Design and synthesis of norendoxifen analogues with dual aromatase inhibitory and estrogen receptor modulatory activities

Article

pubs.acs.org/jmc

Design and Synthesis of Norendoxifen Analogues with Dual

Aromatase Inhibitory and Estrogen Receptor Modulatory Activities

Wei Lv,^†Jinzhong Liu,^‡Todd C. Skaar,^‡David A. Flockhart,^‡and Mark Cushman*^,†

^†Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, and The Purdue University Center for

Cancer Research, Purdue University, 575 Stadium Mall Drive, West Lafayette, Indiana 47907, United States

^‡Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indiana Institute for

Personalized Medicine, Indianapolis, Indiana 46202, United States

S

* Supporting Information

ABSTRACT: Both selective estrogen receptor modulators and aromatase inhibitors are widely used for the treatment of breast

cancer. Compounds with both aromatase inhibitory and estrogen receptor modulatory activities could have special advantages for

treatment of breast cancer. Our previous eﬀorts led to the discovery of norendoxifen as the ﬁrst compound with dual aromatase

inhibitory and estrogen receptor binding activities. To optimize its eﬃcacy and aromatase selectivity versus other cytochrome

P450 enzymes, a series of structurally related norendoxifen analogues were designed and synthesized. The most potent

compound, 4′-hydroxynorendoxifen (10), displayed elevated inhibitory potency against aromatase and enhanced aﬃnity for

estrogen receptors when compared to norendoxifen. The selectivity of 10 for aromatase versus other cytochrome P450 enzymes

was also superior to norendoxifen. 4′-Hydroxynorendoxifen is therefore an interesting lead for further development to obtain

new anticancer agents of potential value for the treatment of breast cancer.

SERM activities. One of the potential beneﬁts of a dual AI/

SERM agent is improved eﬃcacy. It is possible that the AI and

SERM activities could act synergistically to inhibit breast tumor

growth. According to Brodie et al., a combination of the

aromatase inhibitor letrozole and the estrogen receptor

antagonist fulvestrant was more eﬀective than either letrozole

or fulvestrant alone in suppressing breast tumor growth,

especially in delaying the development of tumor resistance.¹⁷

For this reason, dual AI/SERM agents are expected to have

eﬃcacy superior to tamoxifen and conventional aromatase

inhibitors. A second advantage of dual AI/SERM agents could

be fewer side eﬀects. The SERM activity of a dual AI/SERM

agent may stimulate estrogen receptors in noncancerous tissues

and ameliorate the side eﬀects (e.g., osteoporosis, muscu-

loskeletal pain, and cardiovascular events) caused by estrogen

depletion. This hypothesis is supported by the ATAC

(anastrozole, tamoxifen, alone or in combination) trial, which

demonstrated that a combination of the AI anastrozole and the

SERM tamoxifen resulted in fewer bone fractures than when

anastrozole was used alone.^9,18Although the ATAC trial

showed no superior therapeutic eﬀect of the tamoxifen plus

anastrozole combination over anastrozole alone,⁹this result

may not be generalizable to all SERM and AI combinations or

INTRODUCTION

■

Breast cancer is the most frequently diagnosed cancer in

women. It is estimated that one out of eight women in the

United States (about 12%) will develop invasive breast cancer

during the course of her life.¹Breast cancer is second only to

lung cancer as the cause of cancer-related deaths in women.²

Most breast cancer tumors are estrogen receptor (ER) positive,

making them suitable for antiestrogen therapy. The selective

estrogen receptor modulator (SERM) tamoxifen (1, Figure 1)

has been widely used for treatment of ER-positive breast

cancer, with eﬃcacy documented in various randomized clinical

trials.^3,4However, the use of tamoxifen is limited by intrinsic

and acquired drug resistance, and long-term tamoxifen

treatment also increases the occurrence of endometrial

cancer.^3,5,6For postmenopausal breast cancer patients,

aromatase inhibitors (AIs), e.g., letrozole (3) and anastrozole

(4), have been used to inhibit estrogen biosynthesis. Several

comparative clinical trials have demonstrated that AIs are

superior to tamoxifen in the treatment of postmenopausal

women with ER-positive breast cancer.⁷⁻¹¹Unfortunately,

because AIs nonselectively deplete estrogen in the whole body,

they inevitably lead to severe musculoskeletal pain, reduction of

bone density, and increased frequency of fractures and

cardiovascular events.¹²⁻¹⁶

One possible strategy to improve patient compliance and

treatment outcomes is to develop agents with dual AI and

Received: August 7, 2014

Published: March 9, 2015

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Figure 1. Structures of the selective estrogen receptor modulator tamoxifen, its active metabolite 4-hydroxytamoxifen, and the aromatase inhibitors

letrozole and anastrozole.

Figure 2. Structures and biological activities of (E,Z)-, Z- and E-norendoxifen.

to dual AI/SERM agents. It is notable that the serum

concentrations of anastrozole were lower in the combination

arm of the ATAC study, and this fact challenges the generalized

conclusion that all SERM/AI combinations would inevitably

produce no additional beneﬁt relative to an AI alone.

Norendoxifen (5, Figure 2) is a metabolite of tamoxifen. In

2012, we reported that norendoxifen is a potent aromatase

inhibitor and that it has good selectivity for aromatase versus

other cytochrome P450 enzymes.¹⁹In 2013, we disclosed the

ﬁrst synthesis of (E,Z)-norendoxifen (5). Biological testing

results conﬁrmed the aromatase inhibitory activity of (E,Z)-

norendoxifen and further established high aﬃnity for both ER-

α and ER-β.²⁰Next, the E- and Z-norendoxifen isomers (E-5

and Z-5) were prepared via stereoselective synthetic routes.

The biological testing results revealed that E-norendoxifen is

the more potent aromatase inhibitor, while Z-norendoxifen has

higher binding aﬃnity for both ER-α and ER-β.

The potent aromatase inhibitory activity together with the

high binding aﬃnity for both ER-α and ER-β support the

further utilization of norendoxifen as a lead compound for the

development of possible dual AI/SERM agents. Moreover, the

fact that millions of patients have already been exposed to

norendoxifen as a metabolite of tamoxifen supports a high

safety proﬁle expected for norendoxifen and related com-

pounds. In this report, a series of norendoxifen analogues were

designed, synthesized, and tested with the aim to optimize the

eﬃcacy against both aromatase and ER, explore the structure−

activity relationships, and improve the aromatase selectivity

versus other cytochrome P450 enzymes.

activity relationships of previously published analogues,²⁰it was

used to guide further structure-based optimization.

To investigate the interaction of Z-norendoxifen with ER-α, a

hypothetical binding model of Z-norendoxifen in the ligand-

binding site of ER-α was obtained by mutating the crystal

structure of the 4-hydroxytamoxifen (2, Figure 1) complex with

ER-α (PDB ID 3ert²²), followed by full energy minimization

using Amber 10 (Figure 3b). Considering the high structural

similarity between Z-norendoxifen and 4-hydroxytamoxifen, the

model proposed in Figure 3b is a logical one to use for further

structure-based optimization. Because the ligand binding

pocket of ER-β is nearly identical to ER-α (only two residues

are diﬀerent: Met421 and Leu384 in ER-α correspond to Ile

and Met in ER-β, respectively), one might expect that structure

modiﬁcations of norendoxifen would result in similar eﬀects on

binding to both ER-α and ER-β. This notion is generally

supported by the ER-α and ER-β binding data listed in Figure

2. Therefore, molecular modeling of the binding of Z-

norendoxifen to ER-β was not performed.

On the basis of the hypothetical binding models shown in

Figure 3a,b, a series of structurally related norendoxifen

analogues were designed and the optimization strategies are

summarized in Figure 3c. Detailed rationales for the proposed

modiﬁcations are described below.

1. Incorporating a Hydroxyl Group in the para Position of

the “A” Ring. For aromatase, attaching a hydroxyl group in this

position was proposed in order to increase aromatase inhibitory

activity of E-norendoxifen by forming a new hydrogen bond

with the carbonyl group of Ile133 or the guanidine group of

Arg115 (see Figure 3c for ring labeling). For ER, this hydroxyl

group would increase aﬃnity of Z-norendoxifen by hydrogen

bonding to the imidazole ring of His524.

RESULTS AND DISCUSSION

■

Structure-Based Optimization. To assist rational drug

design, the interaction of E-norendoxifen with aromatase was

investigated. A hypothetical binding model of E-norendoxifen

in the crystal structure of the active site of aromatase (PDB ID

3s79²¹) obtained by molecular docking is displayed in Figure

3a.²⁰Because this model is consistent with the structure−

2. Replacing the “B” Ring Hydroxyl Group with Hydrogen

or an Amino Group. The modeling results indicate that the “B”

ring para hydroxyl group of Z-norendoxifen is crucial for ER

binding by forming bifurcated hydrogen bonds with Glu353

and Arg394. This hydroxyl group is also thought to be

important for aromatase inhibitory activity of E-norendoxifen

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functional groups (−CN, imidazole or 1,2,4-triazole) that could

coordinate to the heme iron is therefore expected to improve

aromatase inhibitory activity. Besides iron-coordinating groups,

various alkyl groups were also introduced in this position to

investigate their eﬀects on binding to aromatase and ER.

4. Replacing the Side Chain Terminal Amino Group with

Diﬀerent Substituents, Including Hydrazine, Hydroxyl,

Carboxyl, and Halogens. On the basis of the modeling results,

the terminal amino group is essential for both the aromatase

inhibitory activity of E-norendoxifen and the ER binding

aﬃnity of Z-norendoxifen because it forms a salt bridge with

Asp309 of aromatase and Asp351 of ER. Replacing this amino

group with diﬀerent substituents would be useful to conﬁrm the

importance of a positively charged group in this position for the

biological activity.

5. Replacing the Ether Oxygen with a Methylene Group.

According to the hypothetical binding model of E-norendoxifen

with aromatase, the ether oxygen forms a hydrogen bond with

the side chain of Ser478. The contribution of this hydrogen

bond to the aromatase inhibitory activity could be determined

by eliminating the ether functionality. For ER, the ether oxygen

is proposed to have no direct interaction with surrounding

residues, and therefore replacement of the ether oxygen with a

methylene group would not be expected to aﬀect ER binding. A

potential beneﬁt of replacing the ether oxygen with a methylene

group would be to increase metabolic stability in vivo by

preventing oxidative O-dealkylation.

Chemistry and Biological Activity. Synthesis of (E,Z)-

Norendoxifen Analogues with Diﬀerent Substituents on the

“A” Ring. To synthesize “A” ring hydroxylated (E,Z)-

norendoxifen 10, 4,4′-dihydroxybenzophenone (6) was ﬁrst

alkylated with 2-iodoacetamide (Scheme 1). The benzophe-

a

Scheme 1. Synthesis of 10

Figure 3. Hypothetical binding model of E-norendoxifen in the active

site of aromatase (a) and Z-norendoxifen in the active site of estrogen

receptor-α (b) and the molecular modiﬁcations proposed for

structure-based optimization (c).

because it hydrogen bonds to the backbone carbonyl group of

Leu372. The importance of this hydroxyl group might be

veriﬁed by preparing analogues with the hydroxyl group

replaced by hydrogen or an amino group.

a

Reagents and conditions: (a) ICH₂CONH₂, Cs₂CO₃, DMF, 37%; (b)

3. Introducing Iron-Coordinating Groups or Various Alkyl

Groups in the Location of the Ethyl Side Chain. An iron-

coordinating group (usually imidazole or 1,2,4-triazole) is

present in most aromatase inhibitors (e.g., letrozole (3) and

anastrozole (4)), and it is a crucial pharmacophore for

aromatase inhibitory activity.²³According to the hypothetical

binding model of E-norendoxifen to aromatase, the ethyl side

chain is pointing toward the heme iron, with the distance from

the methyl carbon to heme iron being 3.9 Å. Introducing

Zn, TiCl₄, THF, 55%; (c) LiAlH₄, AlCl₃, THF, 70%.

none 7 and propiophenone 8²⁴were reacted under McMurry

cross-coupling conditions to provide the product 9 with E/Z

ratio 4.5:1. The product 9 quickly isomerized to a 1:1 mixture

of E and Z isomers when dissolved in chloroform and kept at

room temperature overnight. In the last step, deprotection of

the pivaloyl group and reduction of the amide group were

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ﬁnished in one pot to aﬀord the product 10 as a 1:1 mixture of

E and Z isomers.

introducing a hydroxyl group in the para position of the “A”

ring of 10 increased both aromatase inhibitory activity and ER

binding aﬃnity. This supported the expectation that a hydroxyl

group in this position would beneﬁt aromatase inhibitory

activity of E-norendoxifen via hydrogen bonding with Ile133 or

Arg115 and enhance ER binding aﬃnity of Z-norendoxifen by

forming an additional hydrogen bond with His524. Incorporat-

ing a ﬂuorine atom in this position (14a) decreased aromatase

inhibitory activity but only had a minor negative eﬀect on ER

binding. Replacement of the “A” ring with an ethyl group (14b)

decreased both aromatase inhibitory activity and ER binding

aﬃnity. Letrozole was used as a positive control for aromatase

inhibition and it displayed an IC₅₀of 5.3 nM.²⁵

Compound 14a was designed by attaching a ﬂuorine atom to

the “A” ring of norendoxifen. The symmetrical compound 14b

was designed by replacing the benzene “A” ring with an ethyl

group. To prepare 14a,b, 4,4′-dihydroxybenzophenone (6) and

ketones 11a,b were reacted under McMurry cross-coupling

reaction conditions to provide the diphenols 12a,b (Scheme 2).

a

Scheme 2. Synthesis of 14a,b

Synthesis of Norendoxifen Analogues with Diﬀerent

Substituents on the “B” Ring. To validate the importance of

the “B” ring hydroxyl group, an analogue 18 without this

hydroxyl group was synthesized. Starting from 4-hydroxyben-

zophenone (15), the McMurry cross-coupling reaction with

propiophenone provided the phenol 16 (Scheme 3). The

phenolic hydroxyl group was alkylated with 2-iodoacetamide

and followed by LiAlH₄reduction of the amide 17 to aﬀord the

product 18.

a

Scheme 3. Synthesis of 18

a

Reagents and conditions: (a) Zn, TiCl₄, THF, 91−96%; (b)

ICH₂CONH₂, K₂CO₃, acetone, 40−47%; (c) LiAlH₄, AlCl₃, THF,

44−76%.

Treatment of the diphenols 12a,b with one equivalent of 2-

iodoacetamide in the presence of potassium carbonate aﬀorded

the monoalkylated products 13a and 13b in 40% and 47%

yields, respectively. Then the amide group was reduced with

LiAlH₄to provide the desired products 14a,b in good yield,

with 14a being obtained as an isomeric mixture.

a

Reagents and conditions: (a) propiophenone, Zn, TiCl₄, THF, 98%;

(b) ICH₂CONH₂, acetone, K₂CO₃, 73%; (c) LiAlH₄, AlCl₃, THF,

63%.

The biological testing results for compounds 10 and 14a,b

are summarized in Table 1. According to the testing results,

To explore the eﬀect of replacing the “B” ring hydroxy group

with an amino group, compounds 25a and 25b were prepared

as shown in Scheme 4. The benzophenone 21 was prepared via

Friedel−Crafts reaction of benzoyl chloride 19 and anisole 20

as described by Davies et al.²⁶The methoxy group of 21 was

subsequently cleaved, and the phenol was alkylated with

dibromoethane. Treatment of 23 with propiophenone or 8

under McMurry cross-coupling reaction conditions directly

provided the anilines 24a and 24b. In the last step, the side

chain amination and removal of the pivalate group were

ﬁnished in one-pot by treating 24a and 24b with ammonium

hydroxide to aﬀord the products 25a and 25b in good yield.

The biological testing results for compound 18, 25a, and 25b

are summarized in Table 2. According to the testing results,

removing the para hydroxyl group in the “B” ring of

norendoxifen to produce 18 decreased aromatase inhibitory

activity signiﬁcantly and resulted in complete loss of the

binding aﬃnity to both ER-α and ER-β. Replacing the hydroxyl

group of norendoxifen with an amino group in 25a improved

aromatase inhibitory activity but decreased ER binding aﬃnity.

Table 1. Aromatase Inhibitory Activity and Estrogen

Receptor Binding Aﬃnities of 10 and 14a,b

a,b

aromatase (IC₅₀,

nM)

ER-α (EC₅₀,

ER-β (EC₅₀,

compd

R

nM)

norendoxifen −H

102 33

45.0 3.0

1020 300

27.0 4.8

15.0 3.3

87.8 5.8

277 61

35.2 16.8

9.5 0.2

10

−OH

−F

14a

14b

49.2 13.2

202 21

1320

1

a

The values are mean values of at least three experiments.

Compound 14b has no E or Z isomers, while the rest of the

b

compounds were tested as 1:1 mixtures of E and Z isomers.

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a

Scheme 4. Synthesis of 25a,b

Scheme 5. Synthesis of 29a−e

a

Reagents and conditions: (a) AlCl₃, CH₂Cl₂, 55%; (b) HBr, AcOH,

94%; (c) dibromoethane, K₂CO₃, acetone, 68%; (d) propiophenone

or 8, Zn, TiCl₄, THF, 53−55%; (e) NH₄OH, NaI, THF, 52−56%.

These results are consistent with the proposal that this hydroxyl

group binds to aromatase by hydrogen bonding with Leu372

and binds to ER via bifurcated hydrogen bonds with Glu353

and Arg394. Compound 25b displayed elevated potency

against both aromatase and ER when compared with 25a.

This fact is consistent with the results with norendoxifen and

10 showing that incorporating a hydroxyl in the para position

of the “A” ring beneﬁts both aromatase inhibitory activity and

ER binding aﬃnity.

Synthesis of Norendoxifen Analogues with Diﬀerent

Replacements for the Ethyl Side Chain. The synthetic route

for compounds 29a−e is outlined in Scheme 5. The McMurry

cross-coupling reaction of 4,4′-dihydroxybenzophenone 6 and

ketones 26a−e provided the diphenols 27a−e. The diphenols

27a−e were treated with one equivalent of 2-iodoacetamide in

the presence of potassium carbonate to provide the

monoalkylated products 28a−e as the major products. Further

reduction of the amides 28a−e with LiAlH₄aﬀorded the

analogues 29a−e in good yield.

a

Reagents and conditions: (a) Zn, TiCl₄, THF, 65−96%; (b)

ICH₂CONH₂, acetone, K₂CO₃, 27−39%; (c) LiAlH₄, AlCl₃, THF,

54−82%.

Compound 32 was prepared via a slightly revised route

(Scheme 6). 4,4′-Dihydroxybenzophenone 6 was ﬁrst mono-

alkylated with dibromoethane to provide 30 in good yield. The

product 30 underwent McMurry cross-coupling reaction with

benzaldehyde to aﬀord 31. In the last step, the analogue 32 was

obtained by amination of the bromide 31 with ammonium

hydroxide.

To synthesize the conformationally restricted norendoxifen

analogue 36, 4,4′-dihydroxybenzophenone (6) and ketone 33

underwent the McMurry cross-coupling reaction to aﬀord the

diphenol 34 (Scheme 7). The diphenol 34 was monoalkylated

with 2-iodoacetamide followed by LiAlH₄reduction to aﬀord

the product 36 in good yield.

a,b,c

Table 2. Aromatase Inhibitory Activity and Estrogen Receptor Binding Aﬃnities of 18 and 25a,b

b

compd

R₁

R₂

aromatase (IC₅₀, nM)

ER-α (EC₅₀, nM)

ER-β (EC₅₀, nM)

norendoxifen

−H

−OH

−H

−NH₂

102 33

913 100

53.1 1.8

48.1 8.1

27.0 4.8

0% competition

274 44

35.2 16.8

0% competition

182 82

18

25a

25b

144 62

49.9 9.2

a

b

The values are mean values of at least three experiments. Percent ER competition was determined at the concentration of 100000 nM for each

c

compound. Compound 25a were tested as 2.5:1 mixture of E and Z isomers, and the rest of the compounds were tested as 1:1 mixtures of E and Z

isomers.

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a

Scheme 6. Synthesis of 32

Scheme 8. Synthesis of 40−41

a

Reagents and conditions: (a) dibromoethane, acetone, H₂O, K₂CO₃,

36%; (b) benzaldehyde, Zn, TiCl₄, THF, 57%; (c) NH₄OH, NaI,

THF, 75%.

a

Scheme 7. Synthesis of 36

a

Reagents and conditions: (a) NaH, MOMCl, THF, 41%; (b)

Cs₂CO₃, DMF, 50 °C, 72%; (c) NBS, CCl₄; (d) KCN, THF, H₂O; (e)

imidazole, NaH, THF; (f) MeOH, HCl, 64−81% in 3 steps.

spectroscopy as described in the Stereochemistry Determi-

nation section.

The biological testing results for compound 29a−e, 32, 36,

40−41, 44, E-45, and Z-45 are summarized in Table 3.

According to the testing results, replacement of the ethyl group

with diﬀerent alkyl groups (29a−e, 32) had diﬀerent eﬀects on

aromatase, ER-α and ER-β. The ethyl group (norendoxifen)

and chloroethyl group (29b, this group is also presents in the

SERM toremifene) were optimal for aromatase inhibitory

activity, while only the ethyl group was optimal for ER-α

binding aﬃnity. ER-β appeared to tolerate diﬀerent alkyl groups

in this position because norendoxifen, compound 32, and

compounds 29a−c displayed very similar potencies against ER-

β. According to the hypothetical binding mode of Z-

norendoxifen with ER-α (Figure 3b), the ethyl side chain is

situated in a hydrophobic pocket surrounded by Met388,

Met421, and Leu428. In ER-β, the Met421 was replaced with

an Ile residue, which could account for the better tolerance of

ER-β with diﬀerent alkyl groups. Replacement of the ethyl

group with a benzene ring in compound 29e decreased both

aromatase inhibitory activity and ER binding aﬃnity. Similarly,

the cyclized, conformationally restricted analogue 36 of

norendoxifen also showed decreased aromatase inhibitory

activity and ER binding aﬃnity. The incorporation of iron-

coordinating groups in the location of the ethyl group led to the

very potent aromatase inhibitors 40 and 41, but it also

markedly decreased the binding aﬃnity with ER. The increase

of aromatase inhibitory activity might be due to the

coordination of the iron by the nitrile group (40) or imidazole

group (41). Interestingly, the 1,2,4-triazole analogue 44

displayed good aromatase inhibitory activity and moderate

ER binding aﬃnities, while the 1,3,4-triazole analogues E-45

a

Reagents and conditions: (a) Zn, TiCl₄, THF, 85%; (b)

ICH₂CONH₂, K₂CO₃, acetone, 40%; (c) LiAlH₄, AlCl₃, THF, 66%.

To make norendoxifen analogues with an iron-coordinating

group in the location of the ethyl side chain, the diphenol 27a

was treated with one equivalent of methyl chloromethyl ether

to provide the monoprotected product 37 in 41% yield

(Scheme 8). Treatment of the phenol 37 with 38²⁷in the

presence of cesium carbonate converted 37 to 39 in an isolated

yield of 72%. Compound 39 underwent a series of sequential

reactions including bromination with NBS, alkylation of KCN,

and deprotection of MOM and Boc groups with HCl to aﬀord

the product 40 in very good yield. The product 41 with an

imidazole group was also obtained via a similar sequence of

reactions (including bromination with NBS, alkylation of the

anion derived from imidazole, and deprotection of the MOM

and Boc group with HCl).

To prepare 1,2,4-triazole-containing analogues, the inter-

mediate 39 was ﬁrst brominated with one equivalent of NBS

and then treated with 1,2,4-triazole in the presence of NaH

(Scheme 9). As expected, this provided a mixture of two

isomers 42 and 43, which could be separated by silica gel

column chromatography. Intermediate 42 was treated with HCl

to remove the MOM and Boc groups, and this aﬀorded the

product 44 as a 1:1 mixture of E and Z isomers. Treatment of

compound 43 with HCl also provided a 1:1 mixture of E and Z

isomers. Surprisingly, these two isomers Z-45 and E-45 could

be separated by silica gel chromatography. The stereo-

chemistries of Z-45 and E-45 were conﬁrmed by NMR

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a

Scheme 9. Synthesis of 44, Z-45, and E-45

a

Reagents and conditions: (a) NBS, CCl₄; (b) NaH, 1,2,4-triazole, THF; (c) MeOH, HCl, 7−31% in 3 steps.

Table 3. Aromatase Inhibitory Activity and Estrogen Receptor Binding Aﬃnities of 29a−e, 32, 36, 40−41, 44, E-45, and Z-

a,b,c

45

a

b

The values are mean values of at least three experiments. Percent ER competition was determined at the concentration of 100000 nM for each

c

compound. Compound 29e has no E or Z isomers, compound E-45 and Z-45 were tested as pure E or Z isomers, while the rest of the compounds

were tested as 1:1 mixtures of E and Z isomers.

and Z-45 showed moderate aromatase inhibitory activity and

good ER binding aﬃnities.

Synthesis of Norendoxifen Analogues with Diﬀerent

Replacements of the Aminoethoxyl Side Chain. To make

the hydroxy analogue 48 and carboxy analogue 49, the

diphenol 46²⁰was ﬁrst treated with ethyl 2-iodoacetate in the

presence of potassium carbonate to provide the monoalkylated

product 47. Reduction of the ester group with LiAlH₄provided

the hydroxy analogue 48. Hydrolysis of the ester group with

KOH aﬀorded the carboxy compound 49 (Scheme 10).

To make the bromo analogue 50 and the hydrazine analogue

51, the benzophenone 30 was reacted with propiophenone

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a

Scheme 10. Synthesis of 48 and 49

Scheme 12. Synthesis of 55a,b

a

Reagents and conditions: (a) ICH₂CO₂Et, acetone, K₂CO₃, 23%; (b)

LiAlH₄, THF, 65%; (3) KOH, THF, H₂O, 97%.

Reagents and conditions: (a) 1-bromo-2-chloroethane, acetone,

K₂CO₃, 49%; (b) dibromopropane, CH₃CN, Cs₂CO₃, 79%; (c)

propiophenone, Zn, TiCl₄, THF, 96%; (d) LiAlH₄, THF, 58%; (e)

NH₄OH, NaI, THF, 54%.

under McMurry cross-coupling reaction conditions to directly

aﬀord the product 50 in good yield (Scheme 11). Then, the

bromide 50 was reacted with hydrazine to yield the product 51.

Unfortunately, the product 51 was quite unstable and it

decomposed in methanol at room temperature.

binding aﬃnity with ER but decreased aromatase inhibitory

activity signiﬁcantly.

Synthesis of Norendoxifen Analogues in Which the Ether

Oxygen Is Replaced with a Methylene Group. Compounds

61a,b were designed by replacing the ether oxygen with a

methylene group, and the synthetic route is outlined in Scheme

13. The benzophenone 57, which was prepared via Friedel−

Crafts reaction of the commercially available benzoyl chloride

56 and anisole 20, was demethylated and the product 58

underwent the McMurry cross-coupling reaction with propio-

phenone or 8 to aﬀord 59a²⁸and 59b. A Heck coupling

reaction of the bromides 59a,b with acrylamide provided 60a

and 60b. The double bond in the side chain was selectively

reduced by catalytic hydrogenation with Rh(PPh₃)₃Cl. The

pivalate group was cleaved and the amide group was reduced in

one pot with LiAlH₄to provide analogues 61a and 61b.

The biological testing results for compounds 61a,b are

summarized in Table 5. Replacement of the ether oxygen with a

methylene group in 61a decreased aromatase inhibitory activity

when compared with norendoxifen but had no signiﬁcant eﬀect

on ER binding. The decrease of aromatase inhibitory activity

might be due to the loss of the hydrogen bonding of the ether

oxygen with Ser478. Interestingly, compound 61b displayed an

improved aromatase inhibitory activity but a decreased ER

binding aﬃnity when compared with 61a.

a

Scheme 11. Synthesis of 50

a

Reagents and conditions: (a) propiophenone, Zn, TiCl₄, THF, 87%;

(b) N₂H₄·H₂O, THF.

The analogues 55a and 55b were prepared starting from

benzophenone 52,²⁰which was alkylated with 1-bromo-2-

chloroethane or dibromopropane to provide 53a and 53b

(Scheme 12). Treatment of benzophenones 53a and 53b with

propiophenone under McMurry cross-coupling conditions

aﬀorded 54a and 54b. Then, the pivalate group was removed

and the side chain of the compound derived from 54b was

aminated to yield analogues 55a and 55b.

Summary of the Structure−Activity Relationships. In sum,

25 structurally related norendoxifen analogues have been

synthesized and biologically tested. The structure−activity

relationships are summarized in Figure 4. Generally, the

structure−activity relationships are consistent with the

molecular modeling predictions and this supports the reliability

of utilizing the molecular modeling results for further lead

optimization.

The biological testing results for compounds 48−50 and

55a,b are summarized in Table 4. Replacement of the terminal

amino group with a hydroxyl group, carboxyl group, or

halogens in analogues 48−50 and 55a signiﬁcantly impaired

both aromatase inhibitory activity and ER binding aﬃnity. This

demonstrated the importance of a positively charged group in

this position for interaction with Asp309 of aromatase and

Asp351 of ER. Extending the aminoethoxyl side chain to the

aminopropoxyl side chain in 55b had no inﬂuence on the

The Inhibitory Activities of 4′-Hydroxynorendoxifen (10)

Against Other Cytochrome P450 Enzymes. Among the

prepared norendoxifen analogues, the 4′-hydroxynorendoxifen

(10) displayed improved potency against both aromatase and

ER when compared with norendoxifen. Interestingly, our recent

research conﬁrmed that 4′-hydroxynorendoxifen is an active

metabolite of tamoxifen.²⁹The presence of 4′-hydroxynor-

endoxifen in human plasma after tamoxifen treatment suggests

that it might contribute to the clinical eﬀects of tamoxifen in

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a,b,c,d

Table 4. Aromatase Inhibitory Activity and Estrogen Receptor Binding Aﬃnities of 48−50 and 55a,b

b

c

compd

R

aromatase (IC₅₀, nM)

ER-α (EC₅₀, nM)

ER-β (EC₅₀, nM)

norendoxifen

−CH₂NH₂

−CH₂OH

−COOH

−CH₂Br

−CH₂Cl

102 33

30500 2900

3680 190

27.0 4.8

35.2 16.8

56% competition

57% competition

60% competition

40% competition

21.3 5.5

48

62% competition

55% competition

60% competition

62% competition

34.9 11.4

49

50

20% inhibition

27% inhibition

1240 180

55a

55b

−CH₂CH₂NH₂

a

b

The values are mean values of at least three experiments. Percent aromatase inhibition was determined at the concentration of 50000 nM for each

c

d

compound. Percent ER competition was determined at the concentration of 100000 nM for each compound. All compounds were tested as 1:1

mixtures of E and Z isomers.

a

Scheme 13. Synthesis of Analogues 61a,b

hydroxynorendoxifen was selected for further evaluation. To

investigate the likelihood of drug interactions, the inhibitory

activities of 4′-hydroxynorendoxifen against major cytochrome

P450 enzymes were evaluated (Table 6). According to the

testing results, 4′-hydroxynorendoxifen (K_i20.0 nM) is 4-fold

more potent than norendoxifen (K_i77 nM) against aromatase

(CYP19). 4′-Hydroxynorendoxifen also potently inhibits

CYP1A2 (K_i56 nM), while it only displays moderate or

weak inhibitory activities toward other cytochrome P450

enzymes (including CYP3A5, CYP3A4, CYP2D6, and

CYP2A6, K_ifrom 423 to 1640 nM). 4′-Hydroxynorendoxifen

showed elevated selectivity (3-fold) toward CYP19 versus

CYP1A2 when compared with norendoxifen (1-fold). 4′-

Hydroxynorendoxifen also displayed a good selectivity (>21-

fold) toward CYP19 versus all other CYP P450 enzymes tested.

Attempted Synthesis of E- and Z-4′-Hydroxynorendoxifen.

On the basis of previous testing results, E- and Z-norendoxifen

displayed distinct biological activities against aromatase and

ER.²⁰The synthesis of the pure E and Z isomers of 4′-

hydroxynorendoxifen was therefore attempted to provide

material for biological testing.

To prepare the pure Z isomer of 4′-hydroxynorendoxifen,

the propiophenone 8 and benzophenone 52 were ﬁrst reacted

under McMurry cross-coupling conditions and this aﬀorded the

product 62 with E/Z ratio >10:1 (Scheme 14). Further

trituration of 62 with methanol provided the pure E isomer of

62 in 78% yield. Although partial isomerization was observed

during the alkylation of 62 with 2-iodoacetamide, the pure E

isomer of 63 was obtained with 56% yield. The stereochemistry

of 63 was conﬁrmed by NMR spectroscopy as described in the

Stereochemistry Determination section. In the last step, facile

isomerization happened during the LiAlH₄reduction of 63 and

the workup procedures, which resulted in an E/Z ratio at 1:3 in

the product 64.

To prepare the pure E isomer of 4′-hydroxynorendoxifen, the

amide 9 (prepared in Scheme 1, E/Z = 4.5:1) was reduced with

LiAlH₄. Facile isomerization was still observed and the product

65 was obtained with E/Z ratio 3:2 (Scheme 15).

Previously, by using a similar route, we were able to prepare

Z-norendoxifen with E/Z ratio 1:10.²⁰Here, in the case of 4′-

hydroxynorendoxifen, the additional hydroxy group seemed to

accelerate the rate of E/Z isomerization. The fast E/Z

isomerization not only challenged the synthesis of the pure E

and Z isomers of 4′-hydroxynorendoxifen, it also made their

a

Reagents and conditions: (a) AlCl₃, DCM, 89%; (b) HBr, AcOH,

89%; (c) propiophenone or 8, Zn, TiCl₄, THF, 60−61%; (d)

acrylamide, Pd(PPh₃)₄, TEA, DMF; (e) Rh(PPh₃)₃Cl, H₂, MeOH; (f)

LiAlH₄, AlCl₃, THF, 18−34% in 3 steps.

breast cancer patients. Considering its potent AI activity and

the high binding aﬃnity for both ER-α and ER-β, 4′-

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a,b

Table 5. Aromatase Inhibitory Activity and Estrogen Receptor Binding Aﬃnities of 61a,b

compd

R

X

aromatase (IC₅₀, nM)

ER-α (EC₅₀, nM)

ER-β (EC₅₀, nM)

norendoxifen

61a

−H

−OH

−O−

−CH₂−

102 33

7340 450

491 35

27.0 4.8

27.1 15.0

1920 620

35.2 16.8

13.3 1.4

293 187

61b

a

b

The values are mean values of at least three experiments. All compounds were tested as 1:1 mixtures of E and Z isomers.

Figure 4. Summary of structure−activity relationships for the prepared norendoxifen analogues. ^aIn compound 61b, the −OH group is unfavorable

for ER binding aﬃnity.

a

Table 6. Inhibitory Activities of Norendoxifen and 4′-Hydroxynorendoxifen against Major Cytochrome P450 Enzymes

a

norendoxifen

4′-hydroxynorendoxifen

cytochrome P450 enzymes

IC₅₀(nM)

K_i(nM)

IC₅₀(nM)

K_i(nM)

aromatase (CYP19)

recombinant CYP1A2

recombinant CYP3A5

recombinant CYP3A4

recombinant CYP2D6

recombinant CYP2A6

102 33

207 26

77.0 9.5

76.0 3.0

829 62

45.0 3.0

207 56

20.0 4.0

56.0 5.0

855 14

723 27

556 52

285 81

375

6

1880 340

3600 400

6730 660

1640 90

423 124

710 212

no inhibition

6370 980

no inhibition

2180 260

a

The testing results for norendoxifen were previously published.³⁰

biological activity testing diﬃcult. Considering these factors,

further eﬀorts to prepare pure E- and Z-4′-hydroxynorendoxfen

were not attempted.

For compound Z-45, H_bwas ﬁrst assigned by the presence of

NOE correlation with H_a, and then H_cwas assigned by COSY

correlation with H_b. The Z geometry of Z-45 was conﬁrmed by

the NOE correlation between H_cand H_d. For compound E-45,

H_bwas assigned by the NOE correlation with H_a, and then H_c

was assigned by COSY correlation with H_b. Strong NOE

correlations were observed both for H_d-H_eand H_d-H_f, and no

NOE correlation was found between H_dand H_c. Those facts

conﬁrmed the E geometry of E-45. For compound 63, H_bwas

assigned by the NOE correlation with H_a. H_cwas assigned by

COSY correlation with H_b. Strong NOE correlations were

observed both for H_d-H_eand H_d-H_f, and no NOE correlation

Stereochemistry Determination of Compound Z-45, E-45,

and 63. The Z and E geometries of compounds Z-45, E-45,

1

and 63 were conﬁrmed by H−¹H COSY and NOE NMR

spectroscopy as previous described for stereochemistry

determination of norendoxifen²⁰and 4-hydroxytoremifene.³¹

The ¹H−¹H COSY and NOE correlations used for the

stereochemistry determination are summarized in Figure 5,

and the detailed assignment procedures for each molecule are

described below.

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α in the antagonistic conformation.²²This speciﬁc antagonistic

conformation (Figure 7b) is reported to be the origin of the

selective estrogen receptor modulatory activities of 4-

hydroxytamoxifen.^33,34

a

Scheme 14. Synthesis of 64

Considering the structural similarity of Z-norendoxifen and

4-hydroxytamoxifen, a molecular dynamics (MD) simulation

study was performed to explore whether Z-norendoxifen could

trigger and stabilize ER-α in a similar antagonistic conformation

as 4-hydroxytamoxifen. The MD simulation started with the

hypothetical binding mode of Z-norendoxifen in the ligand

binding site of ER-α (as shown in Figure 3b) obtained by

modifying the crystal structure of the 4-hydroxytamoxifen-ER-α

complex (PDB ID 3ert), and the total simulation time was 2 ns.

According to the RMSD during the course of simulations, the

whole system reached an equilibrium state at approximately 1

ns. The RMSD of ER-α ﬁnally stabilized at approximately 2.2 Å,

and the RMSD of Z-norendoxifen was approximately 0.3 Å

(Figure 6a). The distance proﬁles for the key interactions

between Z-norendoxifen and ER-α were also monitored (in

Figure 6c). The simulation results showed that the salt bridge

interaction with Asp 351 and the hydrogen bonds with Glu353

and Arg394 were well maintained during the whole simulation.

Although small ﬂuctuations were observed for the hydrogen

bond with the crystal water molecule, this hydrogen bond was

also present for more than 70% of the total molecular dynamics

simulation time. The low RMSD together with the stable

interaction distance proﬁles indicate that the binding mode of

Z-norendoxifen in the ligand binding site of ER-α is quite stable

and reliable.

a

Reagents and conditions: (a) Zn, TiCl₄, THF, 78%; (b)

ICH₂CONH₂, K₂CO₃, acetone, H₂O, 56%; (c) LiAlH₄, AlCl₃, THF,

2 h, 53%.

a

To investigate the eﬀect of Z-norendoxifen binding on the

repositioning of H-12, two diﬀerent RMSDs were calculated for

H-12 (residues 536−544, Figure 7a). The ﬁrst RMSD was

calculated by ﬁtting H-12 itself, which accounts for the

conformational change of H-12 itself. The second RMSD of

H-12 was calculated by ﬁtting residues 306−535 of ER-α. The

second RSMD accounts for the conformational change of H-12

plus the translocation and rotation of H-12 relative to the rest

of ER-α. According to the results, the RMSD of H-12 by ﬁtting

H-12 itself stayed at 1.0 Å, which indicates only small

conformational changes occurred on H-12. The RMSD of H-

12 obtained by ﬁtting the non-H-12 part of ER-α stayed at 1.5

Å, which is only 0.5 Å larger than that of H-12 itself. The small

diﬀerence between the two RMSDs indicates that H-12 remains

predominantly in the same position on the ER-α surface during

the whole simulation, and the translocation and rotation of H-

12 relative to the other parts of ER-α is very small. An averaged

structure of Z-norendoxifen-ER-α complex was obtained by

averaging 100 snapshots in the last 1 ns of the molecular

dynamics trajectory. The averaged structure was overlapped

with the crystal structure of 4-hydroxytamoxifen−ER-α

complex (PDB ID 3ert, in Figure 7b). The overlap clearly

shows that the H-12 of Z-norendoxifen-ER-α complex is

maintained in the same location as H-12 of the 4-

hydroxytamoxifen−ER-α complex. These results demonstrate

that Z-norendoxifen can stabilize H-12 in the same antagonistic

position as 4-hydroxytamoxifen. Therefore, according to the

molecular dynamics simulation, Z-norendoxifen is likely to

display a similar ER modulation eﬀect as 4-hydroxytamoxifen.

Antagonism of Transcriptional Activity. Neither aﬃnity for

the estrogen receptor nor the presence of a protonated amino

group at the end of the side chain capable of hydrogen bonding

to the Asp351 carboxylate of the estrogen receptor guarantee

any estrogenic or antiestrogenic pharmacological activity of the

Scheme 15. Synthesis of 65

a

Reagents and conditions: (a) LiAlH₄, AlCl₃, THF, 70%.

was found between H_dand H_c. These facts conﬁrmed the E

geometry of 63.

Molecular Dynamics Simulations. The transcriptional

activity of ER upon ligand binding depends on the speciﬁc

ER conformation the binding ligand can trigger, especially with

respect to the position of helix-12 (H-12, residues 536−

544).^22,32When 4-hydroxytamoxifen (the biologically active

form of tamoxifen) binds to ER-α, the dimethylaminoethoxy

side chain projects out and prevents the reorientation of H-12

that is required for coactivator recruitment, thereby locking ER-

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1

Figure 5. H−¹H COSY and NOE correlations used for the stereochemistry determination of compound Z-45, E-45, and 63.

ligand. Changes in the structure of the ligand can be expected

to inﬂuence the pharmacology, and the type of activity can also

be inﬂuenced by mutation of Asp351, as it has been

documented that the Asp351Tyr mutation converts raloxifene

from being an antiestrogen to being an estrogen³⁵and the

Asp351Gly mutation converts 4-hydroxytamoxifen from being

estrogenic to being antiestrogenic.³⁶It is therefore important to

investigate estrogen receptor ligands in functional assays that

monitor the eﬀects of ligand binding on mRNA levels. In the

present case, to assess the abilities of the norendoxifen

analogues to antagonize β-estradiol (E2) transcriptional activity

in MCF-7 cells, 18 of the analogues were tested at a

concentration of 1 μM in minimum essential media (MEM)

supplemented with 10% charcoal stripped fetal bovine serum

(FBS). The reason for choosing these 18 compounds is that

they have relatively high ER binding aﬃnities against ER-α or

ER-β or both. The progesterone receptor expression is

commonly used to assess estrogenic or antiestrogenic activity.³⁷

As shown in Figure 8, the presence of 10 nM E2 was able to

signiﬁcantly increase the mRNA expression of the progesterone

receptor (PGR) gene compared to the control, which

contained 0.1% methanol (vehicle) in the MEM supplemented

with 10% charcoal stripped FBS. The PGR mRNA expression

level with 10 nM E2 stimulation alone was considered as 100%

PGR mRNA expression. Endoxifen was used as a positive

control at a concentration of 1 μM, and it can antagonize the

PGR mRNA expression in the presence of 10 nM E2 to 10%

expression level compared to 10 nM E2 stimulation alone,

which is consistent with the published result.³⁷Among the 18

test compounds, norendoxifen, 10, 14a, 44, E-45, Z-45, 55b,

61a, and 61b were able to antagonize the PGR mRNA

expression level to 32%, 14%, 42%, 47%, 47%, 44%, 33%, 16%,

and 6%, respectively. All of the test compounds have shown

statistically signiﬁcant diﬀerences compared to the control

stimulated by E2 alone. The antiestrogenic eﬀects of the

compounds as monitored by reduction of estradiol-stimulated

mRNA levels correlate weakly with estrogen receptor aﬃnities.

For example, compounds 10 (14% mRNA level) and 61a (16%

mRNA level) both have relatively high aﬃnities for ER-α (15

and 27 nM EC₅₀values, respectively), but 61b (6% mRNA

level) actually reduced mRNA level more than any other

compound tested (Figure 8) but had low aﬃnity for ER-α

(1920 nM EC₅₀value). This may reﬂect the fact that aﬃnities

for the receptors do not necessarily translate directly into

biological eﬀects in functional assays such as antagonism of the

progesterone receptor expression.

CONCLUSION

■

A series of structurally related norendoxifen analogues were

designed by molecular modeling using a structure-based drug

design approach. These analogues were synthesized and

evaluated pharmacologically. Most of them displayed potent

aromatase inhibitory activity and also showed high estrogen

receptor binding aﬃnities. The structure−activity relationships

obtained were generally consistent with the molecular modeling

predictions. According to molecular dynamics simulations, Z-

norendoxifen can stabilize helix H-12 of ER-α in the same

antagonistic conformation as 4-hydroxytamoxifen, and Z-

norendoxifen is likely to display the same ER-α modulatory

activity as 4-hydroxytamoxifen. 4′-Hydroxynorendoxifen (10)

displayed elevated potency against aromatase, higher aﬃnity for

ER-α and ER-β, and was a more potent antagonist of estradiol-

stimulated progesterone receptor mRNA expression in MCF-7

cells when compared to norendoxifen. The aromatase

selectivity versus other cytochrome P450 enzymes for 4′-

hydroxynorendoxifen was also superior to norendoxifen. These

results suggested that the tamoxifen metabolite 4′-hydroxynor-

endoxifen is a promising candidate for further development

toward breast cancer treatment.

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Figure 6. (a) Mass-weighted RMSD of ER-α and Z-norendoxifen during simulations. (b) The interaction diagram of Z-norendoxifen in the ligand-

binding site of ER-α. (c) Time dependence of key interaction distances between Z-norendoxifen and ER-α during simulations.

percentages diﬀer less than 0.40% from the calculated values. For

purities estimated by HPLC, the major peak accounted for ≥95% of

EXPERIMENTAL SECTION

■

General. Melting points were determined using capillary tubes with

the combined total peak area when monitored by a UV detector at 254

a Mel-Temp apparatus and are uncorrected. The nuclear magnetic

nm. The HPLC analyses were performed on a Waters 1525 binary

resonance (¹H and ¹³C NMR) spectra were recorded using a Bruker

HPLC pump/Waters 2487 dual λ absorbance detector system using a

ARX300 spectrometer (300 MHz) with a QNP probe or a Bruker

5 μm C18 reversed phase column. Cytochrome P450 (CYP) inhibitor

screening kits for aromatase (CYP19) inhibition studies were

purchased from BD Biosciences (San Jose, CA). Estrogen receptor

α and β competitor assay kits were purchased from Invitrogen

(Carlsbad, CA).

DRX-2 spectrometer (500 MHz) with a BBO probe. High-resolution

mass spectra were recorded on a double-focusing sector mass

spectrometer with magnetic and electrostatic mass analyzers. The

purities of biologically tested compounds are ≥95% as determined by

HPLC or elemental analyses. For elemental analyses, the observed

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Figure 7. (a) Mass-weighted RMSD of helix-12 (H-12) during molecular dynamics simulations. (b) Overlap of the averaged structure of Z-

norendoxifen (cyan)−ER-α complex (H-12 colored in blue) with the crystal structure of 4-hydroxytamoxifen (pink)−ER-α complex (H-12 colored

in magenta).

General Procedure for the McMurry Cross-Coupling

Reaction. Zinc powder (653 mg, 10 mmol) was suspended in dry

THF (8 mL), and the mixture was cooled to 0 °C. Then, TiCl₄(0.55

mL, 5 mmol) was added dropwise under argon. When the addition

was complete, the mixture was warmed to room temperature and

heated to reﬂux for 2 h. After cooling down, a solution of the

corresponding benzophenone (1 mmol) and ketone (3 mmol) in dry

THF (8 mL) was added, and the mixture was heated at reﬂux in the

dark for 3 h. After being cooled to room temperature, THF was

evaporated. The residue was dissolved in saturated NH₄Cl aqueous

solution (20 mL) and extracted with ethyl acetate (20 mL × 4). The

organic layers were combined, dried over Na₂SO₄, concentrated in

vacuo, and further puriﬁed by silica gel column chromatography to

provide the McMurry cross-coupling product.

General Procedure for the Monoalkylation of Diphenol with

2-Iodoacetamide. A suspension of the corresponding diphenol (1

mmol) and K₂CO₃(415 mg, 3 mmol) in acetone (6 mL) was heated

to reﬂux for 10 min. Then a solution of 2-iodoacetamide (240 mg, 1.3

mmol) in acetone (6 mL) was added in small portions over 3 h and

the mixture was stirred at reﬂux for 1 h. After cooling down, the

solvent was evaporated and the residue was dissolved in saturated

NH₄Cl aqueous solution (30 mL) and extracted with ethyl acetate (30

mL × 4). The organic layers were combined, dried over Na₂SO₄,

concentrated in vacuo, and further puriﬁed by silica gel column

chromatography to provide the monoalkylated product.

General Procedure for the Amide Reduction with LiAlH₄. A

suspension of AlCl₃(400 mg, 3 mmol) and LiAlH₄(380 mg, 10

mmol) in dry THF (10 mL) was stirred under argon and cooled to 0

°C. A solution of the corresponding amide (1 mmol) in dry THF (10

mL) was added. The mixture was warmed to room temperature and

stirred under argon overnight. The reaction was quenched with H₂O

(1 mL), and the THF was evaporated. The residue was dissolved in

saturated NH₄Cl aqueous solution (25 mL) and extracted with ethyl

acetate (25 mL × 5). The organic layers were combined, dried over

Na₂SO₄, concentrated in vacuo, and further puriﬁed by silica gel

column chromatography to provide the reduction product.

2-(4-(4-Hydroxybenzoyl)phenoxy)acetamide (7). A suspen-

sion of 6 (1.00 g, 4.67 mmol) and Cs₂CO₃(4.04 g, 12.4 mmol) in

DMF (10 mL) was heated to 80 °C. A solution of 2-iodoacetamide

(970 mg, 5.24 mmol) in DMF (6 mL) was added in small portions

over 3 h, and the mixture was stirred at 80 °C overnight. After cooling

down, the solvent was evaporated and the residue was dissolved in

saturated NH₄Cl aqueous solution (45 mL) and extracted with ethyl

acetate (30 mL × 6). The organic layers were combined, dried over

Na₂SO₄, concentrated in vacuo, and further puriﬁed by silica gel

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C₂₄H₂₅NO₃·0.8MeOH: C, 74.26; H, 7.09; N, 3.49. Found: C, 74.15;

H, 6.93; N, 3.45.

4,4′-(2-(4-Fluorophenyl)but-1-ene-1,1-diyl)diphenol (12a).

The starting material 6 (1.11 g, 5.18 mmol) and 11a (2.24 g, 14.7

mmol) were reacted according to the general McMurry cross-coupling

reaction procedure, and the product was puriﬁed by silica gel column

chromatography (3:1 hexanes−ethyl acetate) to provide the product

1

12a as a white solid (1.67 g, 96%); mp 197−199 °C. H NMR (300

MHz, methanol-d₄and CDCl₃) δ 7.04−6.98 (m, 4 H), 6.82−6.73 (m,

4 H), 6.65−6.61 (m, 2 H), 6.45−6.41 (m, 2 H), 2.46−2.38 (m, 2 H),

0.86 (t, J = 7.3 Hz, 3 H). ¹³C NMR (75 MHz, methanol-d₄and

CDCl₃) δ 156.8, 155.9, 140.6, 140.1, 136.6, 136.2, 133.3, 132.6, 132.5,

131.9, 116.1, 116.0, 115.7, 115.5, 30.2, 14.7. EIMS m/z (relative

intensity) 334 (M⁺, 100). HREIMS m/z calcd for C₂₂H₁₉FO₂(M⁺)

334.1364, found 334.1366.

4,4′-(2-Ethylbut-1-ene-1,1-diyl)diphenol (12b).³⁸The starting

material 6 (1.05 g, 4.90 mmol) and pentan-3-one (11b, 1.28 g, 14.8

mmol) were reacted according to the general McMurry cross-coupling

reaction procedure, and the product was puriﬁed by silica gel column

chromatography (4:1 hexanes−ethyl acetate) to provide the product

12b as a white solid (1.19 g, 91%); mp 160−162 °C (lit.³⁸163 °C). ¹H

NMR (300 MHz, acetone-d₆) δ 6.94 (m, 4 H), 6.74 (m, 4 H), 2.12 (q,

J = 7.5 Hz, 4 H), 0.98 (t, J = 7.5 Hz, 6 H).

Figure 8. Abilities of norendoxifen analogues (1000 nM) to

antagonize progesterone receptor mRNA expression stimulated by

β-estradiol (10 nM) in MCF-7 cells.

2-(4-(2-(4-Fluorophenyl)-1-(4-hydroxyphenyl)but-1-en-1-yl)-

phenoxy)acetamide (13a). The diphenol 12a (870 mg, 2.60 mmol)

was reacted with 2-iodoacetamide according to the general

monoalkylation procedure for diphenols, and the product was puriﬁed

by silica gel column chromatography (1:2 hexanes−ethyl acetate) to

provide the product 13a as a white solid (410 mg, 40%); mp 160−162

°C. The NMR spectrum shows a nearly 1:1 mixture of E and Z

column chromatography (1:9 hexanes−ethyl acetate) to provide the

1

product 7 as white solid (462 mg, 37%); mp 203−206 °C. H NMR

(500 MHz, methanol-d₄and CDCl₃) δ 7.73−7.70 (m, 2 H), 7.65−7.63

(m, 2 H), 7.00−6.97 (m, 2 H), 6.84−6.82 (m, 2 H), 4.51 (s, 2 H). ¹³C

NMR (125 MHz, methanol-d₄and CDCl₃) δ 195.5, 171.4, 161.6,

160.3, 132.6, 132.1, 131.8, 128.8, 114.9, 114.0, 66.5. ESIMS m/z

(relative intensity) 294 (MNa⁺, 100). HRESIMS m/z calcd for

C₁₅H₁₄NO₄(MH⁺) 272.0923, found 272.0930.

1

isomers. H NMR (300 MHz, methanol-d₄and CDCl₃) δ 7.15−7.11

(m, 2 H), 7.06−6.98 (m, 6 H), 6.90−6.88 (m, 2 H), 6.83−6.75 (m, 8

H), 6.65−6.61 (m, 2 H), 6.58−6.55 (m, 2 H), 6.45−6.42 (m, 2 H),

4.46 (s, 2 H), 4.31 (s, 2 H), 2.45−2.39 (m, 4 H), 0.87 (t, J = 7.3 Hz, 6

H). ¹³C NMR (75 MHz, methanol-d₄and CDCl₃) δ 173.9, 164.1,

160.9, 157.5, 157.0, 156.7, 156.2, 141.5, 141.2, 139.8, 139.7, 138.9,

138.6, 136.1, 135.8, 133.4, 133.3, 132.6, 132.5, 132.0, 131.8, 116.2,

116.0, 115.7, 115.6, 114.9, 68.2, 68.0, 30.2, 14.6. Negative ion ESIMS

m/z (relative intensity) 390 [(M − H⁺)⁻, 100]. Negative ion

HRESIMS m/z calcd for C₂₄H₂₁FNO₃(M − H⁺)⁻390.1506, found

390.1519.

4 - ( 1 - ( 4 - ( 2 - A m i n o - 2 - o x o e t h o x y ) p h e n y l ) - 1 - ( 4 -

hydroxyphenyl)but-1-en-2-yl)phenyl Pivalate (9). Intermediate

7 (90 mg, 0.33 mmol) and 8 (221 mg, 0.943 mmol) were reacted

according to the general McMurry cross-coupling reaction procedure.

The product was further puriﬁed by silica gel column chromatography

(1:2 hexanes−ethyl acetate) to aﬀord the product 9 as a white solid

(85.5 mg, 55%); mp 189−192 °C. NMR shows a nearly 4.5:1 mixture

of E and Z isomers. The mixture isomerized to be a 1:1 mixtue of E

and Z isomers when dissolved in CDCl₃and kept at room temperature

overnight. ¹H NMR (300 MHz, methanol-d₄and CDCl₃) δ 7.15−7.12

(m, 2 H), 7.09−7.05 (m, 4 H), 7.02−6.99 (m, 2 H), 6.90−6.87 (m, 2

H), 6.83−6.74 (m, 8 H), 6.66−6.63 (m, 2 H), 6.58−6.55 (m, 2 H),

6.46−6.43 (m, 2 H), 4.46 (s, 2 H), 4.31 (s, 2 H), 2.47−2.41 (m, 4 H),

1.29 (s, 18 H), 0.91−0.86 (m, 6 H). ¹³C NMR (75 MHz, methanol-d₄

and CDCl₃) δ 179.1, 173.8, 157.4, 157.0, 156.6, 156.2, 150.4, 141.6,

141.5, 141.3, 139.7, 139.0, 138.6, 136.2, 135.8, 133.5, 133.3, 132.1,

132.0, 131.9, 122.1, 116.2, 115.6, 114.9, 68.2, 68.0, 40.3, 30.2, 28.2,

14.7. MALDIMS m/z (relative intensity) 473 (M⁺, 100). HRESIMS

m/z calcd for C₂₉H₃₂NO₅(MH⁺) 474.2281, found 474.2287.

2-(4-(2-Ethyl-1-(4-hydroxyphenyl)but-1-en-1-yl)phenoxy)-

acetamide (13b). The diphenol 12b (295 mg, 1.10 mmol) was

reacted with 2-iodoacetamide according to the general monoalkylation

procedure for diphenols, and the product was puriﬁed by silica gel

column chromatography (2:3 hexanes−ethyl acetate) to provide the

1

product 13b as a white solid (168 mg, 47%); mp 167−169 °C. H

NMR (300 MHz, methanol-d₄and CDCl₃) δ 7.04−7.01 (m, 2 H),

6.92−6.88 (m, 2 H), 6.83−6.79 (m, 2 H), 6.69−6.66 (m, 2 H), 4.41

(s, 2 H), 2.15−2.06 (m, 4 H), 0.98−0.92 (m, 6 H). ¹³C NMR (75

MHz, methanol-d₄and CDCl₃) δ 174.0, 156.9, 156.3, 143.0, 139.2,

137.5, 136.4, 131.8, 131.6, 116.0, 115.4, 68.2, 25.6, 14.4. Negative ion

ESIMS m/z (relative intensity) 324 [(M − H⁺)⁻, 100]. HRESIMS m/

z calcd for C₂₀H₂₃NO₃Na (MNa⁺) 348.1576, found 348.1562.

4-(1-(4-(2-Aminoethoxy)phenyl)-2-(4-ﬂuorophenyl)but-1-

en-1-yl)phenol (14a). The amide 13a (218 mg, 0.557 mmol) was

reacted with LiAlH₄according to the general procedure for amide

reduction with LiAlH₄, and the product was puriﬁed by silica gel

column chromatography (1:9 methanol−dichloromethane) to provide

the product 14a as a colorless oil (160 mg, 76%). The NMR spectrum

shows a 1:1 mixture of E and Z isomers. ¹H NMR (300 MHz,

methanol-d₄) δ 7.11−6.99 (m, 8 H), 6.91−6.73 (m, 10 H), 6.67−6.63

(m, 2 H), 6.57−6.54 (m, 2 H), 6.45−6.42 (m, 2 H), 3.98 (t, J = 5.1

Hz, 2 H), 3.82 (t, J = 5.1 Hz, 2 H), 2.98 (t, J = 5.1 Hz, 2 H), 2.88 (t, J

= 5.1 Hz, 2 H), 2.47−2.40 (m, 4 H), 0.89 (t, J = 7.3 Hz, 6 H). ¹³C

NMR (75 MHz, methanol-d₄) δ 164.2, 160.9, 159.1, 158.3, 157.6,

156.7, 140.9, 140.7, 140.2, 137.7, 137.4, 136.0, 135.7, 133.1, 132.7,

132.6, 131.6, 116.0, 115.8, 115.5, 115.4, 115.2, 114.5, 70.3, 70.0, 41.9,

41.8, 29.9, 14.1. ESIMS m/z (relative intensity) 378 (MH⁺, 100).

HRESIMS m/z calcd for C₂₄H₂₅FNO₂(MH⁺) 378.1870, found

4,4′-(1-(4-(2-Aminoethoxy)phenyl)but-1-ene-1,2-diyl)-

diphenol (10). The amide 9 (84.0 mg, 0.177 mmol) was reacted with

LiAlH₄according the general procedure for amide reduction with

LiAlH₄, and the product was further puriﬁed by silica gel column

chromatography (9:1 dichloromethane−methanol) to provide the

product 10 as a pale-yellow oil (46.6 mg, 70%). The NMR spectrum

shows a 1:1 mixture of E and Z isomers. ¹H NMR (300 MHz,

methanol-d₄) δ 7.07 (m, 2 H), 6.97 (m, 2 H), 6.90−6.86 (m, 6 H),

6.75−6.72 (m, 4 H), 6.64 (m, 2 H), 6.58−6.54 (m, 6 H), 6.41 (m, 2

H), 3.98 (t, J = 5.3 Hz, 2 H), 3.84 (t, J = 5.3 Hz, 2 H), 2.99 (t, J = 5.3

Hz, 2 H), 2.90 (t, J = 5.3 Hz, 2 H), 2.40 (m, 4 H), 0.88 (m, 6 H). ¹³C

NMR (75 MHz, methanol-d₄) δ 158.8, 157.9, 157.2, 156.6, 156.2,

141.9, 141.6, 138.9, 138.4, 138.1, 136.7, 136.4, 135.0, 133.1, 132.0,

131.7, 115.9, 115.7, 115.2, 114.4, 69.5, 69.2, 41.6, 41.5, 29.8, 14.1.

EIMS m/z (relative intensity) 375 (M⁺, 100). HRESIMS m/z calcd for

C₂₄H₂₆NO₃(MH⁺) 376.1913, found 376.1897. Anal. Calcd for

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378.1867. Anal. Calcd for C₂₄H₂₄FNO₂: C, 76.37; H, 6.41; N, 3.71.

Found: C, 76.04; H, 6.54; N, 3.70.

from hexanes (44 mL)−chloroform (22 mL) to provide the product

1

21 as gray needless (1.55 g, 55%); mp 120−122 °C. H NMR (300

4-(1-(4-(2-Aminoethoxy)phenyl)-2-ethylbut-1-en-1-yl)-

phenol (14b). The amide 13b (70 mg, 0.200 mmol) was reacted with

LiAlH₄according to the general procedure of amide reduction with

LiAlH₄, and the product was puriﬁed by silica gel column

chromatography (1:9 methanol−dichloromethane) to provide the

MHz, CDCl₃) δ 8.34−8.31 (m, 2 H), 7.90−7.86 (m, 2 H), 7.82−7.79

(m, 2 H), 7.01−6.97 (m, 2 H), 3.91 (s, 3 H).

(4-Hydroxyphenyl)(4-nitrophenyl)methanone (22).⁴¹A sol-

ution of 21 (1.44 g, 5.60 mmol) in HBr (48% v/v, 15 mL) and glacial

acetic acid (15 mL) was heated at reﬂux for 9 h. After cooling down,

solvent was carefully removed in vacuo. The residue was dissolved in

water (50 mL) and extracted with ethyl acetate (50 mL × 4). The

organic layers were combined and dried over Na₂SO₄. Evaporation of

the solvent provided the product 22 as a yellow solid (1.28 g, 94%);

mp 194−197 °C (lit.⁴¹198−200 °C). ¹H NMR (300 MHz, methanol-

d₄and CDCl₃) δ 8.32−8.29 (m, 2 H), 7.85−7.82 (m, 2 H), 7.71−7.67

(m, 2 H), 6.89−6.85 (m, 2 H).

1

product 14b as a white solid (27.4 mg, 44%); mp 138−140 °C. H

NMR (300 MHz, methanol-d₄) δ 7.00 (m, 2 H), 6.90 (m, 2 H), 6.83

(m, 2 H), 6.67 (m, 2 H), 3.97 (t, J = 5.2 Hz, 2 H), 2.97 (t, J = 5.2 Hz, 2

H), 2.13 (m, 4 H), 0.99 (m, 6 H). ¹³C NMR (75 MHz, methanol-d₄) δ

158.6, 156.7, 142.2, 138.2, 138.0, 136.3, 131.3, 115.7, 115.0, 70.1, 41.8,

25.4, 13.7. ESIMS m/z (relative intensity) 312 (MH⁺, 100). HRESIMS

m/z calcd for C₂₀H₂₆NO₂(MH⁺) 312.1964, found 312.1963. Anal.

Calcd for C₂₀H₂₅NO₂·0.5MeOH: C, 75.20; H, 8.31; N, 4.28. Found:

C, 75.02; H, 8.28; N, 4.23.

(4-(2-Bromoethoxy)phenyl)(4-nitrophenyl)methanone (23).

A suspension of 22 (693 mg, 2.85 mmol) and K₂CO₃(1.53 g, 11.0

mmol) in dibromomethane (5 mL), water (1 mL), and acetone (6

mL) was heated at reﬂux for 4 h. After cooling down, the solvent was

evaporated and the residue was dissolved in water (40 mL) and

extracted with ethyl acetate (40 mL × 3). The organic layers were

combined, dried over Na₂SO₄, concentrated in vacuo, and further

puriﬁed by silica gel column chromatography (80:20 hexanes−ethyl

acetate) to provide the product 23 as a white solid (681 mg, 68%); mp

4-(1,2-Diphenylbut-1-en-1-yl)phenol (16).³⁹The starting ma-

terial 15 (1.01 g, 5.10 mmol) and propiophenone (2.16 g, 16.1 mmol)

were reacted according to the general McMurry cross-coupling

reaction procedure, and the product was puriﬁed by silica gel column

chromatography (85:15 hexanes−ethyl acetate) to provide the product

16 as a yellow oil (1.54 g, 98%). The NMR spectrum shows a 5:1

mixture of E and Z isomers. The mixture quickly isomerized to be a

1:1 mixture of E and Z isomers when dissolved in CDCl₃and kept at

1

132−134 °C. H NMR (300 MHz, CDCl₃) δ 8.35−8.31 (m, 2 H),

1

room temperature overnight. H NMR (300 MHz, CDCl₃) δ 7.37−

7.90−7.86 (m, 2 H), 7.84−7.79 (m, 2 H), 7.03−6.98 (m, 2 H), 4.39 (t,

J = 6.2 Hz, 2 H), 3.68 (t, J = 6.2 Hz, 2 H). ¹³C NMR (75 MHz,

CDCl₃) δ 193.4, 162.4, 149.5, 143.5, 132.7, 130.3, 129.5, 123.5, 114.5,

67.9, 28.5. EIMS m/z (relative intensity) 349 (M⁺, 74), 109 (100).

HREIMS m/z calcd for C₁₅H₁₂NO₄Br (M⁺) 348.9944, found

348.9937.

7.33 (m, 2 H), 7.27−7.24 (m, 4 H), 7.19−7.09 (m, 12 H), 7.02−6.99

(m, 2 H), 6.90−6.87 (m, 2 H), 6.83−6.80 (m, 2 H), 6.76−6.73 (m, 2

H), 6.49−6.46 (m, 2 H), 2.53−2.46 (m, 4 H), 0.98−0.91 (m, 6 H).

2-(4-(1,2-Diphenylbut-1-en-1-yl)phenoxy)acetamide (17). A

mixture of 16 (935 mg, 3.11 mmol), 2-iodoacetamide (1.21 g, 6.54

mmol), and K₂CO₃(1.92 g, 13.9 mmol) was dissolved in acetone (16

mL). The suspension was heated at reﬂux and stirred for 4 h. After

cooling down, the acetone was carefully evaporated and the residue

was dissolved in water (30 mL) and extracted with ethyl acetate (30

mL × 4). The organic layers were combined, dried over Na₂SO₄,

concentrated in vacuo, and further puriﬁed by silica gel column

chromatography (45:55 hexanes−ethyl acetate) to provide the product

17 as a white solid (815 mg, 73%); mp 131−134 °C. The NMR

4-(1-(4-(2-Bromoethoxy)phenyl)-2-phenylbut-1-en-1-yl)-

aniline (24a). The benzophenone 23 (410 mg, 1.17 mmol) and

propiophenone (590 mg, 4.40 mmol) were reacted according to the

general McMurry cross-coupling reaction procedure, and the product

was puriﬁed by silica gel column chromatography (3:1 hexanes−ethyl

acetate) to aﬀord the product 24a as a brown glass (260 mg, 53%).

The NMR spectrum shows a nearly 3:1 mixture of E and Z isomers.

¹H NMR (300 MHz, CDCl₃) δ 7.20−7.08 (m, 8.9 H), 7.04−7.01 (m,

0.7 H, isomer 1), 6.91−6.86 (m, 2 H, isomer 2), 6.80−6.77 (m, 0.7 H,

isomer 1), 6.71−6.68 (m, 0.7 H, isomer 1), 6.65−6.62 (m, 2 H, isomer

2), 6.56−6.52 (m, 0.7 H, isomer 1), 6.38−6.34 (m, 2 H, isomer 2),

4.31 (t, J = 6.2 Hz, 2 H, isomer 2), 4.15 (t, J = 6.2 Hz, 0.7 H, isomer

1), 3.68 (t, J = 6.2 Hz, 2 H, isomer 2), 3.55 (t, J = 6.2 Hz, 0.7 H,

isomer 1), 2.52−2.42 (m, 2.7 H), 0.95−0.89 (m, 4.2 H). EIMS m/z

(relative intensity) 421 (M⁺, 100). HRESIMS m/z calcd for

C₂₄H₂₅NOBr (MH⁺) 422.1119, found 422.1124.

4-(1-(4-Aminophenyl)-1-(4-(2-bromoethoxy)phenyl)but-1-

en-2-yl)phenyl Pivalate (24b). The benzophenone 23 (250 mg,

0.714 mmol) and 8 (523 mg, 2.23 mmol) were reacted according to

the general McMurry cross-coupling reaction procedure, and the

product was puriﬁed by silica gel column chromatography (3:1

hexanes−ethyl acetate) to aﬀord the product 24b as a brown oil (207

mg, 55%). NMR shows a nearly 2.5:1 mixture of E and Z isomers. ¹H

NMR (300 MHz, CDCl₃) δ 7.18−7.09 (m, 5 H), 7.04−7.01 (m, 0.8

H, isomer 1), 6.90−6.86 (m, 5 H), 6.81−6.78 (m, 0.8 H, isomer 1),

6.73−6.70 (m, 0.8 H, isomer 1), 6.68−6.65 (m, 2 H, isomer 2), 6.59−

6.56 (m, 0.8 H, isomer 1), 6.43−6.40 (m, 2 H, isomer 2), 4.31 (t, J =

6.2 Hz, 2 H, isomer 2), 4.16 (t, J = 6.2 Hz, 0.8 H, isomer 1), 3.66 (t, J

= 6.2 Hz, 2 H, isomer 2), 3.55 (t, J = 6.2 Hz, 0.8 H, isomer 1), 2.51−

2.42 (m, 2.8 H), 1.35 (s, 12.6 H), 0.96−0.91 (m, 4.2 H). ¹³C NMR

(75 MHz, CDCl₃) δ 177.1, 156.7, 149.0, 142.9, 140.0, 139.6, 138.2,

137.1, 134.2, 132.1, 131.9, 130.7, 130.5, 120.8, 115.4, 114.9, 114.2,

113.5, 67.8, 67.5, 39.0, 29.7, 29.3, 29.0, 27.1, 13.7. ESIMS m/z (relative

intensity) 522 (MH⁺, 100). HRESIMS m/z calcd for C₂₉H₃₂BrNO₃

(MH⁺) 522.1644, found 522.1647.

1

spectrum shows a 1:1 mixture of E and Z isomers. H NMR (300

MHz, CDCl₃) δ 7.38−7.33 (m, 2 H), 7.25−7.10 (m, 16 H), 7.02−6.99

(m, 2 H), 6.92−6.81 (m, 6 H), 6.58−6.55 (m, 2 H), 4.52 (s, 2 H), 4.36

(s, 2 H), 2.51−2.43 (m, 4 H), 0.97−0.90 (m, 6 H). ¹³C NMR (75

MHz, CDCl₃) δ 171.1, 155.8, 155.0, 143.5, 143.0, 142.3, 142.2, 142.1,

142.0, 137.9, 137.8, 137.5, 137.0, 132.1, 130.9, 130.7, 129.6, 129.4,

128.2, 127.9, 127.8, 127.3, 126.6, 126.1, 125.8, 114.3, 113.5, 67.1, 66.9,

29.0, 13.5. ESIMS m/z (relative intensity) 380 (MNa⁺, 100).

HRESIMS m/z calcd for C₂₄H₂₃NO₂Na (MNa⁺) 380.1627, found

380.1624.

2-(4-(1,2-Diphenylbut-1-en-1-yl)phenoxy)ethan-1-amine

(18).⁴⁰The amide 17 (540 mg, 1.51 mmol) was reacted with LiAlH₄

according to the general procedure of amide reduction with LiAlH₄,

and the product was puriﬁed by silica gel column chromatography (1:9

methanol−dichloromethane) to provide the product 18 as a pale-

yellow oil (328 mg, 63%). The NMR spectrum shows a 1:1 mixture of

E and Z isomers. ¹H NMR (300 MHz, methanol-d₄) δ 7.33−7.30 (m,

2 H), 7.27−7.18 (m, 4 H), 7.14−7.05 (m, 12 H), 6.96−6.91 (m, 4 H),

6.85−6.83 (m, 2 H), 6.77−6.74 (m, 2 H), 6.58−6.55 (m, 2 H), 4.02 (t,

J = 5.3 Hz, 2 H), 3.85 (t, J = 5.3 Hz, 2 H), 3.00 (t, J = 5.3 Hz, 2 H),

2.90 (t, J = 5.3 Hz, 2 H), 2.50−2.40 (m, 4 H), 0.93−0.86 (m, 6 H).

Anal. Calcd for C₂₄H₂₅NO: C, 83.93; H, 7.34; N, 4.08. Found: C,

83.53; H, 7.41; N, 3.98.

(4-Methoxyphenyl)(4-nitrophenyl)methanone (21).²⁶A sol-

ution of 19 (2.04 g, 11.0 mmol) and 20 (6 mL, 32.9 mmol) in dry

dichloromethane (12 mL) was stirred in an ice bath. Aluminum

chloride (1.50 g, 11.2 mmol) was added. The mixture was kept at 0 °C

for 1 h and then warmed to room temperature and stirred overnight.

The reaction mixture was poured into ice−water (40 mL), stirred for

15 min, and extracted with dichloromethane (40 mL × 3). The organic

layers were combined and dried over Na₂SO₄. Solvent was evaporated,

and the residue was washed with hexanes (30 mL) and recrystallized

4-(1-(4-(2-Aminoethoxy)phenyl)-2-phenylbut-1-en-1-yl)-

aniline (25a). A mixture of 24a (177 mg, 0.419 mmol) and NaI (244

mg, 1.62 mmol) was dissolved with DMF (10 mL), and then

ammonium hydroxide aqueous solution (30%, 8 mL) was added. The

solution was heated to 65 °C and stirred in a sealed tube for 24 h.

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After cooling down, the mixture was diluted with distilled water (30

mL) and extracted with ethyl acetate (40 mL × 4). The organic layers

were combined, dried over Na₂SO₄, concentrated in vacuo, and further

puriﬁed by silica gel column chromatography (9:1 dichloromethane−

methanol) to provide the product 25a as a colorless oil (77.4 mg,

52%). The NMR spectrum shows a 2.5:1 mixture of E and Z isomers.

¹H NMR (300 MHz, methanol-d₄) δ 7.14−7.02 (m, 9 H), 6.95−6.89

(m, 2.8 H), 6.77−6.74 (m, 0.8 H, isomer 1), 6.71−6.68 (m, 0.8 H,

isomer 1), 6.60−6.52 (m, 2.8 H), 6.36−6.32 (m, 2 H, isomer 2), 4.00

(t, J = 5.2 Hz, 2 H, isomer 2), 3.82 (t, J = 5.2 Hz, 0.8 H, isomer 1),

2.99 (t, J = 5.2 Hz, 2 H, isomer 2), 2.89 (t, J = 5.2 Hz, 0.8 H, isomer

1), 2.53−2.41 (m, 2.8 H), 0.92−0.86 (m, 4.2 H). ESIMS m/z (relative

intensity) 359 (MH⁺, 100). HRESIMS m/z calcd for C₂₄H₂₇N₂O

(MH⁺) 359.2123, found 359.2116. Anal. Calcd for C₂₄H₂₆N₂O·

0.6MeOH: C, 78.23; H, 7.58; N, 7.42. Found: C, 78.24; H, 7.39; N,

7.39.

4-(1-(4-(2-Aminoethoxy)phenyl)-1-(4-aminophenyl)but-1-

en-2-yl)phenol (25b). A mixture of 24b (181 mg, 0.346 mmol) and

NaI (281 mg, 1.87 mmol) was dissolved with THF (5 mL), and then

ammonium hydroxide aqueous solution (30%, 8 mL) was added. The

solution was heated to 100 °C and stirred in a sealed tube for 24 h.

After cooling down, THF was evaporated and the aqueous solution

was extracted with ethyl acetate (20 mL × 4). The organic layers were

combined, dried over Na₂SO₄, concentrated in vacuo, and further

puriﬁed by silica gel column chromatography (9:1 dichloromethane−

methanol) to provide the product 25b as a yellow glass (72.9 mg,

56%). The NMR spectrum shows a 1:1 mixture of E and Z isomers.

¹H NMR (300 MHz, methanol-d₄) δ 7.10−7.07 (m, 2 H), 6.93−6.86

(m, 2 H), 1.34−1.27 (m, 2 H), 0.79 (t, J = 7.3 Hz, 3 H). ¹³C NMR (75

MHz, methanol-d₄) δ 157.1, 156.3, 144.5, 140.3, 136.6, 136.2, 133.1,

131.7, 130.8, 128.8, 126.8, 115.8, 115.1, 39.0, 23.2, 14.6.

4,4′-(3-Methyl-2-phenylbut-1-ene-1,1-diyl)diphenol (27d).⁴³

The starting material 6 (1.12 g, 5.22 mmol) and 26d (2.30 g, 15.52

mmol) were reacted according to the general McMurry cross-coupling

reaction procedure, and the product was further puriﬁed by silica gel

column chromatography (2:1 hexanes−ethyl acetate) to aﬀord the

product 27d as a white solid (1.63 g, 95%); mp 136−139 °C (lit.⁴³138

°C). ¹H NMR (500 MHz, methanol-d₄and CDCl₃) δ 7.10−7.07 (m, 2

H), 7.04−6.99 (m, 5 H), 6.76−6.73 (m, 2 H), 6.67−6.64 (m, 2 H),

6.36−6.33 (m, 2 H), 3.00−2.96 (m, 1 H), 0.87 (s, 3 H), 0.86 (s, 3 H).

¹³C NMR (125 MHz, methanol-d₄and CDCl₃) δ 154.9, 153.9, 144.7,

140.0, 138.1, 134.8, 134.7, 131.0, 130.7, 130.2, 126.8, 125.4, 114.7,

113.7, 31.4, 21.4.

4,4′-(2,2-Diphenylethene-1,1-diyl)diphenol (27e).⁴⁴The

starting material 6 (0.99 g, 4.6 mmol) and 26e (2.40 g, 13.2 mmol)

were reacted according the general McMurry cross-coupling reaction

procedure, and the product was puriﬁed by silica gel column

chromatography (9:1 hexanes−ethyl acetate) to provide the product

27e as a white solid (1.1 g, 65%); mp 220−222 °C (lit.⁴⁴222.9−223.7

1

°C). H NMR (300 MHz, acetone-d₆) δ 7.10−7.05 (m, 6 H), 7.01−

6.98 (m, 4 H), 6.84−6.81 (m, 4 H), 6.58−6.54 (m, 4 H). ¹³C NMR

(75 MHz acetone-d₆) δ 156.6, 145.3, 141.6, 139.1, 135.8, 133.1, 131.8,

128.2, 126.5, 115.1.

2-(4-(1-(4-Hydroxyphenyl)-2-phenylprop-1-en-1-yl)-

phenoxy)acetamide (28a). The diphenol 27a (200 mg, 0.66 mmol)

was reacted with 2-iodoacetamide according the general mono-

alkylation procedure for diphenols, and the product was puriﬁed by

silica gel column chromatography (1:2 hexanes−ethyl acetate) to

provide the product 28a as a white solid (93.2 mg, 39%); mp 137−140

(m, 8 H), 6.77−6.74 (m, 2 H), 6.70−6.66 (m, 2 H), 6.60−6.54 (m, 8

H), 6.39−6.36 (m, 2 H), 4.00 (t, J = 5.1 Hz, 2 H), 3.86 (t, J = 5.1 Hz, 2

H), 3.01 (t, J = 5.1 Hz, 2 H), 2.93 (t, J = 5.1 Hz, 2 H), 2.48−2.36 (m, 4

H), 0.91−0.86 (m, 6 H). ¹³C NMR (75 MHz, methanol-d₄) δ 158.8,

157.9, 156.6, 147.1, 146.0, 141.5, 141.1, 139.0, 138.5, 138.2, 135.5,

135.1, 133.2, 132.8, 132.0, 131.7, 131.3, 116.3, 115.7, 115.1, 114.3,

69.8, 69.5, 41.7, 41.6, 30.8, 14.2. ESIMS m/z (relative intensity) 375

(MH⁺, 100). HRESIMS m/z calcd for C₂₄H₂₇N₂O₂(MH⁺) 375.2072,

found 375.2070. HPLC purity 96.7% (C-18 reverse phase, MeOH−

H₂O, 90:10).

1

°C. The NMR spectrum shows a 1:1 mixture of E and Z isomers. H

NMR (300 MHz, methanol-d₄and CDCl₃) δ 7.15−6.99 (m, 14 H),

6.88−6.85 (m, 2 H), 6.79−6.74 (m, 4 H), 6.65−6.62 (m, 2 H), 6.55−

6.52 (m, 2 H), 6.45−6.42 (m, 2 H), 4.45 (s, 2 H), 4.30 (s, 2 H), 2.08

(s, 3 H), 2.05 (s, 3 H). ¹³C NMR (75 MHz, methanol-d₄and CDCl₃)

δ 173.7, 157.2, 156.8, 156.5, 145.8, 139.6, 139.2, 138.9, 136.3, 136.0,

135.7, 133.6, 133.4, 132.8, 132.6, 130.6, 129.2, 127.3, 116.2, 115.6,

115.5, 114.8, 68.2, 68.0, 24.6, 24.5. EIMS m/z (relative intensity) 359

(M⁺, 100). HRESIMS m/z calcd for C₂₃H₂₁NO₃Na (MNa⁺) 382.1419,

found 382.1430.

4,4′-(2-Phenylprop-1-ene-1,1-diyl)diphenol (27a).⁴²The

starting material 6 (1.35 g, 6.30 mmol) and acetophenone (26a,

2.14 g, 17.8 mmol) were reacted according to the general McMurry

cross-coupling reaction procedure, and the product was puriﬁed by

silica gel column chromatography (2:1 hexanes−ethyl acetate) to

provide the product 27a as a white solid (1.74 g, 91%); mp 227−229

2-(4-(4-Chloro-1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)-

phenoxy)acetamide (28b). The diphenol 27b (710 mg, 2.02 mmol)

was reacted with 2-iodoacetamide according the general mono-

alkylation procedure of diphenols, and the product was puriﬁed by

silica gel column chromatography (1:2 hexanes−ethyl acetate) to

provide the product 28b as a yellow glass (280 mg, 34%). The NMR

°C (lit.⁴²135 °C). H NMR (500 MHz, methanol-d₄and CDCl₃) δ

1

7.07−7.06 (m, 4 H), 7.01−6.99 (m, 3 H), 6.74−6.72 (m, 2 H), 6.65−

6.63 (m, 2 H), 6.42−6.40 (m, 2 H), 2.05 (s, 3 H). ¹³C NMR (125

MHz, methanol-d₄and CDCl₃) δ 155.1, 154.4, 144.6, 138.6, 135.3,

135.0, 133.4, 131.9, 131.1, 129.1, 127.6, 125.5, 114.5, 113.9, 23.0.

4,4′-(4-Chloro-2-phenylbut-1-ene-1,1-diyl)diphenol (27b).

The starting material 6 (1.05 g, 4.9 mmol) and 26b (2.36 g, 14.0

mmol) were reacted according the general McMurry cross-coupling

reaction procedure, and the product was puriﬁed by silica gel column

chromatography (2:1 hexanes−ethyl acetate) to aﬀord the product

27b as a yellow glass (1.66 g, 96%). ¹H NMR (300 MHz, methanol-d₄

and CDCl₃) δ 7.13−7.06 (m, 7 H), 6.79−6.76 (m, 2 H), 6.68−6.64

(m, 2 H), 6.43−6.40 (m, 2 H), 3.37 (t, J = 7.5 Hz, 2 H), 2.90 (t, J =

7.5 Hz, 2 H). ¹³C NMR (75 MHz, methanol-d₄and CDCl₃) δ 157.1,

156.2, 143.2, 142.9, 135.9, 135.7, 135.6, 133.2, 131.9, 130.9, 129.4,

127.5, 116.3, 115.5, 44.2, 40.0. EIMS m/z (relative intensity) 350 (M⁺,

100). HREIMS m/z calcd for C₂₂H₁₉O₂Cl (M⁺) 350.1068, found

350.1056.

1

spectrum shows a 1:1 mixture of E and Z isomers. H NMR (300

MHz, methanol-d₄and CDCl₃) δ 7.22−7.19 (m, 2 H), 7.13−7.05 (m,

12 H), 6.91−6.88 (m, 2 H), 6.79−6.76 (m, 4 H), 6.65−6.62 (m, 2 H),

6.55−6.52 (m, 2 H), 6.44−6.40 (m, 2 H), 4.46 (s, 2 H), 4.29 (s, 2 H),

3.38−3.34 (m, 4 H), 2.92−2.86 (m, 4 H). ¹³C NMR (75 MHz,

methanol-d₄and CDCl₃) δ 173.6, 157.5, 142.6, 138.3, 138.2, 136.2,

135.4, 135.3, 133.3, 133.1, 132.2, 131.9, 130.9, 129.5, 127.8, 116.4,

115.8, 115.6, 114.9, 68.2, 68.0, 44.2, 39.9. ESIMS m/z (relative

intensity) 430 (MNa⁺, 66), 339 (100). HRESIMS m/z calcd for

C₂₄H₂₂NO₃ClNa (MNa⁺) 430.1186, found 430.1180.

2-(4-(1-(4-Hydroxyphenyl)-2-phenylpent-1-en-1-yl)-

phenoxy)acetamide (28c). The diphenol 27c (940 mg, 2.84 mmol)

was reacted with 2-iodoacetamide according to the general

monoalkylation procedure of diphenols, and the product was puriﬁed

by silica gel column chromatography (1:2 hexanes−ethyl acetate) to

provide the product 28c as a colorless glass (432 mg, 39%). The NMR

4,4′-(2-Phenylpent-1-ene-1,1-diyl)diphenol (27c).⁴²The start-

ing material 6 (1.19 g, 5.55 mmol) and 26c (2.57 g, 17.3 mmol) were

reacted according the general McMurry cross-coupling reaction

procedure, and the product was puriﬁed by silica gel column

chromatography (2:1 hexanes−ethyl acetate) to aﬀord the product

27c as a white solid (1.70 g, 93%); mp 194−196 °C (lit.⁴²142−145

°C). ¹H NMR (300 MHz, methanol-d₄) δ 7.14−6.99 (m, 7 H), 6.78−

6.74 (m, 2 H), 6.67−6.63 (m, 2 H), 6.42−6.38 (m, 2 H), 2.43−2.38

1

spectrum shows a 1:1 mixture of E and Z isomers. H NMR (300

MHz, methanol-d₄and CDCl₃) δ 7.15−6.99 (m, 14 H), 6.92−6.88

(m, 2 H), 6.79−6.74 (m, 4 H), 6.65−6.62 (m, 2 H), 6.56−6.53 (m, 2

H), 6.42−6.39 (m, 2 H), 4.47 (s, 2 H), 4.30 (s, 2 H), 2.41−2.32 (m, 4

H), 1.32−1.22 (m, 4 H), 0.79−0.73 (m, 6 H). ¹³C NMR (75 MHz,

methanol-d₄and CDCl₃) δ 176.4, 159.9, 159.4, 159.0, 158.5, 146.7,

143.9, 143.5, 142.0, 141.6, 141.3, 138.8, 138.5, 135.9, 135.7, 134.6,

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134.4, 133.4, 131.5, 129.6, 118.6, 118.0, 117.9, 117.2, 70.6, 70.4, 41.7,

25.8, 17.6. CIMS m/z (relative intensity) 388 (MH⁺, 100). HRESIMS

m/z calcd for C₂₅H₂₅NO₃Na (MNa⁺) 410.1732, found 410.1733.

2-(4-(1-(4-Hydroxyphenyl)-3-methyl-2-phenylbut-1-enyl)-

phenoxy)acetamide (28d). The diphenol 27d (865 mg, 2.62 mmol)

was reacted with 2-iodoacetamide according to the general

monoalkylation procedure of diphenols, and the product was puriﬁed

by silica gel column chromatography (1:2 hexanes−ethyl acetate) to

provide the product 28d as a white solid (341 mg, 34%); mp 205−206

LiAlH₄according the general procedure of amide reduction with

LiAlH₄, and the product was puriﬁed by silica gel column

chromatography (1:9 methanol−dichloromethane) to provide the

product 29c as a white solid (238 mg, 78%); mp 100−105 °C. The

1

NMR spectrum shows a 1:1 mixture of E and Z isomers. H NMR

(500 MHz, methanol-d₄and CDCl₃) δ 7.10−6.98 (m, 14 H), 6.85−

6.82 (m, 2 H), 6.75−6.71 (m, 4 H), 6.64−6.61 (m, 2 H), 6.49−6.47

(m, 2 H), 6.41−6.39 (m, 2 H), 3.98 (t, J = 5.1 Hz, 2 H), 3.82 (t, J =

5.1 Hz, 2 H), 3.01 (t, J = 5.1 Hz, 2 H), 2.91 (t, J = 5.1 Hz, 2 H), 2.38−

2.32 (m, 4 H), 1.29−1.24 (m, 4 H), 0.76−0.74 (m, 6 H). ¹³C NMR

(125 MHz, methanol-d₄and CDCl₃) δ 157.1, 156.2, 155.3, 154.4,

142.9, 142.8, 139.6, 139.3, 138.2, 136.7, 136.3, 135.0, 134.7, 131.8,

130.5, 129.4, 127.5, 125.6, 114.6, 113.9, 113.7, 113.0, 109.9, 68.6, 68.3,

40.6, 40.4, 37.7, 21.9, 13.8. ESIMS m/z (relative intensity) 374 (MH⁺,

100). HRESIMS m/z calcd for C₂₅H₂₈NO₂(MH⁺) 374.2120, found

374.2121. Anal. Calcd for C₂₅H₂₇NO₂·0.4MeOH: C, 78.97; H, 7.46;

N, 3.63. Found: C, 78.73; H, 7.12; N, 3.77.

4-(1-(4-(2-Aminoethoxy)phenyl)-3-methyl-2-phenylbut-1-

enyl)phenol (29d). The amide 28d (206 mg, 0.532 mmol) was

reacted with LiAlH₄according the general procedure of amide

reduction with LiAlH₄, and the product was puriﬁed by silica gel

column chromatography (1:9 methanol−dichloromethane) to provide

the product 29d as a colorless oil (163 mg, 82%). The NMR spectrum

shows a 1:1 mixture of E and Z isomers. ¹H NMR (500 MHz,

methanol-d₄and CDCl₃) δ 7.15−7.01 (m, 14 H), 6.86−6.83 (m, 2 H),

6.79−6.74 (m, 4 H), 6.69−6.66 (m, 2 H), 6.45−6.43 (m, 2 H), 6.39−

6.36 (m, 2 H), 3.93 (t, J = 5.1 Hz, 2 H), 3.72 (t, J = 5.1 Hz, 2 H),

3.05−2.95 (m, 2 H), 2.96 (t, J = 5.1 Hz, 2 H), 2.82 (t, J = 5.1 Hz, 2 H),

0.90−0.86 (m, 12 H). ¹³C NMR (125 MHz, methanol-d₄and CDCl₃)

δ 157.0, 156.0, 155.2, 154.2, 145.2, 145.0, 139.8, 137.9, 137.8, 136.1,

136.0, 134.5, 134.4, 131.0, 130.7, 130.2, 126.9, 125.5, 114.8, 113.9,

113.8, 112.9, 68.9, 68.6, 40.7, 40.5, 31.5, 31.4, 21.5. APCIMS m/z

(relative intensity) 374 (MH⁺, 100). HRESIMS m/z calcd for

C₂₅H₂₈NO₂(MH⁺) 374.2120, found 374.2120. Anal. Calcd for

C₂₅H₂₇NO₂·0.1MeOH: C, 80.03; H, 7.33; N, 3.72. Found: C, 79.97;

H, 7.00; N, 3.81.

1

°C. The NMR spectrum shows a 1:1 mixture of E and Z isomers. H

NMR (300 MHz, methanol-d₄and CDCl₃) δ 7.18−7.00 (m, 14 H),

6.90−6.87 (m, 2 H), 6.80−6.75 (m, 4 H), 6.68−6.65 (m, 2 H), 6.50−

6.47 (m, 2 H), 6.40−6.36 (m, 2 H), 4.45 (s, 2 H), 4.25 (s, 2 H), 3.05−

2.92 (m, 2 H), 0.90−0.87 (m, 12 H). ¹³C NMR (75 MHz, methanol-

d₄and CDCl₃) δ 173.8, 157.2, 156.7, 156.2, 155.7, 147.1, 146.8, 141.2,

139.2, 138.7, 135.9, 132.7, 132.5, 132.1, 131.9, 131.7, 128.4, 127.1,

116.3, 115.7, 115.4, 114.6, 68.2, 68.0, 33.1, 33.0, 22.9. CIMS m/z

(relative intensity) 388 (MH⁺, 100). HRESIMS m/z calcd for

C₂₅H₂₅NO₃Na (MNa⁺) 410.1732, found 410.1727.

2-(4-(1-(4-Hydroxyphenyl)-2,2-diphenylvinyl)phenoxy)-

acetamide (28e). The diphenol 27e (350 mg, 0.96 mmol) was

reacted with 2-iodoacetamide according to the general monoalkylation

procedure of diphenols, and the product was puriﬁed by silica gel

column chromatography (2:3 hexanes−ethyl acetate) to provide the

1

product 28e as a colorless glass (110 mg, 27%). H NMR (300 MHz,

CDCl₃) δ 7.12−6.97 (m, 12 H), 6.88−6.85 (m, 2 H), 6.65−6.56 (m, 4

H), 4.42 (s, 2 H). ¹³C NMR (75 MHz, CDCl₃) δ 171.8, 155.4, 154.7,

144.0, 139.7, 139.6, 138.1, 135.7, 132.8, 132.7, 131.3, 127.7, 126.2,

114.7, 113.7, 66.8. ESIMS m/z (relative intensity) 444 (MNa⁺, 100).

HRESIMS m/z calcd for C₂₈H₂₃NO₃Na (MNa⁺) 444.1576, found

444.1569.

4-(1-(4-(2-Aminoethoxy)phenyl)-2-phenylprop-1-en-1-yl)-

phenol (29a). The amide 28a (87.0 mg, 0.242 mmol) was reacted

with LiAlH₄according the general procedure of amide reduction with

LiAlH₄, and the product was puriﬁed by silica gel column

chromatography (1:9 methanol−dichloromethane) to provide the

product 29a as a white solid (45.1 mg, 54%); mp 216−218 °C. The

4-(1-(4-(2-Aminoethoxy)phenyl)-2,2-diphenylvinyl)phenol

(29e). The amide 28e (101 mg, 0.24 mmol) was reacted with LiAlH₄

according the general procedure of amide reduction with LiAlH₄, and

the product was puriﬁed by silica gel column chromatography (1:9

methanol−dichloromethane) to provide the product 29e as a white

1

NMR spectrum showed a 1:1 mixture of E and Z isomers. H NMR

(500 MHz, methanol-d₄and CDCl₃) δ 7.10−7.05 (m, 10 H), 7.02−

6.98 (m, 4 H), 6.84−6.82 (m, 2 H), 6.74−6.72 (m, 4 H), 6.64−6.62

(m, 2 H), 6.51−6.49 (m, 2 H), 6.42−6.40 (m, 2 H), 4.00 (t, J = 5.0

Hz, 2 H), 3.85 (t, J = 5.0 Hz, 2 H), 3.04 (t, J = 5.0 Hz, 2 H), 2.95 (t, J

= 5.0 Hz, 2 H), 2.06 (s, 3 H), 2.05 (s, 3 H). ¹³C NMR (125 MHz,

methanol-d₄and CDCl₃) δ 156.9, 156.3, 155.3, 154.6, 144.4, 138.3,

136.7, 136.4, 134.9, 134.7, 134.1, 133.8, 131.9, 131.8, 131.1, 131.0,

129.1, 127.6, 125.6, 114.6, 114.0, 113.7, 113.0, 68.1, 67.8, 40.4, 40.3,

23.1, 23.0. ESIMS m/z (relative intensity) 346 (MH⁺, 100). HRESIMS

m/z calcd for C₂₃H₂₄NO₂(MH⁺) 346.1807, found 346.1803. Anal.

Calcd for C₂₃H₂₃NO₂·0.5MeOH: C, 78.09; H, 6.97; N, 3.88. Found:

C, 77.71; H, 6.72; N, 4.07.

1

solid (62.6 mg, 64%); mp 164−166 °C. H NMR (300 MHz, CDCl₃

and methanol-d₄) δ 7.04−6.94 (m, 10 H), 6.91−6.88 (m, 2 H), 6.81−

6.78 (m, 2 H), 6.60−6.58 (m, 2 H), 6.52−6.49 (m, 2 H), 3.89 (t, J =

5.0 Hz, 2 H), 2.96 (t, J = 5.0 Hz, 2 H). ¹³C NMR (75 MHz, CDCl₃

and methanol-d₄) δ 158.4, 156.7, 145.7, 141.7, 140.4, 138.3, 136.6,

134.0, 132.7, 128.9, 127.3, 115.8, 114.8, 70.0, 42.0. ESIMS m/z

(relative intensity) 408 (MH⁺, 100). HRESIMS m/z calcd for

C₂₈H₂₆NO₂(MH⁺) 408.1964, found 408.1953. Anal. Calcd for

C₂₈H₂₅NO₂·0.6MeOH: C, 80.50; H, 6.47; N, 3.28. Found: C, 80.28;

H, 6.17; N, 3.02.

4-(1-(4-(2-Aminoethoxy)phenyl)-4-chloro-2-phenylbut-1-

en-1-yl)phenol (29b). The amide 28b (240 mg, 0.59 mmol) was

reacted with LiAlH₄according the general procedure of amide

reduction with LiAlH₄, and the product was puriﬁed by silica gel

column chromatography (1:9 methanol−dichloromethane) to provide

the product 29b as a colorless oil (138.7 mg, 60%). The NMR

(4-(2-Bromoethoxy)phenyl)(4-hydroxyphenyl)methanone

(30).⁴⁵A solution of 6 (2.38 g, 11.1 mmol) and K₂CO₃(3.02 g, 21.8

mmol) in 1,2-dibromoethane (15 mL), acetone (30 mL) and water (4

mL) was heated to reﬂux for 4 h. The solvent was evaporated, and the

residue was dissolved with saturated NH₄Cl aqueous solution (50 mL)

and extracted with ethyl acetate (50 mL × 4). The organic layers were

combined, dried over Na₂SO₄, concentrated in vacuo, and further

puriﬁed by silica gel column chromatography (3:2 hexanes−ethyl

acetate) to provide the product 30 as a white solid (1.29 g, 36%); mp

1

spectrum shows a 1:1 mixture of E and Z isomers. H NMR (300

MHz, methanol-d₄and CDCl₃) δ 7.19−7.06 (m, 14 H), 6.90−6.87

(m, 2 H), 6.80−6.74 (m, 4 H), 6.68−6.65 (m, 2 H), 6.53−6.50 (m, 2

H), 6.44−6.40 (m, 2 H), 3.98 (t, J = 5.1 Hz, 2 H), 3.80 (t, J = 5.1 Hz, 2

H), 3.39−3.34 (m, 4 H), 2.99 (t, J = 5.1 Hz, 2 H), 2.92−2.86 (m, 6

H). ¹³C NMR (75 MHz, methanol-d₄and CDCl₃) δ 161.6, 160.8,

159.9, 159.1, 145.5, 145.2, 139.6, 139.5, 138.6, 138.4, 138.0, 137.9,

135.6, 134.4, 133.3, 131.8, 130.1, 118.8, 117.9, 117.0, 72.8, 72.5, 46.4,

44.5, 44.4, 42.4. ESIMS m/z (relative intensity) 394 (MH⁺, 100).

HRESIMS m/z calcd for C₂₄H₂₅NO₂Cl (MH⁺) 394.1574, found

394.1575. Anal. Calcd for C₂₄H₂₄NO₂Cl: C, 73.18; H, 6.14; N, 3.56.

Found: C, 73.41; H, 6.41; N, 3.44.

118−119 °C (lit.⁴⁵139−142 °C). H NMR (500 MHz, methanol-d₄

1

and CDCl₃) δ 7.69−7.66 (m, 2 H), 7.63−7.60 (m, 2 H), 6.91−6.89

(m, 2 H), 6.83−6.81 (m, 2 H), 4.29 (t, J = 6 Hz, 2 H), 3.60 (t, J = 6

Hz, 2 H). ¹³C NMR (125 MHz, methanol-d₄and CDCl₃) δ 195.5,

161.4, 161.3, 132.5, 132.1, 131.0, 128.9, 114.9, 113.9, 67.8, 28.7.

4-(1-(4-(2-Bromoethoxy)phenyl)-2-phenylvinyl)phenol (31).

The benzophenone 30 (200 mg, 0.623 mmol) and benzaldehyde (212

mg, 2.00 mmol) were reacted according to the general McMurry cross-

coupling reaction procedure, and the product was puriﬁed by silica gel

column chromatography (4:1 hexanes−ethyl acetate) to aﬀord the

4-(1-(4-(2-Aminoethoxy)phenyl)-2-phenylpent-1-en-1-yl)-

phenol (29c). The amide 28c (316 mg, 0.82 mmol) was reacted with

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product 31 as a yellow oil (141 mg, 57%). The NMR spectrum shows

a 2:1 mixture of E and Z isomers. The mixture quickly isomerized to

be a 1:1 mixtue of E and Z isomers when dissolved in CDCl₃and kept

at room temperature overnight. ¹H NMR (300 MHz, CDCl₃) δ 7.29−

7.26 (m, 2 H), 7.22−7.19 (m, 2 H), 7.18−7.03 (m, 14 H), 6.88−6.84

(m, 6 H), 6.81−6.76 (m, 4 H), 4.34−4.28 (m, 4 H), 3.69−3.62 (m, 4

H). ¹³C NMR (75 MHz, CDCl₃) δ 157.6, 157.4, 155.4, 155.0, 141.5,

137.7, 137.1, 136.3, 133.5, 132.6, 131.7, 129.4, 129.0, 128.9, 128.0,

126.5, 126.4, 126.3, 115.5. 115.0, 114.7, 114.4, 67.9, 67.8, 29.2, 29.1.

EIMS m/z (relative intensity) 394 (M⁺, 16), 107 (100). Negative ion

HRESIMS m/z calcd for C₂₂H₁₈O₂Br (M − H⁺)⁻393.0490, found

393.0493.

methanol-d₄and CDCl₃) δ 7.15−7.11 (m, 4 H), 7.07−7.02 (m, 4 H),

6.99−6.95 (m, 4 H), 6.84−6.82 (m, 2 H), 6.81−6.79 (m, 2 H), 6.76−

6.57 (m, 6 H), 6.46−6.44 (m, 1 H), 6.40−6.38 (m, 1 H), 3.99 (t, J =

5.1 Hz, 2 H), 3.96 (t, J = 5.1 Hz, 2 H), 3.01 (t, J = 5.1 Hz, 2 H), 2.98

(t, J = 5.1 Hz, 2 H), 2.87−2.85 (m, 8 H). ¹³C NMR (125 MHz,

methanol-d₄and CDCl₃) δ 157.6, 157.1, 155.8, 155.3, 147.3, 147.2,

141.5, 139.0, 138.8, 136.7, 135.7, 135.1, 134.2, 134.1, 130.9, 130.8,

130.2, 126.7, 126.6, 125.1, 124.8, 124.6, 124.5, 124.4, 115.2, 114.3,

114.2, 113.5, 68.8, 40.6, 40.5, 34.2, 34.1, 30.3. EIMS m/z (relative

intensity) 357 (M⁺, 96), 314 (100). HREIMS m/z calcd for

C₂₄H₂₄NO₂(MH⁺) 358.1807, found 358.1801. Anal. Calcd for

C₂₄H₂₃NO₂: C, 80.64; H, 6.49; N, 3.92. Found: C, 80.29; H, 6.44;

N, 3.86.

4-(1-(4-(2-Aminoethoxy)phenyl)-2-phenylvinyl)phenol (32).

A mixture of 31 (141 mg, 0.356 mmol) and NaI (224 mg, 1.49 mmol)

was dissolved with THF (4 mL), and then ammonium hydroxide

aqueous solution (30%, 5 mL) was added. The solution was heated to

70 °C and stirred in a sealed tube for 24 h. After cooling down, THF

was carefully evaporated, and the aqueous layer was extracted with

ethyl acetate (15 mL × 3). The organic layers were combined, dried

over Na₂SO₄, concentrated in vacuo, and further puriﬁed by silica gel

column chromatography (9:1 dichloromethane−methanol). The

puriﬁed product was dissolved in DMSO (2 mL) and then diluted

with water (12 mL). The solid was collected by ﬁltration and dried in

vacuo to provide the product 32 as a white solid (88.4 mg, 75%); mp

75−79 °C. The NMR spectrum shows a nearly 1:1 mixture of E and Z

4-(1-(4-(Methoxymethoxy)phenyl)-2-phenylprop-1-en-1-yl)-

phenol (37). A solution of 27a (247 mg, 0.817 mmol) and NaH (31

mg, 95%, 1.23 mmol) in dry THF (4 mL) was stirred under argon for

10 min, and then methyl chloromethyl ether (0.07 mL, 0.92 mmol)

was added. The mixture was stirred at room temperature overnight

and quenched with saturated NaHCO₃aqueous solution (3 mL). The

solvent was evaporated, and the residue was dissolved with water (15

mL) and extracted with ethyl acetate (15 mL × 4). The organic layers

were combined, dried over Na₂SO₄, concentrated in vacuo, and further

puriﬁed by silica gel column chromatography (85:15 hexanes−ethyl

acetate) to provide the product 37 as a pale-yellow oil (115 mg, 41%).

1

The NMR spectrum showed a 1:1 mixture of E and Z isomers. H

1

NMR (300 MHz, CDCl₃) δ 7.28−7.09 (m, 14 H), 7.04−7.01 (m, 2

H), 6.82−6.78 (m, 4 H), 6.76−6.73 (m, 2 H), 6.71−6.68 (m, 2 H),

6.49−6.46 (m, 2 H), 5.21 (s, 2 H), 5.07 (s, 2 H), 3.53 (s, 3 H), 3.43 (s,

3 H), 2.15 (s, 6 H). ¹³C NMR (75 MHz, CDCl₃) δ 155.8, 155.1,

154.3, 153.6, 144.3, 138.2, 137.4, 137.1, 136.1, 135.8, 134.6, 132.2,

132.0, 131.4, 131.2, 129.3, 127.9, 127.3, 127.2, 127.1, 126.0, 115.7,

115.1, 114.9, 114.3, 94.5, 94.4, 56.1, 56.0, 23.5, 23.4. EIMS m/z

(relative intensity) 346 (M⁺, 100). HREIMS m/z calcd for C₂₃H₂₂O₃

(M⁺) 346.1563, found 346.1558.

isomers. H NMR (500 MHz, DMSO-d₆) δ 7.18−7.16 (m, 2 H),

7.11−7.00 (m, 8 H), 6.98−6.94 (m, 6 H), 6.90−6.84 (m, 6 H), 6.83−

6.81 (m, 2 H), 6.73−6.71 (m, 2 H), 6.69−6.67 (m, 2 H), 3.89−3.87

(m, 4 H), 2.87−2.83 (m, 4 H). ¹³C NMR (125 MHz, DMSO-d₆) δ

158.6, 158.3, 157.6, 157.1, 141.8, 137.9, 135.8, 134.0, 132.5, 131.3,

131.2, 130.7, 129.4, 129.3, 128.8, 128.7, 128.3, 128.2, 126.7, 126.6,

125.5, 125.0, 116.0, 115.4, 115.0, 114.5, 70.5, 41.2. ESIMS m/z

(relative intensity) 332 (MH⁺, 100). HRESIMS m/z calcd for

C₂₂H₂₂NO₂(MH⁺) 332.1651, found 332.1649. Anal. Calcd for

C₂₂H₂₁NO₂·0.1H₂O: C, 79.30; H, 6.41; N, 4.20. Found: C, 79.18;

H, 6.45; N, 3.98.

tert-Butyl (2-(4-(1-(4-(Methoxymethoxy)phenyl)-2-phenyl-

prop-1-en-1-yl)phenoxy) ethyl)carbamate (39). A suspension of

37 (112 mg, 0.323 mmol), 38 (196 mg, 0.621 mmol), and Cs₂CO₃

(254 mg, 0.78 mmol) in dry DMF (2 mL) was stirred at 50 °C under

argon overnight. After cooling down, DMF was removed in vacuo. The

residue was dissolved with water (15 mL) and extracted with ethyl

acetate (15 mL × 4). The organic layers were combined, washed with

1 M KOH solution (20 mL) and brine (20 mL), and dried over

Na₂SO₄. The solvent was evaporated, and the residue was further

puriﬁed by silica gel column chromatography (85:15 hexanes−ethyl

acetate) to provide the product 39 as a transparent oil (114 mg, 72%).

4,4′-((2,3-Dihydro-1H-inden-1-ylidene)methylene)diphenol

(34).⁴⁶The starting material 6 (1.24 g, 5.78 mmol) and ketone 33

(2.18 g, 16.5 mmol) were reacted according to the general McMurry

cross-coupling reaction procedure, and the product was further

puriﬁed by silica gel column chromatography (2:1 hexanes−ethyl

1

acetate) to aﬀord the product 34 as a yellow oil (1.54 g, 85%). H

NMR (300 MHz, methanol-d₄and CDCl₃) δ 7.14−7.11 (m, 1 H),

7.07−7.02 (m, 2 H), 7.00−6.93 (m, 3 H), 6.78−6.68 (m, 5 H), 6.46−

6.43 (m, 1 H), 2.85 (s, 4 H). ¹³C NMR (75 MHz, methanol-d₄and

CDCl₃) δ 157.1, 156.6, 148.7, 143.2, 140.1, 137.0, 136.1, 135.9, 132.4,

131.8, 128.1, 126.7, 126.3, 126.1, 116.7, 115.9, 35.7, 31.9. APCIMS m/

z (relative intensity) 315 (MH⁺, 100).

1

The NMR spectrum showed a 1:1 mixture of E and Z isomers. H

NMR (300 MHz, CDCl₃) δ 7.25−7.10 (m, 14 H), 7.03−7.00 (m, 2

H), 6.89−6.86 (m, 2 H), 6.81−6.78 (m, 4 H), 6.70−6.67 (m, 2 H),

6.57−6.54 (m, 2 H), 5.20 (s, 2 H), 5.06 (s, 2 H), 4.04 (t, J = 5.0 Hz, 2

H), 3.89 (t, J = 5.0 Hz, 2 H), 3.56 (t, J = 5.0 Hz, 2 H), 3.52 (s, 3 H),

3.47 (t, J = 5.0 Hz, 2 H), 3.43 (s, 3 H), 2.15 (s, 3 H), 2.14 (s, 3 H),

1.47 (s, 9 H), 1.44 (s, 9 H). ¹³C NMR (75 MHz, CDCl₃) δ 157.2,

156.5, 155.9, 155.2, 144.3, 138.1, 137.3, 136.9, 136.5, 136.1, 134.6,

132.1, 132.0, 131.2, 131.1, 129.3, 127.9, 127.4, 127.1, 127.0, 126.0,

115.7, 115.1, 113.9, 113.2, 94.5, 94.4, 79.5, 67.1, 66.8, 56.0, 55.9, 40.1,

28.4, 23.4. ESIMS m/z (relative intensity) 512 (MNa⁺, 100).

HRESIMS m/z calcd for C₃₀H₃₅NO₅Na (MNa⁺) 512.2413, found

512.2394.

4-(4-(2-Aminoethoxy)phenyl)-4-(4-hydroxyphenyl)-3-phe-

nylbut-3-enenitrile (40). A solution of 39 (216 mg, 0.441 mmol)

and N-bromosuccinimide (79.1 mg, 0.445 mmol) in CCl₄(6 mL) was

heated at reﬂux under argon for 3 h. After cooling down, the solid was

removed by ﬁltration and the ﬁltrate was concentrated in vacuo. The

residue was dissolved in THF (6 mL), and a solution of KCN (97.5

mg, 1.50 mmol) in water (1.5 mL) was added. The mixture was stirred

at room temperature overnight. The solvent was evaporated, and the

residue was dissolved with water (15 mL) and extracted with ethyl

acetate (15 mL × 4). The organic layers were combined, dried over

Na₂SO₄, concentrated in vacuo, and further puriﬁed by silica gel

column chromatography (7:3 hexanes−ethyl acetate). The puriﬁed

2-(4-((2,3-Dihydro-1H-inden-1-ylidene)(4-hydroxyphenyl)-

methyl)phenoxy)acetamide (35). The diphenol 34 (970 mg, 3.08

mmol) was reacted with 2-iodoacetamide according to the general

monoalkylation procedure of diphenols, and the product was puriﬁed

by silica gel column chromatography (1:2 hexanes−ethyl acetate) to

provide the product 35 as a yellow glass (463 mg, 40%). The NMR

1

spectrum shows a 1:1 mixture of E and Z isomers. H NMR (300

MHz, methanol-d₄and CDCl₃) δ 7.16−7.08 (m, 6 H), 7.03−6.94 (m,

6 H), 6.87−6.69 (m, 10 H), 6.48−6.46 (m, 1 H), 6.39−6.36 (m, 1 H),

4.45 (s, 2 H), 4.42 (s, 2 H), 2.85−2.83 (m, 8 H). ¹³C NMR (75 MHz,

methanol-d₄and CDCl₃) δ 173.8, 157.7, 157.2, 148.8, 142.9, 141.0,

140.7, 139.3, 138.3, 136.5, 135.5, 132.7, 132.4, 131.9, 131.8, 128.4,

126.8, 126.4, 126.2, 116.8, 116.1, 116.0, 115.3, 68.1, 35.8, 35.6, 31.9.

EIMS m/z (relative intensity) 371 (M⁺, 100). HRESIMS m/z calcd for

C₂₄H₂₁NO₃Na (MNa⁺) 394.1419, found 394.1432.

4-((4-(2-Aminoethoxy)phenyl)(2,3-dihydro-1H-inden-1-

ylidene)methyl)phenol (36). The amide 35 (291 mg, 0.783 mmol)

was reacted with LiAlH₄according the general procedure of amide

reduction with LiAlH₄, and the product was puriﬁed by silica gel

column chromatography (1:9 methanol−dichloromethane) to provide

the product 36 as a yellow glass (186 mg, 66%). The NMR spectrum

shows a 1:1 mixture of E and Z isomers. ¹H NMR (500 MHz,

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product was dissolved with methanol (3 mL) and dichloromethane (3

mL), and then concentrated HCl (1.2 mL) was added. The mixture

was stirred at room temperature overnight. The solvent was removed,

and the residue was dissolved with water (20 mL), neutralized with

NaHCO₃to pH = 7, and extracted with ethyl acetate (20 mL × 4).

The organic layers were combined, dried over Na₂SO₄, concentrated

in vacuo, and further puriﬁed by silica gel column chromatography

(9:1 dichloromethane−methanol) to provide the product 40 as a red

glass (132 mg, 81%). The NMR spectrum showed a 1:1 mixture of E

and Z isomers. ¹H NMR (500 MHz, methanol-d₄and CDCl₃) δ 7.18−

7.09 (m, 12 H), 7.07−7.05 (m, 2 H), 6.91−6.89 (m, 2 H), 6.82−6.80

(m, 2 H), 6.77−6.75 (m, 2 H), 6.67−6.65 (m, 2 H), 6.54−6.52 (m, 2

H), 6.46−6.44 (m, 2 H), 3.98 (t, J = 5.1 Hz, 2 H), 3.81 (t, J = 5.1 Hz, 2

H), 3.51 (s, 2 H), 3.48 (s, 2 H), 3.00 (t, J = 5.1 Hz, 2 H), 2.90 (t, J =

5.1 Hz, 2 H). ¹³C NMR (125 MHz, methanol-d₄and CDCl₃) δ 158.2,

157.3, 156.7, 155.8, 144.1, 144.0, 139.9, 134.6, 134.2, 132.9, 132.5,

131.8, 130.5, 129.3, 128.2, 127.0, 126.3, 126.1, 118.4, 115.3, 114.4,

114.3, 113.3, 69.0, 68.7, 40.6, 40.5, 25.2. ESIMS m/z (relative

intensity) 371 (MH⁺, 100). HRESIMS m/z calcd for C₂₄H₂₃N₂O₂

(MH⁺) 371.1759, found 371.1756. Anal. Calcd for C₂₄H₂₂N₂O₂·

0.3MeOH: C, 76.79; H, 6.15; N, 7.37. Found: C, 76.67; H, 5.97; N,

7.44.

4-(1-(4-(2-Aminoethoxy)phenyl)-3-(1H-imidazol-1-yl)-2-phe-

nylprop-1-en-1-yl)phenol (41). A solution of 39 (195 mg, 0.398

mmol) and N-bromosuccinimide (71.3 mg, 0.401 mmol) in dry CCl₄

(6 mL) was heated at reﬂux under argon for 3 h. After cooling down,

the solid was removed by ﬁltration and the ﬁltrate was concentrated in

vacuo. The residue was dissolved in dry THF (6 mL) and added to a

solution of NaH (31.3 mg, 95%, 1.24 mmol) and imidazole (78.4 mg,

1.15 mmol) in dry THF (3 mL). The mixture was stirred at room

temperature overnight. The solvent was evaporated, and the residue

was dissolved with water (20 mL) and extracted with ethyl acetate (20

mL × 4). The organic layers were combined, dried over Na₂SO₄,

concentrated in vacuo, and further puriﬁed by silica gel column

chromatography (97:3 dichloromethane−methanol). The product was

dissolved with methanol (4 mL), and then concentrated HCl (1.2 mL)

was added. The mixture was stirred at room temperature overnight.

The solvent was removed, and the residue was dissolved with water

(20 mL), neutralized with NaHCO₃to pH = 7, and extracted with

ethyl acetate−THF (1:1, 20 mL × 4). The organic layers were

combined, dried over Na₂SO₄, concentrated in vacuo, and further

puriﬁed by silica gel column chromatography (25:5:0.3 dichloro-

methane−methanol−triethylamine) to provide the product 41 as a

pale-yellow glass (105 mg, 64%). The NMR spectrum showed a 1:1

mixture of E and Z isomers. ¹H NMR (300 MHz, methanol-d₄) δ 7.35

(s, 2 H), 7.20−7.17 (m, 2 H), 7.10−7.03 (m, 12 H), 6.98 (s, 1 H),

6.95−6.93 (m, 3 H), 6.85−6.82 (m, 6 H), 6.75−6.71 (m, 2 H), 6.60−

6.56 (m, 2 H), 6.46−6.43 (m, 2 H), 4.94 (s, 2 H), 4.92 (s, 2 H), 4.00

(t, J = 5.2 Hz, 2 H), 3.82 (t, J = 5.2 Hz, 2 H), 2.99 (t, J = 5.2 Hz, 2 H),

2.88 (t, J = 5.2 Hz, 2 H). ¹³C NMR (75 MHz, methanol-d₄) δ 159.8,

159.0, 158.6, 157.7, 145.9, 141.4, 138.4, 136.0, 134.2, 133.6, 133.0,

131.6, 130.9, 129.3, 128.9, 127.9, 120.5, 116.6, 115.7, 115.6, 114.6,

70.3, 70.0, 52.1, 41.8. ESIMS m/z (relative intensity) 412 (MH⁺, 100).

HRESIMS m/z calcd for C₂₆H₂₆N₃O₂(MH⁺) 412.2025, found

412.2023. Anal. Calcd for C₂₆H₂₅N₃O₂·0.6MeOH: C, 74.17; H, 6.41;

N, 9.76. Found: C, 73.97; H, 6.11; N, 9.75.

was added. The mixture was stirred at room temperature overnight.

The solvent was removed, and the residue was dissolved with water

(15 mL), neutralized with NaHCO₃to pH = 7, and extracted with

ethyl acetate−THF (1:1, 15 mL × 4). The organic layers were

combined, dried over Na₂SO₄, concentrated in vacuo, and further

puriﬁed by silica gel column chromatography (25:5:0.3 dichloro-

methane−methanol−triethylamine) to provide the product 44. The

crude product 43 was dissolved with methanol (3 mL), and then

concentrated HCl (0.9 mL) was added. The mixture was stirred at

room temperature overnight. The solvent was removed, and the

residue was dissolved with water (15 mL), neutralized with NaHCO₃

to pH = 7, and extracted with ethyl acetate−THF (1:1, 15 mL × 6).

The organic layers were combined, dried over Na₂SO₄, concentrated

in vacuo, and further puriﬁed by silica gel column chromatography

(25:5:0.3 dichloromethane−methanol−triethylamine) to ﬁrst provide

E-45 and then Z-45.

4-(1-(4-(2-Aminoethoxy)phenyl)-2-phenyl-3-(1H-1,2,4-triazol-1-

yl)prop-1-en-1-yl) phenol (44). The product was obtained as a red

glass (56.1 mg, 30.5%). The NMR spectrum showed a 1:1 mixture of

E and Z isomers. ¹H NMR (300 MHz, methanol-d₄) δ 8.00 (m, 2 H),

7.87 (s, 2 H), 7.43−7.40 (m, 2 H), 7.33−7.29 (m, 2 H), 7.07−6.94

(m, 12 H), 6.85−6.79 (m, 4 H), 6.74−6.70 (m, 2 H), 6.61−6.58 (m, 2

H), 6.45−6.42 (m, 2 H), 5.25 (s, 2 H), 5.22 (s, 2 H), 4.02 (t, J = 5.1

Hz, 2 H), 3.85 (t, J = 5.1 Hz, 2 H), 3.01 (t, J = 5.1 Hz, 2 H), 2.91 (t, J

= 5.1 Hz, 2 H). ¹³C NMR (75 MHz, methanol-d₄) δ 159.8, 159.0,

158.4, 157.6, 151.9, 145.8, 145.3, 141.0, 136.3, 136.0, 134.5, 134.2,

133.1, 132.7, 132.5, 132.2, 130.9, 129.2, 127.9, 116.3, 115.4, 114.6,

70.2, 69.9, 54.9, 41.8. ESIMS m/z (relative intensity) 413 (MH⁺, 72),

344 (100). HRESIMS m/z calcd for C₂₅H₂₅N₄O₂(MH⁺) 413.1978,

found 413.1972. HPLC purity 95.5% (C-18 reverse phase, MeOH−

H₂O, 90:10).

(E)-4-(1-(4-(2-Aminoethoxy)phenyl)-2-phenyl-3-(4H-1,2,4-triazol-

4-yl)prop-1-en-1-yl)phenol (E-45). The product was obtained as a red

1

glass (12.8 mg, 7%). H NMR (300 MHz, methanol-d₄) δ 8.27 (s, 2

H), 7.14−7.08 (m, 7 H), 6.88−6.82 (m, 4 H), 6.65−6.61 (m, 2 H),

5.11 (s, 2 H), 3.89 (t, J = 5.1 Hz, 2 H), 2.94 (t, J = 5.1 Hz, 2 H). ¹³C

NMR (75 MHz, methanol-d₄) δ 157.6, 157.1, 145.2, 143.0, 139.0,

134.1, 132.5, 131.4, 131.1, 129.9, 129.4, 128.0, 126.7, 115.1, 113.1,

68.2, 49.2, 40.1. ESIMS m/z (relative intensity) 413 (MH⁺, 13), 344

(100). HRESIMS m/z calcd for C₂₅H₂₅N₄O₂(MH⁺) 413.1978, found

413.1973. HPLC purity 95.2% (C-18 reverse phase, MeOH−H₂O,

90:10).

(Z)-4-(1-(4-(2-aminoethoxy)phenyl)-2-phenyl-3-(4H-1,2,4-triazol-

4-yl)prop-1-en-1-yl)phenol (Z-45). The product was obtained as a

1

yellow glass (13.8 mg, 7.5%). H NMR (300 MHz, methanol-d₄) δ

8.28 (s, 2 H), 7.24−7.21 (m, 2 H), 7.16−7.11 (m, 5 H), 7.04−7.01

(m, 2 H), 6.77−6.74 (m, 2 H), 6.46−6.43 (m, 2 H), 5.10 (s, 2 H), 4.07

(t, J = 5.2 Hz, 2 H), 3.06 (t, J = 5.2 Hz, 2 H). ¹³C NMR (75 MHz,

methanol-d₄) δ 158.3, 156.2, 145.1, 143.0, 139.0, 134.4, 132.4, 131.4,

130.8, 129.9, 129.4, 128.0, 126.7, 114.4, 113.9, 68.3, 49.2, 40.1. ESIMS

m/z (relative intensity) 413 (MH⁺, 60), 344 (100). HRESIMS m/z

calcd for C₂₅H₂₅N₄O₂(MH⁺) 413.1978, found 413.1976. HPLC purity

95.1% (C-18 reverse phase, MeOH−H₂O, 90:10).

Ethyl 2-(4-(1-(4-Hydroxyphenyl)-2-phenylbut-1-en-1-yl)-

phenoxy)acetate (47). A suspension of 46 (322 mg, 1.02 mmol)

and K₂CO₃(498 mg, 3.60 mmol) in acetone (5 mL) was stirred at

room temperature for 10 min. A solution of ethyl 2-iodoacetate (208

mg, 0.972 mmol) in acetone (3 mL) was added in small portions over

3 h, and the mixture was stirred at room temperature for 1 h. After

cooling down, acetone was carefully evaporated and the residue was

dissolved in saturated NH₄Cl aqueous solution (30 mL) and extracted

with ethyl acetate (30 mL × 4). The organic layers were combined,

dried over Na₂SO₄, concentrated in vacuo, and further puriﬁed by

silica gel column chromatography (4:1 hexanes−ethyl acetate) to

provide a 1:1 mixture of E and Z isomers of 47 as a white solid (95.5

mg, 23%): 160−163 °C. ¹H NMR (300 MHz, methanol-d₄and

CDCl₃) δ 7.13−6.99 (m, 14 H), 6.84−6.81 (m, 2 H), 6.76−6.72 (m, 4

H), 6.64−6.61 (m, 2 H), 6.50−6.47 (m, 2 H), 6.42−6.39 (m, 2 H),

4.59 (s, 2 H), 4.44 (s, 2 H), 4.27−4.15 (m, 4 H), 2.47−2.36 (m, 4 H),

1.28−1.18 (m, 6 H), 0.89−0.83 (m, 6 H). ¹³C NMR (75 MHz,

Procedure for Preparation of 44 and Z-45 and E-45. A

solution of 39 (218 mg, 0.445 mmol) and N-bromosuccinimide (81.3

mg, 0.457 mmol) in dry CCl₄(6 mL) was heated at reﬂux under argon

for 3 h. After cooling down, the solid was removed by ﬁltration and the

ﬁltrate was concentrated in vacuo. The residue was dissolved in dry

THF (6 mL) and added to a solution of NaH (36 mg, 95%, 1.42

mmol) and 1,2,4-triazole (88 mg, 1.27 mmol) in dry THF (3 mL).

The mixture was stirred at room temperature overnight. The solvent

was evaporated, and the residue was dissolved with water (20 mL) and

extracted with ethyl acetate (20 mL × 4). The organic layers were

combined, dried over Na₂SO₄, concentrated in vacuo, and further

puriﬁed by silica gel column chromatography (9:1 dichloromethane−

acetone) to ﬁrst provide 42 and then 43. The crude product 42 was

dissolved with methanol (3 mL), and then concentrated HCl (0.9 mL)

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methanol-d₄and CDCl₃) δ 170.1, 157.8, 156.8, 155.9, 144.0, 142.5,

142.2, 139.2, 138.9, 138.5, 136.5, 136.1, 133.4, 132.0, 131.0, 129.1,

127.2, 116.2, 115.5, 114.7, 66.8, 66.6, 62.9, 62.8, 30.3, 15.3, 14.8. EIMS

m/z (relative intensity) 402 (M⁺, 100). HRESIMS m/z calcd for

C₂₆H₂₆O₄Na (MNa⁺) 425.1729, found 425.1711.

carefully evaporated, and the residue was dissolved in water (15 mL)

and extracted with ethyl acetate (15 mL × 4). The organic layers were

combined, dried over Na₂SO₄, concentrated in vacuo, and further

puriﬁed by silica gel column chromatography (80:20 hexanes−ethyl

acetate) to provide the product 53a as a white solid (141 mg, 49%);

mp 99−101 °C. ¹H NMR (300 MHz, CDCl₃) δ 7.81−7.77 (m, 4 H),

7.18−7.15 (m, 2 H), 6.98−6.95 (m, 2 H), 4.29 (t, J = 5.8 Hz, 2 H),

3.84 (t, J = 5.8 Hz, 2 H), 1.37 (s, 9 H). ¹³C NMR (75 MHz, CDCl₃) δ

194.3, 176.6, 161.7, 154.1, 135.3, 132.5, 131.3, 130.6, 121.4, 114.1,

68.0, 41.6, 39.2, 27.1. CIMS m/z (relative intensity) 361 (MH⁺, 100).

HRESIMS m/z calcd for C₂₀H₂₂O₄Cl (MH⁺) 361.1207, found

367.1202.

4-(1-(4-(2-Hydroxyethoxy)phenyl)-2-phenylbut-1-en-1-yl)-

phenol (48). A suspension of LiAlH₄(160 mg, 3.98 mmol) in dry

THF (5 mL) was stirred under argon and cooled to 0 °C. A solution

of 47 (93 mg, 0.231 mmol) in dry THF (5 mL) was added. The

mixture was warmed to room temperature and stirred under argon

overnight. The reaction was quenched with H₂O (0.5 mL), and the

THF was evaporated. The residue was dissolved in saturated

ammonium chloride aqueous solution (20 mL) and extracted with

ethyl acetate (15 mL × 5). The organic layers were combined, dried

over Na₂SO₄, concentrated in vacuo, and further puriﬁed by silica gel

column chromatography (3:2 hexane−ethyl acetate) to provide the

product 48 as a white solid (54.2 mg, 65%); mp 186−188 °C. The

4-(4-(3-Bromopropoxy)benzoyl)phenyl Pivalate (53b). A

suspension of 52 (198 mg, 0.663 mmol) and Cs₂CO₃(671 mg, 2.06

mmol) in 1,3-dibromopropane (2 mL) and CH₃CN (6 mL) was

stirred at room temperature for 4 h. The solvent was carefully

evaporated, and the residue was dissolved in water (15 mL) and

extracted with ethyl acetate (15 mL × 4). The organic layers were

combined, dried over Na₂SO₄, concentrated in vacuo, and further

puriﬁed by silica gel column chromatography (85:15 hexanes−ethyl

acetate) to provide the product 53b as a white solid (219 mg, 79%);

1

NMR spectrum shows a 1:1 mixture of E and Z isomers. H NMR

(300 MHz, methanol-d₄and CDCl₃) δ 7.13−7.00 (m, 14 H), 6.89−

6.86 (m, 2 H), 6.77−6.72 (m, 4 H), 6.66−6.63 (m, 2 H), 6.54−6.51

(m, 2 H), 6.42−6.39 (m, 2 H), 4.04 (t, J = 4.6 Hz, 2 H), 3.88 (m, 4

H), 3.77 (t, J = 4.6 Hz, 2 H), 2.49−2.41 (m, 4 H), 0.88 (t, J = 7.4 Hz, 6

H). ¹³C NMR (75 MHz, methanol-d₄and CDCl₃) δ 159.0, 158.1,

156.9, 156.0, 144.1, 142.1, 141.9, 139.5, 137.9, 137.5, 136.5, 136.2,

133.3, 133.2, 131.8, 131.0, 129.0, 127.0, 116.0, 115.3, 114.5, 70.5, 70.3,

61.9, 61.8, 30.1, 14.5. ESIMS m/z (relative intensity) 383 (MNa⁺,

100). HRESIMS m/z calcd for C₂₄H₂₄O₃Na (MNa⁺) 383.1623, found

383.1626. Anal. Calcd for C₂₄H₂₄O₃: C, 79.97; H, 6.71. Found: C,

79.92; H, 6.76.

1

mp 87−89 °C. H NMR (300 MHz, CDCl₃) δ 7.80−7.77 (m, 4 H),

7.18−7.15 (m, 2 H), 6.96−6.92 (m, 2 H), 4.15 (t, J = 5.8 Hz, 2 H),

3.58 (t, J = 5.8 Hz, 2 H), 2.33−2.29 (m, 2 H), 1.36 (s, 9 H). ¹³C NMR

(75 MHz, CDCl₃) δ 194.2, 176.6, 162.3, 154.0, 135.4, 132.4, 131.2,

130.2, 121.4, 114.0, 65.5, 39.2, 32.1, 29.8, 27.1. CIMS m/z (relative

intensity) 419 (MH⁺, 100). HRESIMS m/z calcd for C₂₁H₂₃O₄BrNa

(MNa⁺) 441.0677, found 441.0672.

4-(1-(4-(3-Bromopropoxy)phenyl)-2-phenylbut-1-en-1-yl)-

phenyl Pivalate (54b). The benzophenone 53b (180 mg, 0.429

mmol) and propiophenone (209 mg, 1.56 mmol) were reacted

according to the general McMurry cross-coupling reaction procedure,

and the product was puriﬁed by silica gel column chromatography (9:1

hexanes−ethyl acetate) to provide the product 54b as a colorless oil

(215 mg, 96%). The NMR spectrum shows a 3:1 mixture of E and Z

2-(4-(1-(4-Hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenoxy)-

acetic Acid (49). A solution of 2 N aq KOH (2.5 mL) was added to a

solution of 47 (63.0 mg, 0.157 mmol) in THF (2.5 mL). The mixture

was stirred at room temperature overnight. The solvent was

evaporated, and the residue was diluted with water (10 mL) and

acidiﬁed with concentrated HCl to pH < 1. The white suspension was

extracted with ethyl acetate (10 mL × 3). The organic layers were

combined, dried over Na₂SO₄, concentrated in vacuo, and further

puriﬁed by silica gel column chromatography (9:1 dichloromethane−

methanol) to provide the product 49 as a white solid (57.2 mg, 97%);

mp 156−160 °C. The NMR spectrum shows a 1:1 mixture of E and Z

1

isomers. H NMR (300 MHz, CDCl₃) δ 7.27−7.24 (m, 2 H, isomer

1), 7.20−7.11 (m, 7.3 H), 7.09−7.06 (m, 2 H, isomer 1), 6.92−6.87

(m, 1.4 H, isomer 2), 6.80−6.77 (m, 2 H, isomer 1), 6.74−6.71 (m,

0.7 H, isomer 2), 6.57−6.54 (m, 2 H, isomer 1), 4.14 (t, J = 5.7 Hz, 0.7

H, isomer 2), 3.97 (t, J = 5.7 Hz, 2 H, isomer 1), 3.63 (t, J = 5.7 Hz,

0.7 H, isomer 2), 3.55 (t, J = 5.7 Hz, 2 H, isomer 1), 2.54−2.48 (m, 2.7

H), 2.36−2.32 (m, 0.7 H, isomer 2), 2.27−2.22 (m, 2 H, isomer 1),

1.39 (s, 9 H, isomer 1), 1.30 (s, 3 H, isomer 2), 0.99−0.91 (m, 3.9 H).

EIMS m/z (relative intensity) 520 (M⁺, 13), 57 (100). HRESIMS m/z

calcd for C₃₀H₃₃O₃BrNa (MNa⁺) 545.1495, found 545.1492.

1

isomers. H NMR (300 MHz, methanol-d₄) δ 7.16−7.03 (m, 12 H),

7.01−6.98 (m, 2 H), 6.91−6.88 (m, 2 H), 6.77−6.72 (m, 4 H), 6.65−

6.62 (m, 2 H), 6.55−6.52 (m, 2 H), 6.41−6.38 (m, 2 H), 4.51 (s, 2 H),

4.34 (s, 2 H), 2.50−2.40 (m, 4 H), 0.91−0.86 (m, 6 H). ¹³C NMR (75

MHz, methanol-d₄) δ 158.5, 157.6, 157.3, 156.4, 144.0, 142.1, 141.8,

139.6, 138.2, 137.8, 136.3, 135.9, 133.1, 133.0, 131.6, 130.9, 128.9,

127.0, 115.9, 115.4, 115.1, 114.6, 67.5, 30.0, 29.9, 14.0. ESIMS m/z

(relative intensity) 397 (MNa⁺, 100). HRESIMS m/z calcd for

C₂₄H₂₂O₄Na (MNa⁺) 397.1416, found 397.1431. Anal. Calcd for

C₂₄H₂₂O₄·0.8CH₂Cl₂: C, 67.33; H, 5.38. Found: C, 67.05; H, 5.41.

4-(1-(4-(2-Bromoethoxy)phenyl)-2-phenylbut-1-en-1-yl)-

phenol (50).⁴⁷The benzophenone 30 (125 mg, 0.39 mmol) and

propiophenone (199 mg, 1.48 mmol) were reacted according to the

general McMurry cross-coupling reaction procedure, and the product

was puriﬁed by silica gel column chromatography (4:1 hexanes−ethyl

acetate) to aﬀord the product 50 as a white solid (143 mg, 87%); mp

119−122 °C. The NMR spectrum shows a 4:1 mixture of E and Z

isomers. The mixture quickly isomerized to be a 1:1 mixture of E and

Z isomers when dissolved in CDCl₃and kept at room temperature

overnight. ¹H NMR (300 MHz, CDCl₃) δ 7.20−7.08 (m, 14 H),

6.92−6.89 (m, 2 H), 6.82−6.78 (m, 4 H), 6.75−6.72 (m, 2 H), 6.58−

6.55 (m, 2 H), 6.49−6.46 (m, 2 H), 4.32 (t, J = 6.2 Hz, 2 H), 4.16 (t, J

= 6.3 Hz, 2 H), 3.66 (t, J = 6.2 Hz, 2 H), 3.55 (t, J = 6.3 Hz, 2 H),

2.53−2.45 (m, 4 H), 0.95 (t, J = 7.3 Hz, 6 H). ESIMS m/z (relative

intensity) 422 (M⁺, 100). Anal. Calcd for C₂₄H₂₃BrO₂: C, 68.09; H,

5.48. Found: C, 68.18; H, 5.56.

4-(1-(4-(2-Chloroethoxy)phenyl)-2-phenylbut-1-en-1-yl)-

phenol (55a).⁴⁸The benzophenone 53a (129 mg, 0.357 mmol) and

propiophenone (160 mg, 1.19 mmol) were reacted according to the

general McMurry cross-coupling reaction procedure and the crude 54a

underwent the general amide reduction with LiAlH₄, and the product

was puriﬁed by silica gel column chromatography (80:20 hexanes−

ethyl acetate) to provide the product 55a as a pale-yellow oil (79 mg,

58%). The NMR spectrum shows a 1:2 mixture of E and Z isomers.

The mixture isomerized to be a 1:1 mixture of E and Z isomers when

1

dissolved in CDCl₃and kept at room temperature for 1 week. H

NMR (300 MHz, CDCl₃) δ 7.20−7.09 (m, 14 H), 6.92−6.89 (m, 2

H), 6.82−6.78 (m, 4 H), 6.75−6.72 (m, 2 H), 6.58−6.55 (m, 2 H),

6.49−6.46 (m, 2 H), 4.26 (t, J = 5.8 Hz, 2 H), 4.09 (t, J = 5.8 Hz, 2 H),

3.83 (t, J = 5.8 Hz, 2 H), 3.73 (t, J = 5.8 Hz, 2 H), 2.51−2.46 (m, 4 H),

0.94 (t, J = 7.4 Hz, 6 H). HPLC purity 95.9% (C-18 reverse phase,

MeOH−H₂O, 85:15).

4-(1-(4-(3-Aminopropoxy)phenyl)-2-phenylbut-1-en-1-yl)-

phenol (55b). A mixture of 54b (185 mg, 0.355 mmol) and NaI (273

mg, 1.82 mmol) was dissolved with THF (8 mL), and then an aqueous

solution of ammonium hydroxide (30%, 4 mL) was added. The

solution was heated to 70 °C and stirred in a sealed tube for 24 h.

After cooling down, the solvent was carefully evaporated, and the

residue was dissolved in saturated NH₄Cl aqueous solution (20 mL)

and extracted with ethyl acetate (20 mL × 3). The organic layers were

combined, dried over Na₂SO₄, concentrated in vacuo, and further

4-(4-(2-Chloroethoxy)benzoyl)phenyl Pivalate (53a). A sus-

pension of 52 (239 mg, 0.801 mmol), 1-bromo-2-chloroethane (910

mg, 6.35 mmol), and K₂CO₃(616 mg, 4.46 mmol) in acetone (6 mL)

was heated at reﬂux for 4 h. After cooling down, the solvent was

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puriﬁed by silica gel column chromatography (85:15 dichloro-

methane−methanol) to provide the product 55b as a white solid

(71.6 mg, 54%); mp 183−186 °C. The NMR spectrum shows a 1:1

mixture of E and Z isomers. ¹H NMR (500 MHz, DMSO-d₆) δ 7.15−

7.11 (m, 4 H), 7.06−7.02 (m, 8 H), 6.94−6.91 (m, 2 H), 6.88−6.86

(m, 2 H), 6.72−6.70 (m, 2 H), 6.66−6.64 (m, 2 H), 6.56−6.51 (m, 4

H), 6.36−6.34 (m, 2 H), 3.98 (t, J = 6.4 Hz, 2 H), 3.82 (t, J = 6.4 Hz, 2

H), 2.66 (t, J = 6.4 Hz, 2 H), 2.58 (t, J = 6.4 Hz, 2 H), 2.39−2.32 (m, 4

H), 1.76−1.74 (m, 2 H), 1.68−1.63 (m, 2 H), 0.80 (t, J = 7.4 Hz, 6

H). ¹³C NMR (125 MHz, DMSO-d₆) δ 157.7, 156.9, 156.5, 155.6,

142.6, 140.2, 140.0, 138.3, 135.9, 135.6, 134.2, 133.9, 131.7, 130.4,

129.7, 128.3, 128.2, 126.3, 126.2, 115.3, 114.6, 114.3, 113.6, 65.7, 65.5,

38.7, 38.6, 32.9, 32.8, 28.9, 28.8, 13.8. ESIMS m/z (relative intensity)

374 (MH⁺, 100). HRESIMS m/z calcd for C₂₅H₂₈NO₂(MH⁺)

374.2120, found 374.2114. Anal. Calcd for C₂₅H₂₇NO₂·0.3MeOH: C,

79.32; H, 7.42; N, 3.66. Found: C, 79.23; H, 7.29; N, 3.81.

MHz, CDCl₃) δ 177.5, 177.4, 154.6, 153.8, 149.2, 149.1, 142.4, 142.0,

141.6, 140.9, 139.5, 139.3, 137.5, 137.4, 135.2, 134.6, 132.4, 132.0,

131.2, 131.1, 130.6, 130.5, 130.4, 121.0, 120.9, 120.5, 119.8, 115.0,

114.5, 39.0, 29.0, 28.8, 27.0, 13.5, 13.4. EIMS m/z (relative intensity)

478 (M⁺, 86), 257 (100). Negative ion HRESIMS m/z calcd for

C₂₇H₂₆O₃Br (M − H⁺)⁻477.1065, found 477.1079.

4-(1-(4-(3-Aminopropyl)phenyl)-2-phenylbut-1-en-1-yl)-

phenol (61a). A suspension of 59a (157 mg, 0.41 mmol), acrylamide

(360 mg, 5.1 mmol), and Pd(PPh₃)₄(107 mg, 0.093 mmol) in

triethylamine (2 mL) and DMF (6 mL) was stirred under argon and

heated to 120 °C for 24 h. After cooling down, 1 N HCl (10 mL) was

added and the solution was extracted with ethyl acetate (10 mL × 4).

The organic layers were combined, dried over Na₂SO₄, concentrated

in vacuo, and further puriﬁed by silica gel column chromatography

(95:5 dichloromethane−methanol) to provide the product 60a as

yellow solid. The NMR spectrum shows the product is not pure and

still contains a certain amount of acrylamide. The crude product 60a

was combined with Rh(PPh₃)₃Cl (14.0 mg, 0.015 mmol) and

dissolved with methanol (5 mL), and the solution was vigorously

stirred at 40 °C under a hydrogen atmosphere overnight. The solid

was removed by ﬁltration, and the ﬁltrate was concentrated in vacuo.

The residue was dissolved with dry THF (5 mL) and added to a

suspension of AlCl₃(46 mg, 0.344 mmol) and LiAlH₄(165 mg, 4.40

mmol) in dry THF (3 mL) at 0 °C. The mixture was warmed to room

temperature and stirred under argon overnight. The reaction was

quenched with H₂O (0.5 mL), and the THF was evaporated. The

residue was dissolved in saturated NH₄Cl aqueous solution (15 mL)

and extracted with ethyl acetate (15 mL × 5). The organic layers were

combined, dried over Na₂SO₄, concentrated in vacuo, and further

puriﬁed by silica gel column chromatography (15:85 methanol−

dichloromethane) to provide the product 61a as a colorless glass (45.6

mg, 34%). The NMR spectrum shows a 1:1 mixture of E and Z

(4-Bromophenyl)(4-methoxyphenyl)methanone (57).⁴⁹

A

solution of 56 (2.43 g, 11.1 mmol) and 20 (6 mL, 32.9 mmol) in

dry dichloromethane (12 mL) was stirred in an ice bath. Aluminum

chloride (1.51 g, 11.2 mmol) was added. The mixture was kept at 0 °C

for 1 h and then warmed to room temperature and stirred overnight.

The reaction mixture was poured in ice−water (40 mL), stirred for 15

min, and extracted with dichloromethane (40 mL × 4). The organic

layers were combined and dried over Na₂SO₄. Solvent was evaporated,

and the residue was further puriﬁed by silica gel column

chromatography (1:1 hexanes−dichloromethane) to aﬀord the

product 57 as a white solid (2.87 g, 89%); mp 150−153 °C (lit.⁴⁹

1

151−152 °C). H NMR (300 MHz, CDCl₃) δ 7.81−7.78 (m, 2 H),

7.65−7.62 (m, 4 H), 6.98−6.95 (m, 2 H), 3.89 (s, 3 H).

(4-Bromophenyl)(4-hydroxyphenyl)methanone (58).⁵⁰A sol-

ution of 57 (1.45 g, 4.98 mmol) in HBr (48% v/v, 15 mL) and glacial

acetic acid (15 mL) was heated at reﬂux for 7 h. After cooling down,

the solvent was carefully removed in vacuo. The residue was dissolved

in water (40 mL) and extracted with ethyl acetate (40 mL × 3). The

organic layers were combined, washed with saturated NaHCO₃(50

mL) and brine (50 mL), and dried over Na₂SO₄. The solvent was

evaporated, and the residue was further puriﬁed by silica-gel column

chromatography (7:3 hexanes−ethyl acetate) to provide the product

58 as a white solid (1.23 g, 89%); mp 189−191 °C (lit.⁵⁰191 °C). ¹H

NMR (300 MHz, methanol-d₄and CDCl₃) δ 7.53−7.49 (m, 2 H),

7.44−7.38 (m, 4 H), 6.72−6.67 (m, 2 H). ¹³C NMR (75 MHz,

methanol-d₄and CDCl₃) δ 195.3, 162.0, 136.8, 132.7, 131.2, 131.0,

128.0, 126.6, 115.0.

1

isomers. H NMR (300 MHz, methanol-d₄and CDCl₃) δ 7.13−7.00

(m, 16 H), 6.77−6.74 (m, 6 H), 6.66−6.63 (m, 2 H), 6.43−6.40 (m, 2

H), 2.73−2.57 (m, 6 H), 2.49−2.36 (m, 6 H), 1.83−1.78 (m, 2 H),

1.68−1.63 (m, 2 H), 0.90−0.84 (m, 6 H). ¹³C NMR (75 MHz,

methanol-d₄and CDCl₃) δ 156.9, 156.0, 144.0, 142.9, 142.7, 142.5,

142.1, 141.1, 140.1, 139.8, 139.7, 136.4, 136.0, 133.3, 132.1, 131.9,

131.0, 130.7, 129.3, 129.0, 128.9, 128.5, 127.1, 116.1, 115.4, 42.3, 42.1,

35.4, 35.1, 34.2, 34.0, 30.2, 14.6. ESIMS m/z (relative intensity) 358

(MH⁺, 100). HRESIMS m/z calcd for C₂₅H₂₈NO (MH⁺) 358.2171,

found 358.2169. Anal. Calcd for C₂₅H₂₇NO·0.1MeOH: C, 83.58; H,

7.66; N, 3.88. Found: C, 83.43; H, 7.71; N, 3.89.

4,4′-(1-(4-(3-Aminopropyl)phenyl)but-1-ene-1,2-diyl)-

diphenol (61b). A suspension of 59b (375 mg, 0.782 mmol),

acrylamide (193 mg, 2.72 mmol), and Pd(PPh₃)₄(155 mg, 0.134

mmol) in triethylamine (1 mL) and DMF (3 mL) was stirred under

argon and heated to 120 °C for 24 h. After cooling down, 1 N HCl (20

mL) was added and the solution was extracted with ethyl acetate (20

mL × 4). The organic layers were combined, dried over Na₂SO₄,

concentrated in vacuo, and further puriﬁed by silica gel column

chromatography (97:3 dichloromethane−methanol) to provide the

product 60b as a black oil. The NMR spectrum showed the product

60b was not pure and still contained a certain amount of acrylamide.

The crude product 60b was combined with Rh(PPh₃)₃Cl (32 mg,

0.034 mmol) and dissolved with methanol (8 mL), and the mixture

was vigorously stirred at 40 °C under a hydrogen atmosphere

overnight. The solid was removed by ﬁltration, and the ﬁltrate was

concentrated in vacuo. The residue was combined with AlCl₃(88 mg,

0.66 mmol) and LiAlH₄(316 mg, 8.33 mmol), dissolved in dry THF

(10 mL), and stirred at room temperature overnight. The reaction was

quenched with H₂O (1 mL), and THF was evaporated. The residue

was dissolved in saturated NH₄Cl aqueous solution (25 mL) and

extracted with ethyl acetate (25 mL × 6). The organic layers were

combined, dried over Na₂SO₄, concentrated in vacuo, and further

puriﬁed by silica gel column chromatography (ﬁrst eluting with 15:85

methanol−dichloromethane and then 25:5:0.3 dichloromethane−

methanol−triethylamine) to provide the product 61b as a yellow

glass (53.2 mg, 18%). The NMR spectrum shows a 1:1 mixture of E

and Z isomers. ¹H NMR (500 MHz, methanol-d₄) δ 7.17−7.15 (m, 2

4-(1-(4-Bromophenyl)-2-phenylbut-1-en-1-yl)phenol

(59a).²⁸Compounds 58 (332 mg, 1.20 mmol) and propiophenone

(496 mg, 3.70 mmol) were reacted according to the general McMurry

cross-coupling reaction procedure. The product was puriﬁed by silica

gel column chromatography (4:1 hexanes-ethyl acetate) and then

recrystallized from ethanol (5 mL). The product was dissolved in

dichloromethane and allowed to stand at room temperature overnight.

Removal of the solvent in vacuo provided the product 59a as a pale

yellow oil (251 mg, 55%). The NMR spectrum shows a 1:1 mixture of

1

E and Z isomers. H NMR (300 MHz, CDCl₃) δ 7.19−7.05 (m, 16

H), 7.48−7.46 (m, 2 H), 6.82−6.79 (m, 2 H), 6.75−6.72 (m, 2 H),

6.71−6.68 (m, 2 H), 6.48−6.46 (m, 2 H), 2.50−2.42 (m, 4 H),

0.94−0.90 (m, 6 H).

4-(1-(4-Bromophenyl)-1-(4-hydroxyphenyl)but-1-en-2-yl)-

phenyl Pivalate (59b). Compounds 58 (365 mg, 1.32 mmol) and 8

(867 mg, 3.70 mmol) were reacted according to the general McMurry

cross-coupling reaction procedure. The product was puriﬁed by silica

gel column chromatography (4:1 hexanes−ethyl acetate) and then

suspended in ethanol−hexanes (1:10, 11 mL) and ﬁltered. The

product was dissolved in dichloromethane and allowed to stand at

room temperature overnight. Removal of the solvent in vacuo

provided the product 59b as a pale-yellow oil (386 mg, 61%). The

1

NMR spectrum shows a 1:1 mixture of E and Z isomers. H NMR

(300 MHz, CDCl₃) δ 7.48−7.46 (m, 2 H), 7.14−7.08 (m, 8 H), 7.06−

7.04 (m, 2 H), 6.90−6.86 (m, 4 H), 6.80−6.78 (m, 2 H), 6.75−6.73

(m, 2 H), 6.69−6.67 (m, 2 H), 6.48−6.46 (m, 2 H), 2.48−2.42 (m, 4

H), 1.35 (s, 9 H), 1.34 (s, 9 H), 0.94−0.90 (m, 6 H). ¹³C NMR (75

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H), 7.10−7.08 (m, 2 H), 6.98−6.96 (m, 2 H), 6.90−6.82 (m, 6 H),

6.78−6.76 (m, 2 H), 6.74−6.72 (m, 2 H), 6.64−6.61 (m, 2 H), 6.58−

6.56 (m, 2 H), 6.54−6.52 (m, 2 H), 6.41−6.39 (m, 2 H), 2.84 (t, J =

7.6 Hz, 2 H), 2.73 (t, J = 7.6 Hz, 2 H), 2.67 (t, J = 7.6 Hz, 2 H), 2.51

(t, J = 7.6 Hz, 2 H), 2.44−2.34 (m, 4 H), 1.92−1.87 (m, 2 H), 1.80−

1.77 (m, 2 H), 0.90−0.85 (m, 6 H). ¹³C NMR (125 MHz, methanol-

d₄) δ 155.7, 155.2, 154.8, 142.0, 141.7, 140.9, 140.3, 138.8, 137.6,

137.5, 134.9, 134.6, 133.3, 131.5, 130.6, 130.4, 130.1, 129.2, 129.0,

127.6, 126.8, 114.4, 114.2, 114.1, 113.6, 39.4, 39.2, 31.9, 31.7, 30.4,

30.0, 28.3, 28.2, 13.2, 12.6. ESIMS m/z (relative intensity) 374 (MH⁺,

100). HRESIMS m/z calcd for C₂₅H₂₈NO₂(MH⁺) 374.2120, found

374.2119. Anal. Calcd for C₂₅H₂₇NO₂·0.5MeOH: C, 78.63; H, 7.50;

N, 3.60. Found: C, 78.56; H, 7.39; N, 3.63.

reduced following the general LiAlH₄reduction procedure, and the

product was further puriﬁed by silica gel column chromatography (9:1

dichloromethane−methanol) to provide the product 65 as a pale-

yellow oil (46.6 mg, 70%). NMR shows a nearly 3:2 mixture of E and

1

Z isomers. H NMR (300 MHz, methanol-d₄) δ 7.10−7.07 (m, 2 H,

isomer E), 7.00−6.97 (m, 1.2 H, isomer Z), 6.92−6.88 (m, 5.2 H),

6.76−6.72 (m, 2.4 H, isomer Z), 6.66−6.62 (m, 2 H, isomer E), 6.59−

6.55 (m, 4.4 H), 6.43−6.40 (m, 2 H, isomer E), 4.00 (t, J = 5.2 Hz, 2

H, isomer E), 3.86 (t, J = 5.2 Hz, 1.2 H, isomer Z), 2.99 (t, J = 5.2 Hz,

2 H, isomer E), 2.90 (t, J = 5.2 Hz, 1.2 H, isomer Z), 2.44−2.37 (m,

3.2 H), 0.92−0.87 (m, 5 H).

Inhibition of Recombinant Human Aromatase (CYP19) by

Microsomal Incubations. The activity of recombinant aromatase

(CYP19) was determined by measuring the conversion rate of the

ﬂuorometric substrate 7-methoxy-4-triﬂuoromethylcoumarin (MFC)

to its ﬂuorescent metabolite 7-hydroxy-4-triﬂuoromethylcoumarin

(HFC). Experimental procedures were consistent with the published

methodology.⁵¹All of the incubations were performed using

incubation times and protein concentrations that were within the

linear range for reaction velocity. The ﬂuorometric substrate, MFC,

was dissolved in acetonitrile with the ﬁnal concentration of 25 mM. All

tested samples were dissolved in either methanol or DMSO. The

sample solutions (2 μL) were mixed well with 98 μL of NADPH-

Cofactor Mix (16.25 μM NADP⁺, 825.14 μM MgCl₂, 825.14 μM

glucose-6-phosphate, and 0.4 Units/mL glucose-6-phosphate dehy-

drogenase) and were prewarmed for 10 min at 37 °C. Enzyme/

Substrate Mix was prepared with ﬂuorometric substrate, recombinant

human aromatase (CYP19), and 0.1 M potassium phosphate buﬀer

(pH 7.4). Reactions were initiated by adding 100 μL of Enzyme/

Substrate Mix to bring the incubation volume to 200 μL and incubated

for 30 min. All the reactions were stopped by adding 75 μL of 0.1 M

Tris base dissolved in acetonitrile. The amount of ﬂuorescent product

was determined immediately by measuring ﬂuorescent response using

a BioTek (Winooski, VT) Synergy 2 ﬂuorometric plate reader.

Excitation−emission wavelengths for MFC metabolite were 409 and

530 nm. The standard curve for MFC metabolite was constructed

using the appropriate ﬂuorescent metabolite standards. Quantiﬁcation

of samples was performed by applying the linear regression equation of

the standard curve to the ﬂuorescence response. The limit of

quantiﬁcation for the metabolites of MFC was 24.7 pmol with intra-

and interassay coeﬃcients of variation less than 10%.

Kinetic Analysis of Recombinant Human Aromatase

(CYP19). The rates of metabolite formation in the presence of the

test inhibitors were compared with those in the control in which the

inhibitor was replaced with vehicle. The extent of enzyme inhibition

was expressed as the percentage of remaining enzyme activity

compared to the control. IC₅₀values were determined as the inhibitor

concentrations that brought about half reduction in enzyme activity by

ﬁtting all the data to a one-site competition equation using Graphpad

Prism 5.0 (GraphPad Software Inc., San Diego, CA). To characterize

the inhibitory mechanism of norendoxifen against aromatase (CYP19),

all inhibitory data by norendoxifen at diﬀerent substrate concen-

trations were plotted as Lineweaver−Burk plots. The inhibitory

constant K_ivalues were determined by nonlinear least-squares

regression analysis using Graphpad Prism 5.0 (GraphPad Software

Inc., San Diego, CA). Before modeling the data using nonlinear

models, initial information about the inhibitory mechanism was

obtained by visual inspection of Lineweaver−Burk plots. The ﬁnal

decision on the mechanism of inhibition was made on model-derived

parameters, such as R²(or R Square) and absolute sum of squares.

Binding Aﬃnities for Recombinant Human ER-α and ER-β.

The binding aﬃnities to ER-α and ER-β were determined by

measuring the change of polarization value when the ﬂuorescent

estrogen ligand, ES2, was displaced by the tested compounds.

Experimental procedures were consistent with the protocol provided

by Invitrogen. The ﬂuorescent estrogen ligand, ES2, was provided in

methanol/water (4:1, v/v) with the concentration of 1800 nM.

Recombinant human ER-α and ER-β were provided in buﬀer (50 mM

bis-tris propane, 400 mM KCl, 2 mM DTT, 1 mM EDTA, and 10%

glycerol), with concentrations of 734 and 3800 nM, respectively. All

(E)-(1-(4-Hydroxyphenyl)but-1-ene-1,2-diyl)bis(4,1-phenyl-

ene) Bis(2,2-dimethylpropanoate) (62). The substituted propio-

phenone 8 (1.20 g, 5.12 mmol) and benzophenone 52 (611 mg, 2.05

mmol) were reacted according to the general McMurry cross-coupling

reaction procedure. The product was puriﬁed by silica gel column

chromatography (4:1 hexanes−ethyl acetate) and further tutirated

with methanol (15 mL) to aﬀord the product 62 as a white solid (802

1

mg, 78%); mp 218−219 °C. H NMR (500 MHz, methanol-d₄and

CDCl₃) δ 7.20−7.17 (m, 2 H), 7.09−7.06 (m, 2 H), 6.99−6.97 (m, 2

H), 6.82−6.80 (m, 2 H), 6.65−6.62 (m, 2 H), 6.45−6.42 (m, 2 H),

2.40 (q, J = 7.4 Hz, 2 H), 1.31 (s, 9 H), 1.28 (s, 9 H), 0.87 (t, J = 7.4

Hz, 3 H). ¹³C NMR (125 MHz, methanol-d₄and CDCl₃) δ 177.7,

177.6, 154.8, 149.4, 148.9, 141.2, 140.2, 139.8, 138.0, 133.9, 131.8,

130.4, 130.2, 120.8, 120.6, 114.1, 38.9, 38.8, 28.6, 26.7, 26.6, 13.1.

MALDIMS m/z (relative intensity) 500 (M⁺, 100). HRESIMS m/z

calcd for C₃₂H₃₇O₅(MH⁺) 501.2641, found 501.2643.

(E)-(1-(4-(2-Amino-2-oxoethoxy)phenyl)but-1-ene-1,2-diyl)-

bis(4,1-phenylene) Bis(2,2-dimethylpropanoate) (63). A suspen-

sion of 62 (730 mg, 1.46 mmol), 2-iodoacetamide (1.10 g, 5.95

mmol), and K₂CO₃(1.0 g, 7.24 mmol) in acetone−H₂O (19:1, 15

mL) was heated to reﬂux for 3 h. After cooling down, the solvent was

evaporated and the residue was dissolved in saturated aqueous NH₄Cl

solution (30 mL) and extracted with ethyl acetate (30 mL × 6). The

organic layers were combined, dried over Na₂SO₄, concentrated in

vacuo, and further puriﬁed by silica gel column chromatography

(55:45 hexanes−ethyl acetate) to provide the product 63 as a white

solid (455 mg, 56%); mp 167−169 °C. ¹H NMR (300 MHz, CDCl₃)

δ 7.23−7.20 (m, 2 H), 7.11−7.04 (m, 4 H), 6.89−6.86 (m, 2 H),

6.82−6.79 (m, 2 H), 6.59−6.56 (m, 2 H), 4.35 (s, 2 H), 2.46 (q, J =

7.3 Hz, 2 H), 1.36 (s, 9 H), 1.33 (s, 9 H), 0.92 (t, J = 7.3 Hz, 3 H). ¹³C

NMR (75 MHz, CDCl₃) δ 177.0, 171.2, 155.2, 149.8, 149.3, 141.4,

140.7, 139.4, 137.4, 136.5, 132.1, 130.5, 130.3, 121.2, 121.0, 113.7,

66.9, 39.1, 39.0, 29.0, 27.1, 13.5. MALDIMS m/z (relative intensity)

557 (M⁺, 100). HRESIMS m/z calcd for C₃₄H₄₀NO₆(MH⁺)

558.2856, found 558.2855.

4,4′-(1-(4-(2-Aminoethoxy)phenyl)but-1-ene-1,2-diyl)-

diphenol (64). A suspension of AlCl₃(45 mg, 0.34 mmol) and

LiAlH₄(267 mg, 7.03 mmol) in dry THF (5 mL) was stirred under

argon and cooled to 0 °C. A solution of 63 (151 mg, 0.269 mmol) in

dry THF (6 mL) was added. The mixture was warmed to room

temperature and stirred under argon for 2 h. The reaction was

quenched with H₂O (2 mL), and the solvent was evaporated. The

residue was dissolved in saturated NH₄Cl aqueous solution (20 mL)

and extracted with ethyl acetate (20 mL × 4). The organic layers were

combined, dried over Na₂SO₄, concentrated in vacuo, and further

puriﬁed by silica gel column chromatography (9:1 dichloromethane−

methanol) to provide the product 64 as a pale-yellow oil (53.7 mg,

53%). The NMR spectrum showed a nearly 1:3 mixture of E and Z

1

isomers. H NMR (300 MHz, methanol-d₄) δ 7.09−7.07 (m, 0.7 H,

isomer E), 7.00−6.97 (m, 2 H, isomer Z), 6.92−6.87 (m, 3.5 H),

6.76−6.72 (m, 4 H, isomer Z), 6.66−6.63 (m, 0.7 H, isomer E), 6.59−

6.54 (m, 4.8 H), 6.43−6.40 (m, 0.7 H, isomer E), 3.99 (t, J = 5.2 Hz,

0.7 H, isomer E), 3.85 (t, J = 5.2 Hz, 2 H, isomer Z), 2.99 (t, J = 5.2

Hz, 0.7 H, isomer E), 2.90 (t, J = 5.2 Hz, 2 H, isomer Z), 2.44−2.39

(m, 2.7 H), 0.92−0.87 (m, 4.1 H).

4,4′-(1-(4-(2-Aminoethoxy)phenyl)but-1-ene-1,2-diyl)-

diphenol (65). The amide 9 (84.0 mg, 0.177 mmol, E/Z = 4.5:1) was

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Article

tested samples were dissolved in either methanol or DMSO. The

sample solutions (1 μL) were mixed well with 49 μL of ES2 screening

buﬀer (100 mM potassium phosphate, 100 μg/mL BGG, and 0.02%

NaN₃). The ER-α/ES2 complex was prepared with the ﬂuorescent

estrogen ligand ES2, human recombinant ER and ES2 screening buﬀer

with the concentration of 9 nM ES2 and 30 nM ER-α. The ER-β/ES2

complex was prepared with the ﬂuorescent estrogen ligand ES2,

human recombinant ER-β, and ES2 screening buﬀer with the

concentration of 9 nM ES2 and 20 nM ER-β. Reactions were initiated

by adding 50 μL of ER/ES2 complex to bring the incubation volume

to 100 μL and incubated for 2 h avoiding light. The polarization value

was determined by measuring ﬂuorescent response using a BioTek

(Winooski, VT) Synergy 2 ﬂuorometric plate reader. Excitation−

emission wavelengths for ﬂuorescence polarization were 485 and 530

nM. The polarization values in the presence of the test competitors

were compared with those in the control, in which the competitor was

replaced with vehicle. The extent of competition was expressed as the

percentage of remaining polarization compared to the control. EC₅₀

values were determined as the competitor concentrations that brought

about half reduction in polarization value by ﬁtting all the data to a

one-site competition equation using Graphpad Prism 5.0 (GraphPad

Software Inc., San Diego, CA).

Molecular Modeling of the Z-Norendoxifen-ER-α Complex.

The crystal structure of the 4-hydroxytamoxifen and ER-α complex

was obtained from the Protein Data Bank (PDB ID 3ert). The two N-

methyl groups of 4-hydroxytamoxifen were removed, and all crystal

water molecules were removed (except the water that forms bifurcated

hydrogen bonds with Glu353 and Arg394). The resulting ligand−

protein complex was thoroughly energy minimized by use of the

Amber 10 molecular dynamics package. The Amber parm99 force ﬁeld

was used for the protein during energy minimization. For the ligand,

the force ﬁeld parameters were taken from the General Amber Force

Field (GAFF), whereas the atomic partial charges were derived from

the AM1-BCC method implemented by Antechamber.

Molecular Dynamics Simulations of the Z-Norendoxifen−

ER-α Complex. The minimized Z-norendoxifen−ER-α complex was

solvated with a truncated octahedron periodic box explicit solvent

model ﬁlled with TIP3P water. The box was extended 8 Å from the

solute atoms, and sodium ions were added as counterions to neutralize

the system. The whole system was slowly heated to 300 K and

equilibrated for about 100 ps at constant volume. Then, 2 ns of

molecular dynamics simulation at constant pressure were performed.

The lengths of bonds involved in hydrogen atoms were ﬁxed with the

SHAKE algorithm, and the time step of simulation was 2.0 fs. Periodic

boundary conditions were used, and the cutoﬀ for nonbonded

interaction was 10 Å. All molecular dynamics simulations were

performed with the AMBER 14 package.

Cell Culture and Test Compound Treatment. The estrogen

receptor-positive human breast carcinoma cell line MCF-7 was seeded

at a density of 10⁵cells/well in 6-well plates and maintained at 37 °C

under a humidiﬁed atmosphere of 5% CO₂and 95% air in Minimum

Essential Media (MEM) supplemented with 10% fetal bovine serum

(FBS). Before the test compound treatments, the cells were

preconditioned in charcoal-stripped FBS for 72 h to remove the

estrogens from the growth medium containing 10% FBS. The cells

were treated with vehicle (0.1% methanol) alone, 1 μM test

compound, or 1 μM endoxifen (positive control) for 24 h in the

presence of 10 nM β-estradiol (E2) dissolved in MEM supplemented

with 10% charcoal-stripped FBS.

Complementary Deoxyribonucleic Acid (cDNA) Synthesis.

Complementary DNA (cDNA) for the real-time quantitative polymer-

ase chain reaction (PCR) assay was synthesized from DNase-treated

total RNA using the QuantiTect reverse transcription kit (Qiagen Inc.,

Valencia, California, USA).

Real-Time Quantitative Polymerase Chain Reaction (PCR)

for cDNA. The cDNA was ampliﬁed with TaqMan Universal PCR

Master Mix (Applied Biosystems Inc., Carlsbad, CA), and then PCR

was performed in the QuantStudio 12K Flex Real-Time PCR system

(Life Technologies Corp., Carlsbad, CA). Progesterone receptor gene

(PGR, FAM, Hs01556702, Life Technologies Corp., Carlsbad, CA)

was the target gene, while glyceraldehyde-3-phosphate dehydrogenase

(GAPDH, VIC, Hs02758991, Life Technologies Corp., Carlsbad, CA)

gene expression was quantiﬁed to normalize each sample. A total of 40

ampliﬁcation cycles were performed. Quantitative values of

ampliﬁcation were obtained from the threshold cycle (Ct) deﬁned as

the cycle number at which the ﬂuorescent signal is ﬁrst recorded above

the background as determined during the exponential phase of PCR

rather than at the end point. The 2^−ΔΔCtmethod was used to

determine the relative mRNA expression, and the results were

expressed as percentages of antagonism eﬀects compared to E2-

stimulated PGR mRNA expression (considered as 100%). If

ampliﬁcation was not seen by 40 cycles, the measured RNA was

considered to be undetectable.

ASSOCIATED CONTENT

* Supporting Information

SMILES molecular formula strings (CSV). This material is

available free of charge via the Internet at http://pubs.acs.org.

■

S

AUTHOR INFORMATION

Corresponding Author

*Phone: 765-494-1465. Fax: 765-494-6790. E-mail: cushman@

purdue.edu.

■

Notes

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

This research was supported by the Purdue University Center

for Cancer Research and the Indiana University Cancer Center

Joint Funding Award 206330, by the Purdue Center for Cancer

Research grant P30 CA023168, by a Purdue Research

Foundation Research Grant, and by an award from the Floss

Endowment, provided to the Department of Medicinal

Chemistry and Molecular Pharmacology, Purdue University.

W. Lv thanks Dr. Charles Paget for providing the graduate

travel award.

ABBREVIATIONS USED

■

AIs, aromatase inhibitors; ATAC, arimidex, tamoxifen, alone or

in combination; ER, estrogen receptor; MOMCl, methyl

chloromethyl ether; NBS, N-bromosuccinimide; PDB, Protein

Data Bank; SERM, selective estrogen receptor modulator

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DOI: 10.1021/jm501218e

J. Med. Chem. 2015, 58, 2623−2648

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Design and synthesis of norendoxifen analogues with dual aromatase inhibitory and estrogen receptor modulatory activities

DOI: 10.1021/jm501218e

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Article abstract of DOI:10.1021/jm501218e

Full text of DOI:10.1021/jm501218e

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