Peroxisome proliferator-activated receptor agonists with phenethylphenylphthalimide skeleton derived from thalidomide-related liver X receptor antagonists: Relationship between absolute configuration and subtype selectivity

Bioorganic & Medicinal Chemistry 19 (2011) 3156–3172

Contents lists available at ScienceDirect

Bioorganic & Medicinal Chemistry

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

Peroxisome proliferator-activated receptor agonists with phenethylphenylph-

thalimide skeleton derived from thalidomide-related liver X receptor antago-

nists: Relationship between absolute conﬁguration and subtype selectivity

⇑

Kazunori Motoshima, Minoru Ishikawa, Yuichi Hashimoto, Kazuyuki Sugita

Institute of Molecular & Cellular Bioscience, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan

a r t i c l e i n f o

a b s t r a c t

Article history:

Introduction of an alkylcarboxylic acid unit, which is a partial structure of endogenous peroxisome

proliferator-activated receptor (PPAR) ligands, into a phenethylphenylphthalimide skeleton, which

possesses liver X receptor (LXR) antagonistic activity, afforded novel PPAR ligands. The results of

structure–activity relationship analysis and docking studies led us to the potent PPAR agonists 13c–e.

The absolute conﬁguration of 13c–e affects the PPAR subtype selectivity.

Received 18 March 2011

Accepted 30 March 2011

Available online 3 April 2011

Keywords:

PPAR agonist

Molecular design

Nuclear receptor

Subtype selectivity

1. Introduction

an important role in regulating lipid, lipoprotein and glucose

homeostasis.⁴Therefore PPARs have emerged as a novel therapeu-

Peroxisome proliferator-activated receptors (PPARs) are

ligand-activated transcription factors belonging to the nuclear hor-

tic target for treatment of various components of metabolic syn-

drome. Some endogenous and synthetic ligands of PPARs are

illustrated in Fig. 1.

mone receptor superfamily. There are three subtypes, PPAR

a,

PPARd, and PPAR -linolenic acid

c

.¹Lipids, such as linoleic acid (1),

a

We have been engaged in the creation of bioactive compounds

based on the multi-template approach utilizing thalidomide.^13–18

The basis of the multi-template approach is that the number of

three-dimensional spatial structures (fold structures) of human pro-

teins is only approximately 1000, which is much smaller than the

number of human proteins, estimated to be 50,000–70,000.^19–21

Therefore, ignoring physical/chemical interactions, a template/scaf-

fold structure which is spatially complementary to onefold structure

might serve as a multi-template for structural development of li-

gands that would interact speciﬁcally with more than 50–70 differ-

ent human proteins. We have focused on thalidomide as a candidate

multi-template structure. Thalidomide is a hypnotic/sedative drug,

whichwas launched in the1950’s, but was withdrawnfrom themar-

ketinthe1960’sbecauseof severeteratogenicity. Inspiteofthis, tha-

lidomide has been established to be useful for the treatment of

Hansen’s disease and multiple myeloma. Additionally, many reports

have appeared on its therapeutic potential for the treatment of a

range of diseases, including cancers, rheumatoid arthritis, and dia-

betes.^13–18,22We have created many thalidomide analogues with a

(2), and arachidonic acid (3), and eicosanoids, such as prostaglan-

din and leukotriene, are endogenous ligands for all PPARs.^2,3Each

PPAR isotype displays a distinct pattern of tissue distribution and

a distinct pharmacological proﬁle.⁴PPAR

a is mainly expressed in

the liver, where it regulates free fatty acid oxidation, and is also ex-

pressed to a lesser extent in the heart, skeletal muscle, small intes-

tine and kidney.⁵A PPAR

a-selective agonist, fenoﬁbrate (4), has

been used for many years to treat hyperlipidemia and to decrease

serum levels of triglyceride, which is one of the risk factors for

metabolic syndrome.⁶PPARd is expressed in a variety of tissues,

including skin, skeletal muscle, adipose tissue, and heart.⁷A spe-

ciﬁc agonist, GW501516 (5),⁸increased circulating HDL cholesterol

levels and lowered triglyceride.^9,10Consequently, PPARd activation

is thought to be a novel approach for the treatment of metabolic

syndrome. PPAR

the gut, and immune cells. It regulates adipocyte differentiation

and lipid storage in white adipose tissue. Moreover, PPAR coordi-

c is expressed in white and brown adipose tissue,

c

nates glucose metabolism to improve insulin sensitivity. Thiazolid-

inediones such as pioglitazone (6) are in clinical use for the

treatment of type 2 diabetes.^11,12As mentioned above, PPARs play

range of biological activities, including tumor necrosis factor-

(TNF-

) production regulators,^23,24nitric oxide synthase (NOS)

inhibitors,^25,26cyclooxygenase (COX) inhibitors,^27–29liver X recep-

a

tor (LXR) antagonists,^30–33-glucosidase inhibitors,^33–36and glyco-

a

gen phosphorylase inhibitors.³⁷Recently, we have created

⇑

Corresponding author.

E-mail address: sugitakazu@iam.u-tokyo.ac.jp (K. Sugita).

phenethylphenylphthalimide derivatives such as 9, which exhibit

doi:10.1016/j.bmc.2011.03.065

K. Motoshima et al. / Bioorg. Med. Chem. 19 (2011) 3156–3172

3157

Figure 1. (a) Chemical structures of representative endogenous PPAR ligands. (b) Synthetic PPAR agonists. (c) Chemical structures of 22(R)-hydroxycholesterol (7) and

apocholic acid (8).

LXR

a

-selective antagonist activity (Fig. 2).³³Here, we describe the

(Fig. 1c),³⁸so we speculated that it would be possible to separate

PPAR and LXR activities. Therefore, we designed and synthesized

a series of compounds possessing an alkyl carboxyl group (Fig. 2b).

Our designed compounds were prepared as shown in

Schemes 1–3. Introduction of a t-butyl group into p-toluic acid

gave compound 14, and subsequent bromination of 14 with AIBN

and NBS gave 15. Compound 15 was reacted with triphenylphos-

phine to generate triphenylphosphonium salt 16. A diphenyleth-

ene derivative 17 was prepared as an E/Z mixture by means of

Wittig reaction of 4-nitrobenzaldehyde with 16. After simulta-

neous reduction of the nitro group and oleﬁn moiety of compound

17, phenethylphenylphthalimide 19 was obtained by condensation

with phthalic anhydride, followed by alkaline hydrolysis to afford

compound 10. 4-(Bromomethyl)benzoic acid methyl ester was re-

acted with triphenylphosphine to generate triphenylphosphonium

salt 20. Compound 22 was prepared by Wittig reaction of p-aceta-

minobenzaldehyde with 20. After reduction of the oleﬁn moiety of

compound 22, compound 23 was reduced with BH₃, followed by

oxidation by MnO₂to afford the aldehyde intermediate 25. Com-

pound 25 was treated with Wittig reagents 21a–c, followed by

reduction by Pd/C, hydrolysis, condensation with phthalic

anhydride, and alkaline hydrolysis to afford the desired products

11a–c. Introduction of an alkyl carboxyl group into compound 29

gave compounds 30a–c, followed by hydrolysis to afford target

compounds 12a–c.

design, synthesis, and evaluation of the structure–activity relation-

ship of phenethylphenylphthalimide derivatives, aimed at generat-

ing novel PPARs agonists.

2. Results and discussion

2.1. Introduction of alkyl carboxyl group into

phenethylphenylphthalimide skeleton

PPARs and LXRs all belong to the nuclear hormone receptor

superfamily and PPARs are similar to LXR in fold structure

(Fig. 2a).¹Therefore, we speculated that phenethylphenylphthali-

mides possessing LXR-antagonistic activity might be a suitable

scaffold for creation of PPAR ligands. Next, we focused on the dif-

ference of endogenous ligands between PPAR and LXR. The

endogenous ligands of PPAR and LXR are oxysterols such as

22(R)-hydroxycholesterol (7) and unsaturated long-chain fatty

acids such as linoleic acid (1), respectively (Fig. 1a and c).^2,3,38

Although these ligands appear to have diverse structures, they pos-

sess a common feature, that is, hydrophobic partial structure. Thus,

we thought that introduction of an alkyl carboxyl group, which is a

partial structure of endogenous PPAR ligands, into LXRa antagonist

9 might generate PPAR ligands. On the other hand, apocholic acid

(8), which is an oxysterol, has no LXR-agonistic activity

Figure 2. (a) Superposition of X-ray crystal structures of PPARa (green, PDB ID: 2ZNN) and LXRa (magenta, PDB ID: 3IPU). (b) Molecular design of PPAR ligands bearing an

aliphatic carboxyl group.

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K. Motoshima et al. / Bioorg. Med. Chem. 19 (2011) 3156–3172

Scheme 1. Synthesis of 10. Reagents and conditions: (a) t-BuOH, EDC, DMAP, reﬂux; (b) AIBN, NBS, CCl₄, reﬂux; (c) PPh₃, MeCN, reﬂux; (d) 4-nitrobenzaldehyde, K₂CO₃, 18-

crown-6, CH₂Cl₂, reﬂux; (e) H₂, 10% Pd/C, EtOAc, rt; (f) phthalic anhydride, neat, 200 °C; (g) TFA, CH₂Cl₂, rt.

Scheme 2. Synthesis of 11a–c. Reagents and conditions: (a) PPh₃, MeCN, reﬂux; (b) PPh₃, EtOAc, rt; (c) 20, K₂CO₃, 18-crown-6, CH₂Cl₂, reﬂux; (d) H₂(0.2 MPa), 10% Pd/C,

EtOAc, MeOH, rt; (e) LiBH₄, THF, rt; (f) MnO₂, CH₂Cl₂, rt; (g) 21a–c, K₂CO₃, 18-crown-6, CH₂Cl₂, reﬂux; (h) H₂, 10% Pd/C, EtOAc, rt; (i) concd HCl, EtOH, 100 °C; (j) phthalic

anhydride, neat, 200 °C; (k) AcOH, 6 N HCl, 70 °C.

Scheme 3. Synthesis of 12a–c. Reagents and conditions: (a)

x-bromoalkyl carboxylic acid ester, K₂CO₃, DMF, 50 °C; (b) TFA, CH₂Cl₂, rt; (c) AcOH, 6 N HCl, 70 °C.

K. Motoshima et al. / Bioorg. Med. Chem. 19 (2011) 3156–3172

3159

To investigate the cell-level PPAR-agonistic activity, we utilized

a PPAR-responsive reporter gene assay with CMX-GAL4N-hPPAR

LBD as the recombinant receptor gene, TK-MH100x4-LUC as the re-

porter gene, and the CMX b-galactosidase gene for normalization,

as previously reported.³⁹After incubation, cells were assayed for

luciferase reporter gene and b-galactosidase activities. None of

the compounds evaluated in our experiments reduced b-galactosi-

dase activity in the concentration range investigated. Percent efﬁ-

with a t-butyldimethylsilyl (TBS) group and subsequent oxidation

of the primary alcohol gave 32. Compound 32 was treated with

Horner-Emmons reagents, followed by reduction, deprotection of

TBS with TBAF, and oxidation to afford the intermediate 36.

Diphenylethene derivatives 39 were prepared by Wittig reaction

of 36 with ylides 38. After hydrolysis with LiOH, t-butyl esters 41

were obtained by esteriﬁcation of 40. Simultaneous Pd/C reduc-

tion of the nitro group and oleﬁn moiety of compounds 41

and subsequent condensation with phthalic anhydride gave

compounds 43. Compounds 43 were hydrolyzed to afford

compounds 13. Compound 13c was treated with BBr₃to give com-

pound 13b.

cacy (E_max) of PPAR

the maximal stimulatory response, in relation to the activity of

10 M fenoﬁbric acid, 100 nM GW501516, and 10 M ciglitazone,

respectively.

The PPAR-agonistic activities of the synthesized compounds are

shown in Table 1. Compound 11a showed PPAR d dual agonistic

activity (PPAR E_max= 53%, EC₅₀= 11 M; PPARd: E_max= 27%,

EC₅₀= 13 M) (Table 1). Compounds 12a and 12b also showed

weak PPAR d dual agonistic activity and PPAR -selective agonistic

a, PPARd, and PPARc agonists was estimated at

l

As expected, introduction of alkyl chains into 11a enhanced the

PPAR-agonistic activities (Table 2). There is a tendency for

PPAR-agonistic activities to increase with increase of alkyl chain

length at the alkoxy group. Compounds 13d, 13e, and 13c showed

a

a:

l

a

c

the most potent agonistic activities toward PPAR

PPAR , respectively. Compound 13a, which possesses an ethyl

group at the position of carboxylic acid, showed more potent

a, PPARd and

activity, respectively. As a result of docking study using the

c

AUTODOCK 4.2 docking program,⁴⁰12a was suggested to bind to

a

PPAR

a

and PPARd in ways similar to 11a (Fig. S1). Therefore the

and PPARd ago-

or similar agonistic activity, as compared with 11a, and com-

pounds 13c–f, bearing ethyl and alkoxy groups, showed more po-

tent PPAR-agonistic activities than 13a. Docking study suggested

that the alkyl chains of 13d, 13e, and 13c occupy the spaces indi-

cated by red and yellow circles in Figure 3 (Fig. S2).

reason why compound 12a showed weak PPAR

nistic activities compared with those of compound 11a might be

an unfavorable interaction between oxygen of 12a and Cys276

and Ser280 in PPAR

a

a and Cys285 and Thr289 in PPARd. None of

the compounds tested showed LXR-agonistic or antagonistic activ-

ity (data not shown).

2.3. Effects of absolute conﬁguration on the subtype selectivity

2.2. Introduction of alkyl chains into

phenethylphenylphthalimide skeleton: structure-based drug

design

To investigate the effect of absolute conﬁguration on PPAR

activity, racemic 13c–e were separated into their enantiomers by

means of chiral chromatography. The PGME (phenylglycine methyl

ester) method was used to determine the absolute conﬁguration.

The PGME method is a NMR methodology using (S)- and (R)-phen-

ylglycine methyl ester, which enables the determination of the

absolute conﬁgurations of chiral carboxylic acids.^41–43The enanti-

omers were separated by chiral chromatography, and the one

whose retention time was shorter was deﬁned as ‘former’ and

the one whose retention time was longer was deﬁned as ‘latter’.

Each enantiomer was condensed with (S)-PGME to afford the

PGME amides (scheme 5). By comparing the ¹H NMR spectra of

the former and latter amides, the absolute conﬁgurations of these

compounds could be estimated (Figs. S3–5). The PPAR-agonistic

activities of the enantiomers (S)-13c–e and (R)-13c–e were

evaluated.

To generate more potent PPAR agonists, we performed a dock-

ing study using the ^AUTODOCK4.2 docking program.⁴⁰Docking of

11a, which shows PPAR

a/d dual agonistic activity, to PPARa, d,

and indicated that there are two unoccupied spaces in all of

c

the PPAR subtypes, shown by red and yellow circles in Figure 3.

Based on these results, analogs of 11a which possess alkyl chains

directed toward those spaces were designed (Fig. 4). Docking study

indicated that the designed compounds would possess stronger

afﬁnity for both PPAR subtypes, as compared with compound

11a (Table S1).

The designed compounds were prepared as shown in Scheme 4.

Protection of one of the two primary alcohols of p-xylene-a,

a⁰-diol

Table 1

PPAR-agonistic activities of phenethylphenylphthalimides with an aliphatic carboxyl group (10, 11a–c, and 12a–c)

O

CO₂H

m

CO₂H

n

O

N

O

10, 11a-c

12a-c

Compound

m or n

PPARa

PPARd

PPARc

a

E_max(%)

EC₅₀

[lM]

E_max(%)

EC₅₀

[lM]

E_max(%)

EC₅₀[lM]

10

0

2

4

6

1

3

5

14

53

4

8

29

0

33

11

0

27

4

10

1

N.D.

13

N.D.

62

2

7

5

6

N.D.

12

11a

11b

11c

12a

12b

12c

N.D.

29

N.D.

31

6

0

N.D.

a

% Efﬁcacy relative to the positive control, fenoﬁbric acid for PPARa, GW501516 for PPARd, ciglitazone for PPARc.

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K. Motoshima et al. / Bioorg. Med. Chem. 19 (2011) 3156–3172

Figure 3. Compound 11a docked into the X-ray crystal structure of PPARa (PDB ID: 2ZNN), PPARd (PDB ID: 2ZNP) and PPARc (PDB ID: 2ZNO) using the AUTODOCK 4.2 docking

program.

Figure 4. Molecular design based on the docking study.

In the case of 13c and 13d, the (R)-derivatives showed more po-

tent PPAR -agonistic activities than the (S)-derivatives, and the

(S)-derivatives showed more potent PPARd and PPAR agonistic

4. Experimental

a

c

4.1. Reporter gene assay

activities than the (R)-derivatives (Table 3). On the other hand,

(S)-13e showed more potent agonistic activities against all of the

PPAR subtypes, as compared with (R)-13e. These results suggest

that absolute conﬁguration of these compounds affects the subtype

selectivity. The results of docking studies did not seem to account

for these selectivities (Table S1).

Human embryonic kidney (HEK) 293 cells were cultured in Dul-

becco’s modiﬁed Eagle’s medium containing 5% fetal bovine serum

at 37 °C in a humidiﬁed atmosphere of 5% CO₂in air. Transfections

were performed by the calcium phosphate coprecipitation method.

Test compounds with or without each positive control were added

8 h after the transfection, and luciferase and b-galactosidase activ-

ities were assayed using a luminometer and microplate reader,

respectively. Each experiment was performed in triplicate and re-

peated at least twice, and the normalized average values are pre-

sented. The EC₅₀values were reproducible.

2.4. Selectivity for FXR

Farnesoid X receptor (FXR) is ligand-activated transcription fac-

tor belonging to the nuclear hormone receptor superfamily. The

physiological ligands are considered to be bile acids, including

CDCA (44) (Fig. 5).⁴⁴CDCA (44) has partial structures of

22(R)-hydroxycholesterol (steroid skeleton) and fatty acid (alkyl

carboxyl group) (Fig. 5). Therefore, we speculated that our PPAR

agonists might possess FXR-agonistic activity. Thus, we examined

the selectivity of our derivatives for FXR.

The FXR receptor agonist assay system is similar to that of PPAR.

None of the compounds examined showed FXR-agonistic or antag-

onistic activity (Fig. 6 and data not shown, respectively). The lack

of FXR-agonistic activity might be explained in terms of structural

differences, compared with endogenous ligands, in the absolute

conﬁguration of the 3-hydroxyl group in the steroid skeleton and

the absence or presence of a double bond in the steroid skeleton.

4.2. General

Melting points were determined by using a Yanagimoto hot-

stage melting point apparatus and are uncorrected. ¹H NMR spec-

tra were recorded on a JEOL ALPHA500 (500 MHz) spectrometer.

Chemical shifts (d) are expressed in parts per million (ppm) rela-

tive to deuteriochloroform or tetramethylsilane as an internal ref-

erence with coupling constants in Hertz. The abbreviations s, d, t,

dt, q, quin, sex, and m signify singlet, doublet, triplet, doublet

triplet quartet, quintet, sextet and multiplet, respectively. Fast

atom bombardment mass spectra (FAB-MS) and high resolution

mass spectra (HRMS) were recorded on a JEOL JMS-HX110 spec-

trometer with m-nitrobenzyl alcohol. Elemental analyses were

carried out in the Microanalytical Laboratory, Faculty of Pharma-

ceutical Sciences, University of Tokyo, and were within 0.4% of

theoretical values.

3. Conclusion

Introduction of an alkyl carboxyl group, which is a partial struc-

ture of PPAR endogenous ligands, into the phenethylphenylphthal-

imide skeleton, which possesses LXR-antagonistic activity, yielded

novel PPAR ligands. Among them, compound 11a possesses

4.2.1. General procedure A (GP-A)

To a solution of alkanoic acid in tert-butanol were added DMAP

(3.0 equiv) and EDC (2.0 equiv). The reaction mixture was reﬂuxed

for 1–4 h, then poured into water and extracted with EtOAc. The

organic layer was washed with H₂O and brine, and dried over

MgSO₄. The solvent was removed under reduced pressure. The res-

idue was puriﬁed by silica gel column chromatography to give the

target compound.

PPARa/d dual agonistic activity. To generate more potent PPAR

agonists, we performed a docking study, and structure-based drug

design afforded more potent PPAR agonists 13c–e. The absolute

conﬁguration of these compounds affected the subtype selectivity.

Thus, our multi-template approach was adaptable to obtain PPAR

subtype-selective agonists.

K. Motoshima et al. / Bioorg. Med. Chem. 19 (2011) 3156–3172

3161

Scheme 4. Synthesis of 13a–f. Reagents and conditions: (a) TBSCl, imidazole, DMF, rt; (b) PDC, CH₂Cl₂, rt; (c) triethyl 2-phosphonobutyrate, t-BuOK, THF, rt; (d) H₂, 10% Pd/C,

EtOAc, rt; (e) TBAF, THF, 0 °C; (f) PPh₃, toluene, reﬂux; (g) alkyl halide, K₂CO₃, DMF, 40 °C; (h) AIBN, NBS, CCl₄, reﬂux; (i) K₂CO₃, 18-crown-6, CH₂Cl₂, reﬂux; (j) EtOH, 1 M LiOH,

75 °C; (k) t-BuOH, DMAP, EDC, reﬂux; (l) phthalic anhydride, neat, 160 °C; (m) TFA, CH₂Cl₂, rt; (n) BBr₃, CH₂Cl₂, 0 °C.

4.2.2. General procedure B (GP-B)

4.2.3. General procedure C-1 (GP-C-1)

To a solution of substituted toluene in carbon tetrachloride

were added N-bromosuccinimide (1.1 equiv) and 2,2⁰-azobis-

(isobutyronitrile) (0.15 equiv). The mixture was reﬂuxed, then ﬁl-

tered and concentrated. The residue was puriﬁed by silica gel col-

umn chromatography to give the target compound.

To a solution of substituted benzyl halide in acetonitrile was

added triphenylphosphine (1.5 equiv), and the mixture was re-

ﬂuxed. The reaction mixture was concentrated and the residue

was mixed with toluene. The whole was ﬁltered to give the target

compound.

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Table 2

PPAR-agonistic activities of compounds 11a and 13a–f

O

N

O

CO H

2

N

R

O

11a

13a-f

Compound

R

PPARa

PPARd

PPARc

a

E_max(%)

EC₅₀

[lM]

E_max(%)

EC₅₀

[

lM]

E_max(%)

EC₅₀[lM]

11a

13a

13b

13c

13d

13e

13f

—

H

OH

OMe

OEt

On-Pr

On-Bu

53

72

20

73

102

70

11

6.6

14

3.4

1.4

1.7

1.8

27

22

7

24

33

40

32

13

14

25

11

4.8

2.9

3.2

7

42

21

78

49

26

36

23

11

17

8.5

9.3

6.9

7.9

63

a

% Efﬁcacy relative to the positive control, fenoﬁbric acid for PPARa, GW501516 for PPARd, ciglitazone for PPARc.

4.2.4. General procedure C-2 (GP-C-2)

The residue was puriﬁed by silica gel column chromatography to

To a solution of substituted benzyl halide in toluene was added

triphenylphosphine (1.5 equiv) and the mixture was reﬂuxed. After

cooling, the precipitate was collected by ﬁltration to give the target

compound.

give the target compound as an EZ mixture.

4.2.6. General procedure E (GP-E)

Substituted nitrobenzene was dissolved in EtOAc and hydroge-

nated with 10% Pd/C (catalytic amount). The mixture was ﬁltered

through a pad of Celite, and the ﬁltrate was evaporated under re-

duced pressure. The residue was puriﬁed by silica gel column chro-

matography to give the target compound.

4.2.5. General procedure D (GP-D)

To a solution of nitrobenzaldehyde in dehydrated CH₂Cl₂were

added benzyltriphenylphosphonium salt (1.0 equiv), potassium

carbonate (1.1 equiv) and 18-crown-6 (0.18 equiv), and the mix-

ture was reﬂuxed, then ﬁltered and the ﬁltrate was concentrated.

4.2.7. General procedure F (GP-F)

A

mixture of phthalic anhydride and substituted aniline

(1.0 equiv) was heated at 160 or 200 °C for 1 h. After the reaction

was completed, the residue was puriﬁed by silica gel column chro-

matography to give the target compound.

4.2.8. General procedure G (GP-G)

To a solution of the t-Bu ester in CH₂Cl₂was added TFA (the

same amount as that of CH₂Cl₂). The mixture was stirred at rt for

overnight. The solvent was removed under reduced pressure. The

Scheme 5. Synthesis of the PGME amides.

Table 3

PPAR-agonistic activities of (S)- and (R)-13c–e

O

N

CO₂H

OR

13c-e

O

Compound

R

PPAR

a

PPARd

PPARc

a

E_max(%)

EC₅₀

[

lM]

E_max(%)

EC₅₀

[lM]

E_max(%)

EC₅₀[lM]

(S)-13c

(R)-13c

(S)-13d

(R)-13d

(S)-13e

(R)-13e

Me

Et

n-Pr

66

103

69

126

87

8.9

4.5

1.7

1.1

1.7

2.5

41

8

29

12

54

8

7.3

N.D.

1.9

9.7

1.8

102

40

62

23

36

7

7.1

12

3.2

6.9

5.2

N.D.

70

N.D.

a

% Efﬁcacy relative to the positive control, fenoﬁbric acid for PPARa, GW501516 for PPARd, ciglitazone for PPARc.

K. Motoshima et al. / Bioorg. Med. Chem. 19 (2011) 3156–3172

3163

4.2.13. 4-Methylbenzoic acid t-butyl ester (14)

This compound was prepared from p-toluic aicd by means of

GP-A. Compound 14 was obtained in 64% yield as a colorless oil.

¹H NMR (500 MHz, CDCl₃) d: 7.87 (d, 2H, J = 8.2 Hz), 7.21 (d, 2H,

J = 8.2 Hz), 1.67 (s, 3H), 1.59 (s, 9H). FAB-MS m/z: not detected.

4.2.14. 4-(Bromomethyl)benzoic acid t-butyl ester (15)

This compound was prepared from 14 by means of GP-B. Com-

pound 15 was obtained in 94% yield as a colorless oil.

Figure 5. Chemical structures of CDCA (44) and 22(R)-hydroxycholesterol (7).

¹H NMR (500 MHz, CDCl₃) d: 7.96 (d, 2H, J = 8.5 Hz), 7.43 (d, 2H,

J = 8.5 Hz), 4.50 (s, 2H), 1.59 (s, 9H). FAB-MS m/z: 269, 271 [M]⁺.

4.2.15. {[4-(t-Butoxyoxycarbonyl)phenyl]methyl}triphenyl

phosphonium bromide (16)

residue was puriﬁed by silica gel column chromatography to give

the target compound.

This compound was prepared from 15 by means of GP-C-1.

Compound 16 was obtained in 25% yield as a white solid.

¹H NMR (500 MHz, CDCl₃) d: 7.84–7.73 (m, 9H), 7.67–7.58 (m,

6H), 7.19 (dd, 2H, J = 8.5, 2.4 Hz), 7.13 (dd, 2H, J = 8.5, 2.4 Hz),

5.56 (d, 2H, J = 14.6 Hz), 1.56 (s, 9H). FAB-MS m/z: 453 [MꢀBr]⁺.

4.2.9. General procedure H (GP-H)

To a solution of ethyl ester in EtOH was added concd HCl (1/10

amount of EtOH). The mixture was heated at 100 °C for 4–6 h, then

poured into sat. NaHCO₃and extracted with EtOAc. The organic

layer was washed with H₂O and brine, then dried over MgSO₄.

The solvent was removed under reduced pressure. The residue

was puriﬁed by silica gel column chromatography to give the tar-

get compound.

4.2.16. 4-[2-(4-Nitrophenyl)ethenyl]benzoic acid t-butyl ester

(17)

This compound was prepared from 4-nitrobenzaldehyde and 16

by means of GP-D. Compound 17 was obtained in 52% yield as a

pale yellow solid.

4.2.10. General procedure I (GP-I)

¹H NMR (500 MHz, CDCl₃) 17Z d: 8.08 (d, 2H, J = 8.5 Hz), 7.87 (d,

2H, J = 8.5 Hz), 7.35 (d, 2H, J = 9.2 Hz), 7.23 (d, 2H, J = 7.9 Hz), 6.83

(d, 1H, J = 12.2 Hz), 6.71 (d, 1H, J = 12.2 Hz), 1.59 (s, 9H). 17E d: 8.24

(d, 2H, J = 8.5 Hz), 8.01 (d, 2H, J = 7.9 Hz), 7.67 (d, 2H, J = 8.5 Hz),

7.59 (d, 2H, J = 8.5 Hz), 7.29 (d, 1H, J = 16.5 Hz), 7.23 (d, 1H,

J = 16.5 Hz), 1.61 (s, 9H). FAB-MS m/z: 325 [M]⁺, 326 [M+H]⁺.

To a solution of ethyl ester in AcOH was added dropwise 6 N

HCl (1/5 amount of AcOH) at 0 °C. The mixture was heated at

70 °C for 2.5–5 h, then poured into water and extracted with

EtOAc. The organic layer was washed with H₂O and brine, then

dried over MgSO₄. The solvent was removed under reduced pres-

sure. The residue was puriﬁed by silica gel column chromatogra-

phy to give the target compound.

4.2.17. 4-[2-(4-Aminophenyl)ethyl]benzoic acid t-butyl ester

(18)

4.2.11. General procedure J (GP-J)

This compound was prepared from 17 by means of GP-E. Com-

pound 18 was obtained in 90% yield as a white solid.

¹H NMR (500 MHz, CDCl₃) d: 7.88 (d, 2H, J = 7.9 Hz), 7.18 (d, 2H,

J = 7.9 Hz), 6.93 (d, 2H, J = 7.9 Hz), 6.61 (d, 2H, J = 8.5 Hz), 3.57 (br s,

2H), 2.92–2.89 (m, 2H), 2.83–2.79 (m, 2H), 1.59 (s, 9H). FAB-MS m/

z: 297 [M]⁺, 298 [M+H]⁺.

To a solution of 2-methyl-5-nitrophenol (613 mg, 4.0 mmol) in

dehydrated DMF (7 mL) were added potassium carbonate (608 mg,

4.4 mmol) and iodoalkane (12.0 mmol) under an argon atmo-

sphere. The mixture was heated at 40 °C for 2–3 h, then poured

into water and extracted with EtOAc. The organic layer was

washed with H₂O and brine, and dried over MgSO₄. The solvent

was removed under reduced pressure. The residue was puriﬁed

by silica gel column chromatography to give the target compound.

4.2.18. 4-{2-[4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)phenyl]

ethyl}benzoic acid t-butyl ester (19)

This compound was prepared from phthalic anhydride and 18

by means of GP-F. Compound 19 was obtained in 68% yield as a

white solid.

4.2.12. General procedure K (GP-K)

To a solution of ethyl ester in EtOH was added 1 M LiOH (the

same amount as that of EtOH). The mixture was heated at 75 °C

for 3.5–7.5 h, then poured into 2 N HCl and extracted with EtOAc.

The organic layer was washed with H₂O and brine, then dried over

MgSO₄. The solvent was removed under reduced pressure to give

the target compound.

¹H NMR (500 MHz, CDCl₃) d: 7.96 (dd, 2H, J = 5.5, 3.1 Hz), 7.92

(d, 2H, J = 8.5 Hz), 7.79 (dd, 2H, J = 5.5, 3.1 Hz), 7.36 (d, 2H,

J = 7.9 Hz), 7.31 (d, 2H, J = 7.9 Hz), 7.25 (d, 2H, J = 8.5 Hz),

3.00–2.98 (m, 4H), 1.59 (s, 9H). FAB-MS m/z: 427 [M]⁺, 428 [M+H]⁺.

Figure 6. Selectivity of PPAR ligands for FXR.

3164

K. Motoshima et al. / Bioorg. Med. Chem. 19 (2011) 3156–3172

4.2.19. 4-{2-[4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)phenyl]-

ethyl}benzoic acid (10)

4.2.25. 4-[2-(4-Acetylaminophenyl)ethyl]benzoic acid methyl

ester (23)

This compound was prepared from 19 by means of GP-G. Com-

pound 10 was obtained in 86% yield as a white solid.

¹H NMR (500 MHz, DMSO-d₆) d: 7.96 (dd, 2H, J = 5.5, 3.1 Hz),

7.91 (dd, 2H, J = 5.5, 3.1 Hz), 7.87 (d, 2H, J = 8.5 Hz), 7.40–7.38 (m,

2H), 7.39 (d, 2H, J = 8.5 Hz), 7.34 (d, 2H, J = 8.5 Hz), 3.02–3.00 (m,

2H), 2.99–2.96 (m, 2H). FAB-MS m/z: 371 [M]⁺, 372 [M+H]⁺. Anal.

Calcd for C₂₃H₁₇NO₄ꢁ1/3H₂O: C, 73.49; H, 4.69; N, 3.73. Found: C,

73.28; H, 4.77; N, 3.61.

Compound 22 (1.13 g, 3.83 mmol) was dissolved in EtOAc

(20 mL) and MeOH (20 mL), and hydrogenated with 10% Pd/C (cat-

alytic amount). The mixture was ﬁltered through a pad of Celite,

and the ﬁltrate was evaporated under reduced pressure to give

the target compound (1.21 g, q.y.) as a white solid.

¹H NMR (500 MHz, CDCl₃) d: 7.93 (d, 2H, J = 7.9 Hz), 7.39 (d, 2H,

J = 7.9 Hz), 7.20 (d, 2H, J = 7.9 Hz), 7.11 (br s, 1H), 7.08 (d, 2H,

J = 7.9 Hz), 3.90 (s, 3H), 2.96–2.93 (m, 2H), 2.91–2.88 (m, 2H),

2.17 (s, 3H). FAB-MS m/z: 297 [M]⁺, 298 [M+H]⁺.

4.2.20. {[4-(Methoxycarbonyl)phenyl]methyl}triphenyl

phosphonium bromide (20)

4.2.26. N-{4-[2-(4-Hydroxymethylphenyl)ethyl]phenyl}

acetamide (24)

This compound was prepared from 4-(bromomethyl)benzoic

acid methyl ester by means of GP-C-1. Compound 20 was obtained

in 100% yield as a white solid.

To a solution of 23 (29 mg, 0.1 mmol) in dehydrated THF (1 mL)

was added dropwise LiBH₄(4.4 mg, 0.2 mmol) at 0 °C under an ar-

gon atmosphere. The mixture was stirred at rt for 4 h, then poured

into MeOH (1 mL) and sat. NH₄Cl aq (10 mL), and extracted with

EtOAc (10 mL ꢂ 3). The organic layer was washed with H₂O

(10 mL) and brine (10 mL), then dried over MgSO₄. The solvent

was removed under reduced pressure. The residue was puriﬁed

by silica gel column chromatography to give the target compound

(17 mg, 63%) as a white solid.

¹H NMR (500 MHz, CDCl₃) d: 7.80–7.75 (m, 11H), 7.65–7.61 (m,

6H), 7.23 (dd, 2H, J = 8.5, 2.4 Hz), 5.66 (d, 2H, J = 15.3 Hz), 3.88 (s,

3H). FAB-MS m/z: 490 [MꢀBr]⁺.

4.2.21. Ethoxycarbonylmethyl-triphenyl-phosphonium

bromide (21a)

To a solution of triphenylphosphine (787 mg, 3.0 mmol) in

EtOAc (10 mL) was added dropwise ethyl bromoacetate (388

lL,

¹H NMR (500 MHz, CDCl₃) d: 7.39 (d, 2H, J = 7.9 Hz), 7.27 (d, 2H,

J = 7.9 Hz), 7.16 (d, 2H, J = 7.9 Hz), 7.11 (d, 2H, J = 7.9 Hz), 7.10 (br s,

1H), 4.66 (s, 2H), 2.92–2.86 (m, 4H), 2.17 (s, 3H). FAB-MS m/z: 269

[M]⁺, 270 [M+H]⁺.

3.5 mmol). The mixture was stirred at rt for overnight. The whole

was ﬁltered to give the target compound (1.15 g, 89%) as a white

solid.

¹H NMR (500 MHz, CDCl₃) d: 7.94–7.89 (m, 6H), 7.81–7.78

(m, 3H), 7.70–7.66 (m, 6H), 5.60 (d, 2H, J = 13.4 Hz), 4.05 (q,

2H, J = 7.3 Hz), 1.08 (t, 3H, J = 7.3 Hz). FAB-MS m/z: 349

[MꢀBr]⁺.

4.2.27. N-{4-[2-(4-Formylphenyl)ethyl]phenyl}acetamide (25)

To a solution of 24 (17 mg, 0.063 mmol) in CH₂Cl₂(10 mL) was

added MnO₂(55 mg, 0.63 mmol). The mixture was stirred at rt

overnight. The solvent was removed under reduced pressure to

give the target compound (16 mg, 94%) as a white solid.

¹H NMR (500 MHz, CDCl₃) d: 9.97 (s, 1H), 7.78 (d, 2H, J = 7.9 Hz),

7.40 (d, 2H, J = 8.5 Hz), 7.29 (d, 2H, J = 7.9 Hz), 7.21 (br s, 1H), 7.08

(d, 2H, J = 7.9 Hz), 2.99–2.96 (m, 2H), 2.93–2.89 (m, 2H), 2.17 (s,

3H). FAB-MS m/z: 267 [M]⁺, 268 [M+H]⁺.

4.2.22. Ethoxycarbonylpropyl-triphenyl-phosphonium bromide

(21b)

To a solution of triphenylphosphine (918 mg, 3.5 mmol) in

MeCN (5 mL) was added ethyl 4-bromobutyrate (429 lL,

3.0 mmol). The mixture was reﬂuxed for 6 h and concentrated.

The residue was puriﬁed by silica gel column chromatography to

give the target compound (764 mg, 56%) as a white solid.

¹H NMR (500 MHz, CDCl₃) d: 7.92–7.87 (m, 6H), 7.80–7.77 (m,

3H), 7.72–7.68 (m, 6H), 4.12–4.08 (m, 4H), 2.91 (d, 2H,

J = 6.7 Hz), 1.96–1.89 (m, 2H), 1.24 (t, 3H, J = 7.3 Hz). FAB-MS

m/z: 377 [MꢀBr]⁺.

4.2.28. 3-{4-[2-(4-Acetylaminophenyl)ethyl]phenyl}propionic

acid ethyl ester (26a)

This compound was prepared from 25 and 21a by means of GP-

D and GP-E. Compound 26a was obtained in 88% yield in two steps

as a white solid.

¹H NMR (500 MHz, CDCl₃) d: 7.39 (d, 2H, J = 8.5 Hz), 7.13–7.08

(m, 7H), 4.13 (q, 2H, J = 7.3 Hz), 2.92 (t, 2H, J = 7.9 Hz), 2.87–2.85

(m, 4H), 2.60 (t, 2H, J = 7.3 Hz), 2.17 (s, 3H), 1.24 (t, 3H,

J = 7.3 Hz). FAB-MS m/z: 339 [M]⁺, 340 [M+H]⁺.

4.2.23. Ethoxycarbonylpentyl-triphenyl-phosphonium bromide

(21c)

To a solution of triphenylphosphine (918 mg, 3.5 mmol) in

MeCN (5 mL) was added 6-bromohexanoic acid ethyl ester

(669

l

L, 3.0 mmol). The mixture was reﬂuxed for 7 h and concen-

4.2.29. 5-{4-[2-(4-Acetylamino-phenyl)ethyl]phenyl}pentanoic

acid ethyl ester (26b)

trated. The residue was puriﬁed by silica gel column chromatogra-

phy to give the target compound (1.14 g, 78%) as a white foam.

¹H NMR (500 MHz, CDCl₃) d: 7.89–7.85 (m, 6H), 7.81–7.78 (m,

3H), 7.72–7.68 (m, 6H), 4.07 (q, 2H, J = 7.3 Hz), 3.95–3.89 (m,

2H), 2.27 (t, 2H, J = 7.3 Hz), 1.76–1.72 (m, 2H), 1.66–1.58 (m, 4H),

1.22 (t, 3H, J = 7.3 Hz). FAB-MS m/z: 405 [MꢀBr]⁺.

This compound was prepared from 25 and 21b by means of GP-

D and GP-E. Compound 26b was obtained in 41% yield in two steps

as a white solid.

¹H NMR (500 MHz, CDCl₃) d: 7.38 (d, 2H, J = 7.9 Hz), 7.12 (br s,

1H), 7.11 (d, 2H, J = 7.9 Hz), 7.07 (s, 4H), 4.12 (q, 2H, J = 7.3 Hz),

2.86 (s, 4H), 2.59 (t, 2H, J = 7.3 Hz), 2.31 (t, 2H, J = 7.3 Hz), 2.16 (s,

3H), 1.65–1.64 (m, 4H), 1.25 (t, 3H, J = 7.3 Hz). FAB-MS m/z: 367

[M]⁺, 368 [M+H]⁺.

4.2.24. 4-[2-(4-Acetylaminophenyl)vinyl]benzoic acid methyl

ester (22)

This compound was prepared from p-acetaminobenzaldehyde

and 20 by means of GP-D. Compound 22 was obtained in 54% yield

as a white solid.

4.2.30. 7-{4-[2-(4-Acetylaminophenyl)ethyl]phenyl}heptanoic

acid ethyl ester (26c)

This compound was prepared from 25 and 21c by means of

GP-D and GP-E. Compound 26c was obtained in 48% yield in two

steps as a white solid.

¹H NMR (500 MHz, CDCl₃) 22Z d: 7.89 (d, 2H, J = 8.5 Hz), 7.36 (d,

2H, J = 8.5 Hz), 7.30 (d, 2H, J = 8.5 Hz), 7.17 (d, 2H, J = 8.5 Hz), 7.16

(br s, 1H), 6.64 (d, 1H, J = 12.2 Hz), 6.57 (d, 1H, J = 12.2 Hz), 3.90 (s,

3H), 2.17 (s, 3H). FAB-MS m/z: 295 [M]⁺, 296 [M+H]⁺.

¹H NMR (500 MHz, CDCl₃) d: 7.39 (d, 2H, J = 8.5 Hz), 7.18 (br s,

1H), 7.10 (d, 2H, J = 7.9 Hz), 7.06 (s, 4H), 4.12 (q, 2H, J = 7.3 Hz),

K. Motoshima et al. / Bioorg. Med. Chem. 19 (2011) 3156–3172

3165

2.86 (s, 4H), 2.56 (t, 2H, J = 7.3 Hz), 2.28 (t, 2H, J = 7.3 Hz), 2.17 (s,

3H), 1.63–1.58 (m, 4H), 1.34–1.32 (m, 4H), 1.25 (t, 3H, J = 7.3 Hz).

FAB-MS m/z: 395 [M]⁺, 396 [M+H]⁺.

2.58 (t, 2H, J = 7.3 Hz), 2.29 (t, 2H, J = 7.3 Hz), 1.65–1.58 (m, 6H),

1.37–1.34 (m, 2H), 1.25 (t, 3H, J = 7.3 Hz).

4.2.37. 3-(4-{2-[4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)

phenyl]ethyl}phenyl)propionic acid (11a)

This compound was prepared from 28a by means of GP-I. Com-

pound 11a was obtained in 39% yield as colorless needles after

recrystallization from EtOAc/n-hexane.

4.2.31. 3-{4-[2-(4-Aminophenyl)ethyl]phenyl}propionic acid

ethyl ester (27a)

This compound was prepared from 26a by means of GP-H. Com-

pound 47a was obtained in 83% yield as a white solid.

¹H NMR (500 MHz, CDCl₃) d: 7.11 (d, 2H, J = 8.5 Hz), 7.10 (d, 2H,

J = 9.2 Hz), 6.97 (d, 2H, J = 8.5 Hz), 6.62 (d, 2H, J = 7.9 Hz), 4.13 (q,

2H, J = 7.3 Hz), 3.57 (br s, 2H), 2.92 (t, 2H, J = 7.3 Hz), 2.85–2.82

(m, 2H), 2.80–2.77 (m, 2H), 2.60 (t, 2H, J = 7.9 Hz), 1.24 (t, 3H,

J = 7.3 Hz). FAB-MS m/z: 297 [M]⁺, 298 [M+H]⁺.

¹H NMR (500 MHz, CDCl₃) d: 7.96 (dd, 2H, J = 5.5, 3.1 Hz), 7.79

(dd, 2H, J = 5.5, 3.1 Hz), 7.33 (d, 2H, J = 7.9 Hz), 7.28 (d, 2H,

J = 8.5 Hz), 7.14 (d, 2H, J = 8.5 Hz), 7.11 (d, 2H, J = 8.5 Hz), 2.98–

2.95 (m, 2H), 2.96–2.93 (m, 2H), 2.95–2.92 (m, 2H), 2.68 (t, 2H,

J = 7.3 Hz). FAB-MS m/z: 399 [M]⁺, 400 [M+H]⁺. Anal. Calcd for

C₂₅H₂₁NO₄: C, 75.17; H, 5.30; N, 3.51. Found: C, 74.87; H, 5.38;

N, 3.56.

4.2.32. 5-{4-[2-(4-Aminophenyl)ethyl]phenyl}pentanoic acid

ethyl ester (27b)

This compound was prepared from 26b by means of GP-H.

Compound 27b was obtained in 83% yield as a white solid.

¹H NMR (500 MHz, CDCl₃) d: 7.10 (d, 2H, J = 8.5 Hz), 7.08 (d, 2H,

J = 8.5 Hz), 6.98 (d, 2H, J = 7.9 Hz), 6.63 (d, 2H, J = 7.9 Hz), 4.12 (q,

2H, J = 7.3 Hz), 3.56 (br s, 2H), 2.84–2.81 (m, 2H), 2.80–2.77 (m,

2H), 2.60 (t, 2H, J = 7.3 Hz), 2.32 (t, 2H, J = 7.3 Hz), 1.67–1.61 (m,

4H), 1.25 (t, 3H, J = 7.3 Hz). FAB-MS m/z: 325 [M]⁺, 326 [M+H]⁺.

4.2.38. 5-(4-{2-[4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)

phenyl]ethyl}phenyl)pentanoic acid (11b)

This compound was prepared from 28b by means of GP-I. Com-

pound 11b was obtained in 83% yield as a white powder after

recrystallization from CH₂Cl₂/n-hexane.

¹H NMR (500 MHz, CDCl₃) d: 7.96 (dd, 2H, J = 5.5, 3.1 Hz), 7.79

(dd, 2H, J = 5.5, 3.1 Hz), 7.34 (d, 2H, J = 9.2 Hz), 7.32 (d, 2H,

J = 8.5 Hz), 7.13 (d, 2H, J = 8.5 Hz), 7.11 (d, 2H, J = 8.5 Hz), 2.98–

2.95 (m, 2H), 2.94–2.91 (m, 2H), 2.62 (t, 2H, J = 7.3 Hz), 2.38 (t,

2H, J = 7.3 Hz), 1.69–1.67 (m, 4H). FAB-MS m/z: 427 [M]⁺, 428

[M+H]⁺. Anal. Calcd for C₂₇H₂₅NO₄ꢁ1/4H₂O: C, 75.22; H, 5.94; N,

3.25. Found: C, 75.12; H, 5.89; N, 3.18.

4.2.33. 7-{4-[2-(4-Aminophenyl)ethyl]phenyl}heptanoic acid

ethyl ester (27c)

This compound was prepared from 26c by means of GP-H. Com-

pound 27c was obtained in 84% yield as a white solid.

¹H NMR (500 MHz, CDCl₃) d: 7.09 (d, 2H, J = 7.9 Hz), 7.07 (d, 2H,

J = 8.5 Hz), 6.98 (d, 2H, J = 7.9 Hz), 6.63 (d, 2H, J = 7.9 Hz), 4.12 (q,

2H, J = 7.3 Hz), 3.56 (br s, 2H), 2.85–2.81 (m, 2H), 2.80–2.77 (m,

2H), 2.57 (t, 2H, J = 7.3 Hz), 2.28 (t, 2H, J = 7.3 Hz), 1.65–1.58 (m,

6H), 1.36–1.33 (m, 2H), 1.25 (t, 3H, J = 7.3 Hz). FAB-MS m/z: 353

[M]⁺, 354 [M+H]⁺.

4.2.39. 7-(4-{2-[4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)

phenyl]ethyl}phenyl)heptanoic acid (11c)

This compound was prepared from 28c by means of GP-I. Com-

pound 11c was obtained in 74% yield as a white powder after

recrystallization from CH₂Cl₂/n-hexane.

¹H NMR (500 MHz, CDCl₃) d: 7.96 (dd, 2H, J = 5.5, 3.1 Hz), 7.79

(dd, 2H, J = 5.5, 3.1 Hz), 7.36–7.32 (m, 4H), 7.13 (d, 2H, J = 8.5 Hz),

7.10 (d, 2H, J = 8.5 Hz), 2.99–2.95 (m, 2H), 2.94–2.90 (m, 2H),

2.58 (t, 2H, J = 7.3 Hz), 2.35 (t, 2H, J = 7.3 Hz), 1.63 (quin, 2H,

J = 7.3 Hz), 1.38–1.36 (m, 6H). FAB-MS m/z: 455 [M]⁺, 456

[M+H]⁺. Anal. Calcd for C₂₉H₂₉NO₄ꢁ1/3H₂O: C, 75.71; H, 6.46; N,

3.04. Found: C, 75.76; H, 6.43; N, 2.87.

4.2.34. 3-(4-{2-[4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)

phenyl]ethyl}phenyl)propionic acid ethyl ester (28a)

This compound was prepared from phthalic anhydride and 27a

by means of GP-F. Compound 28a was obtained in 75% yield as a

white solid.

¹H NMR (500 MHz, CDCl₃) d: 7.96 (dd, 2H, J = 5.5, 3.1 Hz), 7.79

(dd, 2H, J = 5.5, 3.1 Hz), 7.35 (d, 2H, J = 8.5 Hz), 7.33 (d, 2H,

J = 7.9 Hz), 7.14 (s, 4H), 4.13 (q, 2H, J = 7.3 Hz), 2.98–2.95 (m, 2H),

2.96–2.91 (m, 2H), 2.93–2.90 (m, 2H), 2.62 (t, 2H, J = 7.3 Hz), 1.24

(t, 3H, J = 7.3 Hz). FAB-MS m/z: 427 [M]⁺, 428 [M+H]⁺.

4.2.40. (4-{2-[4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)

phenyl]ethyl}phenoxy)-acetic acid t-butyl ester (30a)

To a solution of 29 (62 mg, 0.18 mmol) in dehydrated DMF

(7 mL) were added potassium carbonate (75 mg, 0.54 mmol) and

bromoacetic acid tert-butyl ester (80 lL, 0.54 mmol) under an ar-

4.2.35. 5-(4-{2-[4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)

phenyl]ethyl}phenyl)pentanoic acid ethyl ester (28b)

This compound was prepared from phthalic anhydride and 27b

by means of GP-F. Compound 28b was obtained in 60% yield as a

white solid.

gon atmosphere. The mixture was heated at 50 °C for 4 h, then

poured into water (60 mL) and extracted with EtOAc (20 mL ꢂ 4).

The organic layer was washed with H₂O (20 mL ꢂ 2) and brine

(20 mL), and dried over MgSO₄. The solvent was removed under re-

duced pressure. The residue was puriﬁed by silica gel column chro-

matography to give the target compound (76 mg, 93%) as a pale

yellow solid.

¹H NMR (500 MHz, CDCl₃) d: 7.96 (dd, 2H, J = 5.5, 3.1 Hz), 7.79

(dd, 2H, J = 5.5, 3.1 Hz), 7.34 (s, 4H), 7.12 (q, 4H, J = 7.3 Hz), 4.12

(q, 2H, J = 7.3 Hz), 2.98–2.95 (m, 2H), 2.93–2.92 (m, 2H), 2.61 (t,

2H, J = 7.3 Hz), 2.32 (t, 2H, J = 7.3 Hz), 1.70–1.63 (m, 4H), 1.25 (t,

3H, J = 7.3 Hz). FAB-MS m/z: 455 [M]⁺, 456 [M+H]⁺.

¹H NMR (500 MHz, CDCl₃) d: 7.96 (dd, 2H, J = 5.5, 3.1 Hz), 7.79

(dd, 2H, J = 5.5, 3.1 Hz), 7.34 (d, 2H, J = 8.5 Hz), 7.31 (d, 2H,

J = 8.5 Hz), 7.12 (d, 2H, J = 8.5 Hz), 6.83 (d, 2H, J = 8.5 Hz), 4.50 (s,

2H), 2.96–2.93 (m, 2H), 2.91–2.88 (m, 2H), 1.49 (s, 9H). FAB-MS

m/z: 457 [M]⁺, 458 [M+H]⁺.

4.2.36. 7-(4-{2-[4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)

phenyl]ethyl}phenyl)heptanoic acid ethyl ester (28c)

This compound was prepared from phthalic anhydride and 27c

by means of GP-F. Compound 28c was obtained in 51% yield as a

white solid.

4.2.41. 4-(4-{2-[4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)

phenyl]ethyl}phenoxy)butyric acid ethyl ester (30b)

To a solution of 29 (34 mg, 0.1 mmol) in dehydrated DMF (4 mL)

were added potassium carbonate (81 mg, 0.59 mmol) and ethyl

¹H NMR (500 MHz, CDCl₃) d: 7.96 (dd, 2H, J = 5.5, 3.1 Hz), 7.79

(dd, 2H, J = 5.5, 3.1 Hz), 7.36–7.33 (m, 4H), 7.12 (q, 4H, J = 7.3 Hz),

4.12 (q, 2H, J = 7.3 Hz), 2.99–2.95 (m, 2H), 2.94–2.90 (m, 2H),

4-bromobutyrate (68

lL, 0.48 mmol) under an argon atmosphere.

The mixture was heated overnight at 60 °C, then poured into water

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K. Motoshima et al. / Bioorg. Med. Chem. 19 (2011) 3156–3172

(30 mL) and extracted with EtOAc (15 mL ꢂ 3). The organic layer

was washed with H₂O (10 mL ꢂ 2) and brine (10 mL), and dried

over MgSO₄. The solvent was removed under reduced pressure.

The residue was puriﬁed by silica gel column chromatography to

give the target compound (35 mg, 76%) as a white solid.

J = 7.3 Hz), 1.68 (quin, 2H, J = 7.3 Hz), 1.55 (quin, 2H, J = 7.3 Hz),

1.40 (quin, 2H, J = 7.3 Hz). FAB-MS m/z: 457 [M]⁺, 458 [M+H]⁺.

Anal. Calcd for C₂₈H₂₇NO₅ꢁ1/4H₂O: C, 72.79; H, 6.00; N, 3.03.

Found: C, 72.98; H, 5.90; N, 2.91.

¹H NMR (500 MHz, CDCl₃) d: 7.96 (dd, 2H, J = 5.5, 3.1 Hz), 7.79

(dd, 2H, J = 4.9, 3.1 Hz), 7.34 (d, 2H, J = 7.9 Hz), 7.31 (d, 2H,

J = 8.5 Hz), 7.11 (d, 2H, J = 8.5 Hz), 6.82 (d, 2H, J = 8.5 Hz), 4.15 (q,

2H, J = 7.3 Hz), 3.99 (t, 2H, J = 6.1 Hz), 2.96–2.92 (m, 2H), 2.90–

2.87 (m, 2H), 2.52 (t, 2H, J = 7.3 Hz), 2.11 (quin, 2H, J = 6.7 Hz),

1.26 (t, 3H, J = 7.3 Hz). FAB-MS m/z: 457 [M]⁺, 458 [M+H]⁺.

4.2.46. [4-(tert-Butyl-dimethyl-silanyloxymethyl)phenyl]

methanol (31)

To a solution of TBSCl (11.4 g, 76 mmol) in dehydrated DMF

(190 mL) were added p-xylene-a,

a⁰-diol (10.36 g, 75 mmol) and

imidazole (10.21 g, 150 mmol) under an argon atmosphere. The

mixture was stirred at rt overnight, then poured into water

(500 mL) and extracted with EtOAc (150 mL ꢂ 3). The organic layer

was washed with H₂O (100 mL ꢂ 2) and brine (100 mL), and dried

over MgSO₄. The solvent was removed under reduced pressure. The

residue was puriﬁed by silica gel column chromatography to give

the target compound (4.97 g, 26%) as a colorless oil.

4.2.42. 6-(4-{2-[4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)

phenyl]ethyl}phenoxy)hexanoic acid ethyl ester (30c)

To a solution of 29 (172 mg, 0.5 mmol) in dehydrated DMF

(4 mL) were added potassium carbonate (138 mg, 1.0 mmol) and

6-bromohexanoic acid ethyl ester (712

l

L, 4.0 mmol) under an ar-

¹H NMR (500 MHz, CDCl₃) d: 7.34 (d, 2H, J = 9.2 Hz), 7.32 (d, 2H,

J = 8.5 Hz), 4.74 (s, 2H), 4.68 (d, 2H, J = 6.1 Hz), 0.94 (s, 9H), 0.10 (s,

6H). FAB-MS m/z: 252 [M]⁺, 253 [M+H]⁺.

gon atmosphere. The mixture was heated for 6 h at 70 °C, then

poured into water (20 mL) and extracted with EtOAc (15 mL ꢂ 3).

The organic layer was washed with H₂O (10 mL ꢂ 2) and brine

(10 mL), and dried over MgSO₄. The solvent was removed under

reduced pressure. The residue was puriﬁed by silica gel column

chromatography to give the target compound (194 mg, 80%) as a

white solid.

4.2.47. 4-(tert-Butyl-dimethyl-silanyloxymethyl)benzaldehyde

(32)

To a solution of 31 (2.57 g, 10.18 mmol) in dehydrated CH₂Cl₂

(20 mL) was added PDC (7.66 g, 20.36 mmol), and the mixture

was stirred at rt overnight. The mixture was ﬁltered through a

pad of Celite, and the ﬁltrate was evaporated under reduced pres-

sure. The residue was puriﬁed by silica gel column chromatogra-

phy to give the target compound (1.95 g, 76%) as a colorless oil.

¹H NMR (500 MHz, CDCl₃) d: 10.00 (s, 1H), 7.85 (d, 2H,

J = 7.9 Hz), 7.49 (d, 2H, J = 7.9 Hz), 4.82 (s, 2H), 0.96 (s, 9H), 0.12

(s, 6H). FAB-MS m/z: 250 [M]⁺, 251 [M+H]⁺.

¹H NMR (500 MHz, CDCl₃) d: 7.96 (dd, 2H, J = 4.9, 3.1 Hz), 7.79

(dd, 2H, J = 5.5, 3.1 Hz), 7.34 (d, 2H, J = 8.5 Hz), 7.31 (d, 2H,

J = 8.5 Hz), 7.11 (d, 2H, J = 8.5 Hz), 6.82 (d, 2H, J = 8.5 Hz), 4.13 (q,

2H, J = 6.7 Hz), 3.95 (t, 2H, J = 6.7 Hz), 2.96–2.93 (m, 2H), 2.90–

2.88 (m, 2H), 2.34 (t, 2H, J = 7.9 Hz), 1.80 (quin, 2H, J = 7.9 Hz),

1.71 (quin, 2H, J = 7.9 Hz), 1.54–1.48 (m, 2H), 1.26 (t, 3H,

J = 6.7 Hz). FAB-MS m/z: 485 [M]⁺, 486 [M+H]⁺.

4.2.43. (4-{2-[4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)

phenyl]ethyl}phenoxy)acetic acid (12a)

4.2.48. 2-[4-(tert-Butyl-dimethyl-silanyloxymethyl)

benzylidene]butyric acid ethyl ester (33)

This compound was prepared from 30a by means of GP-G. Com-

pound 12a was obtained in 100% yield as a white powder after

recrystallization from EtOAc/n-hexane.

Potassium t-butoxide (1.63 g, 14.5 mmol) was suspended in

dehydrated THF (5 mL) under Ar and cooled with ice. Trimethyl

2-phosphonobutyrate (3.44 mL, 14.5 mmol) was added dropwise.

When the addition was completed, the mixture was stirred for

5 min, then compound 32 (3.52 g, 14.06 mmol) dissolved in dehy-

drated THF (20 mL) was added dropwise at 0 °C. The mixture was

stirred for 15 min at rt, then poured into water (40 mL) and ex-

tracted with EtOAc (45 mL ꢂ 3). The organic layer was washed

with H₂O (20 mL ꢂ 2) and brine (20 mL), and dried over MgSO₄.

The solvent was removed under reduced pressure. The residue

was puriﬁed by silica gel column chromatography to give the tar-

get compound (4.67 g, 95%) as a colorless oil.

¹H NMR (500 MHz, CDCl₃) d: 7.96 (dd, 2H, J = 5.5, 3.1 Hz), 7.79

(dd, 2H, J = 5.5, 3.1 Hz), 7.34 (d, 2H, J = 8.5 Hz), 7.29 (d, 2H,

J = 8.5 Hz), 7.13 (d, 2H, J = 8.5 Hz), 6.87 (d, 2H, J = 9.2 Hz), 4.66 (s,

2H), 2.97–2.94 (m, 2H), 2.93–2.90 (m, 2H). FAB-MS m/z: 401

[M]⁺, 402 [M+H]⁺. Anal. Calcd for C₂₄H₁₉NO₅ꢁ1/4H₂O: C, 71.01; H,

4.84; N, 3.45. Found: C, 71.43; H, 4.96; N, 3.46.

4.2.44. 4-(4-{2-[4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)

phenyl]ethyl}phenoxy)butyric acid (12b)

This compound was prepared from 30b by means of GP-I. Com-

pound 12b was obtained in 65% yield as a white powder after

recrystallization from CH₂Cl₂/n-hexane.

¹H NMR (500 MHz, CDCl₃) majord: 7.34 (s, 4H), 4.76 (s, 2H), 4.28

(q, 2H, J = 7.3 Hz), 2.55 (q, 2H, J = 7.3 Hz), 1.35 (t, 3H, J = 7.3 Hz),

1.18 (t, 3H, J = 7.3 Hz), 0.95 (s, 9H), 0.11 (s, 6H). minor d: 7.23 (s,

2H), 7.21 (s, 2H), 4.72 (s, 2H), 4.14 (q, 2H, J = 7.9 Hz), 2.44 (q, 2H,

J = 7.9 Hz), 1.13 (t, 3H, J = 7.3 Hz), 0.93 (s, 9H), 0.09 (s, 6H). FAB-

MS m/z: 348 [M]⁺, 349 [M+H]⁺.

¹H NMR (500 MHz, DMSO-d₆) d: 12.12 (br s, 1H), 7.95 (dd, 2H,

J = 5.5, 3.1 Hz), 7.89 (dd, 2H, J = 5.5, 3.1 Hz), 7.36 (d, 2H,

J = 8.5 Hz), 7.32 (d, 2H, J = 8.5 Hz), 7.16 (d, 2H, J = 8.5 Hz), 6.83 (d,

2H, J = 7.9 Hz), 3.93 (t, 2H, J = 6.7 Hz), 2.92–2.88 (m, 2H), 2.86–

2.83 (m, 2H), 2.36 (t, 2H, J = 7.3 Hz), 1.91 (quin, 2H, J = 6.7 Hz).

FAB-MS m/z: 429 [M]⁺, 430 [M+H]⁺. Anal. Calcd for C₂₆H₂₃NO₅ꢁ1/

5H₂O: C, 72.21; H, 5.44; N, 3.24. Found: C, 72.31; H, 5.28; N, 3.19.

4.2.49. 2-[4-(tert-Butyl-dimethyl-silanyloxymethyl)benzyl]

butyric acid ethyl ester (34)

This compound was prepared from 33 by means of GP-E. Com-

pound 34 was obtained in 95% yield as a colorless oil.

¹H NMR (500 MHz, CDCl₃) d: 7.22 (d, 2H, J = 7.9 Hz), 7.12 (d, 2H,

J = 8.5 Hz), 4.70 (s, 2H), 4.06 (m, 2H), 2.91 (dd, 1H, J = 14.0, 8.5 Hz),

2.72 (dd, 1H, J = 13.4, 6.7 Hz), 2.59–2.53 (m, 1H), 1.67–1.61 (m, 1H),

1.58–1.52 (m, 1H), 1.16 (t, 3H, J = 7.3 Hz), 0.93 (s, 9H), 0.91 (t, 3H,

J = 7.3 Hz), 0.08 (s, 6H). FAB-MS m/z: 350 [M]⁺, 351 [M+H]⁺.

4.2.45. 6-(4-{2-[4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)

phenyl]ethyl}phenoxy)hexanoic acid (12c)

This compound was prepared from 30c by means of GP-I. Com-

pound 12c was obtained in 65% yield as a white powder after

recrystallization from CH₂Cl₂/n-hexane.

¹H NMR (500 MHz, DMSO-d₆) d: 7.95 (dd, 2H, J = 5.5, 3.1 Hz),

7.89 (dd, 2H, J = 5.5, 3.1 Hz), 7.36 (d, 2H, J = 8.5 Hz), 7.32 (d, 2H,

J = 8.5 Hz), 7.15 (d, 2H, J = 8.5 Hz), 6.82 (d, 2H, J = 8.5 Hz), 3.90 (t,

2H, J = 6.7 Hz), 2.92–2.88 (m, 2H), 2.86–2.84 (m, 2H), 2.22 (t, 2H,

4.2.50. 2-(4-Hydroxymethylbenzyl)butyric acid ethyl ester (35)

To a solution of 34 (4.48 g, 12.78 mmol) in dehydrated THF was

added TBAF (1.0 M solution in THF) (14.06 mL, 14.06 mmol) at 0 °C

K. Motoshima et al. / Bioorg. Med. Chem. 19 (2011) 3156–3172

3167

under an argon atmosphere. The mixture was stirred for 20 min,

then poured into water (50 mL) and extracted with EtOAc

(40 mL ꢂ 3). The organic layer was washed with H₂O (20 mL ꢂ 2)

and brine (10 mL), and dried over MgSO₄. The solvent was removed

under reduced pressure. The residue was puriﬁed by silica gel col-

umn chromatography to give the target compound (2.84 g, 94%) as

a colorless oil.

¹H NMR (500 MHz, CDCl₃) d: 7.91 (d, 2H, J = 9.2 Hz), 7.84–7.77

(m, 9H), 7.66–7.62 (m, 6H), 7.45 (dd, 2H, J = 9.2, 2.4 Hz), 5.91 (dd,

2H, J = 15.3 Hz). FAB-MS m/z: 398 [MꢀBr]⁺

4.2.57. (2-Methoxy-4-nitrobenzyl)triphenylphosphonium

bromide (38c)

This compound was prepared from 37c by means of GP-B and

GP-C-2. Compound 38c was obtained in 73% yield as a brown solid.

¹H NMR (500 MHz, CDCl₃) d: 7.85 (dd, 1H, J = 8.5, 2.4 Hz), 7.81–

7.76 (m, 9H), 7.71 (d, 1H, J = 8.5 Hz), 7.68–7.64 (m, 6H), 7.43 (d, 1H,

J = 1.8 Hz), 5.64 (d, 2H, J = 15.3 Hz), 3.34 (s, 3H). FAB-MS m/z: 428

[MꢀBr]⁺.

¹H NMR (500 MHz, CDCl₃) d: 7.27 (d, 2H, J = 7.9 Hz), 7.16 (d, 2H,

J = 7.9 Hz), 4.66 (d, 2H, J = 6.1 Hz), 4.11–4.04 (m, 4H), 2.93 (dd, 1H,

J = 13.4, 8.5 Hz), 2.74 (dd, 1H, J = 14.0, 6.7 Hz), 2.60–2.54 (m, 1H),

1.68–1.62 (m, 1H), 1.58–1.52 (m, 1H), 1.17 (t, 3H, J = 7.3 Hz), 0.92

(t, 3H, J = 7.3 Hz). FAB-MS m/z: 236 [M]⁺.

4.2.51. 2-(4-Formylbenzyl)butyric acid ethyl ester (36)

4.2.58. (2-Ethoxy-4-nitrobenzyl)triphenylphosphonium

bromide (38d)

To a solution of 35 (2.83 g, 11.98 mmol) in dehydrated CH₂Cl₂

(30 mL) was added PDC (6.76 g, 17.97 mmol), and the mixture

was stirred at rt overnight. The mixture was ﬁltered through a

pad of Celite, and the ﬁltrate was evaporated under reduced pres-

sure. The residue was puriﬁed by silica gel column chromatogra-

phy to give the target compound (1.99 g, 71%) as a colorless oil.

¹H NMR (500 MHz, CDCl₃) d: 9.97 (s, 1H), 7.80 (d, 2H, J = 8.5 Hz),

7.34 (d, 2H, J = 7.9 Hz), 4.10–4.03 (m, 2H), 3.01 (dd, 1H, J = 13.4,

9.2 Hz), 2.84 (dd, 1H, J = 13.4, 6.1 Hz), 2.65–2.59 (m, 1H), 1.72–

1.66 (m, 1H), 1.62–1.54 (m, 1H), 1.14 (t, 3H, J = 7.3 Hz), 0.94 (t,

3H, J = 7.3 Hz). FAB-MS m/z: 235 [M+H]⁺.

This compound was prepared from 37d by means of GP-B and

GP-C-2. Compound 38d was obtained in 88% yield as a brown solid.

¹H NMR (500 MHz, CDCl₃) d: 7.81–7.74 (m, 10H), 7.71 (dd, 1H,

J = 8.5, 2.4 Hz), 7.67–7.63 (m, 6H), 7.43 (d, 1H, J = 1.8 Hz), 5.70 (d,

2H, J = 14.6 Hz), 3.59 (q, 2H, J = 7.3 Hz), 1.09 (t, 3H, J = 7.3 Hz).

FAB-MS m/z: 442 [MꢀBr]⁺.

4.2.59. (4-Nitro-2-n-propoxybenzyl)triphenylphosphonium

bromide (38e)

This compound was prepared from 37e by means of GP-B and

GP-C-2. Compound 38e was obtained in 93% yield as a brown solid.

¹H NMR (500 MHz, CDCl₃) d: 7.81–7.73 (m, 10H), 7.70 (dd, 1H,

J = 8.5, 1.2 Hz), 7.67–7.63 (m, 6H), 7.44 (d, 1H, J = 1.8 Hz), 5.71 (d,

2H, J = 15.3 Hz), 3.47 (t, 2H, J = 6.7 Hz), 1.46 (sex, 2H, J = 7.3 Hz),

0.86 (t, 3H, J = 7.3 Hz). FAB-MS m/z: 456 [MꢀBr]⁺.

4.2.52. 2-Methoxy-1-methyl-4-nitrobenzene (37c)

This compound was prepared from 2-methyl-5-nitrophenol and

iodomethane by means of GP-J. Compound 37c was obtained in

96% yield as a brown solid.

¹H NMR (500 MHz, CDCl₃) d: 7.77 (dd, 1H, J = 7.9, 2.4 Hz), 7.66

(d, 1H, J = 2.4 Hz), 7.26 (d, 1H, J = 7.9 Hz), 3.92 (s, 3H), 2.30 (s,

3H). FAB-MS m/z: 167 [M]⁺, 168 [M+H]⁺.

4.2.60. (2-n-Butoxy-4-nitrobenzyl)triphenylphosphonium

bromide (38f)

This compound was prepared from 37f by means of GP-B and

GP-C-2. Compound 38f was obtained in 99% yield as a brown solid.

¹H NMR (500 MHz, CDCl₃) d: 7.81–7.73 (m, 10H), 7.70 (dd, 1H,

J = 8.5, 1.2 Hz), 7.67–7.63 (m, 6H), 7.44 (d, 1H, J = 1.8 Hz), 5.70 (d,

2H, J = 15.3 Hz), 3.52 (t, 2H, J = 6.7 Hz), 1.40 (quin, 2H, J = 6.7 Hz),

1.27 (sex, 2H, J = 7.3 Hz), 0.90 (t, 3H, J = 7.3 Hz). FAB-MS m/z: 470

[MꢀBr]⁺.

4.2.53. 2-Ethoxy-1-methyl-4-nitrobenzene (37d)

This compound was prepared from 2-methyl-5-nitrophenol and

iodoethane by means of GP-J. Compound 37d was obtained in 100%

yield as a brown solid.

¹H NMR (500 MHz, CDCl₃) d: 7.74 (dd, 1H, J = 8.5, 2.4 Hz), 7.64

(d, 1H, J = 2.4 Hz), 7.25 (d, 1H, J = 8.5 Hz), 4.12 (q, 2H, J = 7.3 Hz),

2.30 (s, 3H), 1.48 (t, 3H, J = 7.3 Hz). FAB-MS m/z: 181 [M]⁺, 182

[M+H]⁺.

4.2.61. 2-{4-[2-(4-Nitrophenyl)vinyl]benzyl}butyric acid ethyl

ester (39a)

4.2.54. 1-Methyl-4-nitro-2-n-propoxybenzene (37e)

This compound was prepared from 2-methyl-5-nitrophenol and

1-iodopropane by means of GP-J. Compound 37e was obtained in

96% yield as a brown solid.

This compound was prepared from 36 and 38a by means of

GP-D. Compound 39a was obtained in 100% yield as a yellow oil.

¹H NMR (500 MHz, CDCl₃) 39aZ d: 8.07 (d, 2H, J = 9.2 Hz), 7.37

(d, 2H, J = 9.2 Hz), 7.10 (d, 2H, J = 7.9 Hz), 7.05 (d, 2H, J = 8.5 Hz),

6.77 (d, 1H, J = 12.2 Hz), 6.57 (d, 1H, J = 12.2 Hz), 4.11–4.05 (m,

2H), 2.90 (dd, 1H, J = 14.0, 9.2 Hz), 2.73 (dd, 1H, J = 14.0, 6.7 Hz),

2.60–2.55 (m, 1H), 1.71–1.63 (m, 1H), 1.61–1.52 (m, 1H), 1.17 (t,

3H, J = 7.3 Hz), 0.92 (t, 3H, J = 7.3 Hz). Compound 39aE d: 8.22 (d,

2H, J = 8.5 Hz), 7.62 (d, 2H, J = 9.2 Hz), 7.46 (d, 2H, J = 8.5 Hz),

7.25 (d, 1H, J = 16.5 Hz), 7.20 (d, 2H, J = 8.5 Hz), 7.10 (d, 1H,

J = 16.5 Hz), 4.11–4.05 (m, 2H), 2.95 (dd, 1H, J = 14.0, 9.2 Hz), 2.78

(dd, 1H, J = 14.0, 6.7 Hz), 2.63–2.56 (m, 1H), 1.71–1.64 (m, 1H),

1.62–1.54 (m, 1H), 1.17 (t, 3H, J = 7.3 Hz), 0.92 (t, 3H, J = 7.3 Hz).

FAB-MS m/z: 353 [M]⁺, 354 [M+H]⁺.

¹H NMR (500 MHz, CDCl₃) d: 7.74 (dd, 1H, J = 7.9, 2.4 Hz), 7.64

(d, 1H, J = 1.8 Hz), 7.25 (d, 1H, J = 8.5 Hz), 4.01 (t, 2H, J = 6.7 Hz),

2.31 (s, 3H), 1.88 (sex, 2H, J = 6.7 Hz), 1.08 (t, 3H, J = 7.3 Hz). FAB-

MS m/z: 195 [M]⁺, 196 [M+H]⁺.

4.2.55. 2-Butoxy-1-methyl-4-nitrobenzene (37f)

This compound was prepared from 2-methyl-5-nitrophenol and

1-iodobutane by means of GP-J. Compound 37f was obtained in

93% yield as a brown solid.

¹H NMR (500 MHz, CDCl₃) d: 7.74 (dd, 1H, J = 7.9, 1.8 Hz), 7.64

(d, 1H, J = 1.8 Hz), 7.25 (d, 1H, J = 7.9 Hz), 4.05 (t, 2H, J = 6.7 Hz),

2.30 (s, 3H), 1.86–1.81 (m, 2H), 1.57–1.51 (m, 2H), 1.00 (t, 3H,

J = 7.3 Hz). FAB-MS m/z: 209 [M]⁺, 210 [M+H]⁺.

4.2.62. 2-{4-[2-(2-Methoxy-4-nitrophenyl)vinyl]benzyl}butyric

acid ethyl ester (39c)

This compound was prepared from 36 and 38c by means of GP-

D. Compound 39c was obtained in 86% yield as a yellow oil.

¹H NMR (500 MHz, CDCl₃) 39cZ d: 7.73 (d, 1H, J = 2.4 Hz), 7.62

(dd, 1H, J = 8.5, 2.4 Hz), 7.28–7.24 (m, 1H), 7.08 (d, 2H, J = 7.9 Hz),

7.01 (d, 2H, J = 7.9 Hz), 6.76 (d, 1H, J = 12.2 Hz), 6.61 (d, 1H,

J = 12.2 Hz), 4.11–4.04 (m, 2H), 3.92 (s, 3H), 2.88 (dd, 1H, J = 14.0,

4.2.56. (4-Nitrobenzyl)triphenylphosphonium bromide (38a)

This compound was prepared from 4-nitrobenzyl bromide by

means of GP-C-2. Compound 38a was obtained in 99% yield as a

white solid.

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K. Motoshima et al. / Bioorg. Med. Chem. 19 (2011) 3156–3172

8.5 Hz), 2.70 (dd, 1H, J = 14.0, 6.7 Hz), 2.56–2.52 (m, 1H), 1.70–1.52

(m, 2H), 1.16 (t, 3H, J = 6.7 Hz), 0.91 (t, 3H, J = 7.9 Hz). Compound

39cE d: 7.86 (dd, 1H, J = 8.5, 2.4 Hz), 7.75 (d, 1H, J = 2.4 Hz), 7.69

(d, 1H, J = 8.5 Hz), 7.47 (d, 2H, J = 7.9 Hz), 7.42 (d, 1H, J = 16.5 Hz),

7.23 (d, 2H, J = 16.5 Hz), 7.19 (d, 2H, J = 8.5 Hz), 4.11–4.04 (m,

2H), 3.99 (s, 3H), 2.95 (dd, 1H, J = 13.4, 8.5 Hz), 2.77 (dd, 1H,

J = 14.0, 6.7 Hz), 2.62–2.58 (m, 1H), 1.70–1.52 (m, 2H), 1.17 (t,

3H, J = 7.3 Hz), 0.93 (t, 3H, J = 7.3 Hz). FAB-MS m/z: 383 [M]⁺, 384

[M+H]⁺.

4.2.66. 2-{4-[2-(4-Nitrophenyl)vinyl]benzyl}butyric acid (40a)

This compound was prepared from 39a by means of GP-K. Com-

pound 40a was obtained in 98% yield as a yellow solid.

¹H NMR (500 MHz, CDCl₃) 40aZ d: 8.07 (d, 2H, J = 8.5 Hz), 7.36

(d, 2H, J = 8.5 Hz), 7.11 (d, 2H, J = 6.7 Hz), 7.07 (d, 2H, J = 8.5 Hz),

6.77 (d, 1H, J = 12.2 Hz), 6.57 (d, 1H, J = 12.2 Hz), 2.94 (dd, 1H,

J = 14.0, 8.5 Hz), 2.76 (dd, 1H, J = 14.0, 6.7 Hz), 2.66–2.58 (m, 1H),

1.73–1.58 (m, 2H), 0.97 (t, 3H, J = 7.3 Hz). Compound 40aE d:

8.21 (d, 2H, J = 8.5 Hz), 7.61 (d, 2H, J = 8.5 Hz), 7.47 (d, 2H,

J = 8.5 Hz), 7.24 (d, 1H, J = 16.5 Hz), 7.22 (d, 2H, J = 7.9 Hz), 7.10

(d, 1H, J = 16.5 Hz), 3.00 (dd, 1H, J = 14.0, 7.9 Hz), 2.80 (dd, 1H,

J = 14.0, 6.7 Hz), 2.68–2.61 (m, 1H), 1.73–1.58 (m, 2H), 0.98 (t,

3H, J = 7.3 Hz). FAB-MS m/z: 325 [M]⁺, 326 [M+H]⁺.

4.2.63. 2-{4-[2-(2-Ethoxy-4-nitrophenyl)vinyl]benzyl}butyric

acid ethyl ester (39d)

This compound was prepared from 36 and 38d by means of

GP-D. Compound 39d was obtained in 87% yield as a yellow oil.

¹H NMR (500 MHz, CDCl₃) 39dZ d: 7.70 (d, 1H, J = 1.8 Hz), 7.60

(dd, 1H, J = 8.5, 1.8 Hz), 7.27–7.24 (m, 1H), 7.09 (d, 2H, J = 8.5 Hz),

7.02 (d, 2H, J = 8.5 Hz), 6.74 (d, 1H, J = 12.2 Hz), 6.62 (d, 1H,

J = 12.2 Hz), 4.12–4.04 (m, 4H), 2.88 (dd, 1H, J = 13.4, 9.2 Hz), 2.70

(dd, 1H, J = 13.4, 6.7 Hz), 2.62–2.57 (m, 1H), 1.70–1.52 (m, 2H),

1.17 (t, 3H, J = 6.7 Hz), 0.91 (t, 3H, J = 7.3 Hz). Compound 39dE d:

7.84 (dd, 1H, J = 8.5, 2.4 Hz), 7.73 (d, 1H, J = 2.4 Hz), 7.68 (d, 1H,

J = 8.5 Hz), 7.46 (d, 2H, J = 8.5 Hz), 7.43 (d, 1H, J = 16.5 Hz), 7.27–

7.24 (m, 1H), 7.19 (d, 2H, J = 7.9 Hz), 4.12–4.04 (m, 2H), 2.95 (dd,

1H, J = 13.4, 9.2 Hz), 2.77 (dd, 1H, J = 13.4, 6.7 Hz), 2.62–2.56 (m,

1H), 1.70–1.52 (m, 2H), 1.17 (t, 3H, J = 7.3 Hz), 0.93 (t, 3H,

J = 7.9 Hz). FAB-MS m/z: 397 [M]⁺, 398 [M+H]⁺.

4.2.67. 2-{4-[2-(2-Methoxy-4-nitrophenyl)vinyl]benzyl}butyric

acid (40c)

This compound was prepared from 39c by means of GP-K. Com-

pound 40c was obtained in 96% yield as a yellow solid.

¹H NMR (500 MHz, CDCl₃) 40cZ d: 7.72 (d, 1H, J = 2.4 Hz), 7.63

(dd, 1H, J = 8.5, 2.4 Hz), 7.28–7.24 (m, 1H), 7.09 (d, 1H, J = 8.5 Hz),

7.04 (d, 2H, J = 7.9 Hz), 6.76 (d, 1H, J = 12.2 Hz), 6.61 (d, 1H,

J = 12.2 Hz), 3.90 (s, 3H), 2.92 (dd, 1H, J = 14.0, 8.5 Hz), 2.74 (dd,

1H, J = 14.0, 6.7 Hz), 2.65–2.58 (m, 1H), 1.73–1.55 (m, 2H), 0.96

(t, 3H, J = 7.3 Hz). Compound 40cE d: 7.86 (dd, 1H, J = 8.5, 2.4 Hz),

7.74 (d, 1H, J = 1.8 Hz), 7.68 (d, 1H, J = 8.5 Hz), 7.48 (d, 2H,

J = 7.9 Hz), 7.43 (d, 1H, J = 16.5 Hz), 7.23 (d, 2H, J = 16.5 Hz), 7.21

(dd, 2H, J = 8.5 Hz), 3.98 (s, 3H), 2.99 (dd, 1H, J = 14.0, 8.5 Hz),

2.80 (dd, 1H, J = 13.4, 6.7 Hz), 2.69–2.63 (m, 1H), 1.73–1.55 (m,

2H), 0.98 (t, 3H, J = 7.9 Hz). FAB-MS m/z: 355 [M]⁺, 356 [M+H]⁺.

4.2.64. 2-{4-[2-(4-Nitro-2-n-propoxyphenyl)vinyl]benzyl}

butyric acid ethyl ester (39e)

This compound was prepared from 36 and 38e by means of

GP-D. Compound 39e was obtained in 79% yield as a yellow oil.

¹H NMR (500 MHz, CDCl₃) 39eZ d: 7.71 (d, 1H, J = 2.4 Hz), 7.59

(dd, 1H, J = 8.5, 1.8 Hz), 7.29 (d, 1H, J = 1.8 Hz), 7.10 (d, 2H,

J = 7.9 Hz), 7.02 (d, 2H, J = 7.9 Hz), 6.74 (d, 1H, J = 12.2 Hz), 6.62

(d, 1H, J = 12.8 Hz), 4.11–4.01 (m, 4H), 2.88 (dd, 1H, J = 14.0,

8.5 Hz), 2.70 (dd, 1H, J = 13.4, 6.7 Hz), 2.55–2.53 (m, 1H), 1.82

(sex, 2H, J = 7.3 Hz), 1.68–1.53 (m, 2H), 1.13 (t, 3H, J = 7.9 Hz),

1.05 (t, 3H, J = 7.3 Hz), 0.91 (t, 3H, J = 7.3 Hz). Compound 39eE d:

7.84 (dd, 1H, J = 8.5, 1.8 Hz), 7.73 (d, 1H, J = 1.8 Hz), 7.68 (d, 1H,

J = 8.5 Hz), 7.46 (d, 2H, J = 7.9 Hz), 7.43 (d, 1H, J = 16.5 Hz), 7.27–

7.25 (m, 1H), 7.19 (d, 2H, J = 7.9 Hz), 4.11–4.04 (m, 4H), 2.95 (dd,

1H, J = 14.0, 8.5 Hz), 2.77 (dd, 1H, J = 13.4, 6.7 Hz), 2.62–2.58 (m,

1H), 1.68–1.53 (m, 2H), 1.17 (t, 3H, J = 6.7 Hz), 1.16 (t, 3H,

J = 7.3 Hz), 0.93 (t, 3H, J = 7.3 Hz). FAB-MS m/z: 411 [M]⁺, 412

[M+H]⁺.

4.2.68. 2-{4-[2-(2-Ethoxy-4-nitrophenyl)vinyl]benzyl}butyric

acid (40d)

This compound was prepared from 39d by means of GP-K. Com-

pound 40d was obtained in 100% yield as a yellow oil.

¹H NMR (500 MHz, CDCl₃) 40dZ d: 7.69 (d, 1H, J = 2.4 Hz), 7.61

(dd, 1H, J = 8.5, 2.4 Hz), 7.29–7.21 (m, 1H), 7.10 (d, 2H, J = 7.9 Hz),

7.04 (d, 2H, J = 7.9 Hz), 6.74 (d, 1H, J = 12.2 Hz), 6.62 (d, 1H,

J = 12.2 Hz), 4.15 (q, 2H, J = 6.7 Hz), 2.92 (dd, 1H, J = 14.0, 8.5 Hz),

2.73 (dd, 1H, J = 14.0, 6.7 Hz), 2.65–2.58 (m, 1H), 1.73–1.52 (m,

2H), 1.39 (t, 3H, J = 6.7 Hz), 0.96 (t, 3H, J = 7.3 Hz). Compound

40dE d: 7.83 (dd, 1H, J = 8.5, 1.8 Hz), 7.72 (d, 1H, J = 2.4 Hz), 7.67

(d, 1H, J = 8.5 Hz), 7.48 (d, 2H, J = 7.9 Hz), 7.43 (d, 1H, J = 16.5 Hz),

7.29–7.21 (m, 3H), 4.20 (q, 2H, J = 6.7 Hz), 2.99 (dd, 1H, J = 14.0,

8.5 Hz), 2.80 (dd, 1H, J = 13.4, 6.7 Hz), 2.70–2.63 (m, 1H),

1.73–1.52 (m, 2H), 1.54 (t, 3H, J = 6.7 Hz), 0.98 (t, 3H, J = 7.3 Hz).

FAB-MS m/z: 369 [M]⁺, 370 [M+H]⁺.

4.2.65. 2-{4-[2-(2-n-Butoxy-4-nitrophenyl)vinyl]benzyl}butyric

acid ethyl ester (39f)

4.2.69. 2-{4-[2-(4-Nitro-2-n-propoxyphenyl)vinyl]benzyl}

butyric acid (40e)

This compound was prepared from 39e by means of GP-K. Com-

pound 40e was obtained in 95% yield as a yellow oil.

This compound was prepared from 36 and 38f by means of GP-

D. Compound 39f was obtained in 80% yield as a yellow oil.

¹H NMR (500 MHz, CDCl₃) 39fZ d: 7.71 (d, 1H, J = 2.4 Hz), 7.59

(dd, 1H, J = 8.5, 2.4 Hz), 7.28–7.25 (m, 1H), 7.09 (d, 2H, J = 7.9 Hz),

7.02 (d, 2H, J = 7.9 Hz), 6.73 (d, 1H, J = 12.2 Hz), 6.61 (d, 1H,

J = 12.2 Hz), 4.11–4.03 (m, 4H), 2.88 (dd, 1H, J = 14.0, 8.5 Hz), 2.70

(dd, 1H, J = 14.0, 6.7 Hz), 2.57–2.53 (m, 1H), 1.78 (quin, 2H,

J = 6.7 Hz), 1.70–1.49 (m, 4H), 1.16 (t, 3H, J = 6.7 Hz), 0.98 (t, 3H,

J = 7.3 Hz), 0.91 (t, 3H, J = 7.3 Hz). Compound 39fE d: 7.84 (dd,

1H, J = 8.5, 1.8 Hz), 7.73 (d, 1H, J = 1.8 Hz), 7.67 (d, 1H, J = 8.5 Hz),

7.45 (d, 2H, J = 8.5 Hz), 7.42 (d, 1H, J = 16.5 Hz), 7.28–7.25 (m,

1H), 7.19 (d, 2H, J = 8.5 Hz), 4.13 (t, 2H, J = 6.1 Hz), 4.06 (t, 2H,

J = 7.3 Hz), 2.95 (dd, 1H, J = 13.4, 8.5 Hz), 2.78 (dd, 1H, J = 14.0,

6.7 Hz), 2.63–2.58 (m, 1H), 1.90 (quin, 2H, J = 6.7 Hz), 1.70–1.54

(m, 4H), 1.17 (t, 3H, J = 7.3 Hz), 1.04 (t, 3H, J = 7.3 Hz), 0.93 (t, 3H,

J = 7.9 Hz). FAB-MS m/z: 425 [M]⁺, 426 [M+H]⁺.

¹H NMR (500 MHz, CDCl₃) 40eZ d: 7.70 (d, 1H, J = 1.8 Hz), 7.60

(dd, 1H, J = 7.9, 1.8 Hz), 7.28–7.22 (m, 1H), 7.11 (d, 2H, J = 7.9 Hz),

7.04 (d, 2H, J = 7.9 Hz), 6.74 (d, 1H, J = 12.2 Hz), 6.63 (d, 1H,

J = 12.8 Hz), 4.01 (t, 2H, J = 6.7 Hz), 2.93 (dd, 1H, J = 14.0, 7.9 Hz),

2.73 (dd, 1H, J = 14.0, 6.7 Hz), 2.63–2.59 (m, 1H), 1.81 (sex, 2H,

J = 7.3 Hz), 1.73–1.56 (m, 2H), 1.04 (t, 3H, J = 7.3 Hz), 0.96 (t, 3H,

J = 7.3 Hz). Compound 40eE d: 7.84 (dd, 1H, J = 8.5, 1.8 Hz), 7.73

(d, 1H, J = 2.4 Hz), 7.67 (d, 1H, J = 8.5 Hz), 7.47 (d, 2H, J = 8.5 Hz),

7.43 (d, 1H, J = 16.5 Hz), 7.28–7.22 (m, 1H), 7.22 (d, 2H,

J = 7.9 Hz), 4.09 (t, 2H, J = 6.7 Hz), 2.99 (dd, 1H, J = 14.0, 7.9 Hz),

2.80 (dd, 1H, J = 14.0, 6.7 Hz), 2.70–2.65 (m, 1H), 1.94 (sex, 2H,

J = 7.3 Hz), 1.73–1.56 (m, 2H), 1.13 (t, 3H, J = 7.3 Hz), 0.98 (t, 3H,

J = 7.3 Hz). FAB-MS m/z: 383 [M]⁺, 384 [M+H]⁺.

K. Motoshima et al. / Bioorg. Med. Chem. 19 (2011) 3156–3172

3169

4.2.70. 2-{4-[2-(2-n-Butoxy-4-nitrophenyl)vinyl]benzyl}butyric

acid (40f)

This compound was prepared from 39f by means of GP-K. Com-

pound 40f was obtained in 100% yield as a yellow oil.

¹H NMR (500 MHz, CDCl₃) 41eZ d: 7.71 (d, 1H, J = 2.4 Hz), 7.58

(dd, 1H, J = 8.5, 2.4 Hz), 7.29–7.27 (m, 1H), 7.09 (d, 2H, J = 7.9 Hz),

7.03 (d, 2H, J = 7.9 Hz), 6.74 (d, 1H, J = 12.2 Hz), 6.62 (d, 1H,

J = 12.2 Hz), 4.03 (t, 2H, J = 6.7 Hz), 2.82 (dd, 1H, J = 14.0, 9.2 Hz),

2.67 (dd, 1H, J = 13.4, 6.1 Hz), 2.46–2.43 (m, 1H), 1.83 (sex, 2H,

J = 7.3 Hz), 1.67–1.49 (m, 2H), 1.35 (s, 9H), 1.05 (t, 3H, J = 7.3 Hz),

0.92 (t, 3H, J = 7.9 Hz). Compound 41eE d: 7.84 (dd, 1H, J = 8.5,

2.4 Hz), 7.73 (d, 1H, J = 1.8 Hz), 7.68 (d, 1H, J = 8.5 Hz), 7.45 (d,

2H, J = 7.9 Hz), 7.43 (d, 1H, J = 17.1 Hz), 7.29–7.27 (m, 1H), 7.20

(d, 2H, J = 8.5 Hz), 4.09 (t, 2H, J = 6.7 Hz), 2.90 (dd, 1H, J = 14.0,

9.2 Hz), 2.73 (dd, 1H, J = 13.4, 6.1 Hz), 2.52–2.47 (m, 1H), 1.95

(sex, 2H, J = 7.3 Hz), 1.67–1.49 (m, 2H), 1.36 (s, 9H), 1.13 (t, 3H,

J = 7.3 Hz), 0.94 (t, 3H, J = 7.3 Hz). FAB-MS m/z: 439 [M]⁺, 440

[M+H]⁺.

¹H NMR (500 MHz, CDCl₃) 40fZ d: 7.70 (d, 1H, J = 1.8 Hz), 7.60

(dd, 1H, J = 8.5, 2.4 Hz), 7.28–7.23 (m, 1H), 7.11 (d, 2H, J = 8.5 Hz),

7.04 (d, 2H, J = 7.9 Hz), 6.73 (d, 1H, J = 12.2 Hz), 6.62 (d, 1H,

J = 12.2 Hz), 4.05 (t, 2H, J = 6.7 Hz), 2.93 (dd, 1H, J = 14.0, 8.5 Hz),

2.74 (dd, 1H, J = 13.4, 7.3 Hz), 2.62–2.59 (m, 1H), 1.79–1.73 (m,

2H), 1.72–1.43 (m, 4H), 0.98 (t, 3H, J = 7.9 Hz), 0.96 (t, 3H,

J = 6.7 Hz). Compound 40fE d: 7.83 (dd, 1H, J = 8.5, 1.8 Hz), 7.73

(d, 1H, J = 1.8 Hz), 7.67 (d, 1H, J = 8.5 Hz), 7.47 (d, 2H, J = 8.5 Hz),

7.42 (d, 1H, J = 16.5 Hz), 7.28–7.23 (m, 1H), 7.21 (d, 2H,

J = 7.9 Hz), 4.13 (t, 2H, J = 6.7 Hz), 2.99 (dd, 1H, J = 13.4, 8.5 Hz),

2.81 (dd, 1H, J = 14.0, 7.3 Hz), 2.68–2.65 (m, 1H), 1.93–1.87 (m,

2H), 1.72–1.43 (m, 4H), 1.03 (t, 3H, J = 7.3 Hz), 0.98 (t, 3H,

J = 7.3 Hz). FAB-MS m/z: 397 [M]⁺, 398 [M+H]⁺.

4.2.75. 2-{4-[2-(2-n-Butoxy-4-nitrophenyl)vinyl]benzyl}butyric

acid t-butyl ester (41f)

This compound was prepared from 40f by means of GP-A. Com-

pound 41f was obtained in 33% yield as a yellow oil.

4.2.71. 2-{4-[2-(4-Nitrophenyl)vinyl]benzyl}butyric acid t-butyl

ester (41a)

This compound was prepared from 40a by means of GP-A. Com-

pound 41a was obtained in 27% yield as a yellow oil.

¹H NMR (500 MHz, CDCl₃) 41fZ d: 7.71 (d, 1H, J = 1.8 Hz), 7.57

(dd, 1H, J = 8.5, 2.4 Hz), 7.29–7.26 (m, 1H), 7.09 (d, 2H, J = 7.9 Hz),

7.03 (d, 2H, J = 7.9 Hz), 6.74 (d, 1H, J = 12.2 Hz), 6.61 (d, 1H,

J = 12.2 Hz), 4.07 (t, 2H, J = 6.7 Hz), 2.82 (dd, 1H, J = 14.0, 9.2 Hz),

2.67 (dd, 1H, J = 14.0, 6.7 Hz), 2.48–2.43 (m, 1H), 1.79 (quin, 2H,

J = 6.7 Hz), 1.67–1.48 (m, 4H), 1.35 (s, 9H), 0.98 (t, 3H, J = 7.3 Hz),

0.92 (t, 3H, J = 7.3 Hz). Compound 41fE d: 7.83 (dd, 1H, J = 8.5,

2.4 Hz), 7.73 (d, 1H, J = 1.8 Hz), 7.67 (d, 1H, J = 8.5 Hz), 7.45 (d,

2H, J = 7.9 Hz), 7.42 (d, 1H, J = 16.5 Hz), 7.29–7.26 (m, 1H), 7.20

(d, 2H, J = 7.9 Hz), 4.13 (t, 2H, J = 6.7 Hz), 2.90 (dd, 1H, J = 14.0,

9.2 Hz), 2.73 (dd, 1H, J = 14.0, 6.7 Hz), 2.52–2.47 (m, 1H), 1.90

(quin, 2H, J = 6.7 Hz), 1.67–1.48 (m, 4H), 1.36 (s, 9H), 1.03 (t, 3H,

J = 7.3 Hz), 0.94 (t, 3H, J = 7.3 Hz). FAB-MS m/z: 453 [M]⁺, 454

[M+H]⁺.

¹H NMR (500 MHz, CDCl₃) 41aZ d: 8.06 (d, 2H, J = 9.2 Hz), 7.37

(d, 2H, J = 8.5 Hz), 7.10 (d, 2H, J = 8.5 Hz), 7.07 (d, 2H, J = 7.9 Hz),

6.77 (d, 1H, J = 12.2 Hz), 6.57 (d, 1H, J = 12.2 Hz), 2.83 (dd, 1H,

J = 14.0, 9.2 Hz), 2.69 (dd, 1H, J = 13.4, 6.1 Hz), 2.53–2.45 (m, 1H),

1.68–1.48 (m, 2H), 1.35 (s, 9H), 0.93 (t, 3H, J = 7.9 Hz). Compound

41aE d: 8.21 (d, 2H, J = 9.2 Hz), 7.62 (d, 2H, J = 9.2 Hz), 7.46 (d,

2H, J = 7.9 Hz), 7.24 (d, 1H, J = 16.5 Hz), 7.21 (d, 2H, J = 7.9 Hz),

7.11 (d, 1H, J = 16.5 Hz), 2.90 (dd, 1H, J = 14.0, 9.2 Hz), 2.73 (dd,

1H, J = 14.0, 6.7 Hz), 2.53–2.45 (m, 1H), 1.68–1.48 (m, 2H), 1.36

(s, 9H), 0.94 (t, 3H, J = 7.3 Hz). FAB-MS m/z: 381 [M]⁺, 382 [M+H]⁺.

4.2.72. 2-{4-[2-(2-Methoxy-4-nitrophenyl)vinyl]benzyl}butyric

acid t-butyl ester (41c)

This compound was prepared from 40c by means of GP-A. Com-

pound 41c was obtained in 41% yield as a brown oil.

4.2.76. 2-{4-[2-(4-Aminophenyl)ethyl]benzyl}butyric acid t-

butyl ester (42a)

¹H NMR (500 MHz, CDCl₃) 41cZ d: 7.73 (d, 1H, J = 1.8 Hz), 7.61

(dd, 1H, J = 8.5, 1.8 Hz), 7.29–7.22 (m, 1H), 7.08 (d, 1H, J = 7.9 Hz),

7.03 (d, 2H, J = 7.9 Hz), 6.76 (d, 1H, J = 12.2 Hz), 6.60 (d, 1H,

J = 12.2 Hz), 3.92 (s, 3H), 2.81 (dd, 1H, J = 14.0, 9.2 Hz), 2.67 (dd,

1H, J = 14.0, 7.9 Hz), 2.49–2.42 (m, 1H), 1.67–1.52 (m, 2H), 1.34

(s, 9H), 0.92 (t, 3H, J = 7.3 Hz). Compound 41cE d: 7.86 (dd, 1H,

J = 8.5, 1.2 Hz), 7.75 (d, 1H, J = 1.2 Hz), 7.70 (d, 1H, J = 8.5 Hz),

7.47 (d, 2H, J = 7.9 Hz), 7.43 (d, 1H, J = 16.5 Hz), 7.29–7.22 (m,

1H), 7.20 (d, 2H, J = 7.9 Hz), 3.99 (s, 3H), 2.89 (dd, 1H, J = 13.4,

8.5 Hz), 2.73 (dd, 1H, J = 14.0, 6.7 Hz), 2.52–2.46 (m, 1H), 1.67–

1.52 (m, 2H), 1.36 (s, 9H), 0.94 (t, 3H, J = 7.9 Hz). FAB-MS m/z:

411 [M]⁺, 412 [M+H]⁺.

This compound was prepared from 41a by means of GP-E. Com-

pound 42a was obtained in 97% yield as a white solid.

¹H NMR (500 MHz, CDCl₃) d: 7.07 (s, 4H), 6.96 (d, 2H, J = 7.9 Hz),

6.62 (d, 2H, J = 8.5 Hz), 3.55 (br s, 2H), 2.86–2.77 (m, 5H), 2.67 (dd,

1H, J = 14.0, 6.7 Hz), 2.48–2.42 (m, 1H), 1.62–1.50 (m, 2H), 1.35 (s,

9H), 0.92 (t, 3H, J = 7.3 Hz). FAB-MS m/z: 353 [M]⁺, 354 [M+H]⁺.

4.2.77. 2-{4-[2-(4-Amino-2-methoxyphenyl)ethyl]benzyl}

butyric acid t-butyl ester (42c)

This compound was prepared from 41c by means of GP-E. Com-

pound 42c was obtained in 97% yield as a colorless oil.

¹H NMR (500 MHz, CDCl₃) d: 7.10 (d, 2H, J = 7.9 Hz), 7.07 (d, 2H,

J = 7.9 Hz), 6.85 (d, 1H, J = 7.9 Hz), 6.24 (d, 1H, J = 2.4 Hz), 6.21 (dd,

1H, J = 8.9, 2.4 Hz), 3.77 (s, 3H), 3.59 (br s, 2H), 2.85 (dd, 1H,

J = 14.0, 8.5 Hz), 2.79–2.74 (m, 4H), 2.66 (dd, 1H, J = 14.0, 7.3 Hz),

2.48–2.42 (m, 1H), 1.63–1.48 (m, 2H), 1.36 (s, 9H), 0.91 (t, 3H,

J = 7.3 Hz). FAB-MS m/z: 383 [M]⁺, 384 [M+H]⁺.

4.2.73. 2-{4-[2-(2-Ethoxy-4-nitrophenyl)vinyl]benzyl}butyric

acid t-butyl ester (41d)

This compound was prepared from 40d by means of GP-A. Com-

pound 41d was obtained in 60% yield as a yellow oil.

¹H NMR (500 MHz, CDCl₃) 41dE d: 7.84 (dd, 1H, J = 8.5, 1.8 Hz),

7.73 (d, 1H, J = 2.4 Hz), 7.69 (d, 1H, J = 8.5 Hz), 7.46 (d, 2H,

J = 7.9 Hz), 7.43 (d, 1H, J = 16.5 Hz), 7.28–7.25 (m, 1H), 7.20 (d,

2H, J = 7.9 Hz), 4.20 (q, 2H, J = 7.3 Hz), 2.90 (dd, 1H, J = 14.0,

8.5 Hz), 2.73 (dd, 1H, J = 14.0, 6.7 Hz), 2.51–2.47 (m, 1H), 1.67–

1.52 (m, 5H), 1.36 (s, 9H), 0.94 (t, 3H, J = 7.3 Hz). FAB-MS m/z:

425 [M]⁺, 426 [M+H]⁺.

4.2.78. 2-{4-[2-(4-Amino-2-ethoxyphenyl)ethyl]benzyl}butyric

acid t-butyl ester (42d)

This compound was prepared from 41d by means of GP-E. Com-

pound 42d was obtained in 100% yield as a colorless oil.

¹H NMR (500 MHz, CDCl₃) d: 7.10 (d, 2H, J = 8.5 Hz), 7.07 (d, 2H,

J = 8.5 Hz), 6.86 (d, 1H, J = 7.9 Hz), 6.23 (d, 1H, J = 1.8 Hz), 6.20 (dd,

1H, J = 7.9, 2.4 Hz), 3.98 (q, 2H, J = 6.7 Hz), 3.56 (br s, 2H), 2.85 (dd,

1H, J = 14.0, 8.5 Hz), 2.80–2.74 (m, 4H), 2.67 (dd, 1H, J = 14.0,

6.7 Hz), 2.48–2.42 (m, 1H), 1.63–1.48 (m, 2H), 1.41 (t, 3H,

J = 7.3 Hz), 1.36 (s, 9H), 0.91 (t, 3H, J = 7.3 Hz). FAB-MS m/z: 397

[M]⁺, 398 [M+H]⁺.

4.2.74. 2-{4-[2-(4-Nitro-2-n-propoxyphenyl)vinyl]benzyl}

butyric acid t-butyl ester (41e)

This compound was prepared from 40e by means of GP-A.

Compound 41e was obtained in 55% yield as a yellow oil.

3170

K. Motoshima et al. / Bioorg. Med. Chem. 19 (2011) 3156–3172

4.2.79. 2-{4-[2-(4-Amino-2-propoxyphenyl)ethyl]benzyl}

butyric acid t-butyl ester (42e)

¹H NMR (500 MHz, CDCl₃) d: 7.96 (dd, 2H, J = 5.5, 3.1 Hz), 7.79

(dd, 2H, J = 5.5, 3.1 Hz), 7.24 (d, 1H, J = 7.3 Hz), 7.15 (d, 2H,

J = 7.9 Hz), 7.11 (d, 2H, J = 8.5 Hz), 6.92 (dd, 1H, J = 7.9, 1.8 Hz),

6.89 (d, 1H, J = 1.8 Hz), 3.96 (t, 2H, J = 6.7 Hz), 2.93–2.84 (m, 4H),

2.88–2.84 (m, 1H), 2.69 (dd, 1H, J = 13.4, 6.7 Hz), 2.50–2.44 (m,

1H), 1.86 (sex, 2H, J = 13.4, 6.7 Hz), 1.65–1.52 (m, 2H), 1.36 (s,

9H), 1.08 (t, 3H, J = 7.3 Hz), 0.92 (t, 3H, J = 7.3 Hz). FAB-MS m/z:

541 [M]⁺, 542 [M+H]⁺.

This compound was prepared from 41e by means of GP-E. Com-

pound 42e was obtained in 80% yield as a colorless oil.

¹H NMR (500 MHz, CDCl₃) d: 7.10 (d, 2H, J = 8.5 Hz), 7.08 (d, 2H,

J = 7.9 Hz), 6.86 (d, 1H, J = 7.9 Hz), 6.24 (d, 1H, J = 1.8 Hz), 6.20 (dd,

1H, J = 7.9, 1.8 Hz), 3.88 (t, 2H, J = 6.1 Hz), 3.56 (br s, 2H), 2.84 (dd,

1H, J = 13.4, 8.5 Hz), 2.80–2.75 (m, 4H), 2.67 (dd, 1H, J = 14.0,

6.7 Hz), 2.48–2.43 (m, 1H), 1.83 (sex, 2H, J = 6.7 Hz), 1.63–1.48

(m, 2H), 1.35 (s, 9H), 1.07 (t, 3H, J = 7.3 Hz), 0.92 (t, 3H,

J = 7.3 Hz). FAB-MS m/z: 411 [M]⁺, 412 [M+H]⁺.

4.2.85. 2-(4-{2-[2-n-Butoxy-4-(1,3-dioxo-1,3-dihydro-isoindol-

2-yl)phenyl]ethyl}benzyl)butyric acid t-butyl ester (43f)

This compound was prepared from phthalic anhydride and 42f

by means of GP-F. Compound 43f was obtained in 91% yield as a

pale brown solid.

4.2.80. 2-{4-[2-(4-Amino-2-butoxyphenyl)ethyl]benzyl}butyric

acid t-butyl ester (42f)

This compound was prepared from 41f by means of GP-E. Com-

pound 42f was obtained in 93% yield as a colorless oil.

¹H NMR (500 MHz, CDCl₃) d: 7.10 (d, 2H, J = 7.9 Hz), 7.08 (d, 2H,

J = 7.9 Hz), 6.86 (d, 1H, J = 7.9 Hz), 6.24 (d, 1H, J = 2.4 Hz), 6.20 (dd,

1H, J = 7.9, 2.4 Hz), 3.92 (t, 2H, J = 6.7 Hz), 3.56 (br s, 2H), 2.84 (dd,

1H, J = 14.0, 8.5 Hz), 2.79–2.74 (m, 4H), 2.67 (dd, 1H, J = 14.0,

6.7 Hz), 2.48–2.43 (m, 1H), 1.81–1.76 (m, 2H), 1.63–1.50 (m, 4H),

1.35 (s, 9H), 0.98 (t, 3H, J = 7.3 Hz), 0.92 (t, 3H, J = 7.3 Hz). FAB-

MS m/z: 425 [M]⁺, 426 [M+H]⁺.

¹H NMR (500 MHz, CDCl₃) d: 7.96 (dd, 2H, J = 5.5, 3.1 Hz), 7.79

(dd, 2H, J = 5.5, 3.1 Hz), 7.23 (d, 1H, J = 7.9 Hz), 7.15 (d, 2H,

J = 7.9 Hz), 7.11 (d, 2H, J = 7.9 Hz), 6.92 (dd, 1H, J = 7.3, 1.8 Hz),

6.89 (d, 1H, J = 1.8 Hz), 4.00 (t, 2H, J = 6.7 Hz), 2.93–2.84 (m, 5H),

2.69 (dd, 1H, J = 13.4, 6.7 Hz), 2.50–2.44 (m, 1H), 1.85–1.79 (m,

2H), 1.65–1.52 (m, 4H), 1.36 (s, 9H), 0.99 (t, 3H, J = 7.3 Hz), 0.92

(t, 3H, J = 7.3 Hz). FAB-MS m/z: 555 [M]⁺, 556 [M+H]⁺.

4.2.86. 2-(4-{2-[4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)

phenyl]ethyl}benzyl)butyric acid (13a)

4.2.81. 2-(4-{2-[4-(1,3-Dioxo-1,3-dihydro-isoindol-2-

yl)phenyl]ethyl}benzyl)butyric acid t-butyl ester (43a)

This compound was prepared from phthalic anhydride and 42a

by means of GP-F. Compound 43a was obtained in 89% yield as a

white solid.

This compound was prepared from 43a by means of GP-G. Com-

pound 13a was obtained in 79% yield as a white powder after

recrystallization from CH₂Cl₂/n-hexane.

Mp 180.5–182.0 °C. ¹H NMR (500 MHz, CDCl₃) d: 7.95 (dd, 2H,

J = 5.5, 3.1 Hz), 7.79 (dd, 2H, J = 5.5, 3.1 Hz), 7.29 (d, 2H,

J = 8.5 Hz), 7.22 (d, 2H, J = 8.5 Hz), 7.09 (d, 2H, J = 7.9 Hz), 7.05 (d,

2H, J = 7.9 Hz), 3.00–2.86 (m, 5H), 2.78 (dd, 1H, J = 13.4, 6.1 Hz),

2.64–2.60 (m, 1H), 1.73–1.56 (m, 2H), 0.99 (t, 3H, J = 7.3 Hz).

FAB-MS m/z: 427 [M]⁺, 428 [M+H]⁺. HRMS (FAB) calcd for

¹H NMR (500 MHz, CDCl₃) d: 7.96 (dd, 2H, J = 5.5, 3.1 Hz), 7.79

(dd, 2H, J = 5.5, 3.1 Hz), 7.35 (d, 2H, J = 6.1 Hz), 7.32 (d, 2H,

J = 8.5 Hz), 7.12 (d, 2H, J = 9.2 Hz), 7.11 (d, 2H, J = 8.5 Hz),

2.95–2.92 (m, 4H), 2.86 (dd, 1H, J = 13.4, 8.5 Hz), 2.69 (dd, 1H,

J = 13.4, 6.7 Hz), 2.50–2.44 (m, 1H), 1.62–1.48 (m, 2H), 1.36 (s,

9H), 0.92 (t, 3H, J = 7.3 Hz). FAB-MS m/z: 484 [M+H]⁺.

C

₂₇H₂₅NO₄427.1784; found: 427.1785 (M)⁺.

4.2.87. 2-(4-{2-[4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-2-

hydroxyphenyl]ethyl}benzyl)butyric acid (13b)

To a solution of 13c (25 mg, 0.055 mmol) in dichloromethane

(3 mL) was added dropwise boron tribromide (1.0 M solution in

4.2.82. 2-(4-{2-[4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-2-

methoxyphenyl]ethyl}benzyl)butyric acid t-butyl ester (43c)

This compound was prepared from phthalic anhydride and 42c

by means of GP-F. Compound 43c was obtained in 96% yield as a

pale brown solid.

dichloromethane) (550 lL, 0.55 mmol) at 0 °C. The mixture was

stirred for 15 min, then poured into ice water (10 mL) and CH₂Cl₂

was removed under reduced pressure. EtOAc (30 mL) was added

to the residue. The organic layer was washed with H₂O (10 mL)

and brine (10 mL), then dried over MgSO₄. The solvent was re-

moved under reduced pressure. The residue was puriﬁed by silica

gel column chromatography to give the target compound (4.2 mg,

18%) as a white powder after recrystallization from EtOAc/n-

hexane.

¹H NMR (500 MHz, CDCl₃) d: 7.96 (dd, 2H, J = 5.5, 3.1 Hz), 7.80

(dd, 2H, J = 5.5, 3.1 Hz), 7.23 (d, 1H, J = 7.9 Hz), 7.14 (d, 2H,

J = 7.9 Hz), 7.11 (d, 2H, J = 7.9 Hz), 6.94 (dd, 1H, J = 7.9, 1.8 Hz),

6.91 (d, 1H, J = 1.8 Hz), 3.85 (s, 3H), 2.93–2.84 (m, 5H), 2.68 (dd,

1H, J = 12.8, 6.1 Hz), 2.48–2.44 (m, 1H), 1.62–1.51 (m, 2H), 1.36

(s, 9H), 0.92 (t, 3H, J = 7.3 Hz). FAB-MS m/z: 513 [M]⁺, 514 [M+H]⁺.

4.2.83. 2-(4-{2-[4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-2-

ethoxyphenyl]ethyl}benzyl)butyric acid t-butyl ester (43d)

This compound was prepared from phthalic anhydride and 42d

by means of GP-F. Compound 43d was obtained in 82% yield as a

pale brown solid.

Mp 197.0–199.0 °C. ¹H NMR (500 MHz, DMSO-d₆) d: 12.05 (br s,

1H), 9.71 (s, 1H), 7.94 (dd, 2H, J = 5.5, 3.1 Hz), 7.89 (dd, 2H, J = 5.5,

3.1 Hz), 7.18 (d, 1H, J = 7.9 Hz), 7.16 (d, 2H, J = 7.9 Hz), 7.10 (d, 2H,

J = 7.9 Hz), 6.87 (d, 1H, J = 1.8 Hz), 6.77 (dd, 1H, J = 7.9, 2.4 Hz), 2.82

(s, 4H), 2.79 (dd, 1H, J = 13.4, 8.5 Hz), 2.64 (dd, 1H, J = 14.0, 6.7 Hz),

2.51–2.47 (m, 1H), 1.50–1.46 (m, 2H), 0.86 (t, 3H, J = 7.3 Hz). FAB-

MS m/z: 443 [M]⁺, 444 [M+H]⁺. HRMS (FAB) calcd for C₂₇H₂₅NO₅

443.1733; found: 443.1713 (M)⁺.

¹H NMR (500 MHz, CDCl₃) d: 7.96 (dd, 2H, J = 5.5, 3.1 Hz), 7.79

(dd, 2H, J = 5.5, 3.1 Hz), 7.23 (d, 1H, J = 7.9 Hz), 7.15 (d, 2H,

J = 7.9 Hz), 7.11 (d, 2H, J = 7.9 Hz), 6.93 (dd, 1H, J = 7.9, 1.8 Hz),

6.89 (d, 1H, J = 1.8 Hz), 4.06 (q, 2H, J = 14.0, 7.3 Hz), 2.93–2.84 (m,

5H), 2.68 (dd, 1H, J = 13.4, 6.7 Hz), 2.50–2.44 (m, 1H), 1.64–1.49

(m, 2H), 1.45 (t, 3H, J = 7.3 Hz), 1.36 (s, 9H), 0.92 (t, 3H,

J = 7.3 Hz). FAB-MS m/z: 527 [M]⁺, 528 [M+H]⁺.

4.2.88. 2-(4-{2-[4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-2-

methoxyphenyl]ethyl}benzyl)butyric acid (13c)

This compound was prepared from 43c by means of GP-G. Com-

pound 13c was obtained in 82% yield as a white solid. Chiral sepa-

ration and enantiomeric excess (ee) determination were performed

on CHIRALPAK IA.

Compound (S)-13c: White powder from CH₂Cl₂/n-hexane. Ee

>99%. Mp 168.0–169.5 °C. ¹H NMR (500 MHz, CDCl₃) d: 7.95 (dd,

2H, J = 5.5, 3.1 Hz), 7.79 (dd, 2H, J = 5.5, 3.1 Hz), 7.13 (d, 1H,

4.2.84. 2-(4-{2-[4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-2-n-

propoxy-phenyl]ethyl}benzyl)butyric acid t-butyl ester (43e)

This compound was prepared from phthalic anhydride and 42e

by means of GP-F. Compound 43e was obtained in 81% yield as a

pale brown solid.

K. Motoshima et al. / Bioorg. Med. Chem. 19 (2011) 3156–3172

3171

J = 7.9 Hz), 7.10 (d, 2H, J = 8.5 Hz), 7.09 (d, 2H, J = 8.5 Hz), 6.89 (dd,

C

₃₀H₃₁NO₅485.2202; found: 485.2244 (M)⁺. [

a

]

D

+3.4 (23.2 °C, c

1H, J = 7.9, 1.8 Hz), 6.87 (d, 1H, J = 1.8 Hz), 3.83 (s, 3H), 2.98–2.86

(m, 5H), 2.76 (dd, 1H, J = 10.4, 6.1 Hz), 2.61 (quin, 1H, J = 6.1 Hz),

1.72–1.58 (m, 2H), 0.98 (t, 3H, J = 7.3 Hz). FAB-MS m/z: 457 [M]⁺,

458 [M+H]⁺. HRMS (FAB) calcd for C₂₈H₂₇NO₅457.1889; found:

0.291, CHCl₃).

4.2.91. 2-(4-{2-[2-Butoxy-4-(1,3-dioxo-1,3-dihydro-isoindol-2-

yl)phenyl]ethyl}benzyl)butyric acid (13f)

This compound was prepared from 43f by means of GP-G. Com-

pound 13f was obtained in 76% yield as a white solid.

457.1918 (M)⁺. [

a

]

D

ꢀ6.9 (23.2 °C, c 0.409, CHCl₃).

Compound (R)-13c: White powder from CH₂Cl₂/n-hexane. Ee

>99%. Mp 172.0–173.5 °C. ¹H NMR (500 MHz, CDCl₃) d: 7.95 (dd,

2H, J = 5.5, 3.1 Hz), 7.79 (dd, 2H, J = 5.5, 3.1 Hz), 7.12 (d, 1H,

J = 7.9 Hz), 7.09 (s, 4H), 6.88 (dd, 1H, J = 7.9, 1.8 Hz), 6.86 (d, 1H,

J = 1.8 Hz), 3.83 (s, 3H), 2.97–2.95 (m, 1H), 2.92–2.87 (m, 4H),

2.76 (dd, 1H, J = 10.4, 6.1 Hz), 2.61 (quin, 1H, J = 6.1 Hz), 1.72–

1.67 (m, 1H), 1.67–1.60 (m, 1H), 0.98 (t, 3H, J = 7.3 Hz). FAB-MS

m/z: 457 [M]⁺, 458 [M+H]⁺. HRMS (FAB) calcd for C₂₈H₂₇NO₅

Mp 132.0–133.0 °C. ¹H NMR (500 MHz, CDCl₃) d: 7.95 (dd, 2H,

J = 5.5, 3.1 Hz), 7.79 (dd, 2H, J = 5.5, 3.1 Hz), 7.10 (d, 1H,

J = 8.5 Hz), 6.86 (dd, 1H, J = 6.1, 1.8 Hz), 6.85 (d, 1H, J = 2.4 Hz),

3.98 (t, 2H, J = 6.7 Hz), 2.97–2.86 (m, 5H), 2.77 (dd, 1H, J = 14.0,

6.7 Hz), 2.65–2.59 (m, 1H), 1.85–1.79 (m, 2H), 1.72–1.66 (m, 1H),

1.66–1.58 (m, 1H), 1.59–1.51 (m, 2H), 1.00 (t, 3H, J = 7.3 Hz), 0.98

(t, 3H, J = 7.3 Hz). FAB-MS m/z: 499 [M]⁺, 500 [M+H]⁺. HRMS

(FAB) calcd for C₃₁H₃₃NO₅499.2359; found: 499.2311 (M)⁺.

457.1889; found: 457.1901 (M)⁺. [

a]_D+6.1 (23.2 °C, c 0.397, CHCl₃).

4.2.89. 2-(4-{2-[4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-2-

ethoxyphenyl]ethyl}benzyl)butyric acid (13d)

Acknowledgments

This compound was prepared from 43d by means of GP-G.

Compound 13d was obtained in 89% yield as a white solid. Chiral

separation and enantiomeric excess (ee) determination were

performed on CHIRALPAK IA.

The work described in this paper was partially supported by

Grants-in-Aid for Scientiﬁc Research from The Ministry of Educa-

tion Culture, Sports, Science and Technology, Japan, and the Japan

Society for the Promotion of Science.

Compound (S)-13d: White powder from CH₂Cl₂/n-hexane. Ee

>99%. Mp 160.0–162.0 °C. ¹H NMR (500 MHz, CDCl₃) d: 7.95 (dd,

2H, J = 5.5, 3.1 Hz), 7.79 (dd, 2H, J = 5.5, 3.1 Hz), 7.12 (d, 1H,

J = 7.9 Hz), 7.09 (s, 4H), 6.87 (dd, 1H, J = 7.9, 1.8 Hz), 6.85 (d, 1H,

J = 1.8 Hz), 4.04 (q, 2H, J = 7.3 Hz), 2.97–2.88 (m, 5H), 2.76 (dd,

1H, J = 13.4, 6.1 Hz), 2.61 (quin, 1H, J = 6.1 Hz), 1.73–1.57 (m, 2H),

1.45 (t, 3H, J = 7.3 Hz), 0.98 (t, 3H, J = 7.3 Hz). FAB-MS m/z: 471

[M]⁺, 472 [M+H]⁺. HRMS (FAB) calcd for C₂₉H₂₉NO₅471.2046;

Supplementary data

Supplementary data associated with this article can be found, in

the online version, at doi:10.1016/j.bmc.2011.03.065.

References and notes

found: 471.2032 (M)⁺. [

a

]

D

ꢀ6.7 (23.2 °C, c0.178, CHCl₃).

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Compound (R)-13d: White powder from CH₂Cl₂/n-hexane.

Ee > 99%. Mp 156.5–159.5 °C. ¹H NMR (500 MHz, CDCl₃) d: 7.95

(dd, 2H, J = 5.5, 3.1 Hz), 7.79 (dd, 2H, J = 5.5, 3.1 Hz), 7.12 (d, 1H,

J = 7.9 Hz), 7.09 (s, 4H), 6.87 (dd, 1H, J = 7.9, 1.8 Hz), 6.85 (d, 1H,

J = 1.8 Hz), 4.04 (q, 2H, J = 6.7 Hz), 2.97–2.88 (m, 5H), 2.76 (dd,

1H, J = 13.4, 6.7 Hz), 2.61 (quin, 1H, J = 6.1 Hz), 1.72–1.59 (m, 2H),

1.45 (t, 3H, J = 6.7 Hz), 0.98 (t, 3H, J = 7.3 Hz). FAB-MS m/z: 471

[M]⁺, 472 [M+H]⁺. HRMS (FAB) calcd for C₂₉H₂₉NO₅471.2046;

found: 471.2032 (M)⁺. [

a] +6.5 (23.2 °C, c 0.173, CHCl₃).

D

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4.2.90. 2-(4-{2-[4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-2-

propoxyphenyl]ethyl}benzyl)butyric acid (13e)

This compound was prepared from 43e by means of GP-G. Com-

pound 13e was obtained in 87% yield as a white solid. Chiral sep-

aration and enantiomeric excess (ee) determination were

performed on CHIRALPAK IA.

Compound (S )-13e: White powder from CH₂Cl₂/n-hexane. Ee

>99%. Mp 161.0–164.0 °C. ¹H NMR (500 MHz, CDCl₃) d: 7.95 (dd,

2H, J = 5.5, 3.1 Hz), 7.79 (dd, 2H, J = 5.5, 3.1 Hz), 7.13 (d, 1H,

J = 7.9 Hz), 7.10 (s, 4H), 6.87 (dd, 1H, J = 8.5, 1.8 Hz), 6.85 (d, 1H,

J = 1.8 Hz), 3.93 (t, 2H, J = 6.7 Hz), 2.97–2.88 (m, 5H), 2.76 (dd,

1H, J = 13.4, 6.1 Hz), 2.64–2.59 (m, 1H), 1.86 (sex, 2H, J = 6.7 Hz),

1.72–1.59 (m, 2H), 1.08 (t, 3H, J = 7.3 Hz), 0.98 (t, 3H, J = 6.7 Hz).

FAB-MS m/z: 485 [M]⁺, 486 [M+H]⁺. HRMS (FAB) calcd for

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a]

ꢀ3.6 (23.2 °C, c

D

Compound (R)-13e: White powder from CH₂Cl₂/n-hexane. Ee

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J = 7.3 Hz), 7.10 (s, 4H), 6.87 (dd, 1H, J = 8.5, 1.8 Hz), 6.85 (d, 1H,

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1.72–1.59 (m, 2H), 1.08 (t, 3H, J = 7.3 Hz), 0.98 (t, 3H, J = 7.3 Hz).

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3172

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Article Doi

Peroxisome proliferator-activated receptor agonists with phenethylphenylphthalimide skeleton derived from thalidomide-related liver X receptor antagonists: Relationship between absolute configuration and subtype selectivity

DOI: 10.1016/j.bmc.2011.03.065

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Full text of DOI:10.1016/j.bmc.2011.03.065

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