Biomimetic synthesis and anti-inflammatory evaluation of violacin A analogues

Bioorganic Chemistry 111 (2021) 104898

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Bioorganic Chemistry

journal homepage: www.elsevier.com/locate/bioorg

Biomimetic synthesis and anti-inﬂammatory evaluation of violacin

A analogues

,

,*

Wenxi Wu^a, Yu Mu^a, Bo Liu^a, Zixuan Wang^a, Peipei Guan^a, Li Han^{a *}, Mingguo Jiang^b

,

*

Xueshi Huang^a

^aInstitute of Microbial Pharmaceuticals, College of Life and Health Sciences, Northeastern University, Shenyang 110819, China

^bGuangxi Key Laboratory for Polysaccharide Materials and Modiﬁcations, School of Marine Sciences and Biotechnology, Guangxi University for Nationalities, Nanning

530008, China

A R T I C L E I N F O

A B S T R A C T

Keywords:

Violacin A, a chromanone derivative, isolated from a fermentation broth of Streptomyces violaceoruber, has

excellent anti-inﬂammatory potential. Herein, a biogenetically modeled approach to synthesize violacin A and

twenty-ﬁve analogues was described, which involved the preparation of aromatic polyketide precursor through

Claisen condensation and its spontaneous cyclization. The inhibitory effect on nitric oxide (NO) production of all

synthetic molecules was evaluated by lipopolysaccharide (LPS)-induced Raw264.7 cells. The results revealed that

introduction of aliphatic amine moieties on C-7 obviously improved the anti-inﬂammation effect of violacin A,

and also the aromatic ether instead of ketone group at side chain was favorable to increase the activity. Among

them, analogue 7a and 16d were screened as the most effective anti-inﬂammatory candidates. Molecular

mechanism research revealed that 7a and 16d acquired anti-inﬂammatory ability due to the inhibition of NF-κB

signaling pathway.

Violacin A

Biomimetic synthesis

Anti-inﬂammatory activity

NF-κB

1. Introduction

biosynthetic pathway for violacin A was designed (Scheme 1) according

to the similar natural products in the literature. Violacin A was assumed

Violacin A was ﬁrst isolated from a fermentation broth of Strepto-

myces violaceoruber, and presented excellent anti-inﬂammatory effect

through down-regulating nuclear factor-κB (NF-κB) signaling pathway

[1]. NF-κB pathway plays a critical role in the progress of inﬂammation

and had been used as a potential target for anti-inﬂammatory therapy

[2,3]. The anti-inﬂammatory potential and novel molecular structure of

violacin A have caused our intense concern.

to be biogenetically originated from polyketide precursor, which

derived from the Aldol condensation of the acetyl-CoA and malonyl-CoA

[5]. After that, β-ketoacid product was constructed by Aldol condensa-

tion, aromatization and hydrolyzation [5]. And then, it underwent

spontaneous decarboxylation to form aromatic polyketide precursor [6],

which would produce violacin A through forming cyclic hemiacetal [7].

In the current study, on basis of biosynthetic pathway analysis of vio-

lacin A, a new synthesis strategy was introduced, which greatly short-

ened the reaction period and increased the overall yield to 42%. In order

to further investigate the SAR, a series of analogues (7a-7p and 16a-16i)

were designed and synthesized using the similar approach. The inhibi-

tory effect of all synthesized analogues on nitric oxide (NO) production

was evaluated using lipopolysaccharide (LPS)-induced Raw264.7 cells.

As the most potential chemical molecule, the anti-inﬂammatory mech-

anism of 7a and 16d was related to inhibition of NF-κB signaling

pathway.

Although violacin A has been successful synthesized through eight-

step reaction with 25% total yield in our previous research [4], the

synthetic process and its overall yield could not meet the need for further

research. In addition, our previous preliminary structure–activity rela-

tionship (SAR) studies have revealed that the benzyloxyl group intro-

duction at the C-7 could obviously change the anti-inﬂammatory

activity of violacin A, and the absence of ketone group at the side chain

might not inﬂuence its activity [4]. However, the relative role of 7-O-

substituent and the alkyl side chain on the scaffold in the anti-

inﬂammatory effect of violacin A still needs to be clariﬁed.

In order to construct new synthetic strategy, the plausible

* Corresponding authors.

E-mail addresses: hanli@mail.neu.edu.cn (L. Han), mzxyjiang@gxun.edu.cn (M. Jiang), huangxs@mail.neu.edu.cn (X. Huang).

https://doi.org/10.1016/j.bioorg.2021.104898

Received 5 February 2021; Received in revised form 4 April 2021; Accepted 5 April 2021

Available online 8 April 2021

W. Wu et al.

Bioorganic Chemistry 111 (2021) 104898

2. Results and discussion

4).

To explore the role of alkyl side chain at C-2 in the anti-inﬂammatory

2.1. Chemistry

effect, analogues 16a-16i were prepared using the similar synthetic

approach for violacin A (Scheme 5). The Frise rearrangement of orcinol

(8) was catalyzed by boron triﬂuoride etherate in acetic acid to form 2,4-

dihydroxy-6-methyl phenylacetone (9) [15], which treated with benzyl

chloride and anhydrous K₂CO₃in reﬂuxing acetonitrile to provide the

benzyl ether 10. At the same time, acetals 12a-12f were constructed by

the etheriﬁcation of phenols 11a-11f and 2-(2-bromoethyl)-1,3-dioxo-

lane in the presence of anhydrous K₂CO₃in N,N-Dimethylformamide

(DMF) at 65 ^◦C [16]. Acetals 12a-12f were easily hydrolyzed in acetic

acid aqueous solution at 45 ^◦C to produce aldehydes 13a-13f [17].

Simultaneously, β-hydroxyketones 14a-14i were prepared by Aldol re-

action of 10 and relevant aldehyde (13a-13f, butyraldehyde, pentanal

or hexanal) with LDA in anhydrous THF at ꢀ 78 ^◦C. Afterwards, 14a-14i

underwent oxidation by Dess-Martin periodinane in anhydrous DCM at

According to the biosynthetic pathway analysis, the retrosynthetic

analysis of violacin A was described in Scheme 2. Violacin A was ob-

tained through intramolecular cyclization of aromatic polyketide 4.

Meanwhile, polyketide 4 served as a pretarget molecule, which could be

constructed by Claisen condensation of methyl 2,4-dihydroxy-6-methyl-

benzoate (2) and acetylacetone (3). And then the intermediate 2 could

be prepared from starting material methyl acetoacetate (1).

Guided by the foregoing retrosynthetic strategy, the synthesis was

initiated with the synthesis of intermediate 2 from commercially avail-

able methylacetoacetate (1) following a literature protocol [8]. Ac-

cording to the literature [9,10], aromatic triketone was prepared by the

Claisen condensation of methyl benzoate and dilithioacetylacetone, and

the ortho-hydroxyl aromatic triketone could spontaneously form the

cyclic hemiketal. Herein, intermediate 2 was reacted with bromomethyl

methyl ether (MOMBr) to form MOM ether 2a [11], and then 4a was

obtained through Claisen condensation of 2a and acetylacetone (3) in

the presence of lithium diisopropylamide (LDA) in anhydrous tetrahy-

drofuran (THF). We expected deprotection of MOM ether 4a to give

ortho-hydroxyl aromatic polyketide and further producing violacin A.

Unfortunately, violacin A was not obtained, but the dehydration product

of violacin A (4b) was detected in the reaction system. We speculated

that the dehydration of violacin A happened in the acidic condition after

deprotection of 4a using 1 N HCl. Considering the hemiacetal hydroxyl

of violacin A was easily eliminated to form a conjugated double bond

with the carbonyl group at C-4 under acidic conditions, benzyl group

was introduced to protect free phenolic hydroxyl. Intermediate 2 treated

with benzyl chloride and anhydrous potassium carbonate (K₂CO₃) in

reﬂuxing acetonitrile to get benzyl ether 2b [12]. And then 4c was ob-

tained through Claisen condensation of 2b and acetylacetone (3) in the

◦

0 C to give 1, 3-diketone 15a-15i [18]. Just like that of 4c, 15a-15i

were the mixture of keto-enol tautomers according to their ¹H and ¹³

C

NMR spectra (Figure S111-S128). Finally, the catalytic hydrogenation of

15a-15i in ethanol at room temperature afforded analogues 16a-16i.

2.2. Biological evaluation

2.2.1. NO production inhibition in LPS-induced RAW 264.7 cells

In order to avoid the false positive results in anti-inﬂammatory

evaluation, cytotoxicity of the synthesized molecules against RAW

264.7 cells was measured by MTT assay. As shown in Fig. 1A, all of

synthesized analogues had not obviously cytotoxicity against RAW264.7

cells, except for compounds 7m and 16e.

As a signiﬁcant pro-inﬂammatory mediator, the production of NO in

LPS-stimulated Raw264.7 cells was used to evaluate the anti-

inﬂammatory activity of compound [19,20]. Here, the inhibitory ef-

fect of all synthetic analogues without cytotoxicity on production of NO

were measured by Griess method, and dexamethasone (DXM) was

selected as a positive control. The results indicated that 7b, 7e, 7n, 16b,

16c, and 16f-16i presented comparable inhibitory activity against NO

production to that of violacin A. In particular, 7a, 7d, 16a, and 16d had

stronger inhibitory activities against NO production than violacin A

(Fig. 1B). The further investigation also demonstrated that the anti-

inﬂammatory effect of 7a and 16d were dose-dependent (Fig. 1C, D).

Among the 7-O-substituted analogues, anti-inﬂammatory activities

of molecules with linear aliphatic amine moieties were obviously su-

perior to that of analogues with cycloaliphatic amine moieties (7a-7e vs.

7f-7j). However, the introduction of extra phenol or alcohol units

obviously decreased the anti-inﬂammatory effect (7k, 7l, 7o and 7p),

except for 7n. Analogues 16g-16i showed the similar activities as that of

violacin A. The results indicated that the carbonyl group at the side-

chain was not necessary for anti-inﬂammatory activity. Meanwhile, all

of the analogues (16a-16d and 16f) with aromatic ether moieties

presence of LDA in anhydrous THF. In particular, the ¹H NMR and ¹³

C

NMR spectrum of 4c revealed it’s a mixture of tautomers containing one

bisenol, two monoenol and one unenolized triketone tautomer

(Figure S11, S12) according to literature [10]. Finally, violacin A was

successfully obtained while the benzyl was removed by catalytic hy-

drogenation of 4c in ethanol at room temperature (Scheme 3).

In order to further investigate the effect of 7-O-substituent in the

molecule on anti-inﬂammatory activity, we designed analogues 7a-7p,

structurally characterized by different aliphatic amine, alkyl alcohol and

phenol moieties linked to the C-7 position of molecule by 2-oxy-acetyl

group. To accomplish this, acylation of relevant amines 5a-5j, phenols

5 k–5 m or alcohols 5n–5o with bromoacetyl bromide in the presence of

◦

triethylamine in anhydrous dichloromethane (DCM) at 0 C provided

the intermediate 6a-6o [13,14]. Subsequently, 2-bromoacetamide and

2-bromoacetate further etheriﬁcation with violacin A in the presence of

anhydrous K₂CO₃in acetone at 45 ^◦C to give analogues 7a-7p (Scheme

Scheme 1. Proposed biosynthetic pathway of violacin A.

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W. Wu et al.

Bioorganic Chemistry 111 (2021) 104898

Scheme 2. Retrosynthetic analysis of violacin A.

Scheme 3. Total synthesis of violacin A. Reagents and conditions: (a) NaH (1.3 eq.), LDA (0.95 eq.), anhydrous THF, -78 ^◦C to 0 ^◦C to r.t., 17 h, reﬂux, 26 h; (b)

MOMBr (2.2 eq.), NaH (3.0 eq.), anhydrous THF, 0 ^◦C, 1 h; (c) acetylacetone (3, 2.0 eq.), LAD (4.0 eq.), anhydrous THF, 0 ^◦C to r.t., 12 h; (d) 1N HCl/MeOH (v/v

1:2), r.t., 5 h; (e) BnCl (2.1 eq.), K₂CO₃(3.0 eq.), MeCN, reﬂux, 2.5 h; (f) H₂, 5 % Pd/C (w/w 5:1), EtOH, r.t., 2.5 h.

instead of ketone group at side chain presented the comparative or su-

perior activity compared with that of violacin A. Notably, aromatic ether

moiety with an electron-withdrawing substituent dramatically

improved the anti-inﬂammatory activity of the molecules (16d vs. 16b,

16c).

overall yield to 42%. Meanwhile, twenty-ﬁve analogues of violacin A

were designed and synthesized by the similar strategy. Among ana-

logues, 7a, 7d, 16a and 16d revealed stronger inhibitory activities

against NO production than that of violacin A. The SAR analysis

demonstrated that the carbonyl group at the side-chain was not critical

for the activity. The introduction of aliphatic amine moieties at C-7

position or aromatic ether moiety with an electron-withdrawing sub-

stituent at the side chain could signiﬁcantly enhance the anti-

inﬂammatory activity. Furthermore, the anti-inﬂammatory effect of

synthesized analogues 7a and 16d was closely related with the inhibi-

tion of NF-κB signaling pathway in RAW 264.7 cells. NF-κB signaling

pathway had been widely recognized as a promising therapeutically-

relevant biological target in the therapy of inﬂammatory diseases. 7a

and 16d could be further explored as novel anti-inﬂammatory candi-

dates by in vivo investigation.

2.2.2. 7a and 16d suppresses LPS-induced NF-κB signaling pathway

activation

The NF-κB signaling pathway plays a critical role in the occurrence

and process of inﬂammation [2]. The phosphorylation of IκB-α could

alleviate its inhibitory effects on the activities of NF-κB, which resulted

in the translocation of NF-κB p65 subunit to the nucleus, leaded to the

transcriptional synthesis of pro-inﬂammatory genes, such as NO by

upregulating the expression of inducible nitric synthase (iNOS). The

phosphorylation of p65 subunit was closely associated with the tran-

scriptional activity of NF-κB [21–23]. To further conﬁrm anti-

inﬂammatory potential of synthesized analogues, the effects of 7a and

16d on the regulation of NF-κB signaling pathway and expression of

iNOS were further investigated. As shown in Fig. 2 (A-D and G-J),

4. Material and methods

4.1. Chemisty

phosphorylations of IκB-α and p65 were signiﬁcantly inhibited in LPS-

stimulated Raw 264.7 cells after 7a or 16d treatment. In the mean-

time, the amount of intracellular iNOS signiﬁcantly decreased in the 7a

or 16d-treated cells (Fig. 2 E, F, K and L). The results indicated that 7a

and 16d effectively inhibited LPS-stimulated NF-κB activation and

reduced the expression level of iNOS.

All reagents were purchased from commercial suppliers. Reactions

requiring anhydrous conditions were carried out under an inert atmo-

sphere of dry nitrogen. Fresh THF was obtained by distillation over so-

dium wire using benzophenone as indicator. DCM was freshly distilled

from calcium hydride.

All reactions were monitored by using thin layer chromatography

(TLC) which was performed on Merck Silica Gel 60 F₂₅₄plates, TLC were

visualized by UV radiation (254 nm) or stained by exposure to an

ethanolic solution of concentrated sulfuric acid and anisaldehyde. Silica

gel (300–400 mesh, Qingdao Marine Chemical Ltd., Qingdao, China)

3. Conclusions

In summary, we described a biomimetic synthetic strategy of viola-

cin A, which greatly shortened the reaction period and increased the

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W. Wu et al.

Bioorganic Chemistry 111 (2021) 104898

Scheme 4. Synthesis of violacin A analogues 7a-7p. Reagants and conditions: (a) Bromoacetyl bromide (1.2 eq.), Et₃N (1.5 eq.), anhydrous CH₂Cl₂, 0 ^◦C, 0.5 h; (b)

Violacin A (0.67 eq.), K₂CO₃(1.33 eq.), Acetone, 45 ^◦C, 4 h.

was used for the ﬂash chromatography separations. ¹H NMR (600 MHz)

and ¹³C NMR (150 MHz) spectra were measured on a Bruker AV-600

spectrometer using tetramethylsilane as internal standard in deu-

teriated chloroform (CDCl₃) or dimethyl sulfoxide (DMSO‑d₆). The

coupling constants (J) were expressed in Hertz (Hz), signal multiplicity

was designed as s = singlet, d = doublet, t = triplet, q = quartet, quint =

quintet, sext = sextet, hept = heptet, m = multiplet, br = broad, dd =

doublet of doublets, dt = doublet of triplets, brq = broad quintet.

HRESIMS were measured with an Agilent G6230 TOF mass

spectrometer.

reduced pressure and the resulting residue was diluted with water and

extracted three times with ethyl acetate. The combined organic layers

were washed with brine, dried over Na₂SO₄. After ﬁltration, the solvent

was removed in a rotary evaporator to give residual yellow oil. Puriﬁ-

cation of the crude product by ﬂash chromatography column afforded

the desired product.

4.1.3. General procedure C: Synthesis of aromatic polyketide

According to the literature [10], the solution of LDA (4.0 equiv.) was

added dropwise to the solution of acetylacetone (2.0 equiv.) in anhy-

drous THF at ꢀ 10 ^◦C under an atmosphere of N₂. After stirring for 30

min, the solution of methyl benzoate (1.0 equiv.) in anhydrous THF was

added dropwise. The reaction mixture was stirred at 0 ^◦C for 30 min and

allowed to warm to room temperature with stirring for 12 h. Upon

completion of the reaction, the solution was quenched with a saturated

aqueous solution of NH₄Cl at 0 ^◦C and the organic layer was separated.

Aqueous layer was diluted with brine and extracted three times with

ethyl acetate. The combined organic layers were dried over Na₂SO₄,

after ﬁltration, eliminated under reduced pressure. The residue was

puriﬁed by silica gel column chromatography.

4.1.1. General procedure A: Synthesis of benzyl ether

The mixed solution of corresponding resorcinol (1.0 equiv.), benzyl

chloride (2.1 equiv.) and anhydrous K₂CO₃(3.0 equiv.) in acetonitrile

was stirred for 2.5 h at 85 ^◦C. Upon completion of the reaction, the

mixture was ﬁltered and the ﬁltrate was concentrated under reduced

pressure. The resulting residue was diluted with water and extracted

three times with ethyl acetate. The combined organic layers were

washed with brine, dried over Na₂SO₄, after ﬁltration, concentrated in

vacuo. The residual oil was pulped with n-hexane, ﬁltered with a

Buchner funnel and the ﬁlter cake was washed with n-hexane to provide

the desired product.

4.1.4. Methyl 2,4-dihydroxy-6-methylbenzoate (2)

According to the literature [8], to a suspension of NaH (9.64 g, 60%,

223.6 mmol) in anhydrous THF (100 mL) was added dropwise a solution

of methyl acetoacetate (20.00 g, 172.0 mmol) in anhydrous THF (50 mL)

at 0 ^◦C under an atmosphere of N₂. After stirring for 1 h, the reaction

mixture was cooled to ꢀ 78 ^◦C and LDA (2.0 M solution in THF, 81.7 mL,

163.4 mmol) was added dropwise and stirred for 30 min. After that, the

4.1.2. General procedure B: Catalytic hydrogenation to remove benzyl

A mixture of benzyl ether and 5% Pd/C (20 wt%) in ethanol was

stirred under 1 atmosphere of H₂gas at room temperature for 2.5 h. And

then the reaction mixture was ﬁltered with a Buchner funnel and the

residue was washed with ethanol. The ﬁltrate was concentrated under

4

W. Wu et al.

Bioorganic Chemistry 111 (2021) 104898

Scheme 5. Synthesis of violacin A analogues 16a-16i. Reagants and conditions: (a) BF₃-Et₂O (1.5 eq.), AcOH (10.0 eq.), 3 Å molecular sieve, 90 ^◦C, 24 h; (b) BnCl

(2.1 eq.), K₂CO₃(3.0 eq.), MeCN, reﬂux, 2.5 h; (c) 2-(2-bromoethyl)-1,3-dioxolane (1.1 eq.), K₂CO₃(2.0 eq.), DMF, 65 ^◦C, overnight; (d) AcOH/H₂O (v/v 4:1), 45 ^◦C,

5 h; (e) LAD (2.0 eq.), anhydrous THF, -78 ^◦C, overninght; (f) Dess-Martin reagent (1.3 eq.), anhydrous CH₂Cl₂, 0 ^◦C, 2 h; (g) H₂, 5 % Pd/C (w/w 5:1), EtOH, r.t.,

2.5 h.

mixture was stirred 17 h at room temperature and then was allowed to

warm up 85 ^◦C for additional 26 h. Upon completion of the reaction, the

solution was acidiﬁed with 2 N HCl till pH 2–3 at 0 ^◦C and the organic

layer was separated. Aqueous layer was diluted with brine (50 mL) and

extracted with ethyl acetate (3 × 100 mL), combined organic layers

were dried over Na₂SO₄, ﬁltered and concentrated under reduced

pressure. The crude product was puriﬁed by ﬂash chromatography

column (Petroleum ether/EtOAc, 8:1) to afford compound 2 as a light-

yellow solid (11.78 g, 75.1%). ¹H NMR (600 MHz, Chloroform-d) δ

11.79 (s, 1H), 6.28 (d, J = 2.5 Hz, 1H), 6.23 (d, J = 2.5 Hz, 1H), 5.55

(brs, 1H), 3.93 (s, 3H), 2.49 (s, 3H); ¹³C NMR (150 MHz, Chloroform-d) δ

172.15, 165.25, 160.27, 144.02, 111.35, 105.62, 101.24, 51.93, 24.30.

(s, 2H), 5.15 (s, 2H), 3.89 (s, 3H), 3.47 (s, 3H), 3.46 (s, 3H), 2.28 (s, 3H);

¹³C NMR (150 MHz, Chloroform-d) δ 168.50, 158.72, 155.39, 138.03,

118.48, 110.67, 101.25, 94.78, 94.23, 56.20, 56.11, 52.07, 19.81.

4.1.6. 1-[2,4-bis(methoxymethoxy)-6-methylphenyl]-1,3,5-hexanetrione

(4a)

The tittle compound was synthesized as described in the general

procedure C using LDA (2.0 M solution in THF, 4 mL, 8.0 mmol), ace-

tylacetone (400 mg, 4.0 mmol) and 2a (540 mg, 2.0 mmol) in anhydrous

THF (4 mL). The crude product was puriﬁed by ﬂash chromatography

column (petroleum ether/EtOAc, 10:1) to afford the tittle compound as

a yellow oil (174 mg, 51.5%). The mixture of keto-enol tautomers

containing approximately 31.3% 1^′,5^′-bisenol tautomer (I), 31.3% 1^′-

monoenol tautomer (II), 31.3% 5^′-monoenol tautomer (III) and 6.1%

unenolized triketone tautomer (IV). The ratio of tautomer was calcu-

lated by characteristic proton signals in ¹H NMR according to the

literature [10]. ¹H NMR (600 MHz, Chloroform-d), tautomer I: δ 5.78 (s,

1H), 5.64 (s, 1H), 2.30 (s, 3H), 2.01 (s, 3H); II: δ 5.33 (s, 1H), 2.32 (s,

3H), 2.27 (s, 3H); III: δ5.23 (s, 1H), 3.82 (s, 2H), 2.30 (s, 3H), 2.06 (s,

3H); IV: δ 4.30 (s, 2H), 3.77 (s, 2H), 2.28 (s, 3H), 2.27 (s, 3H).

4.1.5. Methyl 2,4-bis(methoxymethoxy)-6-methylbenzoate (2a)

To a solution of compound 2 (910 mg, 5.0 mmol) in anhydrous THF

(10 mL) was added slowly NaH (600 mg, 60%, 15.0 mmol) at ꢀ 10 ^◦C.

After stirring for 15 min, the solution of bromomethyl methyl ether

(1.37 g, 11.0 mmol) in anhydrous THF (15 mL) was added dropwise, and

then the mixture was stirred for 1 h. Upon completion of the reaction,

the mixture was quenched with a saturated aqueous solution of NH₄Cl

(5 mL) and the organic layer was separated. Aqueous layer was diluted

with brine (10 mL) and extracted with ethyl acetate (3 × 15 mL),

combined organic layers were dried over Na₂SO₄, after ﬁltration,

eliminated under reduced pressure. The crude product was puriﬁed by

ﬂash chromatography column (petroleum ether/EtOAc, 40:1) to afford

the tittle compound as a yellow oil (1.24 g, 91.8%). ¹H NMR (600 MHz,

Chloroform-d) δ 6.67 (d, J = 1.9 Hz, 1H), 6.55 (d, J = 1.9 Hz, 1H), 5.15

4.1.7. 7-hydroxy-5-methyl-2-(2-oxopropyl)-4H-1-benzopyran-4-one (4b)

To a solution of compound 4a (200 mg, 0.6 mmol) in methanol (4

mL) was added 1 N HCl (2 mL) at room temperature. After stirring 2 h,

the solution was concentrated under reduced pressure, and then the

resulting residue was diluted with water (5 mL) and extracted with ethyl

acetate (3 × 5 mL). The combined organic layers were washed with

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W. Wu et al.

Bioorganic Chemistry 111 (2021) 104898

Fig. 1. The cell viability and anti-inﬂammatory activity in LPS-induced RAW264.7 cells. (A) The cell viability was evaluated by MTT assay. (B) The production of NO

was determined by Griess method. RAW264.7 cells were pretreated with synthetic molecule (33 μM) for 2 h and were stimulated by LPS (1 μg / mL) for 24 h, and

then the cell supernatant was collected to detect NO release. (C, D) RAW264.7 cells were pretreated with different concentrations (0, 3.3, 11, and 33 µM) of 7a and

16d for 2 h and then stimulated with or without LPS (1 µg/mL) for 24 h. The data show means ± SD values of three independent experiments (* p < 0.05 vs. control

group; ### p < 0.001 vs. control group; *** p < 0.001 vs. LPS group).

brine, dried over Na₂SO₄, ﬁltered and concentrated in vacuo. The crude

product was puriﬁed by ﬂash chromatography column (petroleum

ether/EtOAc, 8:1) to afford the tittle compound as a yellow oil (98 mg,

71.4%). ¹H NMR (600 MHz, DMSO-d) δ 10.60 (s, 1H), 6.63 (d, J = 2.3

Hz, 1H), 6.60 (d, J = 2.3 Hz, 1H), 6.05 (s, 1H), 3.86 (s, 2H), 2.66 (s, 3H),

2.22 (s, 3H); ¹³C NMR (150 MHz, DMSO-d) δ 207.99, 183.34, 166.23,

165.76, 164.41, 146.79, 121.89, 119.55, 118.07, 105.77, 52.59, 35.06,

27.64.

128.47 (2 × C), 128.10, 127.75, 127.49 (2 × C), 126.83 (2 × C), 117.08,

108.11, 98.45, 70.37, 70.04, 52.02, 19.95.

4.1.9. 1-[2,4-bis(benzyloxy)-6-methylphenyl]-1,3,5-hexanetrione (4c)

The tittle compound was synthesized as described in the general

procedure C using LDA (2.0 M solution in THF, 27.6 mL, 55.2 mmol),

acetylacetone (2.76 g, 27.6 mmol) and 2b (5.00 g, 13.8 mmol) in

anhydrous THF (56 mL). The crude product was puriﬁed by ﬂash

chromatography column (petroleum ether/EtOAc, 8:1) to afford the

tittle compound as a yellow oil (3.23 g, 54.4%). The mixture of keto-enol

tautomers containing approximately 31.3% 1^′,5^′-bisenol tautomer (I),

31.3% 1^′-monoenol tautomer (II), 31.3% 5^′-monoenol tautomer (III) and

6.1% unenolized triketone tautomer (IV). The ratio of tautomer was

caculated by characteristic proton signals in ¹H NMR according to the

literature [10]. ¹H NMR (600 MHz, Chloroform-d), tautomer I: δ 5.84 (s,

1H), 5.40 (s, 1H), 2.33 (s, 3H), 1.96 (s, 3H); II: δ 5.39 (s, 1H), 3.38 (s,

2H), 2.34 (s, 3H), 2.18 (s, 3H); III: δ5.21 (s, 1H), 3.78 (s, 2H), 2.28 (s,

4.1.8. Methyl 2,4-bis(benzyloxy)-6-methylbenzoate (2b)

Followed general procedure A, compound 2 (3.00 g, 16.5 mmol),

benzyl chloride (4.38 g, 34.6 mmol) and anhydrous K₂CO₃(6.83 g, 49.4

mmol) in acetonitrile (100 mL) gave the tittle compound as a white solid

1

(5.41 g, 95.0%). H NMR (600 MHz, Chloroform-d) δ 7.41 – 7.28 (m,

10H), 6.43 (d, J = 2.1 Hz, 1H), 6.43 (d, J = 2.1 Hz, 1H), 5.06 (s, 2H),

5.02 (s, 2H), 3.87 (s, 3H), 2.30 (s, 3H). ¹³C NMR (150 MHz, Chloroform-

d) δ 168.65, 160.36, 157.20, 138.38, 136.69, 136.48, 128.62 (2 × C),

6

W. Wu et al.

Bioorganic Chemistry 111 (2021) 104898

Fig. 2. 7a and 16d inhibited NF-κB activation and iNOS expression in LPS-induced RAW 264.7 cells. RAW 264.7 cells were pretreated with the different concen-

trations (0, 3.3, 11 and 33 µM) of 7a (A-F) and 16d (G-L) for 2 h, then stimulated with or without LPS (1 µg/mL) for 30 min or 24 h (for iNOS protein). IκB-α, p-IκB-α,

p-p65 and iNOS were analyzed by Western blot. The data show means ± SD values of three independent experiments. (## p < 0.01, ###p < 0.001 vs. control group;

* p < 0.05, ** p < 0.01, *** p < 0.001 vs. LPS group).

3H), 2.01 (s, 3H); IV: δ 4.00 (s, 2H), 3.49 (s, 2H), 2.28 (s, 3H), 2.14 (s,

saturated aqueous solution of NaHCO₃(15 mL) was added, extracted

with DCM (3 × 15 mL). The combined organic layers were washed with

brine, dried over Na₂SO₄, ﬁltered and concentrated in vacuo. The crude

product was puriﬁed by ﬂash chromatography column to provide

compound 6a-6o.

3H).

4.1.10. Violacin a

The tittle compound was synthesized as described in the general

procedure B using compound 4a (2.00 g) and 5% Pd/C (400 mg, 20 wt

%) in ethanol (20 mL). Puriﬁcation by ﬂash column chromatography

(CH₂Cl₂/MeOH, 8:1) afforded target compound as a yellow powder

4.1.11.1. 2-bromo-N-propylacetamide (6a). The tittle compound was

synthesized as described in the general procedure using propylamine

(295 mg, 5.0 mmol). The crude product was puriﬁed by ﬂash column

chromatography (CH₂Cl₂/MeOH, 50:1) to afford the desired product as

1

(1.09 g, 95.2% yield). H NMR (600 MHz, DMSO‑d₆) δ 10.35 (s, 1H),

7.08 (d, J = 2.1 Hz, 1H), 6.25 (d, J = 2.3 Hz, 1H), 6.14 (d, J = 2.3 Hz,

1H), 3.04 (dd, J = 16.0, 2.1 Hz, 1H), 3.03 (d, J = 15.0 Hz, 1H), 2.98 (d, J

1

a light yellow oil (587 mg, 65.3% yield). H NMR (600 MHz, Chloro-

= 15.0 Hz, 1H), 2.61 (d, J = 16.0 Hz, 1H), 2.45 (s, 3H), 2.19 (s, 3H); ¹³

C

form-d) δ 6.52 (brs, 1H), 3.88 (s, 2H), 3.25 (q, J = 7.0 Hz, 2H), 1.57

(sext, J = 7.0 Hz, 2H), 0.94 (t, J = 7.0 Hz, 3H); ¹³C NMR (150 MHz,

Chloroform-d) δ 165.23, 41.89, 29.42, 22.57, 11.28.

NMR (150 MHz, DMSO‑d₆) δ 205.58, 191.03, 163.13, 161.33, 142.87,

113.03, 112.34, 101.99, 100.28, 52.75, 47.91, 32.33, 23.03. HRMS

(ESI) m/z calcd for C₁₃H₁₄O₅[M + H]⁺250.0841, found 251.0927.

4.1.11.2. 2-bromo-N,N-dipropylacetamide (6b). The tittle compound

was synthesized as described in the general procedure using dipropyl-

amine (505 mg, 5.0 mmol). The crude product was puriﬁed by ﬂash

column chromatography (CH₂Cl₂/MeOH, 80:1) to afford the desired

product as a light yellow oil (794 mg, 71.6% yield). ¹H NMR (600 MHz,

Chloroform-d) δ 3.84 (s, 2H), 3.29 (t, J = 7.8 Hz, 2H), 3.26 (t, J = 7.8 Hz,

4.1.11. Synthesis of compounds 6a-6o

General procedure: The substituted amine, phenol or alcohol (5a-5o,

5.0 mmol) was dissolved in anhydrous DCM (10 mL) and triethylamine

(756 mg, 7.5 mmol) was added at 0 ^◦C. After that the solution of bro-

moacetyl bromide (1.21 g, 6.0 mmol) in anhydrous DCM (5 mL) was

gradually added. The reaction mixture was stirred for 1.5 h and then the

7

W. Wu et al.

Bioorganic Chemistry 111 (2021) 104898

2H), 1.64 (sext, J = 7.5 Hz, 2H), 1.57 (sext, J = 7.5 Hz, 2H), 0.94 (t, J =

7.5 Hz, 3H), 0.89 (t, J = 7.5 Hz, 3H); ¹³C NMR (150 MHz, Chloroform-d)

δ 166.43, 50.41, 47.69, 26.50, 22.33, 20.47, 11.24 (2 × C).

compound was synthesized as described in the general procedure using

1-(1-piperazinyl)ethanone (640 mg, 5.0 mmol). The crude product was

puriﬁed by ﬂash column chromatography (CH₂Cl₂/MeOH, 20:1) to

afford the desired product as a light yellow oil (710 mg, 57.1% yield). ¹H

NMR (600 MHz, Chloroform-d) δ 3.87 (s, 2H), 3.72 – 3.59 (m, 4H), 3.58

– 3.46 (m, 4H), 2.12 (s, 3H); ¹³C NMR (150 MHz, Chloroform-d) δ

169.25, 165.59, 46.40, 45.69, 42.05, 41.10, 25.48, 21.37; ¹³C NMR

(150 MHz, Chloroform-d) δ 169.04, 165.32, 46.65, 45.93, 41.85, 40.86,

25.56, 21.39.

4.1.11.3. 2-bromo-N,N-bis(1-methylethyl)acetamide (6c). The tittle

compound was synthesized as described in the general procedure using

diisopropylamine (505 mg, 5.0 mmol). The crude product was puriﬁed

by ﬂash column chromatography (CH₂Cl₂/MeOH, 80:1) to afford the

1

desired product as a light yellow oil (746 mg, 67.3% yield). H NMR

(600 MHz, Chloroform-d) δ 3.95 (hept, J = 6.8 Hz, 1H), 3.81 (s, 2H),

3.47 – 3.38 (m, 1H), 1.38 (d, J = 6.8 Hz, 6H), 1.25 (d, J = 6.8 Hz, 6H);

¹³C NMR (150 MHz, Chloroform-d) δ 165.31, 50.44, 46.25, 28.75, 20.67

(2 × C), 20.09 (2 × C).

4.1.11.10. 2-bromo-1-[4-(2-pyridinyl)-1-piperazinyl]ethanone (6j). The

tittle compound was synthesized as described in the general procedure

using 1-(2-pyridinyl)-piperazine (957 mg, 5.0 mmol). The crude product

was puriﬁed by ﬂash column chromatography (CH₂Cl₂/MeOH, 30:1) to

afford the desired product as a light yellow oil (649 mg, 45.7% yield). ¹H

NMR (600 MHz, Chloroform-d) δ 8.20 (dd, J = 5.1, 1.9 Hz, 1H), 7.52

(ddd, J = 8.8, 7.2, 2.0 Hz, 1H), 6.70 – 6.66 (m, 2H), 3.90 (s, 2H), 3.75 (t,

J = 5.4 Hz, 2H), 3.69 (t, J = 5.0 Hz, 2H), 3.64 (t, J = 5.0 Hz, 2H), 3.54 (t,

J = 5.4 Hz, 2H); ¹³C NMR (150 MHz, Chloroform-d) δ 165.40, 158.71,

147.74, 137.92, 114.08, 107.43, 46.38, 45.06 (2 × C), 41.75, 25.72.

4.1.11.4. 2 2-bromo-N,N-dibutylacetamide (6d). The tittle compound

was synthesized as described in the general procedure using dibutyl-

amine (645 mg, 5.0 mmol). The crude product was puriﬁed by ﬂash

column chromatography (CH₂Cl₂/MeOH, 30:1) to afford the desired

product as a light yellow oil (768 mg, 61.5% yield).¹H NMR (600 MHz,

Chloroform-d) δ 3.83 (s, 2H), 3.31 (t, J = 7.7 Hz, 2H), 3.28 (t, J = 7.7 Hz,

2H), 1.59 (quint, J = 7.7 Hz, 2H), 1.52 (quint, J = 7.7 Hz, 2H), 1.38 –

1.28 (m, 4H), 0.96 (t, J = 7.4 Hz, 3H), 0.92 (t, J = 7.4 Hz, 3H); ¹³C NMR

(150 MHz, Chloroform-d) δ 166.27, 48.55, 45.92, 31.27, 29.36, 26.53,

20.10 (2 × C), 13.89, 13.80.

4.1.11.11. Phenyl 2-bromoacetate (6 k). The tittle compound was syn-

thesized as described in the general procedure using phenol (470 mg,

5.0 mmol). The crude product was puriﬁed by ﬂash column chroma-

tography (Petroleum ether/EtOAc, 30:1) to afford the desired product as

1

a light yellow oil (870 mg, 81.0% yield). H NMR (600 MHz, Chloro-

4.1.11.5. 2-bromo-N,N-bis(2-methylpropyl)acetamide (6e). The tittle

compound was synthesized as described in the general procedure using

diisobutylamine (645 mg, 5.0 mmol). The crude product was puriﬁed by

ﬂash column chromatography (CH₂Cl₂/MeOH, 50:1) to afford the

form-d) δ 7.40 (t, J = 7.9 Hz, 2H), 7.26 (t, J = 7.3 Hz, 1H), 7.12 (d, J =

7.9 Hz, 2H), 4.05 (s, 2H); ¹³C NMR (150 MHz, Chloroform-d) δ 165.80,

150.38, 129.56 (2 × C), 126.36, 121.06 (2 × C), 25.56.

1

desired product as a light yellow oil (789 mg, 63.1% yield). H NMR

(600 MHz, Chloroform-d) δ 3.86 (s, 2H), 3.19 (d, J = 7.6 Hz, 2H), 3.14

(d, J = 7.6 Hz, 2H), 2.08 – 2.00 (m, 1H), 1.97 – 1.89 (m, 1H), 0.93 (d, J

= 6.7 Hz, 6H), 0.89 (d, J = 6.7 Hz, 6H); ¹³C NMR (150 MHz, Chloroform-

d) δ 167.20, 56.22, 52.99, 27.89, 26.75, 26.35, 20.08 (2 × C), 20.05 (2

× C).

4.1.11.12. 3-methylphenyl 2-bromoacetate (6 l). The tittle compound

was synthesized as described in the general procedure using 3-methyl-

phenol (540 mg, 5.0 mmol). The crude product was puriﬁed by ﬂash

column chromatography (Petroleum ether/EtOAc, 30:1) to afford the

1

desired product as a light yellow oil (836 mg, 73.1% yield). H NMR

(600 MHz, Chloroform-d) δ 7.28 (t, J = 7.8 Hz, 1H), 7.07 (d, J = 7.8 Hz,

1H), 6.94 (d, J = 2.3 Hz, 1H), 6.92 (dd, J = 7.8, 2.3 Hz, 1H), 4.04 (s, 2H),

2.37 (s, 3H); ¹³C NMR (150 MHz, Chloroform-d) δ 165.91, 150.33,

139.85, 129.27, 127.16, 121.62, 117.99, 25.58, 21.31.

4.1.11.6. 2-bromo-1-(1-pyrrolidinyl)ethanone (6f). The tittle compound

was synthesized as described in the general procedure using pyrrolidine

(355 mg, 5.0 mmol). The crude product was puriﬁed by ﬂash column

chromatography (CH₂Cl₂/MeOH, 40:1) to afford the desired product as

1

a light yellow oil (704 mg, 73.4% yield). H NMR (600 MHz, Chloro-

4.1.11.13. 4-methoxyphenyl 2-bromoacetate (6 m). The tittle compound

was synthesized as described in the general procedure using 4-methox-

yphenol (620 mg, 5.0 mmol). The crude product was puriﬁed by ﬂash

column chromatography (Petroleum ether/EtOAc, 20:1) to afford the

form-d) δ 3.80 (s, 2H), 3.52 (t, J = 6.8 Hz, 2H), 3.49 (t, J = 7.0 Hz, 2H),

2.00 (quint, J = 6.8 Hz, 2H), 1.89 (quint, J = 6.9 Hz, 2H); ¹³C NMR (150

MHz, Chloroform-d) δ 165.07, 47.08, 46.45, 27.39, 26.17, 24.33.

1

desired product as a light yellow oil (988 mg, 80.7% yield). H NMR

(600 MHz, Chloroform-d) δ 7.04 (d, J = 9.0 Hz, 2H), 6.90 (d, J = 9.0 Hz,

2H), 4.03 (s, 2H), 3.80 (s, 3H); ¹³C NMR (150 MHz, Chloroform-d) δ

166.18, 157.57, 143.88, 121.85 (2 × C), 114.51 (2 × C), 55.59, 25.55.

4.1.11.7. 2-bromo-1-(1-piperidinyl)ethanone (6 g). The tittle compound

was synthesized as described in the general procedure using piperidine

(425 mg, 5.0 mmol). The crude product was puriﬁed by ﬂash column

chromatography (CH₂Cl₂/MeOH, 40:1) to afford the desired product as

1

a light yellow oil (773 mg, 75.1% yield). H NMR (600 MHz, Chloro-

4.1.11.14. Cyclopropylmethyl 2-bromoacetate (6n). The tittle compound

was synthesized as described in the general procedure using cyclo-

propanemethanol (360 mg, 5.0 mmol). The crude product was puriﬁed

by ﬂash column chromatography (Petroleum ether/EtOAc, 50:1) to

afford the desired product as a light yellow oil (635 mg, 71.4% yield). ¹H

NMR (600 MHz, Chloroform-d) δ 4.01 (d, J = 7.4 Hz, 2H), 3.86 (s, 2H),

1.19 – 1.12 (m, 1H), 0.61 – 0.58 (m, 2H), 0.35 – 0.29 (m, 2H); ¹³C NMR

(150 MHz, Chloroform-d) δ 167.37, 71.15, 26.10, 9.62, 3.34 (2 × C).

form-d) δ 3.86 (s, 2H), 3.55 (t, J = 5.6 Hz, 2H), 3.44 (t, J = 5.1 Hz, 2H),

1.67 – 1.63 (m, 4H), 1.56 (quint, J = 5.4 Hz, 2H); ¹³C NMR (150 MHz,

Chloroform-d) δ 165.01, 47.92, 43.24, 26.18 (2 × C), 25.36, 24.26.

4.1.11.8. 2-bromo-1-(4-morpholinyl)ethanone (6 h). The tittle com-

pound was synthesized as described in the general procedure using

morpholine (435 mg, 5.0 mmol). The crude product was puriﬁed by

ﬂash column chromatography (CH₂Cl₂/MeOH, 30:1) to afford the

1

desired product as a light yellow oil (720 mg, 69.3% yield). H NMR

4.1.11.15. Cyclohexylmethyl 2-bromoacetate (6o). The tittle compound

was synthesized as described in the general procedure using cyclo-

hexylmethanol (571 mg, 5.0 mmol). The crude product was puriﬁed by

ﬂash column chromatography (Petroleum ether/EtOAc, 50:1) to afford

the desired product as a light yellow oil (838 mg, 76.0% yield). ¹H NMR

(600 MHz, Chloroform-d) δ 3.98 (d, J = 6.6 Hz, 2H), 3.83 (s, 2H), 1.76 –

1.71 (m, 4H), 1.70 – 1.66 (m, 2H), 1.29 – 1.21 (m, 2H), 1.20 – 1.15 (m,

(600 MHz, Chloroform-d) δ 3.85 (s, 2H), 3.74 (t, J = 4.8 Hz, 2H), 3.69 (t,

J = 4.8 Hz, 2H), 3.63 (t, J = 4.8 Hz, 2H), 3.52 (t, J = 4.8 Hz, 2H); ¹³

C

NMR (150 MHz, Chloroform-d) δ 165.41, 66.60, 66.35, 47.15, 42.41,

25.40.

4.1.11.9. 1-(4-acetyl-1-piperazinyl)-2-bromoethanone (6i). The tittle

8

W. Wu et al.

Bioorganic Chemistry 111 (2021) 104898

1H), 1.02 – 0.94 (m, 2H); ¹³C NMR (150 MHz, Chloroform-d) δ 167.34,

71.33, 36.97, 29.48 (2 × C), 26.27, 25.96, 25.59 (2 × C).

4.1.12.4. 2-[[3,4-dihydro-2-hydroxy-5-methyl-2-(2-oxopropyl)-4-oxo-

2H-1-benzo- pyran-7-yl]oxy]-N,N-dibutyl-acetamide (7d). The tittle

compound was synthesized as described in the general procedure using

compound 6d (150 mg, 0.6 mmol). The crude product was puriﬁed by

ﬂash column chromatography (Petroleum ether/EtOAc, 5:1) to afford

the desired product as a white solid (79 mg, 47.1% yield). ¹H NMR (600

MHz, Chloroform-d) δ 6.41 (d, J = 2.5 Hz, 1H), 6.27 (d, J = 2.5 Hz, 1H),

6.09 (brs, 1H), 4.69 (d, J = 13.7 Hz, 1H), 4.66 (d, J = 13.7 Hz, 1H), 3.34

(t, J = 7.7 Hz, 2H), 3.26 (t, J = 7.7 Hz, 2H), 3.24 (d, J = 16.7 Hz, 1H),

2.79 (dd J = 16.0, 1.8 Hz, 1H), 2.77 (d, J = 16.0 Hz, 1H), 2.73 (d, J =

16.7 Hz, 1H), 2.60 (s, 3H), 2.32 (s, 3H), 1.58 (quint, J = 7.7 Hz, 2H),

1.52 (quint, J = 7.7 Hz, 2H), 1.38 – 1.32 (m, 2H), 1.32 – 1.27 (m, 2H),

0.96 (t, J = 7.4 Hz, 3H), 0.92 (t, J = 7.4 Hz, 3H); ¹³C NMR (150 MHz,

Chloroform-d) δ 209.10, 190.09, 166.37, 162.69, 160.84, 143.86,

113.76, 112.79, 100.72, 100.70, 66.82, 49.33, 48.68, 47.07, 45.74,

32.22, 31.04, 29.50, 23.10, 20.16, 20.12, 13.85, 13.82. HRMS (ESI) m/z

calcd for C₂₃H₃₃NO₆[M + H]⁺420.2381, found 420.2401.

4.1.12. Synthesis of compounds 7a-7p

General procedure: The mixed solution of violacin A (100 mg, 0.4

mmol), corresponding 6 or ethyl bromoacetate (0.6 mmol), anhydrous

K₂CO₃(110 mg, 0.8 mmol) in acetone (15 mL) was stirred for 5 h at

45 ^◦C. Upon completion of the reaction, the mixture was ﬁltered and the

ﬁltrate was concentrated under reduced pressure. The resulting residue

was diluted with water (15 mL) and extracted with EtOAc (3 × 15 mL).

The combined organic layers were washed with brine, dried over

Na₂SO₄, ﬁltered and concentrated in vacuo. The crude product was pu-

riﬁed by ﬂash chromatography column to provide compound 7a-7p.

4.1.12.1. 2-[[3,4-dihydro-2-hydroxy-5-methyl-2-(2-oxopropyl)-4-oxo-

2H-1-benzo- pyran-7-yl]oxy]-N-propyl-acetamide (7a). The tittle com-

pound was synthesized as described in the general procedure using

compound 6a (108 mg, 0.6 mmol). The crude product was puriﬁed by

ﬂash column chromatography (Petroleum ether/EtOAc, 2:1) to afford

the desired product as a white solid (60 mg, 43.0% yield). ¹H NMR (600

MHz, Chloroform-d) δ 6.50 (t, J = 6.0 Hz, 1H), 6.40 (d, J = 2.5 Hz, 1H),

6.26 (d, J = 2.5 Hz, 1H), 6.15 (brs, 1H), 4.45 (s, 2H), 3.29 (brq, J = 7.5

Hz, 2H), 3.23 (d, J = 16.7 Hz, 1H), 2.80 (brd, J = 15.9 Hz, 1H), 2.76 (d,

J = 15.9 Hz, 1H), 2.73 (d, J = 16.7 Hz, 1H), 2.60 (s, 3H), 2.33 (s, 3H),

1.55 (sext, J = 7.3 Hz, 2H), 0.92 (t, J = 7.3 Hz, 3H); ¹³C NMR (150 MHz,

Chloroform-d) δ 209.05, 190.09, 167.26, 161.45, 160.93, 144.24,

114.31, 112.60, 100.93, 100.89, 67.06, 49.35, 48.68, 40.81, 32.27,

23.08, 22.77, 11.31. HRMS (ESI) m/z calcd for C₁₈H₂₃NO₆[M + H]⁺

350.1598, found 350.1610.

4.1.12.5. 2-[[3,4-dihydro-2-hydroxy-5-methyl-2-(2-oxopropyl)-4-oxo-

2H-1-benzo- pyran-7-yl]oxy]-N,N-bis(2-methylpropyl)acetamide (7e).

The tittle compound was synthesized as described in the general pro-

cedure using compound 6e (150 mg, 0.6 mmol). The crude product was

puriﬁed by ﬂash column chromatography (Petroleum ether/EtOAc, 3:1)

to afford the desired product as a white solid (71 mg, 42.4% yield). ¹H

NMR (600 MHz, Chloroform-d) δ 6.41 (d, J = 2.6 Hz, 1H), 6.26 (d, J =

2.6 Hz, 1H), 6.06 (brs, 1H), 4.73 (d, J = 13.9 Hz, 1H), 4.70 (d, J = 13.9

Hz, 1H), 3.26 – 3.21 (m, 3H), 3.12 (d, J = 7.6 Hz, 2H), 2.79 (d, J = 15.9

Hz, 1H), 2.76 (d, J = 15.9 Hz, 1H), 2.71 (d, J = 16.7 Hz, 1H), 2.60 (s,

3H), 2.32 (s, 3H), 2.03 – 1.96 (m, 2H), 0.95 (d, J = 6.6 Hz, 6H), 0.86 (d,

J = 6.7 Hz, 6H), 0.85 (d, J = 6.7 Hz, 6H); ¹³C NMR (150 MHz, Chlo-

roform-d) δ 209.11, 190.09, 167.19, 162.65, 160.80, 143.86, 113.76,

112.74, 100.84, 100.70, 66.68, 54.32, 52.57, 49.30, 48.69, 32.25,

27.29, 26.13, 23.09, 20.07 (2 × C), 20.05 (2 × C). HRMS (ESI) m/z calcd

for C₂₃H₃₃NO₆[M + H]⁺420.2381, found 420.2404.

4.1.12.2. 2-[[3,4-dihydro-2-hydroxy-5-methyl-2-(2-oxopropyl)-4-oxo-

2H-1-benzo- pyran-7-yl]oxy]-N,N-dipropyl-acetamide (7b). The tittle

compound was synthesized as described in the general procedure using

compound 6b (133 mg, 0.6 mmol). The crude product was puriﬁed by

ﬂash column chromatography (Petroleum ether/EtOAc, 5:1) to afford

the desired product as a white solid (65 mg, 41.6% yield). ¹H NMR (600

MHz, Chloroform-d) δ 6.41 (d, J = 2.5 Hz, 1H), 6.27 (d, J = 2.5 Hz, 1H),

6.10 (brs, 1H), 4.70 (d, J = 13.6 Hz, 1H), 4.67 (d, J = 13.6 Hz, 1H), 3.31

(t, J = 7.7 Hz, 2H), 3.24 (d, J = 16.7 Hz, 1H), 3.23 (t, J = 7.7 Hz, 2H),

2.80 (d, J = 15.9 Hz, 1H), 2.77 (d, J = 15.9 Hz, 1H), 2.73 (d, J = 16.7 Hz,

1H), 2.60 (s, 3H), 2.32 (s, 3H), 1.67 – 1.60 (m, 2H), 1.60 – 1.54 (m, 2H),

0.95 (t, J = 7.4 Hz, 3H), 0.88 (t, J = 7.4 Hz, 3H); ¹³C NMR (150 MHz,

Chloroform-d) δ 209.07, 190.15, 166.51, 162.69, 160.86, 143.86,

113.77, 112.78, 100.74, 100.71, 66.80, 49.42, 48.89, 48.66, 47.58,

32.23, 23.11, 22.14, 20.64, 11.34, 11.26. HRMS (ESI) m/z calcd for

4.1.12.6. 2,3-dihydro-2-hydroxy-5-methyl-2-(2-oxopropyl)-7-[2-oxo-2-

(1-pyrrolidin- yl)ethoxy]-4H-1-benzopyran-4-one (7f). The tittle com-

pound was synthesized as described in the general procedure using

compound 6f (115 mg, 0.6 mmol). The crude product was puriﬁed by

ﬂash column chromatography (Petroleum ether/EtOAc, 1:1) to afford

the desired product as a white solid (3 mg, 43.6% yield). ¹H NMR (600

MHz, Chloroform-d) δ 6.44 (d, J = 2.5 Hz, 1H), 6.28 (d, J = 2.5 Hz, 1H),

6.12 (brs, 1H), 4.63 (d, J = 13.9 Hz, 1H), 4.60 (d, J = 13.9 Hz, 1H), 3.52

(t, J = 6.9 Hz, 2H), 3.49 (t, J = 7.2 Hz, 2H), 3.24 (d, J = 16.7 Hz, 1H),

2.80 (brd, J = 15.9 Hz, 1H), 2.77 (d, J = 15.9 Hz, 1H), 2.74 (d, J = 16.7

Hz, 1H), 2.60 (s, 3H), 2.32 (s, 3H), 1.99 (quint, J = 7.2 Hz, 2H), 1.87

(quint, J = 6.9 Hz, 2H); ¹³C NMR (150 MHz, Chloroform-d) δ 209.12,

190.14, 165.58, 162.58, 160.88, 143.91, 113.83, 112.83, 100.73,

100.67, 67.43, 49.43, 48.66, 46.28, 45.97, 32.26, 26.24, 23.80, 23.11.

HRMS (ESI) m/z calcd for C₁₉H₂₃NO₆[M + H]⁺362.1598, found

362.1619.

C

₂₁H₂₉NO₆[M + H]⁺392.2068, found 392.2071.

4.1.12.3. 2-[[3,4-dihydro-2-hydroxy-5-methyl-2-(2-oxopropyl)-4-oxo-

2H-1-benzo- pyran-7-yl]oxy]-N,N-bis(1-methylethyl)-acetamide (7c). The

tittle compound was synthesized as described in the general procedure

using compound 6c (133 mg, 0.6 mmol). The crude product was puriﬁed

by ﬂash column chromatography (Petroleum ether/EtOAc, 3:1) to afford

the desired product as a white solid (73 mg, 46.7% yield). ¹H NMR (600

MHz, Chloroform-d) δ 6.43 (d, J = 2.5 Hz, 1H), 6.30 (d, J = 2.5 Hz, 1H),

6.08 (brs, 1H), 4.62 (d, J = 13.2 Hz, 1H), 4.59 (d, J = 13.2 Hz, 1H), 3.96

(hept, J = 6.1 Hz, 1H), 3.45 (hept, J = 6.8 Hz, 1H), 3.25 (d, J = 16.7 Hz,

1H), 2.80 (d, J = 15.9 Hz, 1H), 2.77 (d, J = 15.9 Hz, 1H), 2.72 (d, J =

16.7 Hz, 1H), 2.60 (s, 3H), 2.32 (s, 3H), 1.41 (d, J = 6.8 Hz, 6H), 1.23 (d,

J = 6.1 Hz, 6H); ¹³C NMR (150 MHz, Chloroform-d) δ 209.16, 190.07,

165.71, 162.68, 160.86, 143.90, 113.74, 112.81, 100.74, 100.71, 68.44,

49.26, 48.71 (2 × C), 48.70, 46.26, 32.23, 23.10, 20.90, 20.89, 20.30 (2

× C). HRMS (ESI) m/z calcd for C₂₁H₂₉NO₆[M + H]⁺392.2068, found

392.2088.

4.1.12.7. 2,3-dihydro-2-hydroxy-5-methyl-2-(2-oxopropyl)-7-[2-oxo-2-

(1-piperidinyl)-ethoxy]-4H-1-benzopyran-4-one (7 g). The tittle com-

pound was synthesized as described in the general procedure using

compound 6 g (123 mg, 0.6 mmol). The crude product was puriﬁed by

ﬂash column chromatography (Petroleum ether/EtOAc, 1:1) to afford

the desired product as a white solid (65 mg, 43.3% yield). ¹H NMR (600

MHz, Chloroform-d) δ 6.43 (d, J = 2.5 Hz, 1H), 6.29 (d, J = 2.5 Hz, 1H),

6.12 (d, J = 2.0 Hz, 1H), 4.68 (d, J = 13.4 Hz, 1H), 4.65 (d, J = 13.4 Hz,

1H), 3.61 – 3.52 (m, 2H), 3.46 – 3.40 (m, 2H), 3.24 (d, J = 16.7 Hz, 1H),

2.81 (dd, J = 15.9, 2.2 Hz, 1H), 2.77 (d, J = 15.9 Hz, 1H), 2.74 (d, J =

16.7 Hz, 1H), 2.60 (s, 3H), 2.32 (s, 3H), 1.68 – 1.64 (m, 2H), 1.62 – 1.58

(m, 2H), 1.58 – 1.54 (m, 2H); ¹³C NMR (150 MHz, Chloroform-d) δ

209.07, 190.15, 165.16, 162.55, 160.87, 143.87, 113.80, 112.77,

9

W. Wu et al.

Bioorganic Chemistry 111 (2021) 104898

100.70, 100.68, 67.08, 49.44, 48.62, 46.34, 43.25, 32.22, 26.45, 25.48,

24.37, 23.09. HRMS (ESI) m/z calcd for C₂₀H₂₅NO₆[M + Na]⁺

398.1574, found 398.1586.

6.08 (brs, 1H), 4.87 (s, 2H), 3.26 (d, J = 16.8 Hz, 1H), 2.79 (s, 2H), 2.72

(d, J = 16.8 Hz, 1H), 2.63 (s, 3H), 2.32 (s, 3H); ¹³C NMR (150 MHz,

Chloroform-d) δ 209.13, 190.01, 166.64, 162.05, 160.85, 149.95,

144.16, 129.59 (2 × C), 126.34, 121.18 (2 × C), 114.20, 112.76, 100.85,

100.74, 64.98, 49.20, 48.75, 32.21, 23.10. HRMS (ESI) m/z calcd for

4.1.12.8. 2,3-dihydro-2-hydroxy-5-methyl-2-(2-oxopropyl)-7-[2-oxo-2-

(4-morpholin- yl)ethoxy]-4H-1-benzopyran-4-one (7 h). The tittle com-

pound was synthesized as described in the general procedure using

compound 6 h (125 mg, 0.6 mmol). The crude product was puriﬁed by

ﬂash column chromatography (Petroleum ether/EtOAc, 2:1) to afford

the desired product as a white solid (63 mg, 41.8% yield). ¹H NMR (600

MHz, Chloroform-d) δ 6.42 (d, J = 2.5 Hz, 1H), 6.30 (d, J = 2.5 Hz, 1H),

6.11 (brs, 1H), 4.70 (d, J = 13.4 Hz, 1H), 4.67 (d, J = 13.4 Hz, 1H), 3.69

(t, J = 4.8 Hz, 4H), 3.63 (d, J = 4.8 Hz, 2H), 3.54 (t, J = 4.8 Hz, 2H), 3.25

(d, J = 16.8 Hz, 1H), 2.80 (d, J = 15.9 Hz, 1H), 2.77 (d, J = 15.9 Hz, 1H),

2.74 (d, J = 16.8 Hz, 1H), 2.61 (s, 3H), 2.33 (s, 3H); ¹³C NMR (150 MHz,

Chloroform-d) δ 209.13, 190.06, 165.65, 162.16, 160.87, 144.07,

114.03, 112.63, 100.78, 100.70, 67.07, 66.76, 66.64, 49.33, 48.66,

45.81, 42.42, 32.22, 23.10. HRMS (ESI) m/z calcd for C₁₉H₂₃NO₇[M +

H]⁺378.1547, found 378.1550.

C

₂₁H₂₀O₇[M + H]⁺385.1282, found 385.1282.

4.1.12.12. 3-methylphenyl 2-[[3,4-dihydro-2-hydroxy-5-methyl-2-(2-oxo-

propyl)-4- oxo-2H-1-benzopyran-7-yl]oxy]acetate (7 l). The tittle com-

pound was synthesized as described in the general procedure using

compound 6 l (137 mg, 0.6 mmol). The crude product was puriﬁed by

ﬂash column chromatography (Petroleum ether/EtOAc, 5:1) to afford

the desired product as a white solid (77 mg, 56.3% yield). ¹H NMR (600

MHz, Chloroform-d) δ 7.27 (t, J = 7.9 Hz, 1H), 7.07 (d, J = 7.6 Hz, 1H),

6.93 (brs, 1H), 6.91 (brd, J = 8.0 Hz, 1H), 6.48 (d, J = 2.4 Hz, 1H), 6.32

(d, J = 2.4 Hz, 1H), 6.09 (brs, 1H), 4.85 (s, 2H), 3.25 (d, J = 16.8 Hz,

1H), 2.79 (s, 2H), 2.72 (d, J = 16.8 Hz, 1H), 2.63 (s, 3H), 2.36 (s, 3H),

2.32 (s, 3H); ¹³C NMR (150 MHz, Chloroform-d) δ 209.12, 190.02,

166.72, 162.07, 160.85, 149.89, 144.12, 139.86, 129.28, 127.12,

121.73, 118.10, 114.17, 112.75, 100.84, 100.75, 65.00, 49.20, 48.74,

32.20, 23.10, 21.31. HRMS (ESI) m/z calcd for C₂₂H₂₂O₇[M + H]⁺

399.1438, found 399.1439.

4.1.12.9. 2,3-dihydro-2-hydroxy-5-methyl-2-(2-oxopropyl)-7-[2-oxo-2-

(4-acetyl-1- piperazinyl)ethoxy]-4H-1-benzopyran-4-one (7i). The tittle

compound was synthesized as described in the general procedure using

compound 6i (149 mg, 0.6 mmol). The crude product was puriﬁed by

ﬂash column chromatography (Petroleum ether/EtOAc, 3:1) to afford

the desired product as a white solid (72 mg, 43.1% yield). ¹H NMR (600

MHz, Chloroform-d) δ 6.42 (d, J = 2.5 Hz, 1H), 6.30 (d, J = 2.5 Hz, 1H),

6.14 (brs, 1H), 4.73 (d, J = 13.7 Hz, 1H), 4.70 (d, J = 13.7 Hz, 1H), 3.67

– 3.60 (m, 4H), 3.59 – 3.47 (m, 4H), 3.24 (d, J = 16.7 Hz, 1H), 2.81 (d, J

= 16.0 Hz, 1H), 2.77 (d, J = 16.0 Hz, 1H), 2.74 (d, J = 16.7 Hz, 1H), 2.61

(s, 3H), 2.33 (s, 3H), 2.12 (s, 3H); ¹³C NMR (150 MHz, Chloroform-d) δ

209.05, 190.04, 169.34, 165.93, 162.04, 160.87, 144.14, 114.10,

112.54, 100.79, 100.73, 67.10, 49.37, 48.65, 45.85, 45.08, 42.10,

41.44, 32.23, 23.10, 21.35; ¹³C NMR (150 MHz, Chloroform-d) δ

209.12, 190.04, 169.09, 165.75, 161.94, 160.90, 144.14, 114.15,

112.49, 100.82, 100.68, 67.48, 49.37, 48.65, 46.31, 45.41, 41.96,

41.03, 32.23, 23.10, 21.40. HRMS (ESI) m/z calcd for C₂₁H₂₆N₂O₇[M +

H]⁺419.1813, found 419.1825.

4.1.12.13. 4-methoxphenyl

2-[[3,4-dihydro-2-hydroxy-5-methyl-2-(2-

oxopropyl)-4- oxo-2H-1-benzopyran-7-yl]oxy]acetate (7 m). The tittle

compound was synthesized as described in the general procedure using

compound 6 m (147 mg, 0.6 mmol). The crude product was puriﬁed by

ﬂash column chromatography (Petroleum ether/EtOAc, 1:1) to afford

the desired product as a white solid (73 mg, 51.3% yield). ¹H NMR (600

MHz, Chloroform-d) δ 7.03 (d, J = 9.0 Hz, 2H), 6.90 (d, J = 9.0 Hz, 2H),

6.47 (d, J = 2.5 Hz, 1H), 6.31 (d, J = 2.5 Hz, 1H), 6.08 (brs, 1H), 4.85 (s,

2H), 3.80 (s, 3H), 3.25 (d, J = 16.8 Hz, 1H), 2.79 (s, 2H), 2.72 (d, J =

16.8 Hz, 1H), 2.63 (s, 3H), 2.32 (s, 3H); ¹³C NMR (150 MHz, Chloro-

form-d) δ 209.12, 190.04, 166.99, 162.07, 160.85, 157.55, 144.11,

143.40, 121.96 (2 × C), 114.54 (2 × C), 114.16, 112.74, 100.84, 100.73,

64.97, 55.60, 49.22, 48.72, 32.19, 23.09. HRMS (ESI) m/z calcd for

C

₂₂H₂₂O₈[M + Na]⁺437.1207, found 437.1228.

4.1.12.14. Cyclopropylmethyl 2-[[3,4-dihydro-2-hydroxy-5-methyl-2-(2-

oxopropyl)- 4-oxo-2H-1-benzopyran-7-yl]oxy]acetate (7n). The tittle

compound was synthesized as described in the general procedure using

compound 6n (116 mg, 0.6 mmol). The crude product was puriﬁed by

ﬂash column chromatography (Petroleum ether/EtOAc, 3:1) to afford

the desired product as a white solid (61 mg, 50.2% yield). ¹H NMR (600

MHz, Chloroform-d) δ 6.43 (d, J = 2.5 Hz, 1H), 6.24 (d, J = 2.5 Hz, 1H),

6.05 (brs, 1H), 4.64 (s, 2H), 4.05 (d, J = 7.4 Hz, 2H), 3.25 (d, J = 16.8

Hz, 1H), 2.78 (s, 2H), 2.72 (d, J = 16.8 Hz, 1H), 2.61 (s, 3H), 2.32 (s,

4.1.12.10. 2,3-dihydro-2-hydroxy-5-methyl-2-(2-oxopropyl)-7-[2-oxo-2-

[4-(2-pyri- dinyl)-1-piperazinyl]ethoxy]-4H-1-benzopyran-4-one (7j). The

tittle compound was synthesized as described in the general procedure

using compound 6j (170 mg, 0.6 mmol). The crude product was puriﬁed

by ﬂash column chromatography (Petroleum ether/EtOAc, 2:1) to afford

the desired product as a white solid (62 mg, 34.2% yield). ¹H NMR (600

MHz, Chloroform-d) δ 8.20 (dd, J = 5.0, 1.8 Hz, 1H), 7.52 (ddd, J = 8.6,

7.0, 1.8 Hz, 1H), 6.69 (dd, J = 7.0, 5.0 Hz, 1H), 6.67 (d, J = 8.6 Hz, 1H),

6.45 (d, J = 2.5 Hz, 1H), 6.32 (d, J = 2.5 Hz, 1H), 6.11 (brs, 1H), 4.75 (d,

J = 13.4 Hz, 1H), 4.72 (d, J = 13.4 Hz, 1H), 3.80 – 3.72 (m, 2H), 3.68 –

3.62 (m, 4H), 3.57 – 3.50 (m, 2H), 3.25 (d, J = 16.8 Hz, 1H), 2.79 (d, J =

15.9 Hz, 1H), 2.76 (d, J = 15.9 Hz, 1H), 2.72 (d, J = 16.8 Hz, 1H), 2.61

(s, 3H), 2.33 (s, 3H); ¹³C NMR (150 MHz, Chloroform-d) δ 209.17,

190.01, 165.71, 162.24, 160.89, 158.87, 147.95, 144.11, 137.81,

114.12, 114.05, 112.70, 107.36, 100.80, 100.73, 67.28, 49.28, 48.72,

45.32, 45.19, 45.09, 41.83, 32.26, 23.14. HRMS (ESI) m/z calcd for

3H), 1.19 – 1.12 (m, 1H), 0.61 – 0.57 (m, 2H), 0.32 – 0.28 (m, 2H); ¹³

C

NMR (150 MHz, Chloroform-d) δ 209.11, 190.00, 168.23, 162.28,

160.81, 143.98, 113.97, 112.77, 100.77, 100.67, 70.36, 65.02, 49.23,

48.73, 32.22, 23.08, 9.75, 3.39, 3.38. HRMS (ESI) m/z calcd for

C

₁₉H₂₂O₇[M + Na]⁺385.1258, found 385.1267.

4.1.12.15. Cyclohexylmethyl 2-[[3,4-dihydro-2-hydroxy-5-methyl-2-(2-

oxopropyl)- 4-oxo-2H-1-benzopyran-7-yl]oxy]acetate (7o). The tittle

compound was synthesized as described in the general procedure using

compound 6o (141 mg, 0.6 mmol). The crude product was puriﬁed by

ﬂash column chromatography (Petroleum ether/EtOAc, 3:1) to afford

the desired product as a white solid (73 mg, 52.7% yield). ¹H NMR (600

MHz, Chloroform-d) δ 6.41 (d, J = 2.5 Hz, 1H), 6.23 (d, J = 2.5 Hz, 1H),

6.04 (brs, 1H), 4.63 (s, 2H), 4.02 (d, J = 6.4 Hz, 2H), 3.25 (d, J = 16.8

Hz, 1H), 2.78 (s, 2H), 2.72 (d, J = 16.8 Hz, 1H), 2.61 (s, 3H), 2.32 (s,

3H), 1.74 – 1.68 (m, 4H), 1.67 – 1.64 (m, 2H), 1.27 – 1.19 (m, 2H), 1.18

– 1.10 (m, 1H), 0.98 – 0.90 (m, 2H);.¹³C NMR (150 MHz, Chloroform-d)

δ 209.09, 189.98, 168.23, 162.29, 160.81, 143.99, 113.97, 112.68,

C

₂₄H₂₇N₃O₆[M + Na]⁺476.1792, found 476.1794.

4.1.12.11. Phenyl 2-[[3,4-dihydro-2-hydroxy-5-methyl-2-(2-oxopropyl)-

4-oxo-2H- 1-benzopyran-7-yl]oxy]acetate (7 k). The tittle compound

was synthesized as described in the general procedure using compound

6 k (129 mg, 0.6 mmol). The crude product was puriﬁed by ﬂash column

chromatography (Petroleum ether/EtOAc, 3:1) to afford the desired

product as a white solid (75 mg, 57.5% yield). ¹H NMR (600 MHz,

Chloroform-d) δ 7.40 (t, J = 7.8 Hz, 2H), 7.26 (brt, J = 8.4 Hz, 1H), 7.12

(brd, J = 7.8 Hz, 2H), 6.48 (d, J = 2.5 Hz, 1H), 6.32 (d, J = 2.5 Hz, 1H),

10

W. Wu et al.

Bioorganic Chemistry 111 (2021) 104898

100.77, 100.70, 70.52, 64.95, 49.23, 48.73, 37.01, 32.22, 29.47 (2 × C),

26.22, 25.57 (2 × C), 23.07. HRMS (ESI) m/z calcd for C₂₂H₂₈O₇[M +

Na]⁺427.1727, found 427.1756.

product as a colorless oil (1.43 g, 73.7% yield). ¹H NMR (600 MHz,

Chloroform-d) δ 7.27 (t, J = 7.8 Hz, 2H), 6.94 (t, J = 7.8 Hz, 1H), 6.91 (d,

J = 7.8 Hz, 2H), 5.10 (t, J = 4.8 Hz, 1H), 4.12 (t, J = 6.5 Hz, 2H), 4.03 –

3.95 (m, 2H), 3.91 – 3.85 (m, 2H), 2.16 (dt, J = 6.5, 4.8 Hz, 2H); ¹³

C

NMR (150 MHz, Chloroform-d) δ 158.75, 129.41 (2 × C), 120.68,

114.47 (2 × C), 102.05, 64.91 (2 × C), 63.44, 33.81.

4.1.12.16. Ethyl 2-[[3,4-dihydro-2-hydroxy-5-methyl-2-(2-oxopropyl)-4-

oxo-2H-1- benzopyran-7-yl]oxy]acetate (7p). The tittle compound was

synthesized as described in the general procedure using ethyl bromoa-

cetate (100 mg, 0.6 mmol). The crude product was puriﬁed by ﬂash

column chromatography (Petroleum ether/EtOAc, 5:1) to afford the

4.1.15.2. 2-[2-(3-methylphenoxy)ethyl]-1,3-dioxolane (12b). The tittle

compound was synthesized as described in the general procedure using

3-methylphenol (1.08 g, 10.0 mmol). The crude product was puriﬁed by

ﬂash column chromatography (Petroleum ether/EtOAc, 25:1) to afford

the desired product as a colorless oil (1.46 g, 70.2% yield). ¹H NMR

(600 MHz, Chloroform-d) δ 7.15 (t, J = 7.8 Hz, 1H), 6.76 (d, J = 7.5 Hz,

1H), 6.73 (d, J = 2.3 Hz, 1H), 6.71 (dd, J = 8.1, 2.3 Hz, 1H), 5.09 (t, J =

4.9 Hz, 1H), 4.11 (t, J = 6.5 Hz, 2H), 4.03 – 3.96 (m, 2H), 3.91 – 3.84 (m,

2H), 2.32 (s, 3H), 2.15 (dt, J = 6.5, 4.9 Hz, 2H); ¹³C NMR (150 MHz,

Chloroform-d) δ 158.78, 139.43, 129.14, 121.51, 115.34, 111.32,

102.07, 64.91 (2 × C), 63.40, 33.84, 21.52.

1

desired product as a white solid (76 mg, 68.3% yield). H NMR (600

MHz, Chloroform-d) δ 6.41 (d, J = 2.5 Hz, 1H), 6.22 (d, J = 2.5 Hz, 1H),

6.05 (s, 1H), 4.61 (s, 2H), 4.28 (q, J = 7.1 Hz, 2H), 3.25 (d, J = 16.8 Hz,

1H), 2.78 (s, 2H), 2.72 (d, J = 16.8 Hz, 1H), 2.61 (s, 3H), 2.32 (s, 3H),

1.30 (t, J = 7.1 Hz, 3H); ¹³C NMR (150 MHz, Chloroform-d) δ 209.11,

190.03, 168.09, 162.26, 160.82, 143.99, 113.98, 112.75, 100.78,

100.62, 64.99, 61.59, 49.25, 48.71, 32.21, 23.07, 14.14. HRMS (ESI) m/

z calcd for C₁₇H₂₀O₇[M + H]⁺337.1282, found 337.1256.

4.1.13. 2,4-dihydroxy-6-methylacetophenone (9)

To a mixed solution of orcinol (10.0 g, 80.6 mmol) and 3 Å molecular

sieve in acetic acid (46 mL, 805.5 mmol), boron triﬂuoride etherate

(15.2 mL, 120.9 mmol) was added dropwise at room temperature for 1

4.1.15.3. 2-[2-(4-methoxyphenoxy)ethyl]-1,3-dioxolane

(12c). The

tittle compound was synthesized as described in the general procedure

using 4-methoxyphenol (1.24 g, 10.0 mmol). The crude product was

puriﬁed by ﬂash column chromatography (Petroleum ether/EtOAc,

15:1) to afford the desired product as a colorless oil (1.47 g, 65.6%

yield). ¹H NMR (600 MHz, Chloroform-d) δ 6.85 (d, J = 9.2 Hz, 2H), 6.82

(d, J = 9.2 Hz, 2H), 5.09 (t, J = 4.9 Hz, 1H), 4.07 (t, J = 6.5 Hz, 2H), 4.02

– 3.96 (m, 2H), 3.91 – 3.85 (m, 2H), 3.76 (s, 3H), 2.14 (dt, J = 6.5, 4.9

Hz, 2H); ¹³C NMR (150 MHz, Chloroform-d) δ 153.78, 152.93, 115.46

(2 × C), 114.57 (2 × C), 102.10, 64.91 (2 × C), 64.24, 55.71, 33.90.

◦

h. The mixture was stirred at 90 C for 24 h and then cooled to room

temperature. The reaction solution was quenched by addition of a

saturated aqueous solution of NH₄Cl (25 mL) and was ﬁltered to remove

residual 3 Å molecular sieve. The solvent was removed under vacuum,

and then the residue was diluted with saturated aqueous solution of

NaHCO₃(30 mL) and extracted with ethyl acetate (3 × 50 mL). The

combined organic layers were washed with water and brine, dried over

Na₂SO₄, ﬁltered and concentrated in vacuo. The crude product was

pulped with Et₂O (5 mL), ﬁltered with a Buchner funnel and the solid

was washed with ether (3 mL) to provide compound 9 as a yellow solid

(10.43 g, yield 77.9%). ¹H NMR (600 MHz, DMSO‑d₆) δ 10.60 (brs, 1H),

9.77 (brs, 1H), 6.17 (d, J = 2.1 Hz, 1H), 6.11 (d, J = 2.1 Hz, 1H), 2.43 (s,

3H), 2.17 (s, 3H); ¹³C NMR (150 MHz, DMSO‑d₆) δ 203.60, 160.36,

159.53, 139.56, 119.49, 110.11, 100.75, 32.89, 21.48.

4.1.15.4. 2-[2-[3-(triﬂuoromethyl)phenoxy]ethyl]-1,3-dioxolane (12d).

The tittle compound was synthesized as described in the general pro-

cedure using 3-(triﬂuoromethyl)phenol (1.62 g, 10.0 mmol). The crude

product was puriﬁed by ﬂash column chromatography (Petroleum

ether/EtOAc, 25:1) to afford the desired product as a colorless oil (1.89

g, 72.1% yield). ¹H NMR (600 MHz, Chloroform-d) δ 7.38 (t, J = 8.0 Hz,

1H), 7.20 (d, J = 7.7 Hz, 1H), 7.14 (brs, 1H), 7.07 (dd, J = 8.3, 2.2 Hz,

1H), 5.10 (t, J = 4.8 Hz, 1H), 4.16 (t, J = 6.5 Hz, 2H), 4.04 – 3.97 (m,

2H), 3.93 – 3.86 (m, 2H), 2.18 (dt, J = 6.5, 4.8 Hz, 2H); ¹³C NMR (150

MHz, Chloroform-d) δ 158.90, 131.77 (q, J_C-F= 32.3 Hz), 129.92,

123.96 (q, J_C-F= 272.4 Hz), 117.97, 117.39 (q, J_C-F= 3.9 Hz), 111.27 (q,

J = 3.9 Hz), 101.96, 64.97 (2 × C), 63.89, 33.64.

4.1.14. 1-[2,4-bis(benzyloxy)-6-methylphenyl]ethanone (10)

Followed general procedure A, compound 9 (5.0 g, 30.1 mmol),

benzyl chloride (8.0 g, 63.2 mmol) and anhydrous K₂CO₃(12.5 g, 90.3

mmol) in acetonitrile (100 mL) gave the tittle compound as a white solid

(9.81 g, yield 94.1%). ¹H NMR (600 MHz, Chloroform-d) δ 7.42 – 7.31

(m, 10H), 6.45 (d, J = 2.2 Hz, 1H), 6.43 (d, J = 2.2 Hz, 1H), 5.03 (s, 2H),

5.03 (s, 2H), 2.47 (s, 3H), 2.26 (s, 3H); ¹³C NMR (150 MHz, Chloroform-

d) δ 204.56, 160.15, 157.42, 138.00, 136.48, 136.28, 128.64 (2 × C),

128.60 (2 × C), 128.13, 128.05, 127.51 (2 × C), 127.28 (2 × C), 124.65,

108.53, 97.97, 70.43, 70.05, 32.55, 20.03.

4.1.15.5. 2-[2-[4-(triﬂuoromethyl)phenoxy]ethyl]-1,3-dioxolane (12e).

The tittle compound was synthesized as described in the general pro-

cedure using 4-(triﬂuoromethyl)phenol (1.62 g, 10.0 mmol). The crude

product was puriﬁed by ﬂash column chromatography (Petroleum

ether/EtOAc, 25:1) to afford the desired product as a colorless oil (2.01

g, 76.7% yield). ¹H NMR (600 MHz, Chloroform-d) δ 7.53 (d, J = 8.5 Hz,

2H), 6.96 (d, J = 8.5 Hz, 2H), 5.09 (t, J = 4.8 Hz, 1H), 4.16 (t, J = 6.5 Hz,

2H), 4.04 – 3.97 (m, 2H), 3.93 – 3.86 (m, 2H), 2.18 (td, J = 6.5, 4.8 Hz,

2H); ¹³C NMR (150 MHz, Chloroform-d) δ 161.24, 126.86 (q, J_C-F= 3.7

Hz, 2 × C), 124.44 (q, J_C-F= 271.0 Hz), 122.84 (q, J_C-F= 32.7 Hz),

114.43 (2 × C), 101.83, 64.98 (2 × C), 63.82, 33.59.

4.1.15. Synthesis of compounds 12a-12f

General procedure: The solution of the substituted phenols (11a-11f,

10.0 mmol) and anhydrous K₂CO₃(2.76 g, 20.0 mmol) in DMF (40 mL)

was stirred 30 min at room temperature, and then 2-(2-bromoethyl)-1,3-

dioxolane (1.99 g, 11.0 mmol) was added slowly and the mixture was

allowed to warm up 65 ^◦C overnight. The reaction mixture was ﬁltered

and the ﬁltrate was concentrated under reduced pressure. After that, the

resulting residue was diluted with water (30 mL) and extracted with

ethyl acetate (3 × 30 mL). The combined organic layers were washed

with brine, dried over Na₂SO₄, ﬁltered and concentrated in vacuo. The

crude product was puriﬁed by ﬂash chromatography column to provide

compound 12a-12f.

4.1.15.6. 2-[2-(3-ﬂuorophenoxy)ethyl]-1,3-dioxolane (12f). The tittle

compound was synthesized as described in the general procedure using

3-ﬂuorophenol (1.12 g, 10.0 mmol). The crude product was puriﬁed by

ﬂash column chromatography (Petroleum ether/EtOAc, 25:1) to afford

the desired product as a colorless oil (1.44 g, 67.9% yield). ¹H NMR

(600 MHz, Chloroform-d) δ 7.21 (brq, J = 7.6 Hz, 1H), 6.69 (dd, J = 8.3,

2.3 Hz, 1H), 6.66 – 6.60 (m, 2H), 5.09 (t, J = 4.8 Hz, 1H), 4.10 (t, J = 6.5

Hz, 2H), 4.03 – 3.97 (m, 2H), 3.92 – 3.86 (m, 2H), 2.16 (dt, J = 6.5, 4.8

Hz, 2H); ¹³C NMR (150 MHz, Chloroform-d) δ 163.60 (d, J_C-F= 244.9

Hz), 160.26 (d, J_C-F= 10.9 Hz), 130.14 (d, J_C-F= 10.0 Hz), 110.27 (d, _C-

4.1.15.1. 2-(2-phenoxyethyl)-1,3-dioxolane (12a). The tittle compound

was synthesized as described in the general procedure using phenol

(940 mg, 10.0 mmol). The crude product was puriﬁed by ﬂash column

chromatography (Petroleum ether/EtOAc, 25:1) to afford the desired

11

W. Wu et al.

Bioorganic Chemistry 111 (2021) 104898

_FJ = 2.8 Hz), 107.49 (d, J_C-F= 21.5 Hz), 102.19 (d, J_C-F= 24.9 Hz),

101.90, 64.95 (2 × C), 63.85, 33.64.

7.42 – 7.28 (m, 10H), 6.81 (d, J = 9.2 Hz, 2H), 6.79 (d, J = 9.2 Hz, 2H),

6.45 (d, J = 2.0 Hz, 1H), 6.43 (d, J = 2.0 Hz, 1H), 5.04 (s, 2H), 5.01 (s,

2H), 4.35 – 4.28 (m, 1H), 3.98 (t, J = 6.2 Hz, 2H), 3.76 (s, 3H), 3.41 (brs,

1H), 3.12 (dd, J = 17.3, 2.7 Hz, 1H), 2.87 (dd, J = 17.3, 8.9 Hz, 1H),

2.26 (s, 3H), 1.88 – 1.76 (m, 2H); ¹³C NMR (150 MHz, Chloroform-d) δ

207.64, 160.48, 157.52, 153.73, 152.92, 138.39, 136.38, 135.97,

128.67 (2 × C), 128.66 (2 × C), 128.26, 128.18, 127.51 (2 × C), 127.49

(2 × C), 123.84, 115.38 (2 × C), 114.56 (2 × C), 108.71, 98.02, 70.62,

70.09, 66.00, 65.46, 55.71, 51.19, 35.93, 20.04.

4.1.16. General procedure for the synthesis of compounds 13a-13f

The solution of required compound 12a-12f (2.25 mmol), acetic acid

(20 mL) and water (5 mL) was stirred at 45 ^◦C for 5 h, and the solvent

was then removed under reduced pressure. The residue was diluted with

a saturated aqueous solution of NaHCO₃(20 mL) and extracted with

ethyl acetate (3 × 20 mL). The combined organic layers were washed

with brine, dried over Na₂SO₄and concentrated in vacuo. The resulting

residues (13a-13f) were used without further puriﬁcation [17].

4.1.17.4. 1-[2,4-bis(benzyloxy)-6-methylphenyl]-3-hydroxy-5-[3-(tri-

ﬂuoromethyl)- phenoxy]-1-pentanone (14d). The tittle compound was

synthesized as described in the general procedure using compound 13d

(491 mg, 2.25 mmol). The crude product was puriﬁed by ﬂash column

chromatography (Petroleum ether/EtOAc, 15:1) to afford the desired

product as a yellow oil (386 mg, 45.6% yield). ¹H NMR (600 MHz,

Chloroform-d) δ 7.41 – 7.33 (m, 10H), 7.30 – 7.28 (m, 1H), 7.19 (d, J =

7.6 Hz, 1H), 7.08 (t, J = 2.1 Hz, 1H), 7.01 (dd, J = 8.3, 2.4 Hz, 1H), 6.46

(d, J = 2.2 Hz, 1H), 6.44 (d, J = 2.2 Hz, 1H), 5.04 (s, 2H), 5.01 (s, 2H),

4.33 – 4.27 (m, 1H), 4.07 – 4.01 (m, 2H), 3.45 (brs, 1H), 3.13 (dd, J =

17.4, 2.7 Hz, 1H), 2.85 (dd, J = 17.4, 9.0 Hz, 1H), 2.26 (s, 3H), 1.89 –

1.78 (m, 2H); ¹³C NMR (150 MHz, Chloroform-d) δ 207.73, 160.60,

158.94, 157.63, 138.50, 136.35, 135.90, 131.71 (q, J_C-F= 32.2 Hz),

129.89, 128.68 (4 × C), 128.32, 128.20, 127.56 (2 × C), 127.51 (2 × C),

123.97 (q, J_C-F= 272.4 Hz), 123.68, 117.86, 117.27 (q, J_C-F= 3.9 Hz),

111.30 (q, J_C-F= 3.9 Hz), 108.77, 98.02, 70.67, 70.11, 65.56, 64.87,

51.01, 35.71, 20.09.

4.1.17. Synthesis of compounds 14a-14i

General procedure: A solution of 10 (520 mg, 1.5 mmol) in anhy-

drous THF (2 mL) was added gradually to the solution of LDA (2.0 M

solution in THF, 1.5 mL, 3.0 mmol) in anhydrous THF (3 mL) at ꢀ 78 ^◦C

under an atmosphere of N₂. After 30 min, the solution of corresponding

aldehyde (13a-13f, butyraldehyde, pentanal or hexanal, 2.25 mmol) in

anhydrous THF (2 mL) was added dropwise and the mixture was stirred

overnight. Upon completion of the reaction, the mixture was quenched

by addition of a saturated aqueous solution of NH₄Cl (5 mL) at 0 ^◦C and

the organic layer was separated. Aqueous layer was diluted with brine

(5 mL) and extracted with ethyl acetate (3 × 10 mL), combined organic

layers were dried over Na₂SO₄, ﬁltered, eliminated under reduced

pressure. The crude product was puriﬁed by ﬂash chromatography

column to afford compound 14a-14i.

4.1.17.1. 1-[2,4-bis(benzyloxy)-6-methylphenyl]-3-hydroxy-5-phenoxy-1-

pentanone (14a). The tittle compound was synthesized as described in

the general procedure using compound 13a (338 mg, 2.25 mmol). The

crude product was puriﬁed by ﬂash column chromatography (Petroleum

ether/EtOAc, 15:1) to afford the desired product as a yellow oil (316 mg,

42.4% yield). ¹H NMR (600 MHz, Chloroform-d) δ 7.42 – 7.26 (m, 12H),

6.93 (t, J = 7.3 Hz, 1H), 6.86 (d, J = 8.1 Hz, 2H), 6.45 (brs, 1H), 6.44

(brs, 1H), 5.04 (s, 2H), 5.01 (s, 2H), 4.35 – 4.29 (m, 1H), 4.03 (t, J = 6.2

Hz, 2H), 3.41 (brs, 1H), 3.13 (dd, J = 17.4, 2.8 Hz, 1H), 2.87 (dd, J =

17.3, 8.9 Hz, 1H), 2.26 (s, 3H), 1.90 – 1.78 (m, 2H); ¹³C NMR (150 MHz,

Chloroform-d) δ 207.67, 160.51, 158.75, 157.54, 138.41, 136.38,

135.96, 129.39 (2 × C), 128.68 (2 × C), 128.67 (2 × C), 128.28, 128.18,

127.51 (4 × C), 123.82, 120.64, 114.45 (2 × C), 108.72, 98.02, 70.64,

70.10, 65.92, 64.64, 51.16, 35.85, 20.06.

4.1.17.5. 1-[2,4-bis(benzyloxy)-6-methylphenyl]-3-hydroxy-5-[4-(tri-

ﬂuoromethyl)- phenoxy]-1-pentanone (14e). The tittle compound was

synthesized as described in the general procedure using compound 13e

(491 mg, 2.25 mmol). The crude product was puriﬁed by ﬂash column

chromatography (Petroleum ether/EtOAc, 15:1) to afford the desired

product as a yellow oil (396 mg, 46.7% yield). ¹H NMR (600 MHz,

Chloroform-d) δ 7.51 (d, J = 8.5 Hz, 2H), 7.43 – 7.28 (m, 10H), 6.90 (d,

J = 8.5 Hz, 2H), 6.46 (d, J = 2.1 Hz, 1H), 6.44 (d, J = 2.1 Hz, 1H), 5.04

(s, 2H), 5.01 (s, 2H), 4.32 – 4.26 (m, 1H), 4.09 – 4.03 (m, 2H), 3.44 (brs,

1H), 3.13 (dd, J = 17.4, 2.6 Hz, 1H), 2.85 (dd, J = 17.4, 9.0 Hz, 1H),

2.26 (s, 3H), 1.90 – 1.76 (m, 2H); ¹³C NMR (150 MHz, Chloroform-d) δ

207.70, 161.27, 160.60, 157.62, 138.51, 136.34, 135.92, 128.68 (4 ×

C), 128.30, 128.21, 127.53 (2 × C), 127.51 (2 × C), 126.81 (q, J_C-F= 3.7

Hz, 2 × C), 124.45 (q, J_C-F= 271.0 Hz), 123.66, 122.70 (q, J_C-F= 32.6

Hz), 114.40 (2 × C), 108.77, 98.03, 70.66, 70.11, 65.51, 64.82, 51.01,

35.64, 20.09.

4.1.17.2. 1-[2,4-bis(benzyloxy)-6-methylphenyl]-3-hydroxy-5-(3-methyl-

phenoxy)-1- pentanone (14b). The tittle compound was synthesized as

described in the general procedure using compound 13b (370 mg, 2.25

mmol). The crude product was puriﬁed by ﬂash column chromatog-

raphy (Petroleum ether/EtOAc, 15:1) to afford the desired product as a

yellow oil (309 mg, 40.3% yield). ¹H NMR (600 MHz, Chloroform-d) δ

7.41 – 7.30 (m, 10H), 7.14 (t, J = 7.8 Hz, 1H), 6.75 (brd, J = 7.5 Hz, 1H),

6.69 (d, J = 2.1, 1H), 6.66 (d, J = 8.2, 2.1 Hz, 1H), 6.45 (d, J = 2.2 Hz,

1H), 6.44 (d, J = 2.2 Hz, 1H), 5.04 (s, 2H), 5.01 (s, 2H), 4.34 – 4.29 (m,

1H), 4.02 (t, J = 6.3 Hz, 2H), 3.42 (brs, 1H), 3.12 (dd, J = 17.3, 2.9 Hz,

1H), 2.87 (dd, J = 17.3, 8.9 Hz, 1H), 2.31 (s, 3H), 2.26 (s, 3H), 1.88 –

1.79 (m, 2H); ¹³C NMR (150 MHz, Chloroform-d) δ 207.71, 160.53,

158.80, 157.57, 139.45, 138.45, 136.42, 136.01, 129.17, 128.72 (2 ×

C), 128.71 (2 × C), 128.31, 128.22, 127.55 (2 × C), 127.53 (2 × C),

123.87, 121.52, 115.35, 111.36, 108.75, 98.06, 70.66, 70.14, 66.03,

64.67, 51.21, 35.91, 21.56, 20.10.

4.1.17.6. 1-[2,4-bis(benzyloxy)-6-methylphenyl]-3-hydroxy-5-(3-ﬂuo-

rophenoxy)-1- pentanone (14f). The tittle compound was synthesized as

described in the general procedure using compound 13f (379 mg, 2.25

mmol). The crude product was puriﬁed by ﬂash column chromatog-

raphy (Petroleum ether/EtOAc, 15:1) to afford the desired product as a

yellow oil (342 mg, 44.3% yield). ¹H NMR (600 MHz, Chloroform-d) δ

7.42 – 7.28 (m, 10H), 7.18 (q, J = 7.8 Hz, 1H), 6.65 – 6.61 (m, 2H), 6.56

(brd, J = 10.0 Hz, 1H), 6.46 (d, J = 2.1 Hz, 1H), 6.44 (d, J = 2.1 Hz, 1H),

5.04 (s, 2H), 5.00 (s, 2H), 4.32 – 4.26 (m, 1H), 4.02 – 3.96 (m, 2H), 3.42

(brs, 1H), 3.11 (dd, J = 17.3, 2.7 Hz, 1H), 2.85 (dd, J = 17.3, 8.9 Hz,

1H), 2.26 (s, 3H), 1.87 – 1.75 (m, 2H); ¹³C NMR (150 MHz, Chloroform-

d) δ 207.67, 163.57 (d, J_C-F= 244.8 Hz), 160.56, 160.18 (d, J_C-F= 10.7

Hz), 157.59, 138.46, 136.36, 135.91, 130.10 (d, J_C-F= 10.0 Hz), 128.68

(2 × C), 128.66 (2 × C), 128.31, 128.18, 127.54 (2 × C), 127.50 (2 × C),

123.71, 110.25 (d, J_C-F= 2.8 Hz), 108.75, 107.38 (d, J_C-F= 21.2 Hz),

102.14 (d, J_C-F= 24.8 Hz), 98.01, 70.65, 70.09, 65.63, 64.89, 51.05,

35.69, 20.07.

4.1.17.3. 1-[2,4-bis(benzyloxy)-6-methylphenyl]-3-hydroxy-5-(4-methox-

yphenoxy)-1- pentanone (14c). The tittle compound was synthesized as

described in the general procedure using compound 13c (406 mg, 2.25

mmol). The crude product was puriﬁed by ﬂash column chromatog-

raphy (Petroleum ether/EtOAc, 8:1) to afford the desired product as a

yellow oil (345 mg, 43.7% yield). ¹H NMR (600 MHz, Chloroform-d) δ

4.1.17.7. 1-[2,4-bis(benzyloxy)-6-methylphenyl]-3-hydroxy-1-hexanone

(14 g). The tittle compound was synthesized as described in the general

12

W. Wu et al.

Bioorganic Chemistry 111 (2021) 104898

procedure using butyraldehyde (162 mg, 2.25 mmol). The crude product

was puriﬁed by ﬂash column chromatography (Petroleum ether/EtOAc,

10:1) to afford the desired product as a yellow oil (256 mg, 38.1% yield).

¹H NMR (600 MHz, Chloroform-d) δ 7.42 – 7.32 (m, 10H), 6.45 (d, J =

2.1 Hz, 1H), 6.43 (d, J = 2.1 Hz, 1H), 5.04 (s, 2H), 5.01 (s, 2H), 4.06 –

4.02 (m, 1H), 3.23 (brs, 1H), 3.07 (dd, J = 17.4, 2.4 Hz, 1H), 2.71 (dd, J

= 17.4, 9.3 Hz, 1H), 2.25 (s, 3H), 1.45 – 1.39 (m, 1H), 1.37 – 130 (m,

1H), 1.29 – 1.21 (m, 2H), 0.85 (t, J = 7.2 Hz, 3H); ¹³C NMR (150 MHz,

Chloroform-d) δ 208.26, 160.45, 157.49, 138.32, 136.42, 135.99,

128.66 (2 × C), 128.65 (2 × C), 128.25, 128.17, 127.56 (2 × C), 127.51

(2 × C), 123.99, 108.69, 98.01, 70.64, 70.10, 68.01, 51.14, 38.70,

20.01, 18.56, 14.02.

1H), 6.87 (d, J = 8.2 Hz, 2H), 6.45 (d, J = 2.4 Hz, 2H), 5.87 (s, 1H), 5.03

(s, 4H), 4.23 (t, J = 6.5 Hz, 2H), 2.80 (t, J = 6.5 Hz, 2H), 2.33 (s, 3H); ¹³C

NMR (150 MHz, Chloroform-d) δ 190.61, 186.75, 160.44, 158.47,

157.34, 139.40, 136.59, 136.47, 129.44 (2 × C), 128.64 (2 × C), 128.50

(2 × C), 128.13, 127.83, 127.50 (2 × C), 126.91 (2 × C), 120.93, 119.93,

114.57 (2 × C), 108.65, 104.27, 98.44, 70.48, 70.04, 63.66, 38.41,

20.42. Keto-tautomer: ¹H NMR (600 MHz, Chloroform-d) δ 7.42 – 7.28

(m, 10H), 7.25 – 7.23 (m, 2H), 6.95 (t, J = 7.5 Hz, 1H), 6.82 (d, J = 8.2

Hz, 2H), 6.45 (d, J = 2.4 Hz, 2H), 5.04 (s, 2H), 5.02 (s, 2H), 4.08 (t, J =

6.5 Hz, 2H), 3.98 (s, 2H), 2.80 (t, J = 6.5 Hz, 2H), 2.31 (s, 3H); ¹³C NMR

(150 MHz, Chloroform-d) δ 202.38, 198.80, 160.96, 158.47, 158.16,

139.98, 136.26, 135.74, 129.38 (2 × C), 128.77 (2 × C), 128.68 (2 × C),

128.44, 128.22, 127.82 (2 × C), 127.52 (2 × C), 122.88, 120.81, 114.44

(2 × C), 109.06, 97.89, 70.77, 70.10, 62.36, 59.08, 42.52, 20.52.

4.1.17.8. 1-[2,4-bis(benzyloxy)-6-methylphenyl]-3-hydroxy-1-heptanone

(14 h). The tittle compound was synthesized as described in the general

procedure using pentanal (194 mg, 2.25 mmol). The crude product was

puriﬁed by ﬂash column chromatography (Petroleum ether/EtOAc,

10:1) to afford the desired product as a yellow oil (252 mg, 37.6% yield).

¹H NMR (600 MHz, Chloroform-d) δ 7.41 – 7.33 (m, 10H), 6.45 (d, J =

2.2 Hz, 1H), 6.43 (d, J = 2.2 Hz, 1H), 5.04 (s, 2H), 5.01 (s, 2H), 4.05 –

4.01 (m, 1H), 3.24 (brs, 1H), 3.07 (dd, J = 17.4, 2.4 Hz, 1H), 2.71 (dd, J

= 17.4, 9.3 Hz, 1H), 2.25 (s, 3H), 1.46 – 1.41 (m, 1H), 1.32 – 1.23 (m,

4H), 1.22 – 1.17 (m, 1H), 0.86 (t, J = 7.1 Hz, 3H); ¹³C NMR (150 MHz,

Chloroform-d) δ 208.29, 160.45, 157.49, 138.33, 136.42, 136.01,

128.67 (2 × C), 128.66 (2 × C), 128.26, 128.18, 127.54 (2 × C), 127.51

(2 × C), 124.01, 108.70, 98.02, 70.64, 70.11, 68.29, 51.14, 36.29,

27.53, 22.65, 20.02, 14.05.

4.1.18.2. Mixture of tautomers, 1-[2,4-bis(benzyloxy)-6-methylphenyl]-3-

hydroxy-5-(3- methylphenoxy)-2-penten-1-one and 1-[2,4-bis(benzyloxy)-

6-methylphenyl]-5-(3- methylphenoxy)-1,3- pentanedione (15b). The

tittle compound was synthesized as described in the general procedure

using 14b (255 mg, 0.5 mmol). The crude product was puriﬁed by ﬂash

column chromatography (Petroleum ether/EtOAc, 25:1) to afford the

desired product as a yellow oil (211 mg, 82.4% yield). According to the

characteristic proton signals in ¹H NMR, the product was a mixture of

enol-keto tautomers containing approximately 78.4% enol-tautomer

and 21.6% keto-tautomer. Enol-tautomer: ¹H NMR (600 MHz, Chloro-

form-d) δ 15.63 (brs, 1H), 7.42 – 7.27 (m, 10H), 7.15 (t, J = 7.8 Hz, 1H),

6.77 (brd, J = 8.0 Hz, 1H), 6.70 (d, J = 2.2 Hz, 1H), 6.68 (dd, J = 8.0,

2.2 Hz, 1H), 6.46 (brs, 1H), 6.45 (brs, 1H), 5.87 (s, 1H), 5.03 (s, 4H),

4.22 (t, J = 6.6 Hz, 2H), 2.80 (t, J = 6.6 Hz, 2H), 2.33 (s, 3H), 2.31 (s,

3H); ¹³C NMR (150 MHz, Chloroform-d) δ 190.67, 186.77, 160.44,

158.50, 157.34, 139.49, 139.40, 136.60, 136.48, 129.17, 128.65 (2 ×

C), 128.51 (2 × C), 128.14, 127.83, 127.51 (2 × C), 126.90 (2 × C),

121.76, 119.96, 115.42, 111.43, 108.65, 104.26, 98.45, 70.48, 70.05,

4.1.17.9. 1-[2,4-bis(benzyloxy)-6-methylphenyl]-3-hydroxy-1-octanone

(14i). The tittle compound was synthesized as described in the general

procedure using hexanal (226 mg, 2.25 mmol). The crude product was

puriﬁed by ﬂash column chromatography (Petroleum ether/EtOAc,

10:1) to afford the desired product as a yellow oil (273 mg, 40.7% yield).

¹H NMR (600 MHz, Chloroform-d) δ 7.41 – 7.33 (m, 10H), 6.45 (d, J =

2.2 Hz, 1H), 6.43 (d, J = 2.2 Hz, 1H), 5.04 (s, 2H), 5.01 (s, 2H), 4.05 –

4.01 (m, 1H), 3.24 (d, J = 2.8 Hz, 1H), 3.07 (dd, J = 17.3, 2.4 Hz, 1H),

2.71 (dd, J = 17.4, 9.3 Hz, 1H), 2.25 (s, 3H), 1.45 – 1.40 (m, 1H), 1.34 –

1.31 (m, 1H), 1.30 – 1.20 (m, 6H), 0.87 (t, J = 7.1 Hz, 3H); ¹³C NMR

(150 MHz, Chloroform-d) δ 208.28, 160.44, 157.48, 138.31, 136.42,

136.00, 128.66 (2 × C), 128.65 (2 × C), 128.25, 128.17, 127.52 (2 × C),

127.50 (2 × C), 124.01, 108.69, 98.02, 70.63, 70.10, 68.30, 51.14,

36.58, 31.80, 25.04, 22.59, 20.01, 14.06.

1

63.61, 38.44, 21.51, 20.41. Keto-tautomer: H NMR (600 MHz, Chlo-

roform-d) δ 7.42 – 7.27 (m, 10H), 7.13 (t, 7.8 Hz, 1H), 6.75 (brd, J = 8.4

Hz, 1H), 6.64 (brs, 1H), 6.62 (brd, 8.0 Hz, 1H), 6.46 (brs, 1H), 6.45 (brs,

1H), 5.04 (s, 2H), 5.02 (s, 2H), 4.07 (t, J = 6.4 Hz, 2H), 3.98 (s, 2H), 2.80

(t, J = 6.5 Hz, 2H), 2.30 (s, 6H); ¹³C NMR (150 MHz, Chloroform-d) δ

202.47, 198.83, 160.96, 158.50, 158.16, 140.00, 139.42, 136.27,

135.76, 129.12, 128.77 (2 × C), 128.68 (2 × C), 128.43, 128.22, 127.79

(2 × C), 127.53 (2 × C), 122.90, 121.64, 115.29, 111.33, 109.07, 97.90,

70.76, 70.11, 62.34, 59.08, 42.58, 29.70, 20.53.

4.1.18. Synthesis of compounds 15a-15i

4.1.18.3. Mixture of tautomers, 1-[2,4-bis(benzyloxy)-6-methylphenyl]-3-

hydroxy-5-(4- methoxyphenoxy)-2-penten-1-one and 1-[2,4-bis(benzy-

loxy)-6-methylphenyl]-5-(4- methoxyphenoxy)-1,3- pentanedione (15c).

The tittle compound was synthesized as described in the general pro-

cedure using 14c (264 mg, 0.5 mmol). The crude product was puriﬁed

by ﬂash column chromatography (Petroleum ether/EtOAc, 15:1) to

afford the desired product as a yellow oil (214 mg, 81.2% yield). Ac-

cording to the characteristic proton signals in ¹H NMR, the product was

a mixture of enol-keto tautomers containing approximately 76.9% enol-

tautomer and 23.1% keto-tautomer. Enol-tautomer: ¹H NMR (600 MHz,

Chloroform-d) δ 15.64 (brs, 1H), 7.42 – 7.25 (m, 10H), 6.81 (brs, 4H),

6.45 (d, J = 2.3 Hz, 1H), 6.44 (d, J = 2.3 Hz, 1H), 5.86 (s, 1H), 5.03 (s,

4H), 4.18 (t, J = 6.5 Hz, 2H), 3.76 (s, 3H), 2.77 (t, J = 6.5 Hz, 2H), 2.33

(s, 3H); ¹³C NMR (150 MHz, Chloroform-d) δ 190.71, 186.78, 160.43,

157.33, 153.97, 152.63, 139.39, 136.60, 136.48, 128.64 (2 × C), 128.50

(2 × C), 128.13, 127.82, 127.51 (2 × C), 126.90 (2 × C), 119.96, 115.67

(2 × C), 114.58 (2 × C), 108.65, 104.28, 98.45, 70.47, 70.04, 64.53,

55.70, 38.51, 20.41. Keto-tautomer: ¹H NMR (600 MHz, Chloroform-d) δ

7.42 – 7.25 (m, 10H), 6.80 (d, J = 9.0 Hz, 2H), 6.75 (d, J = 9.0 Hz, 2H),

6.44 (brs, 2H), 5.03 (s, 2H), 5.01 (s, 2H), 4.03 (t, J = 6.4 Hz, 2H), 3.97 (s,

2H), 3.75 (s, 3H), 2.77 (t, J = 6.4 Hz, 2H), 2.30 (s, 3H); ¹³C NMR (150

MHz, Chloroform-d) δ 202.50, 198.83, 160.95, 158.15, 153.87, 152.65,

General procedure: The 14a-14i (0.5 mmol) was dissolved in DCM

(10 mL) and Dess-Martin reagent (275 mg, 0.65 mmol) was added at

0 ^◦C. The mixture was stirred for 2 h and then saturated aqueous solution

of Na₂S₂O₃(3 mL) and saturated aqueous solution of NaHCO₃(5 mL)

were added. After that the organic layer was separated, aqueous layer

was extracted with DCM (3 × 10 mL), combined organic layers were

washed with brine, dried over Na₂SO₄, ﬁltered and concentrated in

vacuo. The crude products were puriﬁed by ﬂash column chromatog-

raphy to give compound 15a-15i.

4.1.18.1. Mixture of tautomers, 1-[2,4-bis(benzyloxy)-6-methylphenyl]-3-

hydroxy-5- phenoxy-2-penten-1-one and 1-[2,4-bis(benzyloxy)-6-methyl-

phenyl]-5-phenoxy-1,3- pentanedione (15a). The tittle compound was

synthesized as described in the general procedure using 14a (249 mg,

0.5 mmol). The crude product was puriﬁed by ﬂash column chroma-

tography (Petroleum ether/EtOAc, 25:1) to afford the desired product as

a yellow oil (201 mg, 80.1% yield). According to the characteristic

proton signals in ¹H NMR, the product was a mixture of enol-keto tau-

tomers containing approximately 76.9% enol-tautomer and 23.1% keto-

tautomer. Enol-tautomer: ¹H NMR (600 MHz, Chloroform-d) δ 15.63

(brs, 1H), 7.42 – 7.28 (m, 10H), 7.28 – 7.26 (m, 2H), 6.95 (t, J = 7.5 Hz,

13

W. Wu et al.

Bioorganic Chemistry 111 (2021) 104898

139.98, 136.27, 135.76, 128.77 (2 × C), 128.68 (2 × C), 128.42, 128.22,

127.79 (2 × C), 127.52 (2 × C), 122.90, 115.47 (2 × C), 114.54 (2 × C),

109.07, 97.90, 70.75, 70.10, 63.18, 59.08, 55.70, 42.65, 20.52.

tittle compound was synthesized as described in the general procedure

using 14f (257 mg, 0.5 mmol). The crude product was puriﬁed by ﬂash

column chromatography (Petroleum ether/EtOAc, 25:1) to afford the

desired product as a yellow oil (197 mg, 76.7% yield). According to the

characteristic proton signals in ¹H NMR, the product was a mixture of

enol-keto tautomers containing approximately 78.7% enol-tautomer

and 21.3% keto-tautomer. Enol-tautomer: ¹H NMR (600 MHz, Chloro-

form-d) δ 15.60 (brs, 1H), 7.41 – 7.27 (m, 10H), 7.20 (brq, J = 8.2 Hz,

1H), 6.68 – 6.62 (m, 2H), 6.58 (dt, J = 10.9, 2.4 Hz, 1H), 6.46 (d, J = 2.5

Hz, 1H), 6.45 (d, J = 2.5 Hz, 1H), 5.86 (s, 1H), 5.04 (s, 2H), 5.03 (s, 2H),

4.20 (t, J = 6.5 Hz, 2H), 2.79 (t, J = 6.5 Hz, 2H), 2.34 (s, 3H); ¹³C NMR

(150 MHz, Chloroform-d) δ 190.40, 186.69, 163.59 (d, J_C-F= 245.2 Hz),

160.52, 159.88 (d, J_C-F= 10.8 Hz), 157.41, 139.49, 136.59, 136.49,

130.22 (d, J_C-F= 9.9 Hz), 128.68 (2 × C), 128.54 (2 × C), 128.18,

127.90, 127.54 (2 × C), 126.97 (2 × C), 119.84, 110.30 (d, J_C-F= 2.8

Hz), 108.71, 107.78 (d, J_C-F= 21.3 Hz), 104.31, 102.37 (d, J_C-F= 24.8

Hz), 98.47, 70.53, 70.08, 64.00, 38.26, 20.46. Keto-tautomer: ¹H NMR

(600 MHz, Chloroform-d) δ 7.41 – 7.27 (m, 10H), 7.20 (brq, J = 8.2 Hz,

1H), 6.68 – 6.62 (m, 2H), 6.52 (dt, J = 10.9, 2.4 Hz, 1H), 6.46 (d, J = 2.5

Hz, 1H), 6.45 (d, J = 2.5 Hz, 1H), 5.04 (s, 2H), 5.02 (s, 2H), 4.04 (t, J =

6.4 Hz, 2H), 3.96 (s, 2H), 2.79 (t, J = 6.4 Hz, 2H), 2.30 (s, 3H); ¹³C NMR

(150 MHz, Chloroform-d) δ 202.10, 198.77, 163.56 (d, J_C-F= 245.1 Hz),

161.04, 159.89 (d, J_C-F= 10.9 Hz), 158.22, 140.04, 136.28, 135.73,

130.16 (d, J_C-F= 10.0 Hz), 128.81 (2 × C), 128.72 (2 × C), 128.52,

128.27, 127.92 (2 × C), 127.56 (2 × C), 122.85, 110.18 (d, J_C-F= 2.7

Hz), 109.12, 107.65 (d, J_C-F= 21.0 Hz), 102.26 (d, J_C-F= 24.8 Hz),

97.92, 70.83, 70.15, 62.70, 59.09, 42.26, 20.55.

4.1.18.4. Mixture of tautomers, 1-[2,4-bis(benzyloxy)-6-methylphenyl]-3-

hydroxy ꢀ 5-[3-(triﬂuoromethyl)-phenoxy]-2-penten-1-one and 1-[2,4-bis

(benzyloxy)-6-methyl

-phenyl]-5-[3-(triﬂuoro-

methyl)phenoxy]-1,3-

pentanedione (15d). The tittle compound was synthesized as described

in the general procedure using 14d (282 mg, 0.5 mmol). The crude

product was puriﬁed by ﬂash column chromatography (Petroleum

ether/EtOAc, 25:1) to afford the desired product as a yellow oil (222 mg,

78.8% yield). According to the characteristic proton signals in ¹H NMR,

the product was a mixture of enol-keto tautomers containing approxi-

mately 76.9% enol-tautomer and 23.1% keto-tautomer. Enol-tautomer:

¹H NMR (600 MHz, Chloroform-d) δ 15.60 (brs, 1H), 7.42 – 7.29 (m,

10H), 7.27 (t, J = 7.4 Hz, 1H), 7.21 (d, J = 8.2 Hz, 1H), 7.10 (brs, 1H),

7.02 (brd, J = 8.2 Hz, 1H), 6.46 (brs, 2H), 5.87 (s, 1H), 5.04 (s, 2H), 5.03

(s, 2H), 4.25 (t, J = 6.5 Hz, 2H), 2.81 (t, J = 6.5 Hz, 2H), 2.34 (s, 3H); ¹³

C

NMR (150 MHz, Chloroform-d) δ 190.30, 186.58, 160.52, 158.64,

157.40, 139.50, 136.55, 136.45, 131.79 (q, J_C-F= 32.3 Hz), 129.96,

128.65 (2 × C), 128.49 (2 × C), 128.15, 127.86, 127.51 (2 × C), 126.93

(2 × C), 123.90 (q, J_C-F= 272.4 Hz), 119.74, 117.98, 117.62 (q, J_C-F

=

3.9 Hz), 111.39 (q, J_C-F= 3.7 Hz), 108.70, 104.32, 98.44, 70.50, 70.05,

63.98, 38.25, 20.44. Keto-tautomer: ¹H NMR (600 MHz, Chloroform-d) δ

7.42 – 7.29 (m, 10H), 7.27 (t, J = 7.4 Hz, 1H), 7.18 (d, J = 8.2 Hz, 1H),

7.04 (brs, 1H), 6.97 (brd, J = 8.3 Hz, 1H), 6.46 (brs, 2H), 5.04 (s, 2H),

5.02 (s, 2H), 4.07 (t, J = 6.5 Hz, 2H), 3.97 (s, 2H), 2.81 (t, J = 6.5 Hz,

2H), 2.31 (s, 3H); ¹³C NMR (150 MHz, Chloroform-d) δ 201.95, 198.72,

161.03, 158.64, 158.21, 140.00, 136.24, 135.69, 131.72 (q, J_C-F= 32.2

Hz), 129.90, 128.78 (2 × C), 128.69 (2 × C), 128.49, 128.24, 127.92 (2

× C), 127.52 (2 × C), 123.92 (q, J_C-F= 272.4 Hz), 122.82, 117.85,

117.48 (q, J_C-F= 3.7 Hz), 111.31 (q, J_C-F= 3.8 Hz), 109.10, 97.89,

70.82, 70.12, 62.66, 59.08, 42.17, 20.52.

4.1.18.7. Mixture of tautomers, 1-[2,4-bis(benzyloxy)-6-methylphenyl]-3-

hydroxy-2- hexen-1-one and 1-[2,4-bis(benzyloxy)-6-methylphenyl]-1,3-

hexanedione (15 g). The tittle compound was synthesized as described

in the general procedure using 14 g (209 mg, 0.5 mmol). The crude

product was puriﬁed by ﬂash column chromatography (Petroleum

ether/EtOAc, 20:1) to afford the desired product as a yellow oil (177 mg,

85.2% yield). According to the characteristic proton signals in ¹H NMR,

the product was a mixture of enol-keto tautomers containing approxi-

mately 80.0% enol-tautomer and 20.0% keto-tautomer. Enol-tautomer:

¹H NMR (600 MHz, Chloroform-d) δ 15.72 (brs, 1H), 7.42 – 7.27 (m,

10H), 6.45 (brs, 2H), 5.76 (s, 1H), 5.04 (s, 2H), 5.03 (s, 2H), 2.33 (s, 3H),

2.28 (t, J = 7.5 Hz, 2H), 1.62 (sext, J = 7.5 Hz, 1H), 0.93 (t, J = 7.5 Hz,

3H); ¹³C NMR (150 MHz, Chloroform-d) δ 193.60, 187.44, 160.29,

157.20, 139.17, 136.64, 136.55, 128.64 (2 × C), 128.45 (2 × C), 128.12,

127.78, 127.51 (2 × C), 126.95 (2 × C), 120.56, 108.57, 103.54, 98.42,

70.46, 70.05, 40.36, 20.32, 19.23, 13.76. Keto-tautomer: ¹H NMR (600

MHz, Chloroform-d) δ 7.42 – 7.27 (m, 10H), 6.44 (brs, 2H), 5.04 (s, 2H),

5.02 (s, 2H), 3.90 (s, 2H), 2.31 (t, J = 7.4 Hz, 2H), 2.30 (s, 3H), 1.46

(sext, J = 7.4 Hz, 2H), 0.80 (t, J = 7.4 Hz, 3H); ¹³C NMR (150 MHz,

Chloroform-d) δ 204.86, 199.26, 160.84, 158.04, 139.85, 136.33,

135.87, 128.73 (2 × C), 128.68 (2 × C), 128.39, 128.20, 127.78 (2 × C),

127.52 (2 × C), 123.13, 109.03, 97.89, 70.74, 70.10, 58.74, 45.17,

20.44, 16.72, 13.55.

4.1.18.5. Mixture of tautomers, 1-[2,4-bis(benzyloxy)-6-methylphenyl]-3-

hydroxy-5- [4-(triﬂuoromethyl)-phenoxy]-2-penten-1-one and 1-[2,4-bis

(benzyloxy)-6-methyl

-phenyl]-5-[4-(triﬂuoro-

methyl)phenoxy]-1,3-

pentanedione (15e). The tittle compound was synthesized as described

in the general procedure using 14e (282 mg, 0.5 mmol). The crude

product was puriﬁed by ﬂash column chromatography (Petroleum

ether/EtOAc, 25:1) to afford the desired product as a yellow oil (226 mg,

80.2% yield). According to the characteristic proton signals in ¹H NMR,

the product was a mixture of enol-keto tautomers containing approxi-

mately 76.9% enol-tautomer and 23.1% keto-tautomer. Enol-tautomer:

¹H NMR (600 MHz, Chloroform-d) δ 15.60 (brs, 1H), 7.51 (d, J = 8.5 Hz,

2H), 7.42 – 7.26 (m, 10H), 6.91 (d, J = 8.5 Hz, 2H), 6.46 (d, J = 2.6 Hz,

2H), 5.87 (s, 1H), 5.04 (s, 2H), 5.03 (s, 2H), 4.26 (t, J = 6.5 Hz, 2H), 2.82

(t, J = 6.5 Hz, 2H), 2.33 (s, 3H); ¹³C NMR (150 MHz, Chloroform-d) δ

190.32, 186.56, 160.95, 160.54, 157.40, 139.50, 136.58, 136.45,

128.66 (2 × C), 128.51 (2 × C), 128.16, 127.86, 127.53 (2 × C), 126.90

(2 × C), 126.85 (q, J_C-F= 3.9 Hz, 2 × C), 124.39 (q, J_C-F= 270.9 Hz),

123.05 (q, J_C-F= 32.7 Hz), 119.72, 114.49 (2 × C), 108.71, 104.32,

98.45, 70.49, 70.06, 63.91, 38.21, 20.45. Keto-tautomer: ¹H NMR (600

MHz, Chloroform-d) δ 7.50 (d, J = 8.5 Hz, 2H), 7.42 – 7.26 (m, 10H),

6.86 (d, J = 8.5 Hz, 2H), 6.46 (d, J = 2.6 Hz, 2H), 5.04 (s, 2H), 5.02 (s,

2H), 4.09 (t, J = 6.3 Hz, 2H), 3.96 (s, 2H), 2.81 (t, J = 6.3 Hz, 2H), 2.30

(s, 3H); ¹³C NMR (150 MHz, Chloroform-d) δ 201.94, 198.72, 161.05,

160.95, 158.22, 140.01, 136.23, 135.71, 128.78 (2 × C), 128.70 (2 × C),

128.51, 128.25, 127.90 (2 × C), 127.52 (2 × C), 126.85 (q, J_C-F= 3.9 Hz,

2 × C), 124.39 (q, J_C-F= 270.9 Hz), 123.05 (q, J_C-F= 32.7 Hz), 122.80,

114.39 (2 × C), 109.11, 97.91, 70.81, 70.13, 62.61, 59.07, 42.13, 20.53.

4.1.18.8. Mixture of tautomers, 1-[2,4-bis(benzyloxy)-6-methylphenyl]-3-

hydroxy-2- hepten-1-one and 1-[2,4-bis(benzyloxy)-6-methylphenyl]-1,3-

heptanedione (15 h). The tittle compound was synthesized as

described in the general procedure using 14 h (216 mg, 0.5 mmol). The

crude product was puriﬁed by ﬂash column chromatography (Petroleum

ether/EtOAc, 20:1) to afford the desired product as a yellow oil (173 mg,

76.7% yield). According to the characteristic proton signals in ¹H NMR,

the product was a mixture of enol-keto tautomers containing approxi-

mately 80.0% enol-tautomer and 20.0% keto-tautomer. Enol-tautomer:

¹H NMR (600 MHz, Chloroform-d) δ 15.72 (s, 1H), 7.42 – 7.27 (m, 10H),

6.45 (brs, 2H), 5.76 (s, 1H), 5.04 (s, 2H), 5.03 (s, 2H), 2.32 (s, 3H), 2.30

(t, J = 7.4 Hz, 2H), 1.57 (quint, J = 7.4 Hz, 2H), 1.34 (sext, J = 7.4 Hz,

2H), 0.90 (t, J = 7.4 Hz, 3H); ¹³C NMR (150 MHz, Chloroform-d) δ

4.1.18.6. Mixture of tautomers, 1-[2,4-bis(benzyloxy)-6-methylphenyl]-3-

hydroxy-5-(3- ﬂuorophenoxy)-2-penten-1-one and 1-[2,4-bis(benzyloxy)-

6-methylphenyl]-5-(3- ﬂuorophenoxy)-1,3- pentanedione (15f). The

14

W. Wu et al.

Bioorganic Chemistry 111 (2021) 104898

193.94, 187.30, 160.28, 157.20, 139.16, 136.65, 136.55, 128.63 (2 ×

C), 128.44 (2 × C), 128.11, 127.77, 127.50 (2 × C), 126.93 (2 × C),

120.54, 108.58, 103.46, 98.43, 70.46, 70.04, 38.22, 27.89, 22.37,

20.31, 13.83. Keto-tautomer: ¹H NMR (600 MHz, Chloroform-d) δ 7.42 –

7.27 (m, 10H), 6.44 (brs, 2H), 5.04 (s, 2H), 5.02 (s, 2H), 3.90 (s, 2H),

2.31 (t, J = 7.4 Hz, 2H), 2.30 (s, 3H), 1.42 (quint, J = 7.4 Hz, 2H), 1.34

(sext, J = 7.4 Hz, 2H), 0.83 (t, J = 7.4 Hz, 3H); ¹³C NMR (150 MHz,

Chloroform-d) δ 204.98, 199.27, 160.84, 158.05, 139.86, 136.33,

135.88, 128.73 (2 × C), 128.67 (2 × C), 128.37, 128.20, 127.74 (2 × C),

127.52 (2 × C), 123.13, 109.04, 97.89, 70.73, 70.10, 58.75, 43.03,

25.37, 22.12, 20.44, 13.83.

DMSO‑d₆) δ 191.39, 163.10, 161.68, 158.75, 142.80, 139.47, 129.70,

121.79, 115.44, 112.90, 112.41, 111.91, 102.06, 101.40, 63.65, 48.37,

39.95, 23.05, 21.57. HRMS (ESI) m/z calcd for C₁₉H₂₀O₅[M + H]⁺

329.1384, found 329.1376.

4.1.19.3. 2,3-dihydro-2,7-dihydroxy-5-methyl-2-[2-(4-methoxyphenoxy)

ethyl]-4H-1-benzopyran-4-one (16c). The tittle compound was synthe-

sized as described in the general procedure B using compound 15c (100

mg) and 5% Pd/C (20 mg, 20 wt%) in ethanol (5 mL). The crude product

was puriﬁed by ﬂash column chromatography (CH₂Cl₂/MeOH, 25:1) to

afford the desired product as a yellow oil (59 mg, 90.3% yield). ¹H NMR

(600 MHz, DMSO‑d₆) δ 10.33 (s, 1H), 6.92 (d, J = 2.1 Hz, 1H), 6.89 (d, J

= 9.1 Hz, 2H), 6.86 (d, J = 9.1 Hz, 2H), 6.26 (d, J = 2.4 Hz, 1H), 6.17 (d,

J = 2.3 Hz, 1H), 4.08 (brt, J = 6.9 Hz, 2H), 3.69 (s, 3H), 3.00 (dd, J =

16.0, 2.2 Hz, 1H), 2.61 (d, J = 16.0 Hz, 1H), 2.46 (s, 3H), 2.33 (dt, J =

13.9, 6.9 Hz, 1H), 2.23 (dt, J = 13.9, 6.6 Hz, 1H); ¹³C NMR (150 MHz,

DMSO‑d₆) δ 191.39, 163.08, 161.68, 153.82, 152.75, 142.80, 115.75 (2

× C), 115.06 (2 × C), 112.89, 112.42, 102.06, 101.41, 64.27, 55.78,

48.38, 40.02, 23.05. HRMS (ESI) m/z calcd for C₁₉H₂₀O₆[M + H]⁺

345.1333, found 345.1316.

4.1.18.9. Mixture of tautomers, 1-[2,4-bis(benzyloxy)-6-methylphenyl]-3-

hydroxy-2- octen-1-one and 1-[2,4-bis(benzyloxy)-6-methylphenyl]-1,3-

octanedione (15i). The tittle compound was synthesized as described

in the general procedure using 14i (224 mg, 0.5 mmol). The crude

product was puriﬁed by ﬂash column chromatography (Petroleum

ether/EtOAc, 20:1) to afford the desired product as a yellow oil (179 mg,

80.7% yield). According to the characteristic proton signals in ¹H NMR,

the product was a mixture of enol-keto tautomers containing approxi-

mately 80.0% enol-tautomer and 20.0% keto-tautomer. Enol-tautomer:

¹H NMR (600 MHz, Chloroform-d) δ 15.72 (brs, 1H), 7.42 – 7.27 (m,

10H), 6.45 (brs, 2H), 5.76 (s, 1H), 5.03 (s, 2H), 5.03 (s, 2H), 2.33 (s, 3H),

2.30 (t, J = 7.4 Hz, 2H), 1.60 (qiunt, J = 7.4 Hz, 2H), 1.34 – 1.26 (m,

4H), 0.88 (t, J = 7.0 Hz, 3H); ¹³C NMR (150 MHz, Chloroform-d) δ

194.04, 187.22, 160.28, 157.19, 139.15, 136.67, 136.55, 128.64 (2 ×

C), 128.45 (2 × C), 128.11, 127.77, 127.50 (2 × C), 126.90 (2 × C),

120.54, 108.58, 103.45, 98.46, 70.46, 70.05, 38.51, 31.44, 25.49,

22.40, 20.31, 13.94. Keto-tautomer: ¹H NMR (600 MHz, Chloroform-d) δ

7.42 – 7.27 (m, 10H), 6.44 (brs, 2H), 5.03 (s, 2H), 5.02 (s, 2H), 3.90 (s,

2H), 2.32 (t, J = 7.5 Hz, 2H), 2.30 (s, 3H), 1.44 (qiunt, J = 7.5 Hz, 2H),

1.23 (qiunt, J = 7.5 Hz, 2H), 1.17 – 1.11 (m, 2H), 0.85 (t, J = 7.3 Hz,

3H);¹³C NMR (150 MHz, Chloroform-d) δ 204.99, 199.27, 160.84,

158.05, 139.86, 136.33, 135.88, 128.73 (2 × C), 128.67 (2 × C), 128.37,

128.20, 127.74 (2 × C), 127.52 (2 × C), 123.13, 109.04, 97.89, 70.73,

70.10, 58.76, 43.29, 31.17, 22.98, 22.42, 20.45, 13.92.

4.1.19.4. 2,3-dihydro-2,7-dihydroxy-5-methyl-2-[2-[3-(triﬂuoromethyl)

phenoxy]- ethyl]-4H-1-benzopyran-4-one (16d). The tittle compound

was synthesized as described in the general procedure B using com-

pound 15d (100 mg) and 5% Pd/C (20 mg, 20 wt%) in ethanol (5 mL).

The crude product was puriﬁed by ﬂash column chromatography

(CH₂Cl₂/MeOH, 25:1) to afford the desired product as a yellow oil (58

mg, 85.3% yield). ¹H NMR (600 MHz, DMSO‑d₆) δ 10.33 (s, 1H), 7.53 (t,

J = 8.3 Hz, 1H), 7.31 – 7.27 (m, 3H), 6.97 (d, J = 2.0 Hz, 1H), 6.26 (d, J

= 2.3 Hz, 1H), 6.18 (d, J = 2.3 Hz, 1H), 4.24 (brt, J = 6.9 Hz, 2H), 3.04

(dd, J = 15.9, 2.0 Hz, 1H), 2.64 (d, J = 15.9 Hz, 1H), 2.47 (s, 3H), 2.39

(dt, J = 14.0, 6.9 Hz, 1H), 2.29 (dt, J = 14.0, 6.8 Hz, 1H); ¹³C NMR (150

MHz, DMSO‑d₆) δ 191.35, 163.09, 161.65, 159.08, 142.80, 131.18,

130.79 (q, J_C-F= 31.5 Hz), 124.49 (q, J_C-F= 272.4 Hz), 119.32, 117.62

(q, J_C-F= 3.9 Hz), 112.91, 112.41, 111.33 (q, J_C-F= 3.9 Hz), 102.07,

101.27, 64.49, 48.25, 39.97, 23.05. HRMS (ESI) m/z calcd for

C

₁₉H₁₇F₃O₅[M + H]⁺383.1101, found 383.1100.

4.1.19. Synthesis of compounds 16a-16i

4.1.19.5. 2,3-dihydro-2,7-dihydroxy-5-methyl-2-[2-[4-(triﬂuoromethyl)

phenoxy]- ethyl]-4H-1-benzopyran-4-one (16e). The tittle compound was

synthesized as described in the general procedure B using compound

15e (100 mg) and 5% Pd/C (20 mg, 20 wt%) in ethanol (5 mL). The

crude product was puriﬁed by ﬂash column chromatography (CH₂Cl₂/

MeOH, 25:1) to afford the desired product as a yellow oil (55 mg, 80.3%

yield). ¹H NMR (600 MHz, DMSO‑d₆) δ 10.33 (s, 1H), 7.66 (d, J = 8.6 Hz,

2H), 7.16 (d, J = 8.6 Hz, 2H), 6.98 (d, J = 2.2 Hz, 1H), 6.26 (d, J = 2.3

Hz, 1H), 6.18 (d, J = 2.3 Hz, 1H), 4.25 (brt, J = 6.9 Hz, 2H), 3.02 (dd, J

= 16.0, 2.2 Hz, 1H), 2.63 (d, J = 15.9 Hz, 1H), 2.46 (s, 3H), 2.39 (dt, J =

14.0, 7.0 Hz, 1H), 2.30 (dt, J = 13.7, 6.6 Hz, 1H); ¹³C NMR (150 MHz,

4.1.19.1. 2,3-dihydro-2,7-dihydroxy-5-methyl-2-(2-phenoxyethyl)-4H-1-

benzopyran-4-one (16a). The tittle compound was synthesized as

described in the general procedure B using compound 15a (100 mg) and

5% Pd/C (20 mg, 20 wt%) in ethanol (5 mL). The crude product was

puriﬁed by ﬂash column chromatography (CH₂Cl₂/MeOH, 25:1) to

afford the desired product as a yellow oil (52 mg, 80.8% yield). ¹H NMR

(600 MHz, DMSO‑d₆) δ 10.32 (s, 1H), 7.31 – 7.27 (m, 2H), 6.96 – 6.92

(m, 4H), 6.26 (d, J = 2.3 Hz, 1H), 6.18 (d, J = 2.3 Hz, 1H), 4.15 (brd, J =

7.0 Hz, 2H), 3.01 (dd, J = 15.9, 1.9 Hz, 1H), 2.62 (d, J = 15.9 Hz, 1H),

2.46 (s, 3H), 2.36 (dt, J = 14.0, 7.0 Hz, 1H), 2.26 (dt, J = 14.0, 6.8 Hz,

1H); ¹³C NMR (150 MHz, DMSO‑d₆) δ 191.37, 163.09, 161.68, 158.73,

142.81, 129.98 (2 × C), 121.06, 114.87 (2 × C), 112.91, 112.43, 102.07,

101.38, 63.73, 48.39, 39.96, 23.03. HRMS (ESI) m/z calcd for C₁₈H₁₈O₅

[M + H]⁺315.1227, found 315.1214.

DMSO‑d₆) δ 191.29, 163.10, 161.63, 161.62, 142.82, 127.43 (q, J_C-F

=

3.9 Hz, 2 × C), 125.04 (q, J_C-F= 272.4 Hz), 121.60 (q, J_C-F= 32.0 Hz),

115.42 (2 × C), 112.93, 112.41, 102.01, 101.26, 64.41, 48.33, 39.72,

23.04. HRMS (ESI) m/z calcd for C₁₉H₁₇F₃O₅[M + H]⁺383.1101, found

383.1118.

4.1.19.2. 2,3-dihydro-2,7-dihydroxy-5-methyl-2-[2-(3-methylphenoxy)

ethyl]-4H-1- benzopyran-4-one (16b). The tittle compound was synthe-

sized as described in the general procedure B using compound 15b (100

mg) and 5% Pd/C (20 mg, 20 wt%) in ethanol (5 mL). The crude product

was puriﬁed by ﬂash column chromatography (CH₂Cl₂/MeOH, 25:1) to

afford the desired product as a yellow oil (59 mg, 89.7% yield). ¹H NMR

(600 MHz, DMSO‑d₆) δ 10.34 (brs, 1H), 7.16 (t, J = 7.8 Hz, 1H), 6.94

(brs, 1H), 6.78 (brs, 1H), 6.77 – 6.73 (m, 2H), 6.26 (d, J = 2.3 Hz, 1H),

6.18 (d, J = 2.3 Hz, 1H), 4.12 (brt, J = 7.0 Hz, 2H), 3.00 (d, J = 16.0 Hz,

1H), 2.62 (d, J = 16.0 Hz, 1H), 2.46 (s, 3H), 2.34 (dt, J = 13.9, 6.9 Hz,

1H), 2.28 (s, 3H), 2.24 (dt, J = 13.9, 6.8 Hz, 1H); ¹³C NMR (150 MHz,

4.1.19.6. 2,3-dihydro-2,7-dihydroxy-5-methyl-2-[2-(3-ﬂuorophenoxy)

ethyl]-4H-1- benzopyran-4-one (16f). The tittle compound was synthe-

sized as described in the general procedure B using compound 15f (100

mg) and 5% Pd/C (20 mg, 20 wt%) in ethanol (5 mL). The crude product

was puriﬁed by ﬂash column chromatography (CH₂Cl₂/MeOH, 25:1) to

afford the desired product as a yellow oil (56 mg, 86.4% yield). ¹H NMR

(600 MHz, DMSO‑d₆) δ 10.35 (brs, 1H), 7.31 (q, J = 7.8 Hz, 1H), 6.96

(brs, 1H), 6.86 (brd, J = 11.3 Hz, 1H), 6.81 (brd, J = 8.4 Hz, 1H), 6.77

(brt, J = 8.4 Hz, 1H), 6.26 (d, J = 2.2 Hz, 1H), 6.18 (d, J = 2.2 Hz, 1H),

4.17 (brt, J = 6.9 Hz, 2H), 3.01 (d, J = 16.0 Hz, 1H), 2.62 (d, J = 16.0

15

W. Wu et al.

Bioorganic Chemistry 111 (2021) 104898

Hz, 1H), 2.46 (s, 3H), 2.36 (dt, J = 13.8, 7.0 Hz, 1H), 2.27 (dt, J = 13.8,

/ well for 24 h. Cells were pretreated with synthetic molecules (33

μ

M)

6.7 Hz, 1H); ¹³C NMR (150 MHz, DMSO‑d₆) δ 191.35, 163.48 (d, J_C-F

=

for 2 h and were induced with LPS (1 μg / mL). After 24 h, the cell su-

242.8 Hz), 163.10, 161.65, 160.27 (d, J_C-F= 11.0 Hz), 142.81, 131.16

(d, J_C-F= 10.1 Hz), 112.92, 112.41, 111.34 (d, J_C-F= 2.7 Hz), 107.67 (d,

J_C-F= 21.2 Hz), 102.39 (d, J_C-F= 24.9 Hz), 102.07, 101.28, 64.38,

48.28, 39.96, 23.05. HRMS (ESI) m/z calcd for C₁₈H₁₇FO₅[M + Na]⁺

355.0952, found 355.0953.

pernatant was collected for further research. The NO production was

measured by Griess reagent assay as previously described [24,25] and

the inhibition of NO production calculation was calculated by formula:

A₅₄₀(LPS) ꢀ A₅₄₀(test com pound)

inhibition rate (\%) =

× 100%

A₅₄₀(LPS) ꢀ A₅₄₀(DMSO)

4.1.19.7. 2,3-dihydro-2,7-dihydroxy-5-methyl-2-propyl-4H-1-benzopyran-

4-one (16 g). The tittle compound was synthesized as described in the

general procedure B using compound 15 g (100 mg) and 5% Pd/C (20

mg, 20 wt%) in ethanol (5 mL). The crude product was puriﬁed by ﬂash

column chromatography (CH₂Cl₂/MeOH, 15:1) to afford the desired

product as a yellow oil (49 mg, 85.7% yield). ¹H NMR (600 MHz,

DMSO‑d₆) δ 10.27 (brs, 1H), 6.61 (s, 1H), 6.23 (d, J = 2.4 Hz, 1H), 6.13

(d, J = 2.4 Hz, 1H), 2.84 (d, J = 15.8 Hz, 1H), 2.47 (d, J = 15.8 Hz, 1H),

2.45 (s, 3H), 1.83 – 1.71 (m, 2H), 1.45 – 1.38 (m, 2H), 0.91 (t, J = 7.4 Hz,

3H); ¹³C NMR (150 MHz, DMSO‑d₆) δ 191.72, 163.04, 162.02, 142.69,

112.69, 112.45, 102.49, 101.98, 47.70, 42.86, 23.03, 17.12, 14.57.

HRMS (ESI) m/z calcd for C₁₃H₁₆O₄[M + H]⁺237.1121, found

237.1118.

4.2.3. Western blotting

RAW264.7 cells were cultured in a 6-well plate with 0.8 × 10⁶cells /

well for 24 h. Cells were pretreated with compound 7a, 16d or positive

control (DXM) for 2 h and then induced with LPS (1 μg / mL). After 30

min or 24 h (for iNOS protein), the cells were harvested and lysed with

RIPA buffer and then the total protein was extracted by Protein

Extraction Kits (Beyotime, Shanghai, China). The concentration of total

protein was determined by BCA protein assay kit (Beyotime, Shanghai,

China). Equal quantities of protein (40–60 μg) were separated by 10%

SDS-PAGE and then were transferred to 0.45 µm PVDF membranes

(Millipore, Billerica, MA, America). The membranes were blocked with

5% milk for 1 h and incubated with the speciﬁc primary antibody p65

(1:1000, ABclonal, Boston, MA, America), p-p65 (1:1000, ABclonal,

Boston, MA, America), IκB-α(1:2000, Cell Signaling Technology, Boston,

4.1.19.8. 2-butyl-2,3-dihydro-2,7-dihydroxy-5-methyl-4H-1-benzopyran-

4-one (16 h). The tittle compound was synthesized as described in the

general procedure B using compound 15 h (100 mg) and 5% Pd/C (20

mg, 20 wt%) in ethanol (5 mL). The crude product was puriﬁed by ﬂash

column chromatography (CH₂Cl₂/MeOH, 15:1) to afford the desired

product as a yellow oil (52 mg, 89.4% yield). ¹H NMR (600 MHz,

DMSO‑d₆) δ 10.26 (s, 1H), 6.60 (d, J = 2.2 Hz, 1H), 6.23 (d, J = 2.3 Hz,

1H), 6.13 (d, J = 2.3 Hz, 1H), 2.83 (d, J = 15.7 Hz, 1H), 2.47 (d, J = 15.7

Hz, 1H), 2.45 (s, 3H), 1.84 – 1.73 (m, 2H), 1.41 – 1.35 (m, 2H), 1.34 –

1.28 (m, 2H), 0.89 (t, J = 7.2 Hz, 3H); ¹³C NMR (150 MHz, DMSO‑d₆) δ

191.71, 163.02, 162.02, 142.69, 112.68, 112.46, 102.57, 101.98, 47.71,

39.98, 25.87, 23.03, 22.76, 14.40. HRMS (ESI) m/z calcd for C₁₄H₁₈O₄

[M + H]⁺251.1278, found 251.1269.

MA, America), p-IκB-α (1:2000, Cell Signaling Technology, Boston, MA,

America) and iNOS (1:2000, Cell Signaling Technology, Boston, MA,

◦

America) overnight at 4 C. After washing three times with TBST, the

membranes were incubated with HRP-secondary antibody for 1 h at

room temperature. At last, the resulting bolts were treated with

enhanced chemiluminescence reagents (Millipore, Billerica, MA,

America) and detected by Bio-Rad ChemiDoc™XRS + System (Bio-Rad,

Hercules, CA, USA).

4.2.4. Statistical analyses

All experiments were repeated at least three times, experimental data

were expressed as mean ± SD and analyzed statistically by Student’s t

test. The differences were assumed to be statistically signiﬁcant at p <

0.05.

4.1.19.9. 2,3-dihydro-2,7-dihydroxy-5-methyl-2-pentyl-4H-1-benzopyran-

4-one (16i). The tittle compound was synthesized as described in the

general procedure B using compound 15i (100 mg) and 5% Pd/C (20

mg, 20 wt%) in ethanol (5 mL). The crude product was puriﬁed by ﬂash

column chromatography (CH₂Cl₂/MeOH, 25:1) to afford the desired

product as a yellow oil (49 mg, 81.9% yield). ¹H NMR (600 MHz,

DMSO‑d₆) δ 10.26 (s, 1H), 6.60 (d, J = 2.1 Hz, 1H), 6.23 (d, J = 2.3 Hz,

1H), 6.12 (d, J = 2.3 Hz, 1H), 2.84 (dd, J = 15.8, 2.1 Hz, 1H), 2.47 (d, J

= 15.9 Hz, 1H), 2.45 (s, 3H), 1.83 – 1.72 (m, 2H), 1.43 – 1.36 (m, 2H),

1.33 – 1.25 (m, 4H), 0.88 (t, J = 7.0 Hz, 3H); ¹³C NMR (150 MHz,

DMSO‑d₆) δ 191.71, 163.01, 162.02, 142.69, 112.68, 112.46, 102.57,

101.97, 47.70, 40.61, 31.82, 23.36, 23.03, 22.52, 14.38. HRMS (ESI) m/

z calcd for C₁₅H₂₀O₄[M + H]⁺265.1434, found 265.1434.

Declaration of Competing Interest

The authors declared no conﬂict of interest.

Acknowledgments

This work was supported by Speciﬁc Research Project of Guangxi for

Research Bases and Talents (Grant No. AD18281066), P. R. China, and

Science and Technology Major Project of Guangxi, P. R. China (Grant

No. AA18242026).

Appendix A. Supplementary material

4.2. Biological activities

Supplementary data to this article can be found online at https://doi.

org/10.1016/j.bioorg.2021.104898.

4.2.1. Cell culture and cell cytotoxicity

The Raw264.7 cells were cultured in DMEM (Corning, Wujiang,

Jiangsu Province, China) supplemented with 10% fetal bovine serum

(Lonsera, Uruguay), 2 mM glutamine (Biological Industries, Israel), 100

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