03 (1H, s), 4.22–4.07 (2H, m), 3.84 (3H, s), 1.20 (3H, t,

J = 7.1). ¹³C NMR (125 MHz, CD₃OD): d_C173.2, 147.7, 146.2,

131.8, 118.0, 113.4, 111.0, 72.6, 60.8, 55.0, 13.0. IR (ATR, ZnSe):

m_max3415, 3178, 1742, 1444, 1368, 1192, 1080, 1023, 811,

6.1.3.8. 1-(4-Hydroxy-3-methoxyphenyl)ethane-1,2-diol (16). 1-(4-

Benzyloxy-3-methoxyphenyl)ethane-1,2-diol 34 (0.106 mmol,

0.029 g) was dissolved in MeOH (2 mL) in a high-pressure hydro-

genation vessel. Pd/C 10% (0.019 g) was then added. The vessel

was installed in the reactor and, after 4 purges, the H₂pressure

was set to 50 psi. After 2 h, the reaction was stopped and the mix-

ture was ﬁltered on a Celite^Òpad. The ﬁltrate was concentrated in

vacuo and the crude product was puriﬁed by silica gel column

chromatography (100% EtOAc), yielding 16 as a brownish solid in

a 78% yield (0083 mmol, 0.015 g). ¹H NMR (400 MHz, CD₃OD): d_H

6.96 (1H, d, J = 1.7), 6.79 (1H, dd, J = 8.2, 1.6), 6.76 (1H, d, J = 8.1),

4.60 (1H, t, J = 6.1), 3.85 (3H, s), 3.59 (2H, d, J = 6.2). ¹³C NMR

(101 MHz, CD₃OD): d_C148.8, 147.0, 134.8, 120.2, 115.9, 111.0,

75.8, 68.8, 56.3. IR (NaCl): m_max3341, 2933, 1604, 1518, 1274,

1153, 1126, 1078, 1031, 877 cm^ꢀ1. HRMS (ESI-TOF, m/z): calcd

for C₉H₁₁O₃(M-H₂O+H)⁺= 167.0703, found 167.0713. This com-

pound has been also previously reported.⁵⁶

745 cm^ꢀ1

. HRMS (ESI-TOF, m/z): calcd for C₁₁H₁₃O₄(M-H₂O

+H)⁺= 209.0808, found 209.0804.

6.1.3.5. Ethyl 3-benzyloxy-4-methoxymandelate (33). Ethyl 3-

hydroxy-4-methoxymandelate 31 (17.7 mmol, 4.00 g) was dis-

solved in 60 mL of anhydrous acetone in an oven-dried three-neck

ﬂask under argon. Potassium carbonate (30.1 mmol, 4.16 g) was

added. After 5 min, benzyl bromide (30.1 mmol, 3.57 mL) was

added and the reaction was reﬂuxed for 24 h or until completion

was shown by TLC (50:50 EtOAc/hexanes). The reaction mixture

was allowed to cool at room temperature, poured into saturated

K₂CO₃and extracted three times with EtOAc. The organic layers

were combined, washed with brine, dried with MgSO₄, concen-

trated in vacuo and puriﬁed by ﬂash chromatography (50:50

6.1.3.9. 1-(3-Hydroxy-4-methoxyphenyl)ethane-1,2-diol (17). 1-(3-

Hydroxy-4-methoxyphenyl)ethane-1,2-diol 17 was prepared using

the same procedure described above for 16, using 35 (0.106 mmol,

0.029 g). Product 17 was obtained as a brownish solid in 61% yield

(0.065 mmol, 0.012 g). mp = 87–91 °C. ¹H NMR (500 MHz, CD₃OD):

d_H6.84 (1H, d, J = 8.3), 6.81 (1H, d, J = 2.0), 6.76 (1H, dd, J = 8.3, 2.0),

4.53 (1H, t, J = 6.1), 3.79 (3H, s), 3.54–3.52 (2H, m). ¹³C NMR

(125 MHz, CD₃OD): d_C147.1, 146.0, 134.8, 117.4, 113.1, 111.1,

74.2, 67.3, 55.0. IR (NaCl): m_max3347, 2935, 1594, 1512, 1440,

1273, 1219, 1130, 1025, 877, 762 cm^ꢀ1. HRMS (ESI-TOF, m/z): calcd

for C₉H₁₁O₃(M-H₂O+H)⁺= 167.0703, found 167.0716. This com-

pound has been also previously reported.⁵⁵

EtOAc/hexanes), giving 33 as

a white solid in a 96% yield

(16.9 mmol, 5.35 g). ¹H NMR (500 MHz, CDCl₃): d_H7.46–7.28

(5H, m), 7.00–6.96 (2H, m), 6.88 (1H, d, J = 8.1), 5.15 (2H, s), 5.05

(1H, s), 4.26–4.17 (1H, m), 4.15–4.06 (1H, m), 3.88 (3H, s), 3.09

(1H, br), 1.18 (3H, t, J = 7.2). ¹³C NMR (125 MHz, CDCl₃): d_C174.0,

150.0, 148.4, 137.2, 131.1, 128.8, 128.1, 127.6, 119.9, 112.4,

111.8, 72.8, 71.2, 62.4, 56.3, 14.3. IR (NaCl): m_max3465, 1732,

1514, 1262, 1231, 1156, 1138, 1081, 1023, 740, 697 cm^ꢀ1. HRMS

(ESI-TOF, m/z): calcd for C₁₈H₁₉O₄(M-H₂O+H)⁺= 299.1278, found

299.1289.

6.1.3.10.

1-(4-Benzyloxy-3-methoxyphenyl)-2-(tert-butyldimethyl-

6.1.3.6.

1-(4-Benzyloxy-3-methoxyphenyl)ethane-1,2-diol(34). At

silyloxy)ethanol (36). At room temperature, 34 (3.26 mmol,

0.891 g), tert-butyldimethylsilyl chloride (3.58 mmol, 0.538 g)

and DMAP (0.06 mmol, 0.024 g) were dissolved in CH₂Cl₂(7 mL)

in an oven-dried ﬂask under argon. Freshly distilled Et₃N was

added (3.58 mmol, 0.500 mL) and the mixture was stirred for

16 h at room temperature under argon. The solution was then

diluted with CH₂Cl₂, washed with water, washed with a saturated

NH₄Cl solution, dried with Na₂SO₄, concentrated in vacuo and puri-

ﬁed by ﬂash chromatography (29:70:1 EtOAc/hexanes/Et₃N), yield-

ing 36 as a transparent oil in a 42% yield (1.36 mmol, 0.531 g). ¹H

NMR (500 MHz, CDCl₃): d_H7.49–7.22 (5H, m), 6.99 (1H, d,

J = 1.9), 6.86 (1H, d, J = 8.2), 6.82 (1H, dd, J = 8.2, 1.9), 5.16 (2H, s),

room temperature, 32 (3.57 mmol, 1.13 g) was dissolved in freshly

distilled Et₂O (27 mL) in an oven-dried three-neck ﬂask under

argon. A solution of LiAlH₄(1 M in THF, 5.37 mmol, 5.37 mL) was

added dropwise. After the addition, the mixture was reﬂuxed until

completion was shown by TLC (50:50 EtOAc/hexanes). The mixture

was then cooled to 0 °C and a solution on HCl 1 N was added. Three

extractions with EtOAc were performed. The organic layers were

combined, washed with brine, dried with MgSO₄, concentrated in

vacuo and puriﬁed by ﬂash chromatography (50:50 EtOAc/hex-

anes), yielding 34 as a white solid in a 96% yield (3.43 mmol,

0.940 g). mp = 67–73 °C. ¹H NMR (500 MHz, CDCl₃): d_H7.38 –7.20

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S. Cardinal et al. / Bioorganic & Medicinal Chemistry xxx (2017) xxx–xxx

11

4.69 (1H, dd, J = 8.6, 2.8), 3.92 (3H, s), 3.74 (1H, dd, J = 10.1, 3.6),

3.55 (1H, dd, J = 10.1, 8.7), 2.97 (1H, d, J = 1.7), 0.93 (9H, s,

J = 3.0), 0.08 (6H, d, J = 0.9). ¹³C NMR (125 MHz, CDCl₃): d_C149.7,

147.7, 137.2, 133.5, 128.5, 127.8, 127.2, 118.5, 113.9, 109.9, 74.1,

71.1, 68.9, 56.0, 25.9, 18.3, ꢀ5.3, ꢀ5.4. IR (ATR, ZnSe): m_max3501,

the reaction was stopped and ﬁltered on a Celite^Òpad. The ﬁltrate

was concentrated in vacuo and the crude product was dissolved in

THF (2 mL). The solution was cooled to 0 °C and TBAF (1 N in THF,

0.150 mmol, 0.150 mL) was added dropwise. After the addition, the

reaction was allowed to warm to room temperature and stirred for

1 h or until completion was shown by TLC (100% EtOAc). Water

was then added to the mixture and three extractions with EtOAc

were performed. The organic layers were combined, washed with

brine, dried with MgSO₄, concentrated in vacuo and puriﬁed by

ﬂash chromatography (100% EtOAc), giving 18 as a brownish solid

in a 60% yield (0.060 mmol, 0.011 g). mp = 112–123 °C. ¹H NMR

(500 MHz, CD₃OD): d_H7.53 (1H, d, J = 2.0), 7.50 (1H, dd, J = 8.2,

2.0), 6.87 (1H, d, J = 8.2), 4.84 (2H, s), 3.91 (3H, s). ¹³C NMR

(125 MHz, CD₃OD): d_C197.1, 152.3, 147.8, 126.2, 122.4, 114.6,

110.0, 64.5, 55.0. IR (NaCl): m_max3339, 2924, 2852, 1674, 1592,

1517, 1276, 1205, 1032, 875 cm^ꢀ1. HRMS (ESI-TOF, m/z): calcd

for C₉H₁₁O₄(M+H)⁺= 183.0652, found 183.0652. This compound

has been also previously reported.⁵⁷

2927, 2854, 1510, 1462, 1251, 1103, 1004, 833, 774, 694 cm^ꢀ1

.

HRMS (ESI-TOF, m/z): calcd for

C₂₂H₃₁O₃Si (M-H₂O

+H)⁺= 371.2037, found 371.2041.

6.1.3.11.

1-(3-Benzyloxy-4-methoxyphenyl)-2-(tert-butyldimethyl-

silyloxy)ethanol (37). 1-(3-Benzyloxy-4-methoxyphenyl)-2-(tert-

butyldimethyl-silyloxy)ethanol 37 was prepared using the same

procedure described above for 36, using 35 (17.7 mmol, 4.85 g).

Product 37 was obtained as a yellowish solid in 76% yield

(13.5 mmol, 5.21 g). ¹H NMR (400 MHz, CDCl₃): d_H7.48–7.28

(5H, m), 6.98–6. 86 (3H, m), 5.16 (2H, s), 4.65 (1H, dd, J = 8.8,

3.6), 3.87 (3H, s), 3.66 (1H, dd, J = 3.6, 10.3), 3.46 (1H, dd, J = 8.8,

10.3), 0.92 (9H, s), 0.07 (3H, s). ¹³C NMR (100 MHz, CDCl₃): d_C

149.6, 148.3, 137.4, 133.0, 128.8, 128.1, 127.8, 119.4, 112.5,

111.8, 74.3, 71.3, 69.2, 56.3, 26.2, 18.6, ꢀ5.1. IR (NaCl): m_max

3487, 2953, 2928, 2857, 1516, 1259, 1136, 1107, 1026, 837,

778 cm^ꢀ1. HRMS (ESI-TOF, m/z): calcd for C₂₂H₃₁O₃Si (M-H₂O

+H)⁺= 371.2037, found 371.2044.

6.1.3.15.

1-(3-Hydroxy-4-methoxyphenyl)-2-hydroxyethanone

19

(19). 1-(3-Hydroxy-4-methoxyphenyl)-2-hydroxyethanone

was prepared using the same procedure described above for 18,

using 39 (0.258 mmol, 0.100 g). Product 19 was obtained as a

brownish solid in 38% yield (0.099 mmol, 0.018 g). mp = 125–

126 °C. ¹H NMR (500 MHz, CD₃OD): d_H7.50 (1H, dd, J = 8.4, 2.1),

7.40 (1H, d, J = 2.1), 7.01 (1H, d, J = 8.5), 4.82 (2H, s), 3.93 (3H, s).

¹³C NMR (125 MHz, CD₃OD): d_C197.4, 152.6, 146.5, 120.6, 113.6,

110.5, 64.5, 55.0. IR (NaCl): m_max3422, 2922, 2852, 1666, 1586,

1514, 1276, 887 cm^ꢀ1. HRMS (ESI-TOF, m/z): calcd for C₉H₁₁O₄

(M+H)⁺= 183.0652, found 183.0648.

6.1.3.12. 1-(4-Benzyloxy-3-methoxyphenyl)-2-(tert-butyl-dimethyl-

silyloxy)ethanone (38). At room temperature, 36 (1.05 mmol,

0407 g) was dissolved in anhydrous CH₂Cl₂(58 mL) in an oven-

dried three-neck ﬂask under argon. The temperature was cooled

to 0 °C and the Dess-Martin periodinane (2.09 mmol, 0.894 g)

was added. The mixture was stirred at 0 °C for 1 h or until comple-

tion was observed by TLC (30:69:1 EtOAc/hexanes/Et₃N). The solu-

tion was then diluted with CH₂Cl₂(50 mL) and 50 mL of a solution

50% NaHSO₃. The organic layer was extracted, washed with satu-

rated NaHCO₃, dried with MgSO₄and concentrated in vacuo. The

crude product was puriﬁed with silica gel column chromatography

(30:70 EtOAc/hexanes), giving 38 as a white solid in a 94% yield

(0.95 mmol, 0.277 g). mp = 48–55 °C. ¹H NMR (500 MHz, CDCl₃):

d_H7.58 (1H, d, J = 2.0), 7.51 (1H, dd, J = 8.4, 2.0), 7.46–7.30 (5H,

m), 6.91 (1H, d, J = 8.4), 5.22 (2H, s), 4.85 (2H, s), 3.94 (3H, s),

0.95 (9H, s), 0.14 (6H, s). ¹³C NMR (125 MHz, CDCl₃): d_C195.9,

152.7, 149.8, 136.4, 128.6, 128.0, 127.2, 122.2, 112.7, 111.4, 71.0,

67.3, 56.1, 25.8, 18.4, ꢀ5.3. IR (ATR, ZnSe): m_max2927, 2854,

1691, 1584, 1509, 1251, 1163, 1014, 880, 776, 698 cm^ꢀ1. HRMS

(ESI-TOF, m/z): calcd for C₂₂H₃₁O₄Si (M+H)⁺= 387.1986, found

387.1996.

6.1.4. Preparation of cross-coupling partners for the synthesis of

isoquebecol

6.1.4.1. Ethyl (3-benzyloxy-4-methoxyphenyl)(oxo)acetate (40). At

room temperature, 33 (1.58 mmol, 0.50 g) was dissolved in anhy-

drous CH₂Cl₂(86 mL) in an oven-dried three-neck ﬂask under

argon. The temperature was cooled to 0 °C and the Dess-Martin

periodinane (3.16 mmol, 1.34 g) was added. The mixture was stir-

red at 0 °C until completion was observed by TLC (50:50 EtOAc/

hexanes). The solution was then diluted with CH₂Cl₂and 100 mL

of a solution 10% Na₂S₂O₃in saturated NaHCO₃was added. The

mixture was stirred for 15 min and the organic layer was extracted,

dried with MgSO₄and concentrated in vacuo. The crude product

(yellowish solid) was puriﬁed by silica gel column chromatography

(50:50 EtOAc/hexanes), yielding 40 as a brownish solid in a 93%

yield (1.47 mmol, 0.462 g). mp = 54–60 °C. ¹H NMR (400 MHz,

CDCl₃): d_H7.67–7.61 (2H, m), 7.48–7.29 (5H, m), 6.94 (1H, d,

J = 8.4), 5.19 (1H, s), 4.41 (2H, q, J = 7.1), 3.88 (3H, s), 1.40 (3H, t,

J = 7.2). ¹³C NMR (100 MHz, CDCl₃): d_C185.1, 164.4, 155.8, 148.7,

136.4, 128.9, 128.4, 127.8, 126.6, 125.7, 113.4, 110.9, 71.2, 62.4,

56.5, 14.4. IR (ATR, ZnSe): m_max2932, 1723, 1662, 1578, 1508,

1430, 1261, 1229, 1141, 1042, 877, 698 cm^ꢀ1. HRMS (ESI-TOF, m/z):

calcd for C₁₈H₁₉O₅(M+H)⁺= 315.1227, found 315.1238.

6.1.3.13. 1-(3-Benzyloxy-4-methoxyphenyl)-2-(tert-butyl-dimethyl-

silyloxy)ethanone (39). 1-(3-benzyloxy-4-methoxyphenyl)-2-(tert-

butyl-dimethyl-silyloxy)ethanone 39 was prepared using the same

procedure described above for 38, using 37 (0.820 mmol, 0.318 g).

Product 39 was obtained as a yellowish solid in a 87% yield

(0.713 mmol, 0.277 g). mp = 39–47 °C. ¹H NMR (400 MHz, CDCl₃):

d_H7.60–7.56 (2H, m), 7.48–7.29 (5H, m), 6.90 (2H, d, J = 8.9), 5.18

(2H, s), 4.84 (2H, s), 3.94 (3H, s), 0.93 (9H, s), 0.12 (3H, s). ¹³C

NMR (100 MHz, CDCl₃): d_C196.1, 154.3, 148.4, 136.7, 128.9,

128.3, 128.1, 127.8, 122.9, 113.0, 110.7, 71.2, 67.4, 56.3, 26.1,

18.8, ꢀ5.1. IR (NaCl): m_max2953, 2929, 2856, 1694, 1595, 1516,

1426, 1267, 1136, 1022, 838, 778 cm^ꢀ1. HRMS (ESI-TOF, m/z): calcd

for C₂₂H₃₁O₄Si (M+H)⁺= 387.1986, found 387.2017.

6.1.4.2. Ethyl 3,3-dibromo-2-(3-benzyloxy-4-methoxyphenyl)pro-

penoate (41). PPh₃(3.11 mmol, 0.818 g) was dissolved in anhy-

drous CH₂Cl₂(2 mL) in an oven-dried three-neck ﬂask under

argon. The temperature was cooled to 0 °C and CBr₄(1.56 mmol,

0.516 g) in solution in 1.5 mL of anhydrous CH₂Cl₂was added

dropwise. The mixture was stirred at 0 °C for 30 min and a solution

of 40 (0.777 mmol, 0.244 g) in 1.5 mL of anhydrous CH₂Cl₂was

added dropwise. The reaction mixture was allowed to warm to

room temperature and stirred for 12 h or until completion was

observed by TLC (20:80 Et₂O/hexanes). Pentane (50 mL) was added

to the mixture, which was stirred for 30 min. After ﬁltration, the

solvent was evaporated in vacuo and the crude product was puri-

6.1.3.14.

1-(4-Hydroxy-3-methoxyphenyl)-2-hydroxyethanone

(18). 1-(4-Benzyloxy-3-methoxyphenyl)-2-(tert-butyl-dimethyl-

silyloxy)ethanone 38 (0.100 mmol, 0.039 g) was dissolved in

MeOH (3 mL) in a high-pressure hydrogenation vessel. Pd/C 10%

(0.020 g) was then added. The vessel was installed in the reactor

and, after 4 purges, the H₂pressure was set to 30 psi. After 16 h,

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12

S. Cardinal et al. / Bioorganic & Medicinal Chemistry xxx (2017) xxx–xxx

ﬁed by silica gel column chromatography (20:80 Et₂O/hexanes),

giving 41 as a white solid in a 72% yield (0.556 mmol, 0.261 g).

mp = 66–69 °C. ¹H NMR (400 MHz, CDCl₃): d_H7.46–7.26 (5H, m),

6.99 (1H, dd, J = 8.3, 2.1), 6.95 (1H, d, J = 2.0), 6.88 (1H, d, J = 8.4),

5.17 (2H, s), 4.23 (2H, q, J = 7.1), 3.90 (3H, s), 1.28 (3H, t, J = 7.1).

¹³C NMR (101 MHz, CDCl₃): d_C166.2, 150.2, 147.7, 141.1, 136.7,

128.6, 127.9, 127.6, 127.3, 121.4, 114.0, 111.3, 94.2, 70.9, 62.2,

55.9, 14.0. IR (ATR, ZnSe): m_max1716, 1509, 1245, 1217, 1191,

1164, 996, 872, 727, 700 cm^ꢀ1. HRMS (ESI-TOF, m/z): calcd for

147.6, 147.3, 144.5, 137.0, 136.9, 136.8, 135.1, 133.1, 131.6,

130.6, 128.4, 128.4, 128.4, 127.8, 127.4, 127.2, 127.2, 124.4,

122.9, 122.4, 116.7, 115.5, 115.0, 111.4, 111.0, 110.8, 70.9, 70.8,

70.7, 60.8, 56.0, 55.9, 55.8, 13.9. IR (NaCl): m_max2955, 2927, 1713,

1600 1513, 1247, 1138, 1023, 736, 697 cm^ꢀ1. HRMS (ESI-TOF,

m/z): calcd for C₄₇H₄₅O₈(M+H)⁺= 737.3109, found 737.3137.

6.1.5.2. Gram scale preparation of ethyl 2,3,3-tris(4-benzyloxy-3-

methoxyphenyl)propenoate (46). Ethyl 3,3-dibromo-2-(4-benzy-

C

₁₉H₂₂Br₂NO₄(M+NH₄)⁺= 485.9910, found 485.9890.

loxy-3-methoxyphenyl)propenoate

44

(3.19 mmol,

1.5 g),

4-benzyloxy-3-methoxyphenylboronic acid 45 (7.97 mmol, 2.06 g),

Pd₂(dba)₃(0.128 mmol, 0.117 g) and 2-dicyclohexylphosphino-

2⁰,6⁰-dimethoxybiphenyl (SPhos ligand) (0.255 mmol, 0.105 g)

were poured in an oven-dried three-neck ﬂask under argon. Three

6.1.4.3. 3-Benzyloxy-4-methoxyphenylboronic acid (42). 4-Bromo-3-

methoxyphenol 25 (0.682 mmol, 0.200 g) was dissolved in freshly

distilled THF (7 mL) in an oven-dried three-neck ﬂask under argon.

The temperature was cooled to ꢀ78 °C and the solution was stirred

for 30 min before dropwise addition of n-BuLi (1.6 N in hexanes,

0.752 mmol, 0.470 mL). Once the addition of n-BuLi was com-

pleted, the mixture was stirred for another 30 min at ꢀ78 °C before

the dropwise addition of trimethyl borate (2.05 mmol, 0.233 mL).

The reaction mixture was allowed to warm to room temperature

and stirred for 5 h. The temperature was cooled to ꢀ20 °C and

HCl 1 N was slowly added to reach pH = 2–3. The reaction mixture

was allowed to warm to room temperature and extracted three

times with EtOAc. The organic layers were combined, washed with

brine, dried with MgSO₄and concentrated in vacuo until precipita-

tion occurred. Hexanes was then added to maximize precipitation.

The solution was ﬁltered and the solid was dried under vacuum.

The precipitation/ﬁltration procedure was repeated twice, giving

42 as a white solid in an 80% yield (0.543 mmol, 0.140 g).

mp = 135–155 °C. ¹H NMR (500 MHz, CDCl₃): d_H7.80 (1H, d,

J = 8.0), 7.70 (1H, s), 7.58–7.29 (6H, m), 7.04 (1H, d, J = 8.0), 5.28

(2H, s), 3.99 (3H, s). ¹³C NMR (125 MHz, CDCl₃): d_C153.6, 147.7,

137.2, 130.3, 128.6, 127.9, 127.5, 120.5, 111.0, 71.3, 55.9. ¹¹B

NMR (160 MHz, CDCl₃): d_B28.6. IR (ATR, ZnSe): m_max1595, 1410,

1319, 1250, 1216, 1179, 1133, 1018, 740, 710 cm^ꢀ1. HRMS (ESI-

TOF, m/z): calcd for C₁₄H₁₄BO₃(M-H₂O+H)⁺= 241.1031, found

241.1049. This compound has been also previously reported.⁵⁸

vacuum/argon purges were made and 10 mL of a DL-a-tocopherol

methoxypolyethylene glycol succinate solution (5 wt.% in H₂O)

was added [commercially available from Sigma-Aldrich: TPGS-

750-M (product 763918)]. Et₃N was also added (9.57 mmol,

1.35 mL) and the suspension was vigorously stirred at room tem-

perature for 5 min and then at 60 °C for 15 h. After cooling to room

temperature, brine was added and the reaction mixture was

extracted three times with EtOAc. The organic layers were com-

bined, washed with brine, dried with MgSO₄and concentrated in

vacuo. The crude product was puriﬁed by silica gel column chro-

matography (30:70 EtOAc/hexanes), yielding 46 as an orange solid

in 75% yield (2.39 mmol, 1.76 g). mp = decomp. ¹H NMR (500 MHz,

CDCl₃): d_H7.48–7.30 (15H, m), 6.86–6.52 (9H, m), 5.19 (2H, s), 5.13

(2H, s), 5.11 (2H, s), 4.04 (2H, q, J = 7.07), 3.82 (3H, s), 3.56 (3H, s),

3.50 (3H, s), 0.99 (3H, t, J = 7.16). ¹³C NMR (125 MHz, CDCl₃): d_C

171.2, 149.1, 148.2, 147.7, 147.4, 144.8, 137.0, 136.9, 135.7,

133.7, 131.9, 131.1, 128.6, 127.3, 127.9, 124.0, 122.1, 115.0,

113.9, 113.5, 113.2, 113.0, 70.8, 61.0, 56.0, 55.7, 13.9. IR (NaCl):

m_max1711, 1511, 1463, 1454, 1262, 1236, 1139, 1129, 1027,

735 cm^ꢀ1

.

HRMS (ESI-TOF, m/z): calcd for C₄₇H₄₅O₈(M

+H)⁺= 731.3109, found 731.3126. We have also previously

reported the preparation of this compound in toluene.³⁶

6.1.6. Preparation of Class C compounds

6.1.5. Double Suzuki-Miyaura coupling in aqueous conditions

Complete coupling results regarding the optimisation work of

this reaction are presented in the Supplementary data.

We have previously reported the synthesis of triarylethene

compound 7,³⁶as well as 9.⁴⁰

6.1.6.1. Ethyl

(8). 2,3,3-Tris(3-benzyloxy-4-methoxyphenyl)propenoate

2,3,3-tris(3-hydroxy-4-methoxyphenyl)propenoate

43

6.1.5.1. Ethyl 2,3,3-tris(3-benzyloxy-4-methoxyphenyl)propenoate

(43). Ethyl 3,3-dibromo-2-(3-benzyloxy-4-methoxyphenyl)pro-

penoate 41 (0.184 mmol, 0.087 g), 4-benzyloxy-3-methoxyphenyl-

boronic acid 42 (0.461 mmol, 0.119 g), Pd₂(dba)₃(0.007 mmol,

0.007 g) and 2-dicyclohexylphosphino-2⁰,6⁰-dimethoxybiphenyl

(SPhos ligand) (0.015 mmol, 0.006 g) were poured in an oven-dried

three-neck ﬂask under argon. Three vacuum/argon purges were

(0.028 mmol, 0.021 g) was dissolved in EtOAc (5 mL) in a high-

pressure hydrogenation vessel. Pd/C 10% (0.01 g) was then added.

The vessel was installed in the reactor and, after 4 purges, the H₂

pressure was set to 50 psi at room temperature. After 20 h, the

reaction was stopped and the mixture was ﬁltered on a Celite^Ò

pad. The ﬁltrate was concentrated in vacuo and the crude product

was puriﬁed by silica gel column chromatography (50:50 EtOAc/

hexanes), giving 8 as brownish solid in a 61% yield (0.017 mmol,

0.008 g). ¹H NMR (500 MHz, CDCl₃): d_H6.81–6.76 (3H, m), 6.71

(1H, d, J = 2.1), 6.67 (1H, d, J = 8.4), 6.63–6.59 (3H, m), 6.54 (1H,

dd, J = 8.3, 2.1), 5.53 (1H, s), 5.47 (1H, s), 5.42 (1H, s), 4.06 (2H, q,

J = 7.1), 3.90 (3H, s), 3.84 (3H, s), 3.83 (3H, s), 1.05 (3H, t, J = 7.1).

¹³C NMR (125 MHz, CDCl₃): d_C170.9, 146.4, 146.0, 145.7, 145.1,

145.1, 144.8, 144.3, 136.1, 134.0, 131.9, 131.2, 123.3, 122.0,

121.3, 117.2, 115.9, 115.7, 110.3, 109.9, 109.8, 60.8, 55.9, 55.8,

55.8, 13.9. IR (NaCl): m_max3434, 2932, 2842, 1706, 1583, 1509,

1441, 1274, 1247, 1130, 1025, 734 cm^ꢀ1. HRMS (ESI-TOF, m/z):

calcd for C₂₆H₂₇O₈(M+H)⁺= 467.1700, found 467.1782.

made and 0.400 mL of a DL-a-tocopherol methoxypolyethylene

glycol succinate solution (5 wt.% in H₂O) was added [commercially

available from Sigma-Aldrich: TPGS-750-M (product 763918)].

Et₃N was also added (0.552 mmol, 0.077 mL) and the suspension

was vigorously stirred at room temperature for 5 min and then

at 60 °C for 20 h. After cooling to room temperature, brine was

added and the reaction mixture was extracted three times with

EtOAc. The organic layers were combined, washed with brine,

dried with MgSO₄and concentrated in vacuo. The crude product

was puriﬁed by silica gel column chromatography (30:70 EtOAc/

hexanes), yielding 43 as an orange solid in

a 69% yield

(0.127 mmol, 0.094 g). ¹H NMR (500 MHz, CDCl₃): d_H7.39–7.23

(15H, m), 6.86 (1H, dd, J = 8.3, 2.0), 6.81 (1H, d, J = 8.3), 6.75 (1H,

d, J = 2.0), 6.73 (1H, d, J = 8.4), 6.67 (1H, dd, J = 8.3, 2.0), 6.65–6.61

(2H, m), 6.54–6.50 (2H, m), 5.00 (2H, s), 4.83 (2H, s), 4.74 (2H, s),

3.97 (2H, q, J = 7.1), 3.91 (3H, s), 3.84 (6H, bs), 0.99 (3H, t, J = 7.1).

¹³C NMR (125 MHz, CDCl₃): d_C171.0, 149.6, 149.1, 148.8, 147.8,

6.1.7. Preparation of Class D compounds: isoquebecol 2, 2.3.3-

triphenylpropanol 3 and precursors

The preparation of 1 and 4 has been previously reported by our

group.³⁶

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S. Cardinal et al. / Bioorganic & Medicinal Chemistry xxx (2017) xxx–xxx

13

6.1.7.1. Ethyl 2,3,3-tris(3-hydroxy-4-methoxyphenyl)propanoate

(5). Ethyl 2,3,3-tris(3-benzyloxy-4-methoxyphenyl)propenoate

distilled anhydrous THF (4 mL) in an oven-dried three-neck ﬂask

under argon. The temperature was cooled to 0 °C and LiAlH₄(1 N

in THF, 0.363 mmol, 0.363 mL) was added dropwise. The mixture

was allowed to warm room temperature and the reaction was

heated at 50 °C for 15 h. The reaction mixture was cooled to 0 °C

and HCl 1 N was added dropwise until pH 2–3. The mixture was

extracted three times with EtOAc. The organic layers were com-

bined, dried with MgSO₄, concentrated in vacuo and puriﬁed by sil-

ica gel column chromatography (50:50 EtOAc/hexanes), yielding 3

as a gummy white solid in a 47% yield (0.114 mmol, 0.033 g). ¹H

NMR (500 MHz, CDCl₃): d_H7.47–7.43 (2H, m), 7.37–7.31 (3H, m),

7.28–7.17 (6H, m), 7.15–7.07 (3H, m), 7.02–6.97 (1H, m), 4.36

(1H, d, J = 11.3), 3.76–3.64 (3H, m). ¹³C NMR (125 MHz, CDCl₃):

d_C143.4, 142.9, 140.8, 128.8, 128.8, 128.5, 128.3, 128.2, 128.0,

126.7, 126.6, 125.9, 66.1, 53.7, 52.3. IR (NaCl): m_max3559, 3417,

43 (0.068 mmol, 0.05 g) was dissolved in freshly distilled MeOH

(5 mL) in a high-pressure hydrogenation vessel. Pd/C 10% (0.03 g)

was then added. The vessel was installed in the reactor and, after

4 purges, the H₂pressure was set to 286 psi and the temperature

to 50 °C. After 24 h, the reaction was stopped. The mixture was ﬁl-

tered on a Celite^Òpad. The ﬁltrate was concentrated in vacuo and

the crude product was puriﬁed by silica gel column chromatogra-

phy (60:40 EtOAc/hexanes), giving 5 as a yellowish solid in a 66%

yield (0.045 mmol, 0.017 g). ¹H NMR (500 MHz, CD₃OD): d_H6.87–

6.82 (3H, m), 6.81 (1H, d, J = 8.2), 6.72 (1H, dd, J = 8.3, 1.9), 6.69

(1H, d, J = 8.3), 6.61 (1H, d, J = 2.0), 6.59 (1H, d, J = 8.3), 6.53 (1H,

dd, J = 8.3, 2.1), 4.37 (1H, d, J = 12.4), 4.23 (1H, d, J = 12.3), 3.97–

3.85 (2H, m), 3.79 (3H, s), 3.74 (3H, s), 3.68 (3H, s), 1.01 (3H, t,

J = 7.1). ¹³C NMR (125 MHz, CD₃OD): d_C173.7, 146.7, 146.2,

145.9, 145.8, 145.8, 145.5, 136.6, 135.3, 130.1, 120.1, 119.4,

118.5, 115.1, 114.9, 114.7, 111.2, 110.9, 72.1, 60.3, 56.3, 55.0,

54.8, 53.3, 12.8. IR (NaCl): m_max3445, 2949, 1718, 1593, 1510,

1439, 1274, 1131, 1026, 762 cm^ꢀ1. HRMS (ESI-TOF, m/z): calcd

for C₂₆H₃₂NO₈(M+NH₄)⁺= 486.2122, found 486.2117.

3085, 3061, 2925, 1600, 1451, 1494, 1060, 1032, 747, 700 cm^ꢀ1

.

HRMS (ESI-TOF, m/z): calcd for C₂₁H₂₄NO (M+NH₄)⁺= 306.1852,

found 306.1905.

6.2. Investigation of biological activity of studied compounds

6.1.7.2. Ethyl 2,3,3-triphenylpropanoate (6). This compound was

prepared with the same procedure described for 5, using 9

(0.487 mmol, 0.160 g). Product 6 was obtained as a white solid in

a 94% yield (0.458 mmol, 0.152 g). mp = 110–114 °C. ¹H NMR

(500 MHz, CDCl₃): d_H7.46 (2H, dd, J = 8.3, 1.1), 7.36–7.29 (4H,

m), 7.24–7.14 (4H, m), 7.12–7.06 (4H, m), 7.05–6.99 (1H, m),

4.73 (1H, d, J = 12.3), 4.47 (1H, d, J = 12.3), 4.04–3.87 (2H, m),

1.01 (3H, t, J = 7.1). ¹³C NMR (125 MHz, CDCl₃): d_C172.7, 142.9,

141.6, 137.1, 128.6, 128.6, 128.3, 128.3, 128.2, 127.8, 127.3,

126.6, 126.2, 60.7, 56.9, 54.9, 13.9. IR (NaCl): m_max3029, 2929,

1721, 1498, 1453, 1370, 1299, 1171, 1159, 1095, 697 cm^ꢀ1. HRMS

6.2.1. Preparation of macrophage cells

U937 human monocytes (ATCC CRL-1593.2) from the American

Type Culture Collection (Manassas, VA, USA) were cultivated in

RPMI-1640 supplemented with 10% fetal bovine serum (FBS) and

100 mg/mL of penicillin G/streptomycin at 37 °C in a 5% CO₂atmo-

sphere. The monocytes (2.5 ꢁ 10⁵cells/mL) were then incubated in

RPMI-10% FBS containing 100 ng/mL of phorbol myristic acid

[PMA, Sigma-Aldrich] for 48 h to induce differentiation into adher-

ent macrophage-like cells. Adherent macrophage-like cells were

harvested by scraping and were centrifuged at 1200g for 5 min.

The cells were washed, suspended in RPMI-1% FBS at a concentra-

tion of 1 ꢁ 10⁶cells/mL, seeded into the wells of a 12-well micro-

plate (1 ꢁ 10⁶cells/well) and incubated overnight at 37 °C in a 5%

CO₂atmosphere, prior of their use for the two following sets of

analysis.

(ESI-TOF, m/z): calcd for

C

₂₃H₂₃O₂(M+H)⁺= 331.1693, found

331.1703. This compound has been also previously reported.⁵⁹

6.1.7.3. Preparation of isoquebecol [2,3,3-tris(3-hydroxy-4-methoxy-

phenyl)propan-1-ol] (2). Ethyl 2,3,3-tris(3-hydroxy-4-methoxy-

phenyl)propanoate

5 (0.03 mmol, 0.014 g) was dissolved in

freshly distilled anhydrous THF (5 mL) in an oven-dried three-neck

ﬂask under argon. The temperature was cooled to 0 °C and LiAlH₄

(1 N in THF, 0.358 mmol, 0.358 mL) was added dropwise. The mix-

ture was allowed to warm to room temperature and the reaction

was reﬂuxed for 13 h. The reaction mixture was cooled to 0 °C

and HCl 1 N was added dropwise until pH 2–3. The mixture was

extracted three times with EtOAc. The organic layers were com-

bined, dried with MgSO₄, concentrated in vacuo and puriﬁed by sil-

ica gel column chromatography (70:30 EtOAc/hexanes), yielding

isoquebecol 2 as a white solid in a 31% yield (0.009 mmol,

0.004 g). This reaction was done only once, due to the very small

quantity of 5. The low yield is attributed to accidental loss of sol-

vent during overnight heating. ¹H NMR (500 MHz, acetone-d₆):

d_H7.44 (1H, s), 7.20 (2H, s), 6.97 (1H, d, J = 2.2), 6.91 (1H, dd,

J = 8.3, 2.2), 6.87–6.84 (2H, m), 6.81 (1H, d, J = 2.2), 6.76 (1H, dd,

J = 8.3, 2.1), 6.73–6.70 (2H, m), 6.63 (1H, d, J = 8.3), 4.19 (1H, d,

J = 11.8), 3.80 (3H, s), 3.74 (3H, s), 3.68 (3H, s), 3.55 (5H, m). ¹³C

NMR (125 MHz, acetone-d₆): d_C147.3, 146.7, 146.6, 146.3, 146.0,

139.2, 138.5, 136.6, 132.7, 129.5, 121.2, 120.2, 119.8, 116.6,

116.1, 115.5, 112.4, 111.8, 111.6, 66.5, 56.3, 56.0, 53.0, 52.2. IR

6.2.2. Evaluation of cytotoxicity

The above-mentioned prepared macrophage-like cells were

treated with 2-fold serial dilutions of the compounds 1–21

(1000–7.81 mM). After 24 h, cell viability is determined with an

MTT [3-(4,5-diethylthiazol-2-yl)-2,5-diphenyltetrazolium bro-

mide] assay, following the manufacturer’s protocol (Roche Diag-

nostics, Mannheim, Germany). Detailed results of those assays

are presented in the Supplementary data.

6.2.3. Evaluation of IL-6 secretion by LPS-stimulated macrophages

The above-mentioned macrophage-like prepared cells were

treated (2 h) with non-cytotoxic concentrations of compounds

1–21, prior to being stimulated with Aggregatibacter actino-

mycetemcomitans ATCC 29522 lipopolysaccharide (LPS) at a ﬁnal

concentration of 1 mg/mL. After a 24 h incubation at 37 °C in a

5% CO₂atmosphere, the culture medium supernatants were

collected and stored at ꢀ20 °C until used. Cells incubated in a

culture medium with or without the compounds and stimulated

or not with LPS were used as controls. Enzyme-linked

immunosorbent assay (ELISA) kits (eBioscience Inc., San Diego,

CA, USA) were used to quantify IL-6 concentrations according to

the manufacturer’s protocols. Two independent experiments were

(NaCl): m

_max2929, 1592, 1509, 1439, 1270, 1130, 1027 cm^ꢀ1. HRMS

(ESI-TOF, m/z): calcd for C₂₄H₃₀NO₇(M+NH₄)⁺= 444.2017, found

444.2022. COSY and HSQC NMR studies were also performed (see

supplementary data).

performed in triplicate and

a representative set of data

(means standard deviations) was used to determine the activity

of each compound. Detailed results of those assays are presented

in the Supplementary data.

6.1.7.4. Preparation of 2,3,3-triphenylpropanol (3). Ethyl 2,3,3-triph-

enylpropanoate 6 (0.242 mmol, 0.080 g) was dissolved in freshly

Please cite this article in press as: Cardinal S., et al. Bioorg. Med. Chem. (2017), http://dx.doi.org/10.1016/j.bmc.2017.01.050

14

S. Cardinal et al. / Bioorganic & Medicinal Chemistry xxx (2017) xxx–xxx

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