Synthesis of non-prenyl analogues of baccharin as selective and potent inhibitors for aldo-keto reductase 1C3

Bioorganic & Medicinal Chemistry 22 (2014) 5220–5233

Contents lists available at ScienceDirect

Bioorganic & Medicinal Chemistry

journal homepage: w ww.elsevier.com/locate/bmc

Synthesis of non-prenyl analogues of baccharin as selective

and potent inhibitors for aldo-keto reductase 1C3

b

a

c

Satoshi Endo ^a,, Dawei Hu , Toshiyuki Matsunaga , Yoko Otsuji , Ossama El-Kabbani ,

⇑

Mahmoud Kandeel ^d,, Akira Ikari ^a, Akira Hara ^d, Yukio Kitade ^d, Naoki Toyooka ^b,e

^aGifu Pharmaceutical University, Gifu 501-1196, Japan

^bGraduate School of Innovative Life Science, University of Toyama, Toyama 930-8555, Japan

^cMonash Institute of Pharmaceutical Sciences, Parkville, Victoria 3052, Australia

^dDepartment of Biomolecular Science, Faculty of Engineering, Gifu University, Gifu 501-1193, Japan

^eGraduate School of Science and Technology for Research, University of Toyama, Toyama 930-8555, Japan

a r t i c l e i n f o

a b s t r a c t

Article history:

Inhibitors of a human member (AKR1C3) of the aldo-keto reductase superfamily are regarded as prom-

ising therapeutics for the treatment of prostatic and breast cancers. Baccharin [3-prenyl-4-(dihydrocin-

namoyloxy)cinnamic acid], a component of propolis, was shown to be both potent (K_i56 nM) and

highly isoform-selective inhibitor of AKR1C3. In this study, a series of derivatives of baccharin were syn-

thesized by replacing the 3-prenyl moiety with aryl and alkyl ether moieties, and their inhibitory activ-

ities for the enzyme were evaluated. Among them, two benzyl ether derivatives, 6m and 6n, showed an

equivalent inhibitory potency to baccharin. The molecular docking of 6m in AKR1C3 has allowed the

design and synthesis of (E)-3-{3-[(3-hydroxybenzyl)oxy]-4-[(3-phenylpropanoyl)oxy]phenyl}acrylic acid

(14) with improved potency (K_i6.4 nM) and selectivity comparable to baccharin. Additionally, 14 signif-

icantly decreased the cellular metabolism of androsterone and cytotoxic 4-oxo-2-nonenal by AKR1C3 at

much lower concentrations than baccharin.

Received 26 June 2014

Revised 6 August 2014

Accepted 7 August 2014

Available online 14 August 2014

Keywords:

Aldo-keto reductase

AKR1C3

Baccharin

Inhibitor

Selectivity

Cancer

1. Introduction

antiproliferative effect of baccharin against human prostatic cancer

PC3 cells.⁷

Baccharin (Fig. 1) is a constituent in the ethanol extract of

Brazilian propolis,¹which is a natural resinous substance collected

by honeybees and has been used in alternative medicine to treat

inﬂammation, liver disorders, and stomach ulcers. Baccharin

has several biological activities, such as growth suppressive and

antiproliferative effects on cancer cell lines,^1–4inhibition of

hypoxia-inducible factor-1 expression,⁵and preventive effect on

genotoxicity induced by methyl methanesulfonate and hydrogen

peroxide.⁶In addition, we have recently found that baccharin is a

selective and potent inhibitor of a human member of the aldo-keto

reductase (AKR) superfamily, AKR1C3, and this correlates with the

AKR1C3 (17b-hydroxysteroid dehydrogenase type 5) plays a

pivotal role in androgen biosynthesis especially in the prostate,

where the enzyme catalyzes the NADPH-linked reduction of weak

androgen precursors to testosterone and 5a-dihydrotestoster-

one.^8,9The enzyme is one of the most highly upregulated enzymes

in castrate-resistant prostate cancer, and is a target for drug devel-

opment of the prostate cancer.^8–10AKR1C3 is also responsible for

estrogen synthesis by reducing estrone into 17b-estradiol,¹¹and

exhibits prostaglandin (PG) F synthase activity, which leads to

decreases in the levels of antiproliferative PGD₂and 15-deoxy-

D

^12,14-PGJ₂.^11,12Since AKR1C3 is also upregulated in breast

cancer,¹¹it is suggested to be implicated in the development and

progression of both breast and prostatic cancers. Furthermore,

AKR1C3 has been reported to be responsible for developing resis-

tance of cancer cells to anticancer drugs such as human oxalipla-

tin,¹³cisplatin,¹⁴and anthracyclines.^15,16Thus, this enzyme has

been recognized as a potential therapeutic target for the treatment

of the above types of cancers and chemoresistance.

Abbreviations: AKR, aldo-keto reductase; ONE, 4-oxo-2-nonenal; PG,

prostaglandin.

⇑

Corresponding author. Tel.: +81 58 237 5979; fax: +81 58 237 3931.

E-mail address: sendo@gifu-pu.ac.jp (S. Endo).

Present address: Department of Physiology, Biochemistry and Pharmacology,

Faculty of Veterinary Medicine and Animal Resources, King Faisal University, Alhofuf,

Alehsa 31892, Saudi Arabia.

http://dx.doi.org/10.1016/j.bmc.2014.08.007

S. Endo et al. / Bioorg. Med. Chem. 22 (2014) 5220–5233

5221

by removal of MOM protecting group. The condensation of 5a–5p

with hydrocinnamoyl chloride gave esters (6a–6z). Compounds

(7w–7z) were obtained by removal of THP protecting group of

6w–6z.

Within the synthesized compounds having a series of aliphatic

ethers (Table 1) instead of the prenyl moiety of baccharin, the IC₅₀

values for these ethers in the inhibition of AKR1C3 tended to

decrease with increasing the aliphatic chain lengths, and 6j having

n-butyl ether showed the highest inhibitory potency. However, the

compounds having benzyl ethers (6f, 6i and 6m–6p), except for 6h

having 4-chlorobenzyl ether and 6k having phenethyl ether, exhib-

ited more potent inhibition than 6j. Among these benzyl ethers,

6m with 4-methylbenzyl ether and 6n with 3-ﬂuorobenzyl ether

were the most potent, although their IC₅₀values were the same

as that for baccharin.

Compounds (6q–6u and 7w–7y) are derivatives of 6m and 6n,

which have ﬂuoro or hydroxyl group on the phenyl rings in their

dihydrocinnamoyloxy moieties, as shown in Table 2. These deriva-

tives inhibited AKR1C3 less potently compared with the mother

compounds (6m and 6n). In addition, the compounds having the

hydroxyphenyl rings (7w–7y) inhibited AKR1C4 (IC₅₀values for

Figure 1. Structure of baccharin [3-prenyl-4-(dihydrocinnamoyloxy)cinnamic

acid]. The prenyl moiety is circled.

AKR1C3 shares at least an 84% amino acid sequence identity

with other human AKR1C isoforms (AKR1C1, AKR1C2 and AKR1C4)

that play distinct roles in the metabolism of steroid hormones and

bile acids such as 20- and/or 3-hydroxysteroid dehydrogenases.¹¹

The inhibitory selectivity to AKR1C3 over the other AKR1C isoforms

is required for the development of drugs targeting this enzyme.

During the past ﬁve years, many synthetic and natural compounds

that show inhibitory effects on AKR1C3 have been reported, as

reviewed by recent literature.^8,16,17Among the synthetic inhibitors,

3-[3,4-dihydroisoquinolin-2(1H)-ylsulfonyl]benzoic acids,¹⁸N-

phenylanthranilate derivatives,¹⁹1-[4-(piperidin-1-ylsulfonyl)

phenyl]pyrrolidin-2-ones,²⁰morpholylureas,²¹indomethacin ana-

logues²²and N-(2-hydroxyphenyl)-2,4-dioxo-5-thiazolidineaceta-

mide²³show high inhibitory potency (IC₅₀values of less than

7w, 7x, 7y and 7z were 1.7, 0.28, 0.72 and 2.9 lM, respectively),

although the other synthesized compounds (6a–6u) did not show

signiﬁcant inhibition towards AKR1C4. Thus, the dihydrocinna-

moyloxy moiety itself is the most suitable constituent for the

selective and potent inhibition of AKR1C3.

2.2. Synthesis of baccharin derivatives based on its docked

model

0.2 lM) and selectivity (more than 300-fold against the other three

AKR1C isoforms). Out of the natural compounds, baccharin is the

most potent and selective inhibitor showing an IC₅₀value of

0.11 lM and more than 900-fold selectivity to AKR1C3 over the

To design more potent and selective baccharin-based inhibitors,

we constructed a model of docked 6m in the AKR1C3–NADP⁺com-

plex (Fig. 2A). In this model, the orientation of 6m in the binding

site and its interactions with amino acids resembled those in its

previously reported baccharin-docked model.⁷However, the

4-methylbenzyl ether moiety of 6m was bulky compared to the

3-prenyl moiety of baccharin, and its aromatic ring was in close

proximity to the hydroxyl group of Tyr24, which also formed a

H-bond interaction with the side chain of Arg226 that was posi-

tioned at a distance of 3.7 Å from the aromatic ring. This raised a

possibility that an introduction of the hydroxyl group in the benzyl

ether of 6m at m-position (i.e., 14) forms a new H-bond interaction

with the phenolic side-chain of Tyr24. The suggested interaction

(2.7 Å) was indeed predicted in a 14-docked model (Fig. 2B), and

its distance was shorter than the H-bond distance between Tyr24

and Arg226. To conﬁrm the interaction of the 3-hydroxybenzyl

ether moiety of 14 predicted from the docked model, we synthe-

sized 14 and its methoxy derivative (13b) using the approach out-

lined in Scheme 2. Benzylation of dianion of 1 gave rise to benzyl

ethers (9a and 9b),²⁵which were converted to unsaturated esters

(11a and 11b) after protection of phenols as THP ethers (10a and

10b). Compound 13b was synthesized via the carboxylic acid 12b

as described in Scheme 1. Compound 14 was obtained by deprotec-

tion of MOM group in 13b.

Compound 14 with the 3-hydroxyl group on the phenyl ring in

the benzyl ether moiety inhibited AKR1C3 approximately 5-fold

more potently (IC₅₀20 nM) than baccharin, and its inhibitory

selectivity was compared with that of baccharin (Table 3).

Although 14 showed a lower IC₅₀value towards AKR1C4 than bac-

charin, its selectivity towards AKR1C3 (IC₅₀ratios of other AKR1C

isoforms/AKR1C3) was comparable to that of baccharin. In contrast

to 14, 13b, methyl ether of 14, signiﬁcantly decreased the inhibi-

tion potency towards AKR1C3. The marked decline in inhibition

by 13b may be due to the alteration in orientation of its 3-

methoxybenzyl ester moiety against Tyr24, Leu54 and Trp227, as

well as the lack of the hydrogen bond interaction seen in the

other three AKR1C isoforms.⁷Due to its high inhibitory selectivity,

baccharin represents a promising lead for the development of more

potent and speciﬁc agents targeting AKR1C3. However, baccharin

has a prenyl moiety that is difﬁcult to be synthetically modiﬁed.

In this study, we designed and synthesized non-prenyl derivatives

based on the structural knowledge of the type of interactions

between AKR1C3 and baccharin suggested by the previous molecu-

lar docking and site-directed mutagenesis studies.⁷

2. Results and discussion

2.1. Synthesis of non-prenyl derivatives of baccharin and their

inhibitory potencies

In our earlier molecular docking of baccharin [3-prenyl-4-(dihy-

drocinnamoyloxy)cinnamic acid] in AKR1C3 and site-directed

mutagenesis studies,⁷the following interactions were suggested

to be important for tight binding. (1) The carbonyl group of the

esteriﬁed dihydrocinnamoyloxy moiety is in close proximity to

the enzyme’s active site residues, Tyr55 and His117. (2) The car-

boxyl group of the cinnamic acid moiety forms a strong H-bond

interaction with Ser118, in addition to hydrophobic/van der Waals

interactions with Met120 and Phe311. In addition, the structure–

inhibitory activity relationship of propolis-derived cinnamic acids

suggests that the 3-prenyl moiety of baccharin is responsible for

the selective binding to AKR1C3.⁷Since the modiﬁcation of the pre-

nyl substituent is synthetically difﬁcult, we ﬁrst synthesized deriv-

atives having 3-aliphatic and aryl ethers from commercially

available 3,4-dihydroxybenzaldehyde 1 instead of the 3-prenyl

moiety (Scheme 1). The compounds (3a–3p) were synthesized by

the alkylation of phenol (2).²⁴The Horner–Wadsworth–Emmons

reaction of 3a–3p gave their unsaturated esters (4a–4p), which

were converted to carboxylic acids (5a–5p) by hydrolysis followed

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S. Endo et al. / Bioorg. Med. Chem. 22 (2014) 5220–5233

Scheme 1. Synthesis of non-prenyl derivatives of baccharin (6a–6v and 7w–7z).

Table 1

Effects of replacement of 3-prenyl moiety of baccharin with aliphatic and aromatic

esters on inhibition of AKR1C3

Table 2

Effect of introduction of ﬂuoro and hydroxy groups in the dihydrocinnamoyloxy

moieties of 6m and 6n on AKR1C3 inhibition

a

Compound

R₁

IC₅₀(lM)

Compound

R2^a

IC₅₀(lM)

Baccharin

6b

Prenyl

Me

0.11

4.5 0.2

6m derivatives

6a

6d

6e

6j

6c

6l

6g

6f

6m

6o

6n

6i

6p

6h

6k

Et

Propyl

i-Propyl

Butyl

0.97 0.09

2.2 0.2

3.1 0.1

0.42 0.06

0.56 0.02

1.1 0.1

0.85 0.05

0.39 0.01

0.11 0.01

0.32 0.03

0.11 0.01

0.22 0.02

0.36 0.01

0.89 0.1

0.57 0.08

6t

3-Fluoro

4-Fluoro

2,4,6-Triﬂuoro

4-Hydroxy

3-Hydroxy

0.16 0.01

0.47 0.01

0.54 0.01

0.77 0.01

0.91 0.02

6v

6u

7z

7y

i-Butyl

(E)-But-2-en-1-yl

2-Methylallyl

Benzyl

4-Methylbenzyl

2-Fluorobenzyl

3-Fluorobenzyl

4-Fluorobenzyl

3,5-Diﬂuorobenzyl

4-Chlorobenzyl

Phenethyl

6n derivatives

6q

6r

6s

7x

7w

3-Fluoro

4-Fluoro

2,4,6-Triﬂuoro

3-Hydroxy

4-Hydroxy

0.40 0.02

0.54 0.02

0.58 0.04

0.80 0.07

0.84 0.02

a

R₂of 6m with R₁= 4-methylbenzyl ester and of 6n with R₁= 3-ﬂuorobenzyl

ester as shown in Scheme 1.

a

R₁of compounds 6a–p with R₂= H in Scheme 1.

are comparable or superior to those of the other synthetic inhibi-

tors (IC₅₀, 24–210 nM).^19–23Compound 14 inhibited competitively

with respect to the alcohol substrate in the S-1-tetralol oxidation

by AKR1C3, showing its K_ivalue of 6.4 0.5 nM, which is lower

than that for baccharin (K_i56 nM). The K_ivalue for 14 is

14-docked model. The inhibitory potency of 14 is slightly lower

than the 3-[3,4-dihydroisoquinolin-2(1H)-ylsulfonyl]benzoic acids

that are the most potent inhibitors known (IC₅₀, 6–13 nM),¹⁸but

S. Endo et al. / Bioorg. Med. Chem. 22 (2014) 5220–5233

5223

Figure 2. Models of docked compounds, 6m (A) and 14 (B), in the AKR1C3–NADP⁺complex. In addition to the enzyme’s residues within 3.5 Å from the inhibitors, Arg226 that

forms a H-bond interaction with Tyr24 is depicted, although its distances from the benzyl ether moieties of 6m and 14 are 3.8 and 3.6 Å, respectively. The possible H-bond

interactions are illustrated as dotted lines with their distances given in Å.

Scheme 2. Synthesis of compounds 13b and 14.

5224

S. Endo et al. / Bioorg. Med. Chem. 22 (2014) 5220–5233

Table 3

3. Conclusion

Inhibitory properties of 14 and 13b on AKR1C3 and other human AKR1C isoforms

a

Compound

IC₅₀

(

l

M) and inhibitory selectivity

In this study, a series of derivatives of baccharin, a selective

AKR1C3 inhibitor, were synthesized by replacing the 3-prenyl moi-

ety with aryl and alkyl ether moieties, and their inhibitory activi-

ties for the enzyme were evaluated. Two benzyl ether

derivatives, 6m and 6n, showed an equivalent inhibitory potency

to baccharin, although no improvement in the inhibitory potency

was achieved by the introduction of ﬂuoro- and hydroxyl groups

in the dihydrocinnamoyloxy moieties of 6m and 6n. The molecular

docking of 6m in the crystal structure of AKR1C3 has allowed the

design of a novel baccharin-based inhibitor (14) with improved

potency (K_i6.4 nM), which may be due to the introduction of a

new interaction between the 3-hydroxyl group of the benzyl moi-

ety of 14 and Tyr24 of the enzyme. The inhibitory selectivity of 14

for AKR1C3 over other human AKR1C isoforms was comparable or

superior to that of baccharin. Moreover, 14 signiﬁcantly decreased

the cellular metabolism of androsterone and cytotoxic ONE by

AKR1C3 at much lower concentrations than baccharin. Our synthe-

sis and evaluation results of compound 14 are indicative of its efﬁ-

cacy as a potential candidate for both biological tools and the

development of new therapeutics for cancers, in which AKR1C3

is overexpressed.

AKR1C3

0.11

AKR1C1

AKR1C2

AKR1C4

Baccharin

14

>100

102

(927)

(>909)

>100

0.020 0.004

0.96 0.09

81

3

20

3

(4050)

>100

(>5000)

>100

(1000)

>100

(>104)

13b

(>104)

a

Inhibitory selectivity is shown as an IC₅₀ratio of other enzyme/AKR1C3 in the

parenthesis.

comparable to those for an estrogen spiro-d-lactone, EM1404 (K_i

6.9 nM)²⁶and tolfenamic acid (K_i8 nM),²⁷which were previously

reported to show the lowest K_ivalues for AKR1C3.

2.3. Effect of compound 14 on cellular metabolism by AKR1C3

Compound 14 and baccharin were compared for their effects on

cellular metabolism of androsterone (5

which is rapidly reduced into

a

-androstan-3 -ol-17-one),

a

5

a

-androstane-3a,17b-diol by

AKR1C3 highly expressed in A549 cells.⁷Compound 14 inhibited

4. Experimental section

the androsterone metabolism more potently than baccharin, and

was effective from 0.05

lM, showing an IC₅₀value of 8 lM, which

4.1. General procedure for alkylation of 2

was 20 M for baccharin (Fig. 3A). We also compared the effects of

l

14 and baccharin on cellular metabolism of 4-oxo-2-nonenal (ONE)

by AKR1C3 (Fig. 3B). ONE is highly cytotoxic towards cultured cells

including bovine aortic endothelial cells,²⁸and approximately 70%

of the bovine aortic endothelial cells were killed by 24-h treatment

To a stirred solution of 2²⁴(1 mmol) in acetone (4 mL) were

added K₂CO₃(2 mmol), and alkyl halide (3 mmol), and the result-

ing mixture was reﬂuxed for 12 h. After cooling, the reaction mix-

ture was ﬁltered through celite. The ﬁltrate was removed under

reduced pressure, and the residue was chromatographed on silica

gel (15 g, hexane/acetone = 30:1) to give the corresponding com-

pound. Compounds 3a–f²⁹and 3j³⁰were known compounds.

of 15 l

M ONE. Since ONE is efﬁciently metabolized by AKR1C3,¹⁴

the cytotoxicity of ONE against the cells was signiﬁcantly sup-

pressed by the overexpression of AKR1C3. The suppressive effect

of the AKR1C3 overexpression on the cytotoxicity by ONE was

abrogated by the addition of 14 or baccharin in a dose dependent

manner, in which 14 was effective at its lower concentrations than

baccharin. The results clearly indicate that 14 was a more potent

inhibitor than baccharin in cellular level.

4.1.1. 4-(Methoxymethoxy)-3-[(2-

methylallyl)oxy]benzaldehyde (3g)

Yield: 56%; ¹H NMR (400 MHz, CDCl₃): d 1.87 (3H, s), 3.56 (3H,

s), 4.61 (2H, s), 5.05 (1H, br s), 5.15 (1H, br s), 5.36 (2H, s), 7.29 (1H,

Figure 3. Inhibitory effects of compound 14 and baccharin on cellular metabolism of androsterone and ONE by AKR1C3. (A) Inhibition of reductive metabolism of

androsterone in A549 cells by 14 and baccharin. The cells were incubated with 50 M androsterone for 24 h in the presence of the indicated concentrations of 14 ( ) and

l

baccharin (

), and the substrate and its metabolite 5a-androstane-3a,17b-diol in the medium were determined by LC/MS. The inhibition percentages of the activity are

expressed as the means SD (n = 3). ^⁄Signiﬁcant difference from the cells treated with baccharin, p < 0.05. (B) Protective effect of AKR1C3 overexpression against ONE-

induced cytotoxicity and its suppression by 14 and baccharin. The cells were transfected for 48 h with the expression vector alone (control) or the vector carrying AKR1C3

cDNA (1C3). The cells were pretreated for 2 h with the indicated concentrations of baccharin or 14 before treating for 24 h with 15

represent the means SD (n = 3), in which that of the ONE-nontreated control cells ( ) was taken as 100%. Cells: ONE-treated control and 1C3 cells (

1C3 cells ( ); ONE-treated 1C3 cells pretreated with baccharin ( ); and ONE-treated 1C3 cells pretreated with 14 (

). ^⁄Signiﬁcant difference from the ONE-treated

control cells, p < 0.05. ^#Signiﬁcant difference from the ONE-treated 1C3 cells, p < 0.05.

lM ONE (+), and their viability values

); ONE-nontreated

S. Endo et al. / Bioorg. Med. Chem. 22 (2014) 5220–5233

5225

d, J = 7.0 Hz), 7.45 (1H, s), 7.46 (1H, d, J = 7.0 Hz), 9.88 (1H, s); ¹³C

NMR (125 MHz, CDCl₃): d 19.2, 56.4, 72.4, 94.9, 111.7, 113.0,

115.2, 126.1, 130.9, 139.9, 149.2, 152.2, 190.9; IR (neat): 1690,

1506, 1263, 1128 cm^À1; MS (EI): m/z 236 (M⁺); HRMS: Calcd for

(neat): 1688, 1595, 1506, 1263 cm^À1;MS (EI): m/z 290 (M⁺);

HRMS: Calcd for C₁₆H₁₅O₄290.0954, Found: 290.0954.

4.1.8. 3-[(2-Fluorobenzyl)oxy]-4-

C

₁₃H₁₆O₄236.1049, Found: 236.1048.

(methoxymethoxy)benzaldehyde (3o)

Yield: 55%; mp: 56–58 °C; ¹H NMR (400 MHz, CDCl₃): d 3.51

(3H, s), 5.25 (2H, s), 5.30 (2H, s), 7.16–7.26 (4H, m), 7.28–7.51

(3H, m), 9.85 (1H, s); ¹³C NMR (125 MHz, CDCl₃): d 56.5, 64.9,

95.0, 112.5, 115.4 (d, J = 21 Hz), 115.6, 123.6 (d, J = 21 Hz), 124.3

(d, J = 3.7 Hz), 126.45, 129.7 (d, J = 3.7 Hz), 130.0 (d, J = 8.6 Hz),

131.1, 149.1, 152.5, 160.5 (d, J = 248 Hz), 190.8; IR (KBr): 1690,

1508, 1263, 1128 cm^À1; MS (EI): m/z 290 (M⁺); HRMS: Calcd for

4.1.2. 3-[(4-Chlorobenzyl)oxy]-4-

(methoxymethoxy)benzaldehyde (3h)

Yield: 99%; mp: 56–58 °C; ¹H NMR (400 MHz, CDCl₃): d 3.50

(3H, s), 5.15 (2H, s), 5.30 (2H, s), 7.35 (2H, d, J = 7.3 Hz), 7.27–

7.43 (5H, m), 9.82 (1H, s); ¹³C NMR (125 MHz, CDCl₃): d 56.5,

70.1, 95.50, 111.9, 115.3, 126.7, 128.7, 128.8, 131.0, 134.8, 149.0,

152.4, 190.8; IR (KBr): 1684, 1508, 1265, 1128 cm^À1; MS (EI):

m/z 306 (M⁺); HRMS: Calcd for C₁₆H₁₅ClO₄306.0659, Found:

306.0656.

C₁₆H₁₅FO₄290.0954, Found: 290.0954.

4.1.9. 3-[(3,5-Diﬂuorobenzyl)oxy]-4-

(methoxymethoxy)benzaldehyde (3p)

4.1.3. 3-[(4-Fluorobenzyl)oxy]-4-

(methoxymethoxy)benzaldehyde (3i)

Yield: 66%; mp: 79–81 °C; ¹H NMR (400 MHz, CDCl₃): d 3.54

(3H, s), 5.20 (2H, s), 5.32 (2H, s), 6.76 (1H, m), 6.99 (2H,

J = 5.7 Hz), 7.29 (1H, d, J = 8.3 Hz), 7.42 (1H, d, J = 1.7 Hz), 7.47

(1H, dd, J = 6.3, 2.0 Hz); ¹³C NMR (125 MHz, CDCl₃): d 56.6, 69.5,

95.0, 103.4 (t, J = 26 Hz), 109.7 (t, J = 6.1 Hz), 111.8, 115.3, 127.0,

140.4 (t, J = 9.2 Hz), 148.7, 152.5, 163.1 (d, J = 249 Hz), 163.2 (d,

Yield: 99%; ¹H NMR (400 MHz, CDCl₃): d 3.52 (3H, s), 5.16 (2H,

s), 5.32 (2H, s), 7.07 (2H, t, J = 8.3 Hz), 7.29 (1H, s), 7.41–7.47 (4H,

m), 9.84 (1H, s), ¹³C NMR (125 MHz, CDCl₃): 56.6, 70.3, 95.1,

112.1, 115.5, 115.7 (d, J = 22 Hz), 126.8, 129.4 (d, J = 7.2 Hz),

131.1, 132.2 (d, J = 3.7 Hz), 149.2. 152.6, 162.7 (d, J = 245 Hz),

191.0; IR (neat): 1688, 1595, 1506, 1263 cm^À1; MS (EI): m/z 290

(M⁺); HRMS: Calcd for C₁₆H₁₅FO₄290.0954, Found: 290.0954.

J = 249 Hz), 190.7; IR (KBr): 2831, 1690, 1601, 1269, 1126 cm^À1

;

MS (EI): m/z 308 (M⁺); HRMS: Calcd for C₁₆H₁₄F₂O₄308.0860,

Found: 308.0858.

4.1.4. 4-(Methoxymethoxy)-3-phenethoxybenzaldehyde (3k)

Yield: 75%; ¹H NMR (400 MHz, CDCl₃): d 3.18 (2H, t, J = 7.2 Hz),

3.50 (3H, s), 4.30 (2H, t, J = 7.2 Hz), 5.25 (2H, s), 7.23–7.26 (3H, m),

7.31–7.32 (3H, m), 7.41–7.43 (2H, m), 9.85 (1H, s), ¹³C NMR

(125 MHz, CDCl₃): d 35.5, 56.4, 69.6, 95.0, 111.1, 115.5, 126.2,

126.6, 128.5, 129.0, 131.1, 137.7, 149.4, 152.2, 190.9; IR (neat):

1689, 1505, 1264, 1125 cm^À1; MS (EI): m/z 286 (M⁺); HRMS: Calcd

for C₁₇H₁₈O₄286.1205, Found: 286.1204.

4.2. General procedure for Horner–Wadsworth–Emmons

reaction of 3

To a stirred suspension of NaH (1.2 mmol) in THF (4 mL) was

added diethyl phosphonoacetate (1.2 mmol) at 0 °C, and the result-

ing solution was stirred for 30 min. A THF solution (1 mL Â 2) of 3

(1 mmol) was added at 0 °C to the reaction mixture, and the result-

ing mixture was stirred for 12 h at room temperature. The reaction

was quenched by H₂O, and the aqueous mixture was extracted

with CH₂Cl₂(5 mL Â 3). The organic extracts were combined, dried

over Na₂SO₄, and the solvent was removed under reduced pres-

sure. The residue was chromatographed on silica gel (15 g, hex-

ane/acetone = 100:1–80:1) to give the corresponding ester.

Compounds 4b³¹and 4f³²were known compounds. Compounds

4a, 4c, 4d, and 4e were converted to known 5a, 5c, 5d, and 5e,

whose spectral data were identical with those of 5a, 5c, 5d, and 5e.

4.1.5. 3-But-2-enyloxy-4-methoxymethoxybenzaldehyde (3l)

Yield: 61%; ¹H NMR (500 MHz, CDCl₃): d 1.76 (3H, d, J = 6.0 Hz),

3.52 (3H, s), 4.59 (2H, d, J = 6.0 Hz), 5.31 (2H, s), 5.77 (1H, m), 5.87

(1H, m), 7.26 (1H, s), 7.65 (1H, d, J = 8.0 Hz), 7.42–7.44 (1H, m),

9.86 (1H, s); ¹³C NMR (125 MHz, CDCl₃): d 17.6, 56.2, 69.3, 94.7,

111.1, 114.9, 125.2, 125.8, 130.8, 130.9, 149.0, 152.1, 190.7; IR

(neat): 1689, 1506, 1261, 1127 cm^À1; MS (EI): m/z 236 (M⁺);

HRMS: Calcd for C₁₃H₁₆O₄236.1049, Found: 236.1047.

4.2.1. (E)-Ethyl 3-[4-(methoxymethoxy)-3-[(2-

methylallyl)oxy)phenyl]acrylate (4g)

4.1.6. 4-(Methoxymethoxy)-3-[(4-

methylbenzyl)oxy]benzaldehyde (3m)

Yield: 73%; ¹H NMR (400 MHz, CDCl₃): d 1.34 (3H, t, J = 7.2 Hz),

1.84 (3H, s), 3.52 (3H, s), 4.25 (2H, quint, J = 7.2 Hz), 4.54 (2H, s),

5.01 (1H, s), 5.11 (1H, s), 5.26 (2H, s), 6.27 (1H, d, J = 16.0 Hz),

7.07 (1H, br s), 7.09 (1H, d, J = 8.4 Hz), 7.12 (1H, d, J = 8.4 Hz),

7.60 (1H, d, J = 16.0 Hz); ¹³C NMR (125 MHz, CDCl₃): d 14.3, 19.2,

56.2, 60.3, 72.6, 95.2, 122.7, 112.9, 116.4, 116.5, 122.2, 128.8,

140.4, 144.3, 148.7, 149.0, 167.1; IR (neat): 1707, 1508, 1254,

1157 cm^À1; MS (EI): m/z 306 (M⁺); HRMS: Calcd for C₁₇H₂₂O₅

306.1467, Found: 306.1468.

Yield: 73%; mp: 71–72 °C; ¹H NMR (400 MHz, CDCl₃): d 2.35

(3H, s), 3.52 (3H, s), 5.19 (2H, s), 5.31 (2H, s), 7.19 (2H, d,

J = 7.8 Hz), 7.26 (1H, d, J = 7.7 Hz), 7.34 (2H, d, J = 7.8 Hz), 7.42

(1H, d, J = 7.7 Hz), 7.47 (1H, s); ¹³C NMR (125 MHz, CDCl₃): d

21.1, 56.4, 70.7, 94.9, 112.1, 115.4, 126.2, 127.5, 129.2, 131.0,

133.2, 149.3, 152.4, 190.9; IR (KBr): 1690, 1506, 1267,

1126 cm^À1; MS (EI): m/z 286 (M⁺); HRMS: Calcd for C₁₇H₁₈O₄

286.1205, Found: 286.1204.

4.2.2. (E)-Ethyl 3-{3-[(4-chlorobenzyl)oxy]-4-

(methoxymethoxy)phenyl}acrylate (4h)

4.1.7. 3-[(3-Fluorobenzyl)oxy]-4-

(methoxymethoxy)benzaldehyde (3n)

Yield: 81%; ¹H NMR (400 MHz, CDCl₃): d 1.43 (3H, t, J = 7.2 Hz),

3.62 (3H, s), 4.34 (2H, q, J = 7.2 Hz), 5.23 (2H, s), 5.35 (2H, s), 6.35

(1H, d, J = 16.0 Hz), 7.16 (1H, s), 7.19 (1H, dd, J = 8.3, 1.71 Hz),

7.44–7.49 (4H, m), 7.66 (1H, d, J = 16.0 Hz); ¹³C NMR (125 MHz,

CDCl₃): d 14.3, 56.3, 60.4, 70.3, 95.2, 113.3, 116.6, 116.7, 122.6,

128.6, 128.8, 128.9, 133.8, 135.2, 144.1, 148.8, 149.0, 167.0; IR

(neat): 1705, 1508, 1256, 1157 cm^À1; MS (EI): m/z 376 (M⁺);

HRMS: Calcd for C₂₀H₂₁ClO₅376.1087, Found: 376.1087.

Yield: 60%; ¹H NMR (400 MHz, CDCl₃): d 3.57 (3H, s), 5.24 (2H,

s), 5.38 (2H, s), 7.05 (1H, m), 7.22 (1H, s), 7.25 (1H, d, J = 6.8 Hz),

7.32 (1H, d, J = 8.8 Hz), 7.36–7.39 (1H, m), 7.48 (1H, s), 7.50 (1H,

dd, J = 4.6, 2.0 Hz), 9.88 (1H, s); ¹³C NMR (125 MHz, CDCl₃): d

56.5, 70.0, 95.0, 112.0, 114.1 (d, J = 22 Hz), 115.0 (d, J = 22 Hz),

115.3, 122.6 (d, J = 2.4 Hz), 126.6, 130.2 (d, J = 7.4 Hz), 131.0,

139.0 (d, J = 7.4 Hz), 149.0, 152.4, 163.0 (d, J = 247 Hz), 190.8; IR

5226

S. Endo et al. / Bioorg. Med. Chem. 22 (2014) 5220–5233

4.2.3. (E)-Ethyl 3-{3-[(4-ﬂuorobenzyl)oxy]-4-

(methoxymethoxy)phenyl}acrylate (4i)

1.7 Hz), 7.10 (1H, s), 7.11 (1H, dd, J = 7.1, 2.0 Hz), 7.151–7.230

(2H, m), 7.40–7.38 (1H, m), 7.57 (1H, d, J = 15.9 Hz), ¹³C NMR

(125 MHz, CDCl₃): d 14.3, 56.3, 60.3, 70.2, 95.2, 113.2, 114.0 (d,

J = 22 Hz), 114.8 (d, J = 22 Hz), 116.55, 116.63, 122.5 (d,

J = 2.4 Hz), 122.6, 128.8, 130.1 (d, J = 7.4 Hz), 139.3 (d, J = 7.4 Hz),

144.0, 148.7, 149.0, 163.0 (d, J = 247 Hz), 167.0; IR (neat): 1701,

1510, 1251, 1130 cm^À1; MS (EI): m/z 360 (M⁺); HRMS: Calcd for

Yield: 72%; ¹H NMR (400 MHz, CDCl₃): d 1.33 (3H, t, J = 7.1 Hz),

3.51 (3H, s), 4.24 (2H, q, J = 7.1 Hz), 5.12 (2H, s), 5.25 (2H, s), 6.26

(1H, d, J = 15.9 Hz), 7.04–7.11 (4H, m), 7.14 (1H, d, J = 8.1 Hz),

7.41 (2H, dd, J = 5.4, 3.4 Hz), ¹³C NMR (125 MHz, CDCl₃): d 14.3,

56.3, 60.4, 70.4, 95.2, 113.3, 115.5 (d, J = 21 Hz), 116.6, 122.6,

128.9, 129.2 (d, J = 8.5 Hz), 132.4 (J = 2.5 Hz), 144.1, 148.8, 149.0,

C₂₀H₂₁FO₅360.1373, Found: 360.1374.

162.5 (J = 246 Hz), 167.1; IR (neat): 1705, 1514, 1256, 1157 cm^À1

;

MS (EI): m/z 360 (M⁺); HRMS: Calcd for C₂₀H₂₁FO₅360.1373,

4.2.9. (E)-Ethyl 3-{3-[(2-ﬂuorobenzyl)oxy]-4-

Found: 360.1375.

(methoxymethoxy)phenyl}acrylate (4o)

Yield: 99%; ¹H NMR (400 MHz, CDCl₃): d 1.33 (3H, t, J = 7.1 Hz),

3.51 (3H, s), 4.25 (2H, quin, J = 7.1 Hz), 5.23 (2H, s), 5.25 (2H, s),

6.28 (1H, d, J = 15.9 Hz), 7.10–7.16 (5H, m), 7.28 (1H, t,

J = 8.1 Hz), 7.52 (1H, t, J = 8.1 Hz), 7.60 (1H, d, J = 15.9 Hz); ¹³C

NMR (125 MHz, CDCl₃): d 14.3, 56.3, 60.4, 64.8, 64.9, 95.3, 113.3,

115.4 (d, J = 21 Hz), 116.7 (d, J = 7.3 Hz), 122.7, 123.8 (d,

J = 21 Hz), 124.3 (d, J = 3.7 Hz), 129.0, 129.6, 129.7, 129.8 (d,

J = 7.3 Hz), 144.2, 148.8, 149.0, 160.4 (d, J = 247 Hz), 167.1; IR

(neat): 1705, 1508, 1256, 1159 cm^À1; MS (EI): m/z 360 (M⁺);

HRMS: Calcd for C₂₀H₂₁FO₅360.1373, Found: 360.1372.

4.2.4. (E)-Ethyl 3-[3-butoxy-4-

(methoxymethoxy)phenyl]acrylate (4j)

Yield: 93%, ¹H NMR (400 MHz, CDCl₃): d 0.978 (3H, t, J = 7.3 Hz),

1.33 (3H, t, J = 7.1 Hz), 1.52 (2H, sex, J = 7.3 Hz), 1.81 (2H, quint,

J = 7.3 Hz), 3.51 (3H, s), 4.04 (2H, t, J = 7.3 Hz), 4.26 (2H, t,

J = 7.1 Hz), 5.24 (2H, s), 6.31 (1H, d, J = 15.9 Hz), 7.04 (1H,

d, J = 7.3 Hz), 7.05 (1H, s), 7.11 (1H, d, J = 8.8 Hz), 7.61 (1H, d,

J = 15.9 Hz), ¹³C NMR (125 MHz, CDCl₃): d 13.8, 14.3, 19.2, 31.2,

56.3, 60.4, 68.7, 95.3, 112.0, 116.5, 116.9, 122.0, 129.0, 144.4,

148.7, 149.6, 167.2; IR (neat): 1715, 1508, 1256, 1159 cm^À1; MS

(EI): m/z 308 (M⁺); HRMS: Calcd for C₁₇H₂₄O₅308.1624, Found:

308.1621.

4.2.10. (E)-Ethyl-3-{3-[(3,5-diﬂuorobenzyl)oxy]-4-

(methoxymethoxy)phenyl}acrylate (4p)

Yield: 87%; mp: 78–80 °C; ¹H NMR (400 MHz, CDCl₃): d 1.33

(3H, t, J = 7.1 Hz), 3.53 (3H, s), 4.25 (2H, quin, J = 7.1 Hz), 5.14

(2H, s), 5.28 (2H, s), 6.26 (1H, d, J = 16.0 Hz), 6.76 (1H, t,

J = 8.8 Hz), 6.98 (2H, d, J = 6.1 Hz), 7.04 (1H, s), 7.15 (2H, quin,

J = 8.8 Hz), 7.57 (1H, d, J = 16.0 Hz); ¹³C NMR (125 MHz, CDCl₃): d

14.3, 56.4, 60.5, 69.8, 95.2, 103.4 (t, J = 28 Hz), 109.6 (d,

J = 6.1 Hz), 109.7 (d, J = 6.1 Hz), 113.3, 116.5, 116.8, 122.9, 128.9,

140.8 (t, J = 9.8 Hz), 144.0, 148.5, 149.0, 163.2 (d, J = 249 Hz),

163.3 (d, J = 249 Hz), 167.0; IR (KBr): 1701, 1510, 1252,

1130 cm^À1; MS (EI): m/z 378 (M⁺); HRMS: Calcd for C₂₀H₂₀F₂O₅

378.1279, Found: 378.1275.

4.2.5. (E)-Ethyl 3-[4-(methoxymethoxy)-3-

phenethoxyphenyl]acrylate (4k)

Yield: 95%; ¹H NMR (400 MHz, CDCl₃): d 1.33 (3H, t, J = 7.2 Hz),

3.16 (2H, t, J = 7.2 Hz), 3.51 (3H, s), 4.22–4.27 (4H, m), 5.20 (2H, s),

6.27 (1H, d, J = 15.9 Hz), 7.07 (1H, dd, J = 9.5, 1.7 Hz), 7.10 (1H, s),

7.11 (1H, d, J = 8.3 Hz), 7.30–7.35 (5H, m), 7.61 (1H, d,

J = 15.9 Hz); ¹³C NMR (125 MHz, CDCl₃): d 14.3, 35.7, 56.3, 60.4,

69.8, 95.3, 112.2, 116.6, 116.9, 122.3, 126.6, 128.5, 129.0, 137.9,

144.3, 148.7, 149.3, 167.1; IR (neat): 1707, 1508, 1256,

1159 cm^À1; MS (EI): m/z 356 (M⁺); HRMS: Calcd for C₂₁H₂₄O₅

356.1624, Found: 356.1623.

4.3. General procedure for the synthesis of carboxylic acids

(5f–5p)

4.2.6. (E)-Ethyl 3-[3-((E)-but-2-en-1-yloxy)-4-

(methoxymethoxy)phenyl]acrylate (41)

Yield: 84%; mp: 88–90 °C; ¹H NMR (400 MHz, CDCl₃): d 1.34

(3H, t, J = 7.1 Hz), 1.75 (3H, d, J = 5.7 Hz), 3.51 (3H, s), 4.25 (2H, q,

J = 7.1 Hz), 4.55 (2H, d, J = 5.7 Hz), 5.25 (2H, s), 5.75 (1H, m), 5.87

(1H, m), 6.29 (1H, d, J = 16.0 Hz), 7.08 (1H, s), 7.14 (2H, d,

J = 8.8 Hz); 7.61 (1H, d, J = 16.0 Hz); ¹³C NMR (125 MHz, CDCl₃): d

14.3, 17.9, 56.3, 60.4, 69.7, 95.2, 112.5, 116.4, 116.4, 122.1, 125.7,

128.8, 130.9, 144.4, 148.9, 149.0, 167.2; IR (KBr): 1715, 1508,

To a stirred solution of the ester (4, 1 mmol) in MeOH/H₂O (3:1)

was added LiOHÁH₂O (2 mmol), and the resulting mixture was

reﬂuxed for 2 h. After cooling, the reaction was quenched by 10%

HCl. The aqueous mixture was extracted with EtOAc (5 mL Â 3).

The organic extracts were combined, dried over Na₂SO₄, and evap-

orated. To the residue were added THF (4 mL), and 10% HCl (5

drop), and the resulting mixture was reﬂuxed for 12 h. After cool-

ing, the reaction mixture was saturated with NaCl, and the aqueous

mixture was extracted with hot EtOAc (5 mL Â 5). The organic

extracts were combined, dried over Na₂SO₄, and evaporated. The

residue was chromatographed on silica gel (15 g, CH₂Cl₂only) to

give the corresponding carboxylic acid. Compounds 5a,³³5b,³⁴

5c,³⁵5d,³⁶and 5e³⁵were known compounds.

1256, 1159 cm^À1

;

MS (EI): m/z 306 (M⁺); HRMS: Calcd for

C₁₇H₂₂O₅306.1467, Found: 306.1469.

4.2.7. (E)-Ethyl 3-{4-(methoxymethoxy)-3-[(4-

methylbenzyl)oxy]phenyl}acrylate (4m)

Yield: 96%; ¹H NMR (400 MHz, CDCl₃): d 1.33 (3H, t, J = 7.1 Hz),

2.36 (3H, s), 3.51 (3H, s), 4.24 (2H, q, J = 7.1 Hz), 5.13 (2H, s), 5.25

(2H, s), 6.25 (1H, d, J = 15.9 Hz), 7.08 (1H, d, J = 7.3 Hz), 7.09 (1H,

s), 7.13 (1H, d, J = 8.8 Hz), 7.18 (2H, d, J = 7.8 Hz), 7.32 (2H, d,

J = 7.8 Hz), 7.57 (1H, d, J = 15.9 Hz); ¹³C NMR (125 MHz, CDCl₃): d

14.3, 21.1, 56.3, 60.3, 70.9, 95.2, 113.3, 116.5, 116.7, 122.3, 127.3,

128.8, 129.2, 133.6, 137.7, 144.3, 148.9, 149.1, 167.1; IR (neat):

1705, 1508, 1256, 1157 cm^À1; MS (EI): m/z 356 (M⁺); HRMS: Calcd

for C₂₁H₂₄O₅356.1624, Found: 356.1627.

4.3.1. (E)-3-[3-(Benzyloxy)-4-hydroxyphenyl]acrylic acid (5f)

Yield: 88%; mp: 180–184 °C; ¹H NMR (400 MHz, CDCl₃): d 5.13

(2H, s), 5.28 (2H, s), 6.24 (1H, d, J = 15.9 Hz), 6.93 (1H, d, J = 8.5 Hz),

7.10 (1H, d, J = 6.8 Hz), 7.11 (1H, s), 7.36–7.42 (5H, m), 7.65 (1H, d,

J = 15.9 Hz); ¹³C NMR (125 MHz, CDCl₃): d 70.3, 113.5, 116.2, 116.4,

123.6, 126.2, 128.3, 128.9, 137.7, 145.0, 147.3, 147.6, 150.0, 168.5;

IR (KBr): 3028, 1684, 1514, 1271, 1200 cm^À1, MS (EI): m/z 270

(M⁺); HRMS: Calcd for C₁₆H₁₄O₄270.0892, Found: 270.0890.

4.2.8. (E)-Ethyl 3-{3-[(3-ﬂuorobenzyl)oxy]-4-

(methoxymethoxy)phenyl}acrylate (4n)

4.3.2. (E)-3-{4-Hydroxy-3-[(2-methylallyl)oxy]phenyl}acrylic

acid (5g)

Yield: 87%; ¹H NMR (400 MHz, CDCl₃): d 1.35 (3H, t, J = 7.1 Hz),

3.53 (3H, s), 4.25 (2H, t, J = 7.1 Hz), 5.16 (2H, s), 5.18 (2H, s), 6.25

(1H, d, J = 15.9 Hz), 7.02 (1H, t, J = 7.6 Hz), 7.07 (1H, dd, J = 6.3,

Yield: 99%; mp: 145–147 °C; ¹H NMR (400 MHz, CDCl₃): d 1.77

(3H, s), 4.51 (2H, s), 4.93 (1H, s), 5.10 (1H, s), 6.31 (1H, d,

S. Endo et al. / Bioorg. Med. Chem. 22 (2014) 5220–5233

5227

J = 15.8 Hz), 6.80 (1H, d, J = 8.3 Hz), 7.06 (1H, dd, J = 6.3, 2.0 Hz),

7.26 (1H, d, J = 2.3 Hz), 7.45 (d, J = 15.8 Hz); ¹³C NMR (125 MHz,

CDCl₃): 19.8, 72.1, 112.9, 113.3, 116.1, 116.3, 123.5, 126.2, 141.5,

145.0, 147.2, 149.8, 168.5; IR (KBr): 3524, 1693, 1516, 1277,

1165 cm^À1; MS (EI): m/z 234 (M⁺); HRMS: Calcd for C₁₃H₁₄O₄

234.0892, Found: 234.0981.

(2H, d, J = 7.9 Hz), 7.69 (1H, d, J = 15.9 Hz); ¹³C NMR (100 MHz,

CDCl₃): d 21.2, 70.7, 111.1, 114.4, 115.0, 123.7, 126.6, 128.1,

129.5, 146.1, 147.1, 147.5, 148.6, 148.8, 161.9, 182.6; IR (KBr):

3535, 2945, 1684, 1510, 1269 cm^À1; MS (EI): m/z 284 (M⁺); HRMS:

Calcd for C₁₇H₁₆O₄284.1049, Found: 284.1051.

4.3.9. (E)-3-{3-[(3-Fluorobenzyl)oxy]-4-hydroxyphenyl}acrylic

acid (5n)

4.3.3. (E)-3-{3-[(4-Chlorobenzyl)oxy]-4-hydroxyphenyl}acrylic

acid (5h)

Yield: 95%; mp: 157–158 °C; ¹H NMR (400 MHz, CDCl₃): d 2.12

(3H, s), 5.15 (2H, s), 6.25 (1H, d, J = 15.9 Hz), 6.97 (1H, d, J = 8.1 Hz),

7.09 (2H, s), 7.14 (2H, d, J = 8.1 Hz), 7.20 (1H, d, J = 8.1 Hz), 7.40

(1H, q, J = 5.9 Hz), 7.68 (1H, d, J = 15.7 Hz); ¹³C NMR (125 MHz,

DMSO-d₆): d 69.5, 113.6, 114.7, 114.9 (d, J = 7.4 Hz), 115.2 (d,

J = 19.0 Hz), 116.3 (d, J = 19 Hz), 121.3, 123.8, 124.0 (d, J = 2.5 Hz),

126.3, 130.9 (d, J = 7.4 Hz), 144.9, 147.1, 149.9, 163.8 (d,

Yield: 99%; mp: 188–190 °C; ¹H NMR (400 MHz, CDCl₃): d 5.16

(1H, s), 6.30 (1H, d, J = 16.0 Hz), 6.99 (1H, d, J = 8.5 Hz), 7.13 (1H, s),

7.17 (1H, d, J = 8.5 Hz), 7.35–7.49 (4H, m), 7.71 (1H, d, J = 16.0 Hz);

¹³C NMR (125 MHz, DMSO-d₆): d 69.0, 113.1, 115.8, 115.9, 123.3,

125.7, 128.4, 129.6, 132.4, 136.3, 144.4, 146.6, 149.5, 168.0; IR

(KBr): 3065, 1684, 1514, 1269 cm^À1; MS (EI): m/z 304 (M⁺); HRMS:

Calcd for C₁₆H₁₃ClO₄304.0502, Found: 304.0502.

J = 243 Hz), 168.5; IR (KBr): 3535, 2928, 1684, 1514, 1273 cm^À1

;

MS (EI): m/z 288 (M⁺); HRMS: Calcd for C₁₆H₁₃FO₄288.0798,

4.3.4. (E)-3-{3-[(4-Fluorobenzyl)oxy]-4-hydroxyphenyl}acrylic

acid (5i)

Found: 288.0796.

Yield: 78%; mp: 216–218 °C; ¹H NMR (400 MHz, CDCl₃): d 5.11

(2H, s), 6.26 (1H, d, J = 16.0 Hz), 6.95 (1H, d, J = 8.1 Hz), 7.10 (4H,

m), 7.41 (2H, dd, J = 5.1, 4.4 Hz), 7.68 (1H, d, J = 16.0 Hz); ¹³C

NMR (125 MHz, DMSO-d₆): d 69.5, 113.6, 115.7 (d, J = 22 Hz),

116.2, 116.4, 123.7, 126.2, 130.5 (d, J = 8.5 Hz), 133.9 (d,

J = 2.4 Hz), 144.9, 147.2, 150.0, 162.2 (d, J = 243 Hz), 168.5; IR

(KBr): 2934, 1682, 1512, 1273, 1190 cm^À1, MS (EI): m/z 288 (M⁺);

HRMS: Calcd for C₁₆H₁₃FO₄288.0798, Found: 288.0796.

4.3.10. (E)-3-{3-[(2-Fluorobenzyl)oxy]-4-hydroxyphenyl}acrylic

acid (5o)

Yield: 86%; mp: 172–174 °C; ¹H NMR (400 MHz, CDCl₃): d 5.20

(2H, s), 5.28 (2H, s), 5.92 (1H, br), 6.26 (1H, d, J = 15.9 Hz), 6.94 (1H,

d, J = 8.1 Hz), 7.11–7.20 (5H, m), 7.36 (1H, t, J = 7.1 Hz), 7.42 (1H, t,

J = 7.1 Hz), 7.66 (1H, d, J = 15.9 Hz); ¹³C NMR (125 MHz, DMSO-d₆):

d 64.6, 113.5, 115.8 (d, J = 21 Hz), 116.4 (d, J = 21 Hz), 123.8, 124.5

(d, J = 8.6 Hz), 125.0 (d, J = 2.5 Hz), 126.3, 130.8 (d, J = 8.6 Hz),

131.3, 131.3, 144.9, 147.3, 149.9, 160.9 (d, J = 246 Hz), 168.5; IR

(KBr): 3425, 2968, 1686, 1516, 1274, 1180 cm^À1; MS (EI): m/z

288 (M⁺); HRMS: Calcd for C₁₆H₁₃FO₄288.0798, Found: 288.0796.

4.3.5. (E)-3-(3-Butoxy-4-hydroxyphenyl)acrylic acid (5j)

Yield: 99%; mp: 129–131 °C; ¹H NMR (400 MHz, CDCl₃): d 0.99

(3H, t, J = 7.3 Hz), 1.51 (2H, sex, J = 7.3 Hz), 1.83 (2H, quin,

J = 7.3 Hz), 4.09 (2H, t, J = 7.3 Hz), 5.92 (1H, s), 6.28 (1H, d,

J = 15.9 Hz), 6.93 (1H, d, J = 8.1 Hz), 7.04 (1H, s), 7.08 (1H, dd,

J = 6.1, 2.0 Hz), 7.69 (1H, d, J = 15.9 Hz); ¹³C NMR (125 MHz,

DMSO-d₆): d 14.3, 19.2, 31.3, 68.5, 112.8, 114.8, 116.1, 123.2,

126.3, 145.1, 147.8, 149.8, 168.6; IR (KBr): 2939, 1690, 1516,

1269 cm^À1; MS (EI): m/z 236 (M⁺); HRMS: Calcd for C₁₃H₁₆O₄

236.1049, Found: 236.1049.

4.3.11. (E)-3-{3-[(3,5-Diﬂuorobenzyl)oxy]-4-

hydroxyphenyl}acrylic acid (5p)

Yield: 82%; mp: 207–209 °C; ¹H NMR (400 MHz, CDCl₃): d 5.14

(1H, s), 6.25 (1H, d, J = 15.9 Hz), 6.83 (1H, t, J = 8.3 Hz), 6.98–7.00

(3H, m), 7.05 (1H, s), 7.15 (1H, d, J = 8.3 Hz), 7.66 (1H, d,

J = 15.9 Hz), ¹³C NMR (125 MHz, DMSO-d₆): d 69.1, 103.6 (t,

J = 26 Hz), 110.8 (d, J = 6.1 Hz), 111. (d, J = 6.1 Hz), 113.7, 116.4,

116.7, 124.1, 126.5, 142.5 (t, J = 9.2 Hz), 144.9, 146.4, 146.9,

150.0, 162.9 (d, J = 247 Hz), 163.0 (d, J = 247 Hz), 168.6; IR (KBr):

3543, 1684, 1516, 1277 cm^À1; MS (EI): m/z 378 (M⁺); HRMS: Calcd

for C₁₆H₁₂F₂O₄306.0704, Found: 306.0701.

4.3.6. (E)-3-(4-Hydroxy-3-phenethoxyphenyl)acrylic acid (5k)

Yield: 92%, mp: 147–149 °C; ¹H NMR (500 MHz, DMSO-d₆): d

3.03 (2H, t, J = 7.2 Hz), 4.19 (2H, t, J = 7.2 Hz), 6.34 (1H, d,

J = 16.0 Hz), 6.78 (1H, d, J = 8.3 Hz), 7.05 (1H, dd, J = 6.6, 1.7 Hz),

7.19 (1H, t, J = 7.2 Hz), 7.25–7.29 (3H, m), 7.32 (2H, d, J = 7.2 Hz),

7.47 (1H, d, J = 16.0 Hz); ¹³C NMR (125 MHz, DMSO-d₆): d 35.6,

69.6, 113.1, 116.16, 116.21, 123.5, 126.4, 126.8, 128.8, 129.6,

138.9, 145.0, 147.6, 149.8, 168.6; IR (KBr): 2974, 1693, 1516,

1165 cm^À1; MS (EI): m/z 284 (M⁺); HRMS: Calcd for C₁₇H₁₆O₄

284.1049, Found: 284.1051.

4.4. General procedure for condensation reaction of 5

Method A: 6a–6p: To a stirred solution of carboxylic acid (5,

1 mmol) in CH₂Cl₂(8 mL) were added Et₃N (6 mmol), and hydrocin-

namoyl chloride (2 mmol) at 0 °C, and the resulting mixture was

stirred for 12 h at room temperature. 10% HCl (aq) was added to

the reaction mixture, and the resulting mixture was stirred for

30 min. The aqueous mixture was extracted with EtOAc

(5 mL Â 3). The organic extracts were combined, dried over

Na₂SO₄, and evaporated. The residue was chromatographed on silica

gel (15 g, hexane/acetone = 20:1–5:1) to give corresponding ester.

Method B: 6q–6z: To a stirred solution of carboxylic acid in

CH₂Cl₂(8 mL) were added EDCÁHCl (1.2 equiv), DMAP (0.1 equiv),

and compound 5 (1 mmol). The reaction mixture was stirred over-

night at room temperature. The solvent was removed under

reduced pressure, and the residue was chromatographed on silica

gel (15 g, hexane/acetone = 10:1–3:1) to give corresponding ester.

4.3.7. (E)-3-{3-[(E)-But-2-en-1-yloxy]-4-hydroxyphenyl}acrylic

acid (5l)

Yield: 85%; mp: 151–152 °C; ¹H NMR (400 MHz, CDCl₃): d 1.78

(3H, d, J = 5.6 Hz), 4.56 (2H, d, J = 5.6 Hz), 5.72 (1H, m), 5.87–5.95

(2H, m), 6.28 (1H, d, J = 16.1 Hz), 6.93 (1H, d, J = 8.3 Hz), 7.06 (1H,

s), 7.10 (1H, dd, J = 6.3, 1.8 Hz), 7.69 (1H, d, J = 16.1 Hz); ¹³C NMR

(125 MHz, DMSO-d₆): d 18.1, 69.3, 113.2, 116.1, 116.2, 123.3,

126.2, 127.2, 130.1, 145.0, 147.3, 149.9, 168.5; IR (KBr): 2924,

1684, 1512, 1267 cm^À1; MS (EI): m/z 234 (M⁺); HRMS: Calcd for

C₁₃H₁₄O₄234.0892, Found: 234.0892.

4.3.8. (E)-3-{4-Hydroxy-3-[(4-methylbenzyl)oxy]phenyl}acrylic

acid (5m)

4.4.1. (E)-3-{3-Ethoxy-4-[(3-

phenylpropanoyl)oxy]phenyl}acrylic acid (6a)

Yield: 90%; mp: 151–153 °C; ¹H NMR (400 MHz, CDCl₃): d 2.38

(3H, s), 5.10 (2H, s), 6.25 (1H, d, J = 15.9 Hz), 6.94 (1H, d, J = 7.8 Hz),

7.11 (1H, d, J = 8.5 Hz), 7.12 (1H, s), 7.22 (2H, d, J = 7.9 Hz), 7.32

Yield: 47%; mp: 145–147 °C; ¹H NMR (400 MHz, CDCl₃): d 1.35

(3H, t, J = 7.0 Hz), 2.89 (2H, t, J = 7.8 Hz), 3.08 (2H, t, J = 7.8 Hz), 4.05

(2H, q, J = 7.0 Hz), 6.35 (1H, d, J = 15.9 Hz), 6.98 (1H, d, J = 7.8 Hz),

5228

S. Endo et al. / Bioorg. Med. Chem. 22 (2014) 5220–5233

7.08–7.09 (3H, m), 7.20–7.32 (4H, m), 7.69 (1H, d, J = 15.9 Hz); ¹³

C

4.4.7. (E)-3-{3-[(2-Methylallyl)oxy]-4-[(3-

NMR (125 MHz, CDCl₃): d 14.6, 31.0, 35.5, 64.4, 112.4, 117.4, 121.5,

123.2, 126.4, 128.3, 128.6, 132.8, 140.2, 142.0, 146.4, 150.8, 170.7,

172.1; IR (KBr): 2978, 1761, 1674, 1263, 1124 cm^À1; MS (EI): m/z

340 (M⁺); HRMS: Calcd for C₂₀H₂₀O₅340.1311, Found: 340.1309.

phenylpropanoyl)oxy]phenyl}acrylic acid (6g)

Yield: 65%; mp: 110–112 °C; ¹H NMR (400 MHz, CDCl₃): d 1.79

(3H, s), 2.92 (2H, t, J = 7.7 Hz), 3.09 (2H, t, J = 7.7 Hz), 4.46 (2H, s),

5.00 (1H, s), 5.07 (1H, s), 6.36 (1H, d, J = 15.9 Hz), 7.01 (1H, d,

J = 8.3 Hz), 7.10 (1H, s), 7.13 (1H, d, J = 8.3 Hz), 7.24–7.34 (5H, m),

7.69 (1H, d, J = 15.9 Hz); ¹³C NMR (125 MHz, CDCl₃): d 19.2, 30.9,

35.5, 72.3, 112.8, 113.1, 117.4, 121.6, 123.3, 126.4, 128.4, 128.6,

132.8, 139.7, 140.1, 142.0, 146.3, 150.5, 170.6, 171.7; IR (KBr):

2928, 1763, 1692, 1132 cm^À1; MS (EI): 366 m/z (M⁺); HRMS: Calcd

for C₂₂H₂₂O₅366.1467, Found: 366.1465.

4.4.2. (E)-3-{3-Methoxy-4-[(3-

phenylpropanoyl)oxy]phenyl}acrylic acid (6b)

Yield: 41%; mp: 163–165 °C; ¹H NMR (400 MHz, CDCl₃): d 2.91

(2H, t, J = 7.6 Hz), 3.07 (2H, t, J = 7.6 Hz), 3.81 (3H, s), 6.37 (1H, d,

J = 16.0 Hz), 6.97 (1H, d, J = 8.1 Hz), 7.09 (1H, s), 7.10 (1H, d,

J = 8.1 Hz), 7.22–7.31 (5H, m), 7.70 (1H, d, J = 16.0 Hz); ¹³C NMR

(125 MHz, CDCl₃): d 30.8, 35.5, 55.9, 111.4, 117.4, 121.6, 123.3,

126.4, 128.4, 128.5, 132.9, 140.1, 141.8, 146.3, 151.4, 170.7,

172.1; IR (KBr): 2936, 1674, 1508, 1265, 1126 cm^À1; MS (EI): m/z

326 (M⁺); HRMS: Calcd for C₁₉H₁₈O₅326.1154, Found: 326.1156.

4.4.8. (E)-3-{3-[(4-Chlorobenzyl)oxy]-4-[(3-

phenylpropanoyl)oxy]phenyl}acrylic acid (6h)

Yield: 47%; mp: 158–160 °C; ¹H NMR (400 MHz, CDCl₃): d 2.87

(2H, t, J = 8.1 Hz), 3.00 (2H, t, J = 8.1 Hz), 5.05 (2H, s), 6.34 (1H, d,

J = 15.9 Hz), 7.03 (1H, d, J = 8.1 Hz), 7.12 (1H, s), 7.15–7.36 (10H,

m), 7.68 (1H, d, J = 15.9 Hz); ¹³C NMR (125 MHz, CDCl₃): d 30.8,

35.5, 69.9, 112.9, 117.5, 122.0, 123.4, 126.4, 128.3, 128.5, 128.7,

128.8, 132.8, 134.0, 134.5, 140.0, 142.2, 146.1, 150.3, 170.7,

172.2; IR (KBr): 2928, 1763, 1692, 1259, 1121 cm^À1; MS (EI): m/z

436 (M⁺); HRMS: Calcd for C₂₅H₂₁ClO₅436.1078, Found: 436.1073.

4.4.3. (E)-3-{3-Isobutoxy-4-[(3-

phenylpropanoyl)oxy]phenyl}acrylic acid (6c)

Yield: 42%; mp: 116–118 °C; ¹H NMR (400 MHz, CDCl₃): d 0.97

(6H, d, J = 7.8 Hz), 2.03 (1H, m); 2.89 (2H, t, J = 7.6 Hz), 3.07 (2H, t,

J = 7.6 Hz), 3.74 (2H, d, J = 7.6 Hz), 6.36 (1H, d, J = 15.8 Hz), 6.98

(1H, d, J = 7.8 Hz), 7.08 (1H, s), 7.10 (1H, d, J = 7.8 Hz), 7.24–7.31

(5H, m), 7.70 (1H, d, J = 15.8 Hz); ¹³C NMR (125 MHz, CDCl₃): d

19.1, 28.2, 30.9, 35.6, 74.9, 112.1, 117.3, 121.4, 123.1, 126.4,

128.3, 128.6, 132.8, 140.2, 141.9, 146.3, 150.9, 170.6, 172.0; IR

(KBr): 2965, 1762, 1691, 1265, 1123 cm^À1MS (EI): m/z 368 (M⁺);

HRMS: Calcd for C₂₂H₂₄O₅368.1624, Found: 368.1624.

4.4.9. (E)-3-{3-[(4-Fluorobenzyl)oxy]-4-[(3-

phenylpropanoyl)oxy]phenyl}acrylic acid (6i)

Yield: 22%; mp: 130–132 °C; ¹H NMR (400 MHz, CDCl₃): d 2.84

(2H, t, J = 7.8 Hz), 3.00 (2H, t, J = 7.8 Hz), 5.05 (2H, s), 6.35 (1H, d,

J = 16.0 Hz), 7.05 (4H, dd, J = 8.1, 8.30 Hz), 7.14–7.31 (6H, m), 7.35

(2H, dd, J = 5.4, 2.9 Hz), 7.69 (1H, d, J = 16.0 Hz), ¹³C NMR

(125 MHz, CDCl₃): d 30.9, 35.6, 70.1, 112.9, 115.6 (d, J = 22 Hz),

117.5, 122.0, 123.4, 126.4, 128.3, 128.6, 129.3 (d, J = 8.6 Hz),

131.9 (d, J = 2.5 Hz), 132.9, 140.1, 142.2, 146.1, 150.4, 162.6 (d,

J = 245 Hz), 170.7, 171.6; IR (KBr): 2926, 1761, 1512, 1261,

1121 cm^À1; MS (EI): m/z 420 (M⁺); HRMS: Calcd for C₂₅H₂₁FO₅

420.1373, Found: 420.1375.

4.4.4. (E)-3-{3-Propoxy-4-[(3-

phenylpropanoyl)oxy]phenyl}acrylic acid (6d)

Yield: 42%, mp: 114–116 °C; ¹H NMR (400 MHz, CDCl₃): d 1.00

(3H, t, J = 6.3 Hz), 1.77 (2H, quin, J = 6.3 Hz), 2.91 (2H, t,

J = 7.9 Hz), 3.09 (2H, t, J = 7.9 Hz), 3.96 (2H, t, J = 6.3 Hz), 6.38

(1H, d, J = 15.8 Hz), 7.00 (1H, d, J = 7.7 Hz), 7.11 (1H, s), 7.12 (1H,

d, J = 7.7 Hz), 7.23–7.28 (3H, m), 7.32 (2H, t, J = 7.7 Hz), 7.71 (1H,

d, J = 15.8 Hz); ¹³C NMR (125 MHz, CDCl₃): d 10.4, 22.4, 31.0,

35.5, 70.2, 112.3, 117.5, 121.4, 123.1, 126.4, 128.3, 128.5, 132.9,

140.2, 142.0, 146.2, 150.9, 170.6, 172.0; IR (KBr): 2966, 1763,

1690, 1263, 1124 cm^À1; MS (EI): m/z 354 (M⁺); HRMS: Calcd for

4.4.10. (E)-3-{3-Butoxy-4-[(3-

phenylpropanoyl)oxy]phenyl}acrylic acid (6j)

Yield: 41%; mp: 92–94 °C; ¹H NMR (400 MHz, CDCl₃): d 1.00

(3H, t, J = 7.3 Hz), 1.49 (2H, sex, J = 7.3 Hz), 1.77 (2H, quin,

J = 7.3 Hz), 2.94 (2H, t, J = 7.9 Hz), 3.13 (2H, t, J = 7.9 Hz), 4.04

(2H, t, J = 7.3 Hz), 6.42 (1H, d, J = 15.9 Hz), 7.04 (1H, d, J = 8.5 Hz),

7.14 (1H, s), 7.15 (1H, d, J = 7.1 Hz), 7.26–7.38 (5H, m), 7.75 (1H,

d, J = 15.9 Hz), ¹³C NMR (125 MHz, CDCl₃): d 13.9, 19.2, 31.2,

35.7, 68.6, 112.3, 117.4, 121.1, 123.3, 126.5, 128.5, 128.7, 140.2,

140.3, 146.4, 164.2, 165.6, 170.7, 171.7; IR (KBr): 2932, 1761,

1690, 1263, 1126 cm^À1; MS (EI): m/z 368 (M⁺); HRMS: Calcd for

C₂₁H₂₂O₅354.1467, Found: 354.1467.

4.4.5. (E)-3-{3-Isopropoxy-4-[(3-

phenylpropanoyl)oxy]phenyl}acrylic acid (6e)

Yield: 63%; mp: 141–143 °C; ¹H NMR (400 MHz, CDCl₃): d 1.28

(6H, d, J = 6.1 Hz), 2.88 (2H, t, J = 7.8 Hz), 3.07 (2H, t, J = 7.8 Hz),

4.54 (1H, sept, J = 6.1 Hz), 6.35 (1H,d, J = 16.0 Hz), 6.98 (1H, d,

J = 8.5 Hz), 7.10–7.16 (2H, m), 7.20–7.32 (5H, m), 7.69 (1H, d,

J = 16.0 Hz); ¹³C NMR (125 MHz, CDCl₃): d 21.9, 30.88, 30.93,

35.6, 71.3, 114.0, 117.4, 121.2, 123.4, 126.4, 128.3, 128.5, 132.8,

140.2, 142.8, 146.3, 149.7, 170.6, 172.1; IR (KBr): 2960, 1684,

1506, 1269, 1128 cm^À1; MS (EI): m/z 354 (M⁺); HRMS: Calcd for

C₂₂H₂₄O₅368.1624, Found: 368.1621.

4.4.11. (E)-3-{3-Phenethoxy-4-[(3-

phenylpropanoyl)oxy]phenyl}acrylic acid (6k)

Yield: 40%; mp: 82–84 °C; ¹H NMR (400 MHz, CDCl₃): d 2.83

(2H, t, J = 7.4 Hz), 3.02 (4H, t, J = 7.4 Hz), 4.20 (2H, t, J = 7.4 Hz),

6.31 (1H, d, J = 15.9 Hz), 6.97 (1H, d, J = 8.1 Hz), 7.07 (1H, s), 7.08

(1H, d, J = 8.1 Hz), 7.26–7.30 (5H, m), 7.66 (1H, d, J = 15.9 Hz); ¹³C

NMR (125 MHz, CDCl₃): d 30.8, 35.4, 35.5, 69.3, 112.4, 117.4,

121.7, 123.3, 126.4, 126.6, 128.4, 128.5, 128.6, 128.9, 132.8,

137.6, 140.2, 142.0, 146.3, 150.7, 170.6, 172.0; IR (KBr): 2924,

1763, 1692, 1261, 1124 cm^À1; MS (EI): m/z 416 (M⁺); HRMS: Calcd

for C₂₆H₂₄O₅416.1624, Found: 416.1628.

C₂₁H₂₂O₅354.1467, Found: 354.1464.

4.4.6. (E)-3-{3-(Benzyloxy)-4-[(3-

phenylpropanoyl)oxy]phenyl}acrylic acid (6f)

Yield: 62%; mp: 138–140 °C; ¹H NMR (400 MHz, CDCl₃): d 2.73

(2H, t, J = 7.8 Hz), 2.87 (2H, t, J = 7.8 Hz), 4.96 (2H, s), 6.21 (1H, d,

J = 16.0 Hz), 6.89 (1H, d, J = 8.6 Hz), 7.01 (2H, d, J = 8.6 Hz), 7.09

(3H, t, J = 7.4 Hz), 7.12–7.17 (2H, m), 7.20–7.26 (5H, m); ¹³C NMR

(125 MHz, CDCl₃): d 30.9, 35.6, 70.8, 113.0, 117.6, 121.8, 123.3,

126.4, 127.4, 128.2, 128.3, 128.5, 128.6, 132.9, 136.1, 140.1,

142.2, 146.0, 150.5, 170.8, 171.5; IR (KBr): 2926, 1761, 1690,

1508, 1261, 1123 cm^À1; MS (EI): m/z 402 (M⁺); HRMS: Calcd for

4.4.12. (E)-3-{3-[(E)-But-2-en-1-yloxy]-4-[(3-

phenylpropanoyl)oxy]phenyl}acrylic acid (6l)

Yield: 41%; mp: 100–102 °C; ¹H NMR (400 MHz, CDCl₃): d 1.74

(3H, d, J = 5.9 Hz), 2.92 (2H, t, J = 7.9 Hz), 3.09 (2H, t, J = 7.9 Hz),

4.49 (2H, d, J = 5.9 Hz), 5.61–5.69 (1H, m), 5.81–5.86 (1H, m),

C₂₅H₂₂O₅402.1467, Found 402.1465.

S. Endo et al. / Bioorg. Med. Chem. 22 (2014) 5220–5233

5229

6.36 (1H, d, J = 16.1 Hz), 7.00 (1H, d, J = 8.1 Hz), 7.12 (1H, s), 7.13

(1H, dd, J = 5.4, 2.3 Hz), 7.22–7.34 (5H, m), 7.71 (1H, d,

J = 16.1 Hz); ¹³C NMR (125 MHz, CDCl₃): d 17.9, 30.9, 35.6, 69.6,

113.1, 117.3, 121.6, 123.3, 125.4, 126.4, 128.4, 128.6, 130.7,

140.2, 142.2, 146.4, 150.6, 170.7, 171.2; IR (KBr): 2926, 1761,

NMR (125 MHz, CDCl₃): d 30.5, 30.9, 35.2, 69.9, 112.9, 113.3 (d,

J = 21 Hz), 114.1 (d, J = 21 Hz), 115.2 (d, J = 21 Hz), 115.3

(d, J = 21 Hz), 117.4, 122.1, 122.61 (d, J = 2.4 Hz), 123.4, 123.9

(d, J = 2.4 Hz), 130.0 (d, J = 8.6 Hz), 130.3 (d, J = 8.6 Hz), 133.0,

138.7 (d, J = 7.3 Hz), 142.1, 142.6 (d, J = 7.3 Hz), 146.0, 150.3,

162.9 (J = 247 Hz), 163.0 (J = 247 Hz), 170.4, 170.7; IR (KBr):

2862, 1765, 1682, 1261, 1121 cm^À1; MS (EI): m/z 438 (M⁺); HRMS:

Calcd for C₂₅H₂₀F₂O₅438.1279, Found: 438.1283.

1690, 1124 cm^À1

;

MS (EI): m/z 366 (M⁺); HRMS: Calcd for

C₂₂H₂₂O₅366.1467, Found: 366.1464.

4.4.13. (E)-3-{3-[(4-Methylbenzyl)oxy]-4-[(3-

phenylpropanoyl)oxy]phenyl}acrylic acid (6m)

4.4.18. (E)-3-{3-[(3-Fluorobenzyl)oxy]-4-[(3-(4-

ﬂuorophenyl)propanoyl)oxy]phenyl}acrylic acid (6r)

Yield: 41%; mp: 148–150 °C; ¹H NMR (400 MHz, CDCl₃): d 2.35

(3H, s), 2.84 (2H, t, J = 7.8 Hz), 2.98 (2H, t, J = 7.8 Hz), 5.05 (2H, s),

6.34 (1H, d, J = 16.0 Hz),7.02 (1H, d, J = 7.8 Hz), 7.14 (1H, d,

J = 7.8 Hz), 7.12 (1H, s), 7.17–7.29 (9H, m), 7.68 (1H, d,

J = 16.0 Hz); ¹³C NMR (125 MHz, CDCl₃): d 21.8, 30.9, 35.6, 70.7,

113.0, 117.4, 121.8,123.2, 126.3, 127.5, 128.3, 128.5, 129.3, 132.8,

133.0, 138.0, 140.2, 142.3, 146.3, 150.6, 170.7, 172.1; IR (KBr):

2924, 1759, 1686, 1259, 1130 cm^À1; MS (EI): m/z 356 (M⁺); HRMS:

Calcd for C₂₆H₂₄O₅416.1624, Found: 416.1620.

Yield: 50%; mp: 154–155 °C; ¹H NMR (500 MHz, CDCl₃): d 2.86

(2H, t, J = 8.0 Hz), 2.99 (2H, t, J = 8.0 Hz), 5.08 (2H, s), 6.35 (1H, d,

J = 16.0 Hz), 6.96 (2H, t, J = 7.9 Hz), 7.04 (2H, d, J = 7.9 Hz), 7.12–

7.19 (6H, m), 7.34 (1H, quin, J = 7.9 Hz), 7.69 (1H, d, J = 16.0 Hz);

¹³C NMR (125 MHz, CDCl₃): d 30.1, 35.7, 70.0, 106.4, 113.0, 114.2

(d, J = 21 Hz), 115.2, 115.4 (d, J = 21 Hz), 115.8, 117.7, 122.2,

122.7 (d, J = 2.5 Hz), 122.8, 123.5, 129.9 (d, J = 8,6 Hz), 130.4 (d,

J = 8.6 Hz), 133.1, 135.8 (d, J = 3.7 Hz), 138.8 (d, J = 7.3 Hz), 142.2,

146.2, 150.4, 157.4 (d, J = 7.3 Hz), 159.7 (d, J = 247 Hz), 160.7 (d,

J = 247 Hz), 168.2, 170.6; IR (KBr): 2928, 1763, 1630, 1259,

1119 cm^À1; MS (EI): m/z 438 (M⁺); HRMS: Calcd for C₂₅H₂₀F₂O₅

438.1279, Found: 438.1278.

4.4.14. (E)-3-{3-[(3-Fluorobenzyl)oxy]-4-[(3-

phenylpropanoyl)oxy]phenyl}acrylic acid (6n)

Yield: 56%; mp: 115–117 °C; ¹H NMR (400 MHz, CDCl₃): d 2.84

(2H, t, J = 8.3 Hz), 2.95 (2H, t, J = 8.3 Hz), 5.02 (2H, s), 6.28 (1H, d,

J = 15.9 Hz), 6.97 (2H, d, J = 8.1 Hz), 7.05 (1H, s), 7.08 (2H, d,

J = 7.6 Hz), 7.15–7.23 (7H, m), 7.60 (1H, d, J = 15.9 Hz), ¹³C NMR

(125 MHz, CDCl₃): d 30.9, 35.6, 69.9, 112.9, 114.3 (d, J = 21 Hz),

115.1 (d, J = 21 Hz), 117.6, 122.1, 122.6 (d, J = 2.4 Hz), 123.4,

126.4, 128.3, 128.5, 130.2 (d, J = 7.4 Hz), 132.9, 138.7 (d,

J = 7.4 Hz), 140.1, 142.2, 146.1, 150.3, 163.0 (d, J = 247 Hz), 170.7,

171.7; IR (KBr): 2924, 1767, 1693, 1261, 1121 cm^À1; MS (EI): m/z

420 (M⁺); HRMS: Calcd for C₂₅H₂₁FO₅420.1373, Found: 420.1370.

4.4.19. (E)-3-{3-[(3-Fluorobenzyl)oxy]-4-[(3-(2,4,6-

triﬂuorophenyl)propanoyl)oxy]phenyl}acrylic acid (6s)

Yield: 59%; mp: 178–180 °C; ¹H NMR (400 MHz, DMSO-d₆):

d 2.83 (2H, t, J = 7.2 Hz), 2.91 (2H, t, J = 7.2 Hz), 5.19 (2H, s), 6.56

(1H, d, J = 16.0 Hz), 7.11–7.17 (5H, m), 7.20 (1H, d, J = 7.8 Hz),

7.28 (1H, dd, J = 6.9, 1.1 Hz), 7.41 (1H, quin, J = 7.8 Hz), 7.53 (1H,

d, J = 16.0 Hz), 7.56 (1H, s); ¹³C NMR (125 MHz, DMSO-d₆):

d 17.7, 33.1, 69.5, 101.0 (t, J = 28 Hz), 113.5, 114.3 (d, J = 23 Hz),

115.2 (d, J = 23 Hz), 120.2, 122.5, 123.6, 131.0 (d, J = 8.6 Hz),

133.9, 140.1 (d, J = 7.4 Hz), 141.5, 143.7, 150.3, 160.1, 161.4 (d,

J = 245 Hz), 162.7 (d, J = 245 Hz), 168.1, 170.2; IR (KBr): 2926,

1771, 1684, 1252, 1117 cm^À1; MS (EI): m/z 474 (M⁺); HRMS: Calcd

for C₂₅H₁₈F₄O₅474.1090, Found: 474.1087.

4.4.15. (E)-3-{3-[(2-Fluorobenzyl)oxy]-4-[(3-

phenylpropanoyl)oxy]phenyl}acrylic acid (6o)

Yield: 21%; mp: 143–144 °C; ¹H NMR (400 MHz, CDCl₃): d 2.87

(2H, t, J = 7.7 Hz), 3.01 (2H, t, J = 7.7 Hz), 5.17 (2H, s), 6.37 (1H, d,

J = 15.9 Hz) (2H, d, J = 8.1 Hz), 7.08–7.31 (9H, m), 7.40 (1H, t,

J = 7.3 Hz),7.70 (1H, d, J = 15.9 Hz); ¹³C NMR (125 MHz, CDCl₃):

d 30.9, 35.6, 64.5, 113.1, 115.4 (d, J = 21 Hz), 117.6, 122.1, 123.3

(d, J = 21 Hz), 124.4 (d, J = 3.7 Hz), 126.4, 128.3, 128.5, 129.6 (d,

J = 3.7 Hz), 130.04 (d, J = 8.6 Hz), 132.9, 140.1, 142.3, 146.0, 146.1,

150.3, 160.5 (d, J = 248 Hz), 190.8; IR (KBr): 2932, 1763, 1690,

4.4.20. (E)-3-{4-[(3-(3-Fluorophenyl)propanoyl)oxy]-3-[(4-

methylbenzyl)oxy]phenyl}acrylic acid (6t)

Yield: 48%, mp: 171–173 °C; ¹H NMR (400 MHz, CDCl₃): d 2.38

(3H, s), 2.83 (2H, t, J = 8.0 Hz), 2.96 (2H, t, J = 8.0 Hz), 5.07 (2H, s),

6.35 (1H, d, J = 16.1 Hz), 6.91 (1H, d, J = 8.0 Hz), 6.96 (1H, d,

J = 8.0 Hz), 7.02 (2H, d, J = 8.0 Hz), 7.16–7.28 (7H, m), 7.70 (1H, d,

J = 16.1 Hz); ¹³C NMR (125 MHz, CDCl₃): d 21.3, 30.7, 35.3, 70.9,

89.7, 113.1, 113.4 (d, J = 21 Hz), 115.4 (d, J = 21 Hz), 117.5, 121.9,

123.3, 124.0 (d, J = 2.5 Hz), 127.7, 129.4, 130.1 (d, J = 8.5 Hz),

133.1 (d, J = 8.5 Hz), 138.2, 142.3, 142.8, 146.4, 150.7, 163.0

(J = 247 Hz), 170.6, 171.8; IR (KBr): 2924, 1763, 1693, 1259,

1121 cm^À1; MS (EI): m/z 434 (M⁺); HRMS: Calcd for C₂₆H₂₃FO₅

434.1520, Found: 434.1528.

;

1263, 1124 cm^À1MS (EI): m/z 420 (M⁺); HRMS: Calcd for

C₂₅H₂₁FO₅420.1373, Found: 420.1376.

4.4.16. (E)-3-{3-[(3,5-Diﬂuorobenzyl)oxy]-4-[(3-

phenylpropanoyl)oxy]phenyl}acrylic acid (6p)

Yield: 33%; mp: 119–121 °C; ¹H NMR (400 MHz, CDCl₃): d 2.91

(2H, t, J = 7.1 Hz), 3.05 (2H, t, J = 7.1 Hz), 5.06 (2H, s), 6.35 (1H, d,

J = 16.1 Hz), 6.78 (1H, t, J = 8.9 Hz), 6.92 (2H, d, J = 5.6 Hz), 7.04

(1H, d, J = 8.1 Hz), 7.08 (1H, d, J = 2.0 Hz), 7.18–7.32 (6H, m), 7.69

(1H, d, J = 16.1 Hz); ¹³C NMR (125 MHz, CDCl₃): d 31.0, 35.7, 69.5,

103.7 (t, J = 26 Hz), 109.8 (d, J = 6.1 Hz), 109.9 (d, J = 6.1 Hz),

113.0, 117.7, 122.4, 123.7, 126.5, 128.4, 128.7, 133.1, 140.1 (t,

J = 9.8 Hz), 142.21, 146.1, 150.2, 160.2, 163.2 (d, J = 248 Hz), 163.4

(d, J = 248 Hz), 170.7, 171.7; IR (KBr): 2926, 1695, 1632, 1261,

1121 cm^À1; MS (EI): m/z 438 (M⁺); HRMS: Calcd for C₂₅H₂₀F₂O₅

438.1279, Found: 438.1283.

4.4.21. (E)-3-{3-[(4-Methylbenzyl)oxy]-4-[(3-(2,4,6-

triﬂuorophenyl)propanoyl)oxy]phenyl}acrylic acid (6u)

Yield: 84%; mp: 159–161 °C; ¹H NMR (400 MHz, CDCl₃): d 2.35

(3H, s), 2.81 (2H, t, J = 7.8 Hz), 3.00 (2H, t, J = 7.8 Hz), 5.06 (2H, s),

6.35 (1H, d, J = 16.0 Hz), 6.64 (2H, t, J = 8.1 Hz), 7.06 (1H, d,

J = 8.5 Hz), 7.14–7.26 (6H, m), 7.69 (1H, d, J = 16.0 Hz); ¹³C NMR

(125 MHz, CDCl₃): d 17.7, 21.3, 33.3, 70.9, 100.0 (d, J = 8.6 Hz),

100.2 (d, J = 4.9 Hz), 100.4 (d, J = 26 Hz), 113.1, 117.4, 121.9,

123.3, 127.5, 129.4, 133.1 (d, J = 15 Hz), 138.1, 142.3, 146.4,

4.4.17. (E)-3-{3-[(3-Fluorobenzyl)oxy]-4-[(3-(3-

ﬂuorophenyl)propanoyl)oxy]phenyl}acrylic acid (6q)

Yield: 63%, mp: 152–153 °C; ¹H NMR (500 MHz, CDCl₃): d 2.88

(2H, t, J = 7.5 Hz), 3.02 (2H, t, J = 7.5 Hz), 5.09 (2H, s), 6.35 (1H, d,

J = 15.8 Hz), 6.88–7.03 (4H, m), 7.05 (1H, d, J = 8.0 Hz), 7.10–7.25

(5H, m), 7.34 (1H, quin, J = 8.0 Hz), 7.70 (1H, d, J = 15.8 Hz), ¹³C

150.7, 170.1, 171.6; IR (KBr): 2926, 1767, 1630, 1258, 1115 cm^À1

;

MS (EI): m/z 470 (M⁺); HRMS: Calcd for C₂₆H₂₁F₃O₅470.1341,

Found: 470.1342.

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S. Endo et al. / Bioorg. Med. Chem. 22 (2014) 5220–5233

4.4.22. (E)-3-{4-[(3-(4-Fluorophenyl)propanoyl)oxy]-3-[(4-

methylbenzyl)oxy]phenyl}acrylic acid (6v)

(1H, d, J = 8.1 Hz), 7.02 (1H, d, J = 8.1 Hz), 7.08–7.31 (9H, m), 7.69

(1H, d, J = 16.1 Hz); ¹³C NMR (125 MHz, CDCl₃): d 18.79, 21.72,

25.19, 30.10, 30.56, 35.81, 62.03, 70.75, 96.45, 113.02, 115.34,

116.55, 117.39, 121.74, 123.24, 127.52, 129.18, 129.28, 129.37,

129.49, 132.82, 133.07, 137.97, 142.28, 146.16, 150.59, 154.29,

155.54, 170.87, 171.53; IR (neat): 1684, 1508, 1121 cm^À1; MS

(EI): m/z 432 (M⁺À84); HRMS: Calcd for C₂₆H₂₄O₆432.1573,

Found: 432.1570.

Yield: 67%; mp: 168–170 °C;¹H NMR (400 MHz, CDCl₃): d 2.35

(3H, s), 2.82 (2H, t, J = 7.6 Hz), 2.95 (2H, t, J = 7.6 Hz), 5.05 (2H, s),

6.35 (1H, d, J = 15.9 Hz), 6.95 (2H, t, J = 8.7 Hz), 7.02 (1H, d,

J = 7.6 Hz), 7.12–7.19 (8H, m), 7.69 (1H, d, J = 15.9 Hz); ¹³C NMR

(125 MHz, CDCl₃):

d 21.2, 30.0, 35.6, 70.8, 113.0, 115.3 (d,

J = 21 Hz), 117.4, 121.8, 123.2, 127.6, 129.3, 129.8 (d, J = 8.6 Hz),

132.8, 133.0, 135.8 (d, J = 3.6 Hz), 138.0, 142.2, 146.3, 150.6,

161.5 (d, J = 245 Hz), 170.6, 171.9; IR (KBr): 2924, 1763, 1630,

4.5. General procedure for deprotection of the tetrahydro-2H-

pyran-2-yl moiety

1512, 1119 cm^À1

;

MS (EI): m/z 434 (M⁺); HRMS: Calcd for

C₂₆H₂₃FO₅434.1530, Found: 434.1526.

To a stirred solution of ester (6w–6z, 1 mmol) in CH₂Cl₂/MeOH

(3:1) were added PPTS (0.3 mmol), and the resulting mixture was

reﬂuxed for 12 h. The solvent was removed under reduced pres-

sure, and the residue was chromatographed on silica gel (15 g,

CH₂Cl₂/MeOH = 80:1–70:1) to give corresponding compound.

4.4.23. (E)-3-{3-[(3-Fluorobenzyl)oxy]-4-{3-{4-[(tetrahydro-2H-

pyran-2-yl)oxy]phenyl}propanoyloxyphenyl}acrylic acid (6w)

Yield: 43%; mp: 152–154 °C; ¹H NMR (500 MHz, CDCl₃): d 1.52–

2.01 (6H, m), 2.85 (2H, t, J = 7.8 Hz), 2.97 (2H, t, J = 7.8 Hz), 3.58–

3.60 (1H, m), 3.89–3.92 (1H, m), 5.10 (2H, s), 5.37 (1H, t,

J = 3.0 Hz), 6.35 (1H, d, J = 16.0 Hz), 6.97 (2H, d, J = 8.3 Hz), 7.04

(2H, d, J = 8.3 Hz), 7.12–7.18 (6H, m), 7.32–7.37 (1H, m), 7.69

(1H, d, J = 16.0 Hz); ¹³C NMR (125 MHz, CDCl₃): d 18.8, 25.2, 29.7,

30.0, 35.8, 62.1, 70.0, 96.5, 113.0, 114.1 (d, J = 22 Hz), 115.1 (d,

J = 22 Hz), 116.6, 117.3 (d, J = 2.5 Hz), 122.0, 122.6, 123.5, 129.2,

129.6, 130.2 (d, J = 7.3 Hz), 132.9, 138.8 (d, J = 7.3 Hz), 142.2,

146.0, 150.3, 162.9 (d, J = 248 Hz), 170.7, 173.2, IR (KBr): 2926,

1741, 1685, 1263, 1137 cm^À1; MS (EI): m/z 436 (M⁺À84); HRMS:

Calcd for C₂₅H₂₁FO₆436.1322, Found: 436.1324.

4.5.1. (E)-3-{3-[(3-Fluorobenzyl)oxy]-4-[(3-(4-

hydroxyphenyl)propanoyl)oxy]phenyl}acrylic acid (7w)

Yield: 95%; mp: 155–157 °C; ¹H NMR (400 MHz, CDCl₃): d 2.84

(2H, t, J = 7.7 Hz), 2.96 (2H, t, J = 7.7 Hz), 5.09 (2H, s), 6.34 (1H, d,

J = 16.1 Hz), 6.75 (2H, d, J = 8.3 Hz), 7.04 (2H, d, J = 8.3 Hz), 7.08–

7.18 (6H, m), 7.34 (1H, quin, J = 7.8 Hz), 7.68 (1H, d, J = 16.1 Hz);

¹³C NMR (125 MHz, CDCl₃): d 30.0, 31.9, 35.7, 69.4, 113.5, 114.4

(d, J = 21 Hz), 115.2 (d, J = 21 Hz), 115.6, 120.1, 122.5, 123.7,

129.6, 131.0 (d, J = 7.4 Hz), 133.7, 140.1 (d, J = 7.4 Hz), 141.7,

143.7, 150.3, 156.2, 162.7 (J = 243 Hz), 168.1, 171.0; IR (KBr):

3400, 2930, 1692, 1516, 1261, 1123 cm^À1; MS (EI): m/z 436 (M⁺);

HRMS: Calcd for C₂₅H₂₁FO₆436.1322, Found: 436.1325.

4.4.24. (E)-3-{3-[(3-Fluorobenzyl)oxy]-4-[(3-(3-((tetrahydro-2H-

pyran-2-yl)oxy)phenyl)propanoyl)oxy]phenyl}acrylic acid (6x)

Yield: 42%; mp: 117–119 °C; ¹H NMR (400 MHz, CDCl₃): d 1.26–

2.05 (6H, m), 2.88 (2H, t, J = 7.7 Hz), 2.98 (2H, t, J = 7.7 Hz), 3.60

(1H, d, J = 11.5 Hz), 3.89 (1H, t, J = 8.8 Hz), 5.09 (2H, s), 5.41 (1H,

m), 6.34 (1H, d, J = 15.9 Hz), 6.79 (1H, d, J = 7.9 Hz), 6.65 (1H, d,

J = 7.9 Hz), 6.92 (1H, s), 7.01 (1H, d, J = 8.3 Hz), 7.06 (1H, d,

J = 8.3 Hz), 7.12–7.22 (5H, m), 7.34 (1H, quin, J = 7.9 Hz), 7.69

(1H, d, J = 15.9 Hz); ¹³C NMR (100 MHz, CDCl₃): d 18.73, 25.16,

30.33, 30.83, 35.44, 62.00, 69.84, 96.24, 112.91, 114.1 (d,

J = 22 Hz), 114.31, 115.1 (d, J = 22 Hz), 116.52, 117.55, 121.54,

122.00, 122.6 (d, J = 2.4 Hz), 123.39, 129.43, 130.2 (d, J = 7.4 Hz),

132.86, 138.7 (d, J = 7.4 Hz), 141.53, 142.14, 146.02, 150.25,

157.17, 163.1 (d, J = 246 Hz), 170.66, 171.82; IR (KBr): 2945,

1693, 1258, 1123 cm^À1; MS (EI): m/z 436 (M⁺À84); HRMS: Calcd

for C₂₅H₂₁FO₆436.1322, Found: 436.1322.

4.5.2. (E)-3-{3-[(3-Fluorobenzyl)oxy]-4-[(3-(3-

hydroxyphenyl)propanoyl)oxy]phenyl}acrylic acid (7x)

Yield: 73%; mp: 176–178 °C; ¹H NMR (400 MHz, CDCl₃): d 2.87

(2H, t, J = 7.8 Hz), 2.98 (2H, t, J = 7.8 Hz), 5.09 (1H, s), 6.34 (1H, d,

J = 15.9 Hz), 6.68 (1H, d, J = 8.1 Hz), 6.71 (1H, s), 6.79 (1H, d,

J = 8.1 Hz), 7.05 (2H, d, J = 8.1 Hz), 7.12–7.18 (5H, m), 7.34 (1H,

quin, J = 8.1 Hz), 7.68 (1H, d, J = 15.9 Hz); ¹³C NMR (125 MHz,

DMSO-d₆): d 30.7, 35.2, 69.4, 113.6 (d, J = 22 Hz), 114.4 (d,

J = 22 Hz), 115.1, 115.7, 119.3, 120.2, 122.4, 123.7, 129.8, 130.2

(d, J = 3.7 Hz), 131.0 (d, J = 7.4 Hz), 133.7, 140.1 (d, J = 7.4 Hz),

141.7, 142.0, 143.7, 150.3, 157.9, 159.0, 162.7 (d, J = 245 Hz),

168.1, 170.9; IR (KBr): 3649, 1684, 1508, 1261, 1123 cm^À1; MS

(EI): m/z 436 (M⁺); HRMS: Calcd for C₂₅H₂₁FO₆436.1322, Found:

436.1322.

4.4.25. (E)-3-{3-[(4-Methylbenzyl)oxy]-4-[(3-(3-((tetrahydro-

2H-pyran-2-yl)oxy)phenyl)propanoyl)oxy]phenyl}acrylic acid

(6y)

4.5.3. (E)-3-{4-[(3-(3-Hydroxyphenyl)propanoyl)oxy]-3-[(4-

methylbenzyl)oxy]phenyl}acrylic acid (7y)

Yield: 27%; ¹H NMR (400 MHz, CDCl₃): d 1.26–2.35 (6H, m), 2.83

(2H, t, J = 7.8 Hz), 2.94 (2H, t, J = 7.8 Hz), 3.60 (1H, d, J = 11.2 Hz),

3.91 (1H, t, J = 9.0 Hz), 5.06 (2H, s), 5.41 (1H, m), 6.34 (1H, d,

J = 15.9 Hz), 6.67 (1H, s), 6.82 (1H, d, J = 7.8 Hz), 6.91 (1H, s), 6.92

(1H, d, J = 7.8 Hz), 7.04 (1H, d, J = 7.8 Hz), 7.13–7.22 (6H, m), 7.68

(1H, d, J = 15.9 Hz); ¹³C NMR (100 MHz,CDCl₃): d 18.73, 21.14,

25.16, 30.34, 30.85, 35.45, 61.99, 70.71, 96.24, 112.99, 114.19,

116.56, 117.37, 121.53, 121.73, 123.21, 129.26, 129.39, 132.78,

133.04, 137.94, 141.64, 142.27, 146.22, 150.55, 157.16, 170.74,

171.86; IR (neat): 1684, 1506, 1259, 1121 cm^À1; MS (EI): m/z 432

(M⁺-84); HRMS: Calcd for C₂₆H₂₄O₆432.1573, Found: 432.1570.

Yield: 53%; mp: 172–174 °C; ¹H NMR (400 MHz, CDCl₃): d 2.83

(2H, t, J = 7.6 Hz), 2.94 (2H, t, J = 7.6 Hz), 5.06 (2H, s), 6.24 (1H, d,

J = 16.0 Hz), 6.67 (1H, s), 6.68 (1H, d, J = 7.3 Hz), 6.76 (1H,

d, J = 7.3 Hz), 7.03 (1H, d, J = 7.3 Hz), 7.13–7.20 (7H, m), 7.68 (1H,

d, J = 16.0 Hz); ¹³C NMR (125 MHz, DMSO-d₆): 21.3, 30.7, 31.2,

35.2, 70.3, 113.6, 113.7, 115.7, 119.3, 120.1, 122.2, 123.6, 128.1,

129.5, 129.8, 133.7, 134.1, 137.7, 141.8, 142.0, 143.8, 150.6,

157.9, 168.1, 170.9; IR (KBr): 3400, 2923, 1686, 1261, 1123 cm^À1

;

MS (EI): m/z 432 (M⁺); HRMS: Calcd for C₂₆H₂₄O₆432.1573, Found:

432.1570.

4.5.4. (E)-3-{[4-(3-(4-Hydroxyphenyl)propanoyl)oxy]-3-[(4-

methylbenzyl)oxy]phenyl}acrylic acid (7z)

4.4.26. (E)-3-{3-[(4-Methylbenzyl)oxy]-4-[(3-(4-((tetrahydro-

2H-pyran-2-yl)oxy)phenyl)propanoyl)oxy]phenyl}acrylic acid

(6z)

Yield: 43%; mp: 155–157 °C; ¹H NMR (400 MHz, CDCl₃): d 2.80

(2H, t, J = 8.3 Hz), 2.92 (2H, t, J = 8.3 Hz), 5.05, (2H, s), 6.34 (1H, d,

J = 16.1 Hz), 6.74 (2H, d, J = 8.5 Hz), 7.02 (1H, d, J = 8.3 Hz), 7.06

(2H, d, J = 8.3 Hz), 7.13–7.28 (6H, m), 7.68 (1H, d, J = 16.1 Hz); ¹³C

NMR (125 MHz, DMSO-d₆): d 21.3, 29.9, 35.7, 70.3, 113.6, 115.6,

Yield: 61%; ¹H NMR (400 MHz, CDCl₃): d 2.35 (3H, s), 2.81 (2H, t,

J = 8.3 Hz), 2.93 (2H, t, J = 8.3 Hz), 3.59 (1H, d, J = 11.7 Hz), 3.91 (1H,

t, J = 6.3 Hz), 5.05 (2H, s), 5.37 (1H, m), 6.34 (1H, d, J = 16.1 Hz), 6.97

S. Endo et al. / Bioorg. Med. Chem. 22 (2014) 5220–5233

5231

120.1, 123.6, 128.1, 129.5, 129.6, 130.7, 133.6, 134.1, 137.7, 141.7,

143.7, 150.6, 168.1, 171.0; IR (KBr): 2926, 1685, 1516, 1264,

1121 cm^À1; MS (EI): m/z 432 (M⁺); HRMS: Calcd for C₂₆H₂₄O₆

432.1573, Found: 432.1569.

J = 8.0 Hz), 5.17 (2H, s), 5.61 (1H, t, J = 6.1 Hz), 6.86 (1H, dd,

J = 5.7, 2.6 Hz), 7.03 (1H, d, J = 6.3 Hz), 7.05 (1H, s), 7.27 (1H, m),

7.30 (1H, t, J = 7.5 Hz), 7.45 (1H, dd, J = 6.3, 2.0 Hz), 7.50 (1H, d,

J = 2.0 Hz); ¹³C NMR (125 MHz, CDCl₃): d 18.1, 24.8, 29.8, 54.8,

61.6, 70.2, 96.5, 112.1, 112.5, 113.2, 115.8, 118.9, 126.2, 129.3,

130.5, 138.1, 149.1, 152.2, 159.5, 190.6; IR (KBr): 1684, 1508,

1273, 1123 cm^À1; MS (EI): m/z 258 (M⁺À84); HRMS: Calcd for

4.6. General procedure for benzylation

To a stirred solution of 1 (1 mmol) in DMSO (8 mL) was added

NaH (2.2 mmol) at 0 °C, and the reaction mixture was stirred for

30 min. Benzyl chloride (1 mmol) was added to the reaction mix-

ture, and the resulting mixture was stirred for 12 h at room tem-

perature. The reaction was quenched by 10% HCl (pH ꢀ 4), and

the aqueous mixture was extracted with EtOAc (5 mL Â 3). The

organic extracts were combined, dried over Na₂SO₄, and evapo-

rated. The residue was chromatographed on silica gel (15 g, hex-

ane/acetone = 10:1–50:1) to give corresponding benzyl ether.

C₁₅H₁₄O₄258.0892, Found: 258.0892.

4.8. General procedure for Horner–Wadsworth–Emmons

reaction of 10

Compounds 10a and 10b were esteriﬁed as described for the

synthesis of 4.

4.8.1. (E)-Ethyl-3-{3-[(3-(methoxymethoxy)benzyl)oxy]-4-

[(tetrahydro-2H-pyran-2-yl)-oxy]phenyl}acrylate (11a)

Yield: 82%; ¹H NMR (400 MHz, CDCl₃): d 1.33 (3H, t, J = 7.1 Hz),

1.63–1.96 (6H, m), 3.47 (3H, s), 3.61 (1H, d, J = 11.1 Hz), 3.95 (1H, t,

J = 7.8 Hz), 4.24 (2H, quint, J = 7.1 Hz), 5.11 (2H, s), 5.18 (2H, s), 5.51

(1H, t, J = 5.9 Hz), 6.27 (1H, d, J = 15.9 Hz), 6.98 (1H, dd, J = 5.6,

2.7 Hz), 7.08–7.16 (5H, m), 7.30 (1H, t, J = 7.8 Hz), 7.58 (1H, d,

J = 15.9 Hz); ¹³C NMR (125 MHz, CDCl₃): d 14.8, 18.3, 25.0, 30.0,

55.8, 60.2, 61.8, 70.9, 94.2, 96.9, 114.0, 114.8, 115.6, 116.2, 117.3,

122.7, 128.5, 129.4, 138.6, 144.2, 149.0, 149.1, 157.3, 167.0; IR

(neat): 1684, 1508, 1121 cm^À1; MS (EI): m/z 358 (M⁺À84); HRMS:

Calcd for C₂₀H₂₀O₆358.1416, Found: 358.1419.

4.6.1. 4-Hydroxy-3-[3-

(methoxymethoxy)benzyloxy]benzaldehyde (9a)

Yield: 92%; ¹H NMR (400 MHz, CDCl₃): d 3.49 (3H, s), 5.16 (2H,

s), 5.21 (2H, s), 6.22 (1H, br), 7.06 (2H, d, J = 8.3 Hz), 7.11 (1H, s),

7.34 (1H, t, J = 7.9 Hz), 7.44 (1H, t, J = 6.8, 1.3 Hz), 7.49 (1H, d,

J = 1.7 Hz); ¹³C NMR (125 MHz, CDCl₃): d 56.0, 71.0, 94.3, 110.3,

114.7, 115.8, 116.4, 121.4, 127.6, 129.8, 129.9, 137.0, 146.3,

151.8, 157.5, 190.8; IR (neat): 1684, 1508, 1288, 1151 cm^À1; MS

(EI): m/z 288 (M⁺); HRMS: Calcd for C₁₆H₁₆O₅288.0998, Found:

288.0999.

4.6.2. 4-Hydroxy-3-[(3-methoxybenzyl)oxy]benzaldehyde (9b)

Yield: 92%; mp: 92–93 °C; ¹H NMR (500 MHz, CDCl₃): d 3.83

(3H, s), 5.15 (2H, s), 6.22 (1H, br), 6.92 (H, dd, J = 5.7, 2.6 Hz),

6.93 (1H, s), 7.01 (1H, d, J = 7.5 Hz), 7.06 (1H, d, J = 8.0 Hz), 7.34

(1H, t, J = 8.0 Hz), 7.45 (1H, dd, J = 6.3, 1.7 Hz), 7.50 (1H, d,

J = 1.7 Hz); ¹³C NMR (125 MHz, CDCl₃): d 55.2, 71.0, 110.3, 113.5,

113.9, 114.7, 120.1, 127.5, 129.7, 129.8, 136.9, 146.3, 151.9,

159.8, 190.8; IR (KBr): 3368, 1686, 1597, 1292, 1271 cm^À1; MS

(EI): m/z 258 (M⁺); HRMS: Calcd for C₁₅H₁₄O₄258.0892, Found:

258.0892.

4.8.2. (E)-Ethyl-3-{3-[(3-methoxybenzyl)oxy]-4-[(tetrahydro-

2H-pyran-2-yl)oxy]phenyl}acrylate (11b)

Yield: 96%; ¹H NMR (500 MHz, CDCl₃): d 1.33 (3H, t, J = 7.2 Hz),

1.56–2.17 (6H, m), 3.59–3.63 (1H, m), 3.82 (3H, s), 3.94 (1H, t,

J = 8.0 Hz), 4.24 (2H, quin, J = 7.2 Hz), 5.12 (2H, s), 5.51 (1H, m),

6.28 (1H, d, J = 15.9 Hz), 6.85 (1H, dd, J = 6.3, 2.3 Hz), 7.02 (1H, d,

J = 7.8 Hz), 7.05 (1H, s), 7.10–7.16 (3H, m), 7.29 (1H, t, J = 7.8 Hz),

7.59 (1H, d, J = 15.9 Hz); ¹³C NMR (125 MHz, CDCl₃): d 14.2, 18.3,

25.0, 30.0, 54.9, 60.1, 61.7, 70.8, 96.8, 112.2, 113.2, 113.8, 116.2,

117.7, 119.0, 122.6, 128.5, 129.3, 138.5, 144.2, 148.9, 149.1,

159.6, 166.9; IR (neat): 1707, 1508, 1258, 1165 cm^À1; MS (EI): m/z

328 (M⁺À84); HRMS: Calcd for C₁₉H₂₀O₅328.1311, Found:

328.1309.

4.7. General procedure for protection of 9

To a stirred solution of 9 (1 mmol) in CH₂Cl₂(4 mL) were added

3.4-dihydro-2H-pyran (1.1 mmol), and PPTS (0.2 mmol), and the

resulting mixture was reﬂuxed for 12 h. After cooling, the reaction

was quenched by satd NaHCO₃(aq), and the aqueous mixture was

extracted with CH₂Cl₂(5 mL Â 3). The organic extracts were com-

bined, dried over Na₂SO₄, and evaporated. The residue was chro-

matographed on silica gel (15 g, hexane/acetone = 40:1–20:1) to

give corresponding compound.

4.9. General procedure for hydrolysis and deprotection of 11

To a stirred solution of 11 (1 mmol) in MeOH/H₂O (3:1) was

added LiOHÁH₂O (2 mmol), and the resulting mixture was reﬂuxed

for 2 h. After cooling, the reaction was quenched by 10% HCl (aq),

and the aqueous mixture was extracted with EtOAc (5 mL Â 3).

The organic extracts were combined, dried over Na₂SO₄, and evap-

orated. To the residue were added CH₂Cl₂/MeOH (3:1) and PPTS

(0.3 mmol), and the resulting mixture was stirred for 12 h at room

temperature. The solvent was removed under reduced pressure,

and the residue was chromatographed on silica gel (15 g, CH₂Cl₂/

MeOH = 80:1–70:1) to give corresponding compound.

4.7.1. 3-{[3-(Methoxymethoxy)benzyl]oxy}-4-[(tetrahydro-2H-

pyran-2-yl)oxy]benzaldehyde (10a)

Yield: 61%; ¹H NMR (400 MHz, CDCl₃): d 1.60–2.06 (6H, m), 3.64

(1H, d, J = 11.0 Hz), 3.90 (1H, t, J = 8.1 Hz), 5.16 (2H, s), 5.19 (2H, s),

5.60 (1H, t, J = 5.6 Hz), 6.99 (1H, dd, J = 4.9, 2.7 Hz), 7.10 (1H, d,

J = 7.6 Hz), 7.18 (1H, s), 7.27–7.32 (2H, m), 7.45 (1H, dd, J = 6.3,

2.0 Hz), 7.49 (1H, d, J = 7.8 Hz); ¹³C NMR (125 MHz, CDCl₃):

d 18.1, 24.8, 29.8, 54.8, 61.6, 70.4, 96.5, 97.1, 112.1, 112.5, 113.2,

115.8, 118.9, 126.2, 129.5, 130.5, 138.7, 149.1, 152.2, 159.5,

190.6; IR (neat): 1689, 1514, 1267, 1153 cm^À1; MS (EI): m/z 288

(M⁺À84); HRMS: Calcd for C₁₆H₁₆O₅288.0998, Found: 288.1000.

4.9.1. (E)-3-{4-Hydroxy-3-[(3-

(methoxymethoxy)benzyl)oxy]phenyl}acrylic acid (12a)

Yield: 99%; ¹H NMR (400 MHz, CDCl₃): d 3.51 (3H, s), 5.12 (2H,

s), 5.20 (2H, s), 6.26 (1H, d, J = 15.9 Hz), 6.95 (1H, d, J = 8.1 Hz),

7.05–7.14 (5H, m), 7.34 (1H, t, J = 8.1 Hz), 7.67 (1H, d,

J = 15.9 Hz); ¹³C NMR (125 MHz, CDCl₃): d 56.0, 71.0, 94.3, 111.3,

114.7, 115.1, 115.6, 116.4, 121.2, 123.7, 126.6, 129.9, 137.3,

146.0, 146.9, 148.6, 157.5, 172.3; IR (neat): 2361, 1684, 1508,

1271 cm^À1; MS (EI): m/z 330 (M⁺); HRMS: Calcd for C₁₈H₁₈O₆

330.1103, Found: 330.1106.

4.7.2. 3-[(3-Methoxybenzyl)oxy]-4-[(tetrahydro-2H-pyran-2-

yl)oxy]benzaldehyde (10b)

Yield: 63%; mp: 73–77 °C; ¹H NMR (500 MHz, CDCl₃): d 1.55–

2.17 (6H, m), 3.64 (1H, d, J = 7.1 Hz), 3.82 (3H, s), 3.90 (1H, t,

5232

S. Endo et al. / Bioorg. Med. Chem. 22 (2014) 5220–5233

4.9.2. (E)-3-{4-Hydroxy-3-[(3-

4.12. Biological assays

methoxybenzyl)oxy]phenyl}acrylic acid (12b)

Yield: 89%; mp: 167–169 °C; ¹H NMR (500 MHz, CDCl₃): d 3.83

(3H, s), 5.13 (2H, s), 6.26 (1H, d, J = 15.9 Hz), 6.91–6.97 (3H, m);

7.01 (1H, d, J = 8.0 Hz), 7.12 (2H, m), 7.34 (1H, t, J = 7.7 Hz), 7.67

(1H, d, J = 15.9 Hz); ¹³C NMR (125 MHz, DMSO-d₆): d 55.6, 70.2,

113.5, 113.7, 113.8, 116.2, 116.4, 120.4, 123.7, 126.3, 130.0,

139.3, 145.0, 147.3, 150.0, 159.9, 168.6; IR (KBr): 2939, 1684,

4.12.1. Materials

Baccharin was gifted by API Co. Ltd (Gifu, Japan). ONE and ste-

roids were obtained from Cayman Chemical (Ann Arbor, MI, United

States) and Steraloids (Newport, RI, United States), respectively.

Human A549 cells were obtained from the American Type Culture

Collection (Manassas, VA, United States), and bovine aortic endo-

thelial cells were generous gifts from Taisho Pharmaceutical Co.

(Saitama, Japan).

1514, 1271 cm^À1

;

MS (EI): m/z 300 (M⁺); HRMS: Calcd for

C₁₇H₁₆O₅300.0998_,Found: 300.1000.

4.10. General procedure for the synthesis of 13

4.12.2. Preparation of recombinant enzymes

Recombinant AKR1C1,³⁷AKR1C2,³⁸AKR1C3,³⁹and AKR1C4³⁷

were prepared and puriﬁed to homogeneity, as described previously.

Compounds 13a and 13b were synthesized as described for the

synthesis of 6a–6z.

4.12.3. Assay of enzyme activity

The dehydrogenase activities of the AKR1C isoforms were deter-

mined at 25 °C by measuring the rate of change in NADPH ﬂuores-

cence (at 455 nm with an excitation wavelength of 340 nm).⁷The

IC₅₀values for inhibitors were determined in the reaction mixture

that consisted of 0.1 M potassium phosphate, pH 7.4, 0.25 mM

NADP⁺, S-1-tetralol (0.1 mM for AKR1C1 and 1 mM for other

AKR1C isoforms), and enzyme, in a total volume of 2.0 mL. Kinetic

studies in the presence of inhibitors were carried out in the NADP⁺-

linked S-1-tetralol oxidation over a range of ﬁve substrate concen-

trations (0.33–2 mM) at a saturating concentration (0.25 mM) of

NADP⁺. The IC₅₀and K_ivalues are expressed as the means SD of

at least three determinations.

4.10.1. (E)-3-{3-{[3-(Methoxymethoxy)benzyl]oxy}-4-[(3-

phenylpropanoyl)oxy]phenyl}acrylic acid (13a)

Yield: 93%; ¹H NMR (500 MHz, CDCl₃): d 2.88 (2H, t, J = 8.0 Hz),

3.02 (2H, t, J = 8.0 Hz), 3.44 (3H, s), 5.01 (2H, s), 5.16 (2H, s), 6.34

(1H, d, J = 16.0 Hz), 6.99–7.29 (12H, m), 7.68 (1H, d, J = 16.0 Hz);

¹³C NMR (125 MHz, CDCl₃): d 30.8, 35.5, 56.0, 70.5, 94.3, 113.0,

115.0, 115.9, 117.4, 120.6, 121.9, 123.3, 126.3, 128.3, 128.5,

129.7, 132.8, 137.7, 140.1, 142.2, 146.2, 150.5, 157.5, 170.7,

171.7; IR (neat): 2927, 1762, 1685, 1259, 1121 cm^À1; MS (EI):

m/z 462 (M⁺); HRMS: Calcd for C₂₇H₂₆O₇462.1679, Found:

462.1677.

4.10.2. (E)-3-{3-[(3-Methoxybenzyl)oxy]-4-[(3-

phenylpropanoyl)oxy]phenyl}acrylic acid (13b)

4.12.4. Molecular modeling

Atomic coordinates for the AKR1C3–NADP⁺–ﬂufenamic acid

complex (PDB code: 1S2C)⁴⁰were obtained from the RCSB Protein

Data Bank. The structure was prepared using the Maestro (Schrö-

dinger, LLC) software package Version 8.5, as described previ-

Yield: 54%; mp: 97–99 °C; ¹H NMR (500 MHz, CDCl₃): d 2.79

(2H, t, J = 7.4 Hz), 3.02 (2H, t, J = 7.4 Hz), 3.80 (3H, s), 5.08 (2H, s),

6.34 (1H, d, J = 15.9 Hz), 6.86 (1H, dd, J = 5.3, 2.3 Hz), 6.95 (1H, s),

6.96 (1H, d, J = 8.0 Hz), 7.03 (1H, d, J = 8.0 Hz), 7.14–7.18 (2H, m),

7.20–7.24 (3H, m), 7.28–7.31 (3H, m), 7.68 (1H, d, J = 15.9 Hz),

¹³C NMR (125 MHz, CDCl₃): d 30.9, 35.6, 55.2, 70.6, 112.8, 113.0,

113.6, 117.3, 119.3, 121.8, 123.3, 126.4, 128.3, 128.5, 129.7,

132.9, 137.7, 140.2, 142.2, 146.2, 150.5, 159.9, 170.7, 171.4; IR

(KBr): 2934, 1763, 1690, 1265, 1122 cm^À1; MS (EI): m/z 432

(M⁺); HRMS: Calcd for C₂₆H₂₄O₆423.1573, Found: 432.1572.

ously.⁴¹The ligand (6m or 14) was subjected to

a full

minimization using the program LigPrep prior to the docking.

The docking calculations for the ligands were performed using

the program Glide 5.0⁴²on a Linux workstation (for 6m-docked

model) and Molegro Virtual Docker 5.5 (for 14-docked model)

under the conditions described previously.⁴³Among the poses gen-

erated, the poses showing a distance of less than 3.5 Å between the

docked molecules and the catalytically important residues, Tyr55

and His117, were selected initially. Finally, we selected the

pose, in which the ligand positioned in the substrate binding

site of the enzyme most similarly to baccharin in the previously

reported model, which is supported by the site-directed

mutagenesis results.⁷The ﬁgure showing the docked model was

generated using PyMOL (DeLano Scientiﬁc).

4.11. Synthesis of 14

To a stirred solution of the ester (13b, 1.85 mmol) in THF (5 mL)

was added 10% HCl (aq, 15 drops), and the resulting mixture was

heated to 40 °C for 16 h. After cooling, the reaction was quenched

by H₂O. The aqueous mixture was extracted with EtOAc (5 mL Â 3).

The organic extracts were combined, dried over Na₂SO₄, and evap-

orated. The residue was chromatographed on silica gel (15 g, hex-

ane/acetone = 8:1–2:1) to give 14.

4.12.5. Cell culture experiments

The cells were cultured in Dulbecco’s modiﬁed Eagle’s medium

supplemented with 10% fetal bovine serum, 100 U/mL penicillin,

and 100 lg/mL streptomycin at 37 °C in a humidiﬁed incubator

4.11.1. (E)-3-{3-[(3-Hydroxybenzyl)oxy]-4-[(3-

containing 5% CO₂. The analysis of the metabolism of androsterone

in A549 cells was carried out as described previously.⁷The trans-

fection of the pGW1 plasmids harboring the cDNA for AKR1C3 into

bovine aortic endothelial cells,^7,14and the overexpression of the

enzyme was conﬁrmed by Western blotting using the antibody

against AKR1C3, in contrast to no immunopositive band in the

extract of the control cells transfected with the vector alone.¹⁴Fol-

phenylpropanoyl)oxy]phenyl}acrylic acid (14)

Yield: 52%; mp: 150–152 °C; ¹H NMR (400 MHz, CDCl₃): d 2.89

(2H, t, J = 7.6 Hz), 3.03 (2H, t, J = 7.6 Hz), 5.05 (2H, s), 6.31 (1H, d,

J = 15.7 Hz), 6.78 (1H, dd, J = 6.1, 1.9 Hz), 6.83 (1H, s), 6.91 (1H,

d, J = 7.8 Hz), 7.01 (1H, d, J = 8.1 Hz), 7.09 (1H, s), 7.12 (1H, d,

J = 8.1 Hz), 7.19–7.31 (6H, m), 7.66 (1H, d, J = 15.9 Hz); ¹³C NMR

(125 MHz, CDCl₃): d 31.0, 35.7, 70.4, 113.1, 114.1, 115.3, 115.7,

119.2, 121.9, 123.3, 126.5, 128.4, 128.6, 133.0, 140.2, 142.2,

146.2, 150.5, 156.2, 171.3, 171.4; IR (KBr): 3030, 1686, 1508,

lowing the treatment of 15 lM ONE for 24 h, the cell viability was

measured by a tetrazolium dye-based cytotoxicity assay using

2-(4-iodophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetra-

zolium monosodium salt,⁴⁴and expressed as % of control culture

;

1263, 1121 cm^À1MS (EI): m/z 418 (M⁺); HRMS: Calcd for

C₂₅H₂₂O₆418.1416, Found: 418.1413.

S. Endo et al. / Bioorg. Med. Chem. 22 (2014) 5220–5233

5233

19. Adeniji, A. O.; Twenter, B. M.; Byrns, M. C.; Jin, Y.; Chen, M.; Winkler, J. D.;

Penning, T. M. J. Med. Chem. 2012 , 55 , 2311.

conditions. Data are expressed as means SD of at least three indepen-

dent experiments. Statistical evaluation of the data was performed by

using the unpaired Student’s t-test and ANOVA followed by Fisher’s

test. A p value <0.05 was considered statistically signiﬁcant.

20. Heinrich, D. M.; Flanagan, J. U.; Jamieson, S. M.; Silva, S.; Rigoreau, L. J.; Trivier,

E.; Raynham, T.; Turnbull, A. P.; Denny, W. A. Eur. J. Med. Chem. 2013 , 62 , 738.

21. Flanagan, J. U.; Atwell, G. J.; Heinrich, D. M.; Brooke, D. G.; Silva, S.; Rigoreau, L.

J.; Trivier, E.; Turnbull, A. P.; Raynham, T.; Jamieson, S. M.; Denny, W. A. Bioorg.

Med. Chem. 2014 , 22 , 967.

Acknowledgment

22. Liedtke, A. J.; Adeniji, A. O.; Chen, M.; Byrns, M. C.; Jin, Y.; Christianson, D. W.;

Marnett, L. J.; Penning, T. M. J. Med. Chem. 2013 , 56 , 2429.

ˇ ˇ

23. Brozic, P.; Turk, S.; Adeniji, A. O.; Konc, J.; Janezic, D.; Penning, T. M.; Lanišnik,

This work is supported in part by JSPS Grant-in-Aid for Young

Scientists (B) from the Japan Society for the Promotion of Science

Grant Number 24790114.

ˇ

T.; Rizner, T.; Gobec, S. J. Med. Chem. 2012 , 55 , 7417.

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Article Doi

Synthesis of non-prenyl analogues of baccharin as selective and potent inhibitors for aldo-keto reductase 1C3

DOI: 10.1016/j.bmc.2014.08.007

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