An expeditious synthesis of tamoxifen, a representative SERM (selective estrogen receptor modulator), via the three-component coupling reaction among aromatic aldehyde, cinnamyltrimethylsilane, and β-chlorophenetole

Available online at www.sciencedirect.com

Bioorganic & Medicinal Chemistry 15 (2007) 7599–7617

An expeditious synthesis of tamoxifen, a representative

SERM (selective estrogen receptor modulator), via the

three-component coupling reaction among aromatic aldehyde,

cinnamyltrimethylsilane, and b-chlorophenetole

Isamu Shiina,^a,*Yoshiyuki Sano,^aKenya Nakata,^aMasahiko Suzuki,^a

Toshikazu Yokoyama,^aAkane Sasaki,^aTomoko Orikasa,^aTomomi Miyamoto,^a

Masahiko Ikekita,^bYukitoshi Nagahara^band Yoshimune Hasome^b

^aDepartment of Applied Chemistry, Faculty of Science, Tokyo University of Science,

Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan

^bDepartment of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science,

Yamazaki, Noda, Chiba 278-8510, Japan

Received 2 July 2007; revised 31 August 2007; accepted 5 September 2007

Available online 12 September 2007

Abstract—Two new synthetic pathways to the anti-cancer agent tamoxifen and its derivatives were developed. The ﬁrst route

involved the aldol reaction of benzyl phenyl ketone with acetaldehyde followed by Friedel–Crafts substitution with anisole in the

presence of Cl₂Si(OTf)₂to produce 1,1,2-triaryl-3-acetoxybutane, a precursor of the tamoxifen derivatives. The second one utilized

the novel three-component coupling reaction among aromatic aldehydes, cinnamyltrimethylsilane, and aromatic nucleophiles using

HfCl₄as a Lewis acid catalyst to produce 3,4,4-triarylbutene, that is also a valuable intermediate of the tamoxifen derivatives. The

former strategy requires a total of 10 steps from the aldol formation to the ﬁnal conversion to tamoxifen, whereas the latter needs

only three or four steps to produce tamoxifen and droloxifene including the installation of the side-chain moiety and the base-

induced double-bond migration to form the tetra-substituted oleﬁn structure. This synthetic strategy seems to serve as a new and

practical pathway to prepare not only the tamoxifen derivatives but also the other SERMs (selective estrogen receptor modulators)

including estrogen-dependent breast cancer and osteoporosis agents.

1. Introduction

one of the hydroxy derivatives of tamoxifen, had ﬁrst

been developed as a breast cancer agent,^6–9but is also

expected to be a therapeutic drug candidate for post-

menopausal and senile osteoporosis.^4,10–12

Tamoxifen (1) has been therapeutically used for wo-

men’s breast cancer as an anti-estrogenic agent since

the 1970s (Fig. 1). It was found that 1 also functioned

as an estrogenic agent against bone and fat metabolism,

that meant its eﬀect was variable depending on the tissue

or organ. Therefore, 1 is now recognized as one of the

selective estrogen receptor modulators (SERMs).^1–5

Based on this investigation, a large number of studies

to develop new agents for osteoporosis from the tamox-

ifen derivatives have been examined. Droloxifene (2),

There are three types of general methods for the construc-

tionofthebasicskeletonof1anditsderivatives(Scheme 1).

One of them includes the formation of the double-bond

functionalities of the oleﬁn III by a dehydration reaction

of the resulting tertiary alcohols II which are generated by

the Grignard reaction of benzyl phenyl ketones I with aro-

matic nucleophiles (Eq. 1).^13–17On the other hand, the de-

sired tetra-substituted oleﬁn III could be also synthesized

by the reductive cross-coupling reaction of unsymmetri-

cal aromatic carbonyl compounds IV and V using low-va-

lent titanium species (Eq. 2).^18,19In the other syntheses,

ethylene moieties are constructed during the early syn-

thetic stage and the successive coupling of the oleﬁns with

Keywords: Tamoxifen; Droloxifene; Three-component coupling; Cinn-

amyltrimethylsilane; Aromatic aldehyde; Hafnium tetrachloride.

*

Corresponding author. Tel.: +81 3 3260 4271; fax: +81 3 3260

5609; e-mail: shiina@ch.kagu.tus.ac.jp

doi:10.1016/j.bmc.2007.09.008

7600

I. Shiina et al. / Bioorg. Med. Chem. 15 (2007) 7599–7617

Figure 1. Representative selective estrogen receptor modulators (SERMs).

Scheme 1. General strategies to produce tamoxifen structure (Eqs. 1–4).

metallated aromatics is carried out in the presence of a

transition metal catalyst such as palladium, nickel, and

platinum species toproduce the desired substituted oleﬁns

III as shown in Eqs. 3 and 4.^20–27

We now report a new synthetic route to SERMs includ-

ing tamoxifen via the aldol reaction of benzyl phenyl ke-

tone with acetaldehyde or the novel three-component

coupling reaction among aromatic aldehydes, cinnamyl-

trimethylsilane, and aromatic nucleophiles.²⁸The latter

method was ﬁnally optimized for the preparation of 1

and 2, and it was proved that these compounds were

produced in very short steps (three steps for 1, and four

steps for 2).²⁹

Although several approaches classiﬁed into the above

strategies for the synthesis of the tamoxifen derivatives

have been developed, multiple synthetic steps are re-

quired to produce 1 and its derivatives.

I. Shiina et al. / Bioorg. Med. Chem. 15 (2007) 7599–7617

7601

2. Result and discussion

product 8 was predominantly produced without forming

the desired 3,4,4-triaryl-2-butene (9).

2.1. Chemistry

Next, we tried to perform the Friedel–Crafts alkylation

of 1,3-diacetoxy compound 11a and 11b in Scheme 4

with anisole in the presence of Cl₂Si(OTf)₂, which was

found in our previous study to be a suitable catalyst

for the reaction of benzyl silyl ether with an aromatic

compound.^31,32The mixture of stereoisomers of aldol

4 was ﬁrst reduced to the corresponding 1,3-diols 10a

and 10b by LiBH₄. Relative stereochemistries of these

compounds were determined by the NOE experiment

after converting to the acetonide derivatives 12a and

12b, as depicted in Scheme 4. Treatment of syn,anti-diol

10a and syn,syn-diol 10b with acetic anhydride in the

presence of DMAP aﬀorded the intermediary diacetates

11a and 11b, respectively, in satisfactory yields. Fortu-

nately, the desired electrophilic substitution reaction of

11a and 11b smoothly proceeded and the targeted

1,1,2-triaryl-3-acetoxybutanes 13a and 13b were ob-

tained in good yields. The successive transformations

of 13a and 13b were carried out to produce the desired

identical syn-3,4,4-triarylbutene 15 via three steps.

2.1.1. Synthesis of tamoxifen through aldol reaction. We

ﬁrst considered that a novel route to access the basic

skeleton A could be developed using the intermediate

3,4,4-triaryl-2-butene B because the double-bond in B

should be migrated to the position of that in the stable

structure A as shown in Scheme 2 The aldol product C

derived from aromatic ketone D could be a suitable

compound to be converted into B by introducing the

anisole fragment at the C-1 position of C.

According to this retrosynthetic analysis, the prelimin-

ary experiments depicted in Scheme 3 were carried out.

Allylic acetate 7 was ﬁrst obtained via three steps from

alcohol 4, which was prepared by the aldol reaction of

benzyl phenyl ketone (3) with acetaldehyde. Next, the

Friedel–Crafts aromatic substitution of 7 with anisole

was examined using the molybdenum carbonyl catalyst

ˇ

´

developed by Kocovsky et al. for the reaction of cinn-

amyl acetate with anisole;³⁰however, the c-attacked

Scheme 2. Retrosynthetic route to the basic skeleton of tamoxifen via the aldol reaction.

Scheme 3. Preliminary synthetic approach to triarylbutene structure via aldol condensation and Friedel–Crafts alkylation of allylic benzylic alcohol

and anisole. Reagents and conditions: (a) LDA, CH₃CHO, THF, ꢀ78 ꢁC, 1 h (94%); (b) p-TsOHÆH₂O, Na₂SO₄, benzene, reﬂux, 1 h (86%, E/

Z = 1:1); (c) i—NaBH₄, CeCl₃, MeOH, 0 ꢁC, 15 min; ii—NaBH₄, CeCl₃, MeOH, rt, 12 h (90% from (E)-5); (d) Ac₂O, Et₃N, DMAP, CH₂Cl₂, rt,

15 min (78%); (e) [Mo(CO)₄Br₂]₂, anisole, rt, 5 min (97%).

7602

I. Shiina et al. / Bioorg. Med. Chem. 15 (2007) 7599–7617

After several trials to migrate the double-bond in 15 un-

der basic or acidic conditions, it was found that BuOK

thanes were synthesized by the Friedel–Crafts alkylation

reaction of aromatic nucleophiles, such as anisole with

benzyl silyl ethers.³¹Furthermore, C⁰might be easily

prepared from benzaldehyde by the allylation with cinn-

amyl-type nucleophile D⁰in the presence of a Lewis acid

catalyst. Therefore, it was planned to explore an im-

proved method for the synthesis of 1 through the inter-

mediate B⁰using the coupling reactions among aromatic

aldehydes, allylic nucleophile D⁰, and aromatic nucleo-

philes, followed by the double-bond migration.

t

in DMSO promoted the desired reaction to form the

requisite oleﬁn 16 from 15 in 97% yield (Scheme 5).³³

We ﬁnally obtained tamoxifen (1) via the successive

deprotection of 16 and installation of the dimethylami-

noethyl moiety into the hydroxyl group of 17 by a con-

ventional method.

2.1.2. Synthesis of tamoxifen through three-component

coupling reaction. As described in the former section, we

found a new pathway to tamoxifen (1) using the aldol

reaction as a key step to prepare the desired backbone

via electrophiles 11a and 11b; however, this route re-

quired more than 10 steps to form the ﬁnal targeted

compound. At this stage, we decided to use the interme-

diate B⁰(in Scheme 6) identiﬁed with 15 (in Scheme 4)

for reducing the number of steps to prepare 1. It was

anticipated that the preparation of the key intermediates

B⁰could be realized by the acid catalyzed substitution of

C⁰with anisole because several substituted diarylme-

Based on the above hypothesis, we examined to develop

a novel three-component coupling reaction to aﬀord

3,4,4-triaryl butenes VII through the allylation reaction

of aromatic aldehydes and successive Friedel–Crafts

type alkylation of the resulting homoallyl silyl ethers

VI with aromatic nucleophiles (Ar–H) in the presence

of a Lewis acid catalyst (Scheme 7).³²Since this interme-

diate VII could be transformed into the tetra-substituted

oleﬁn VIII already shown in Scheme 5, we considered

that this methodology might be applied to the synthesis

Scheme 4. A preliminary study of tamoxifen synthesis via aldol and Friedel–Crafts type alkylation of benzylic acetate and anisole. Reagents and

conditions: (a) LiBH₄, THF, ꢀ78 ꢁC, 30 min (66% of 10a, 22% of 10b); (b) Ac₂O, Et₃N, DMAP, CH₂Cl₂, rt, 1 h (99% of 11a, 82% of 11b); (c)

Me₂C(OMe)₂, p-TsOHÆH₂O, CH₂Cl₂, rt, 5 min (91% of 12a, quant. of 12b); (d) anisole, Cl₂Si(OTf)₂, rt, 4 h (98% of 13a, 92% of 13b); (e) i—NaOH,

MeOH, 50 ꢁC, 5 h (81% from 13a, 99% from 13b); ii—MsCl, Et₃N, DMAP, CH₂Cl₂, rt, 1 h (quant. of 14a, quant. of 14b); (f) NaOH, MeOH, 75 ꢁC,

4 h (95% of 15 and 5% of (E)-9 from 14a, 60% of 15 and 40% of (Z)-9 from 14b).

I. Shiina et al. / Bioorg. Med. Chem. 15 (2007) 7599–7617

7603

t

Scheme 5. Double-bond migration reaction and installation of the side-chain structure of tamoxifen. Reagents and conditions: (a) BuOK, DMSO,

rt, 15 min (97%, E/Z = ca. 1:1); (b) BBr₃, CH₂Cl₂, ꢀ78 ꢁC, 2 h (quant.); (c) NaH, ClCH₂CH₂NMe₂, DMF, 50 ꢁC, 30 min (95%, E/Z = 46:54).

Scheme 6. Revised retrosynthetic route to the basic skeleton of tamoxifen via allylation.

Scheme 7. An improved synthetic pathway to tamoxifen derivatives via the three-component coupling reaction.

of tamoxifen derivatives; that is, the three-component

coupling among benzaldehyde, cinnamyltrimethylsi-

lane,^34,35and anisole to produce intermediate VII, fol-

lowed by the successive double-bond migration and

the side-chain installation to form 1,1,2-triaryl butenes

VIII which correspond to the basic skeleton of 1.^28,29,36

allyltrimethylsilane (Entry 1). When Cl₂Hf(OTf)₂or

Hf(OTf)₄was used for the reaction, a regioisomeric

mixture of the corresponding triarylmethanes 18 was

only obtained in 51% or 23% yield (Entry 3 or 4).

Second, TMSCl or TMSOTf was added to the reac-

tion mixture as a co-catalyst in order to increase the

activity of HfCl₄as shown in Entries 5-8.³⁷It was

then proved that the use of a mixture of a stoichiom-

etric amount of HfCl₄and 50 mol% TMSOTf was the

most eﬀective combination for this reaction, and the

desired trisubstituted butene 15 was produced in

57% yield via a one-pot operation (Entry 8). As

shown in Entries 9–12, the three-component coupling

reaction among the halogenated aromatic aldehydes,

First, benzaldehyde and cinnamyltrimethylsilane were

chosen as substrates to optimize the reaction condi-

tions for the three-component coupling reaction (Ta-

ble 1). Unfortunately, HfCl₄is not very eﬀective for

the reaction of benzaldehyde with cinnamyltrimethylsi-

lane in the anisole solvent because the reactivity of

cinnamyltrimethylsilane is lower compared to that of

7604

I. Shiina et al. / Bioorg. Med. Chem. 15 (2007) 7599–7617

Table 1. The three-component coupling reaction among aromatic aldehydes, cinnamyltrimethylsilane, and anisole using Lewis acid catalysts

Entry

X

Catalyst

Product

Yield/%

(o-)/(p-)

Yield of 18/%

1

H

HfCl₄

Cl₃Hf(OTf)

15

19

20

21

22

23

24

36

49

0

30/70

—

20

15

51

23

14

11

6

2

H

3

H

Cl₂Hf(OTf)₂

Hf(OTf)₄

4

H

0

—

5

H

HfCl₄+ TMSCl (0.5)

HfCl₄+ TMSCl (1)

HfCl₄+ TMSOTf (0.2)

HfCl₄+ TMSOTf (0.5)

HfCl₄

39

33

37

57

73

61

70

73

72

79

27/73

31/69

30/70

19/81

35/65

9/91

6

H

7

H

8

H

4

9

3-Br

3-l

18

3

10^a

11

12

13

14^a

HfCl₄

4-Br

4-l

14

7

HfCl₄

HfCl₄+ TMSOTf (0.5)

HfCl₄

16/84

19/81

2/98

3-PivO

4-PivO

11

1

^aThe reaction was carried out for 1 h.

cinnamyltrimethylsilane, and anisole, smoothly pro-

ceeded to give the products 19–22 in the presence of

HfCl₄without a co-catalyst since the reactivity of

these substituted aromatic aldehydes is higher than

that of benzaldehyde. Furthermore, 3- or 4-pivaloyl-

oxybenzaldehyde was also utilized for this system

using the combined catalyst or HfCl₄alone to form

the corresponding butene 23 or 24 in good yield (En-

tries 13 and 14).

matic aldehydes. It is noted that these halogenated

derivatives might not be eﬃciently prepared by the tran-

sition metal coupling methodology since the aryl halide

parts competitively react to form by-products under the

cross-coupling reaction conditions.

2.1.3. Synthesis of droloxifene through improved three-

component coupling reaction. Next, we planned to apply

this strategy to the synthesis of droloxifene (2) as

shown in Scheme 10. The three-component coupling

reaction among 3-pivaloyloxybenzaldehyde, cinnamyl-

trimethylsilane, and anisole proceeded to give the cor-

The migration of the double-bond in p-15 was then car-

ried out according to the procedure developed in

Scheme 5 (vide supra), and a geometric mixture of the

tetra-substituted alkenes 16 was produced in nearly

quantitative yield (Scheme 8). The deprotection of 16

and alkylation of the phenol moieties aﬀorded an iso-

meric mixture of the target compounds 1 and then these

isomers were separated by preparative TLC.^15,38

According to this improved method, we accomplished

the total synthesis of (Z)-1 in only four steps from benz-

aldehyde. Furthermore, the resulting (E)-1 was isomer-

ized to enrich the desired Z-isomer (Z/E = ca. 1:1) by

the reported procedure;^16,39therefore, (Z)-1 was ob-

tained in a 28% total yield from the starting substrate

(benzaldehyde) using this transformation and the second

separation of the geometric isomers.

responding 3,4,4-trisubstituted butene 23 in

a

satisfactory yield (Table 1, Entry 13) and it was then

converted to the desired intermediate 33 as well as the

case for the synthesis of 1. However, the chemoselec-

tive installation of the N,N-dimethylaminoethyl side-

chain to the framework of 33 required a complicated

roundabout pathway (eight steps) due to the existence

of a deprotection step for cleaving the O-methyl group

of 33 that originated from the anisole moiety of the

three-component coupling.²⁹

Based on the preliminary study of the synthesis of 2

using anisole in the key coupling, it was again planned

to use b-chlorophenetole (2-chloroethyl phenyl ether)

as a second nucleophile instead of anisole to the interme-

diary homoallyl silyl ethers C⁰in order to decrease the

total steps for the synthesis of 2 from the starting mate-

rials (Scheme 11). It seems that the chloroethoxy group

in the coupling product B⁰⁰will be easily converted to the

corresponding dialkylaminoethoxy group in A⁰⁰by the

treatment with a secondary dialkylamine before carrying

out the oleﬁn migration promoted by the basic catalyst.

This synthetic approach would be practically applicable

The substituted derivatives of 1 were also prepared in

good yields by a similar protocol as shown in Scheme

9. Successive double-bond migrations of 19–22 again

took place to aﬀord the desired tetra-substituted oleﬁns

in good yields. The usual treatments of these isomers

with BBr₃and NaH/ClCH₂CH₂NMe₂ÆHCl produced

the 3- or 4-halogenated tamoxifen relatives ((E)-29–

32)⁴⁰in good total yields from the corresponding aro-

I. Shiina et al. / Bioorg. Med. Chem. 15 (2007) 7599–7617

7605

Scheme 8. New synthetic pathway to tamoxifen via three-component coupling reaction. Reagents and conditions: (a) HfCl₄, TMSOTf, rt, 2 h, (57%,

(o-)/(p-) = 30:70); (b) ^tBuOK, DMSO, rt, 15 min (97% from p-15, E/Z = ca. 1:1); (c) BBr₃, CH₂Cl₂, ꢀ78 ꢁC, 2 h (quant.); (d) NaH, ClCH₂CH₂NMe₂,

DMF, 50 ꢁC, 30 min (51% of (Z)-1, 44% of (E)-1); (e) TfOH, CH₂Cl₂, 0 ꢁC, 3 h, (97% of 1 [51% of (Z)-1, 46% of (E)-1] from (E)-1).

Scheme 9. New synthetic pathway to tamoxifen derivatives via three-component coupling reaction. Reagents and conditions: (a) ^tBuOK, DMSO, rt,

15 min (68% of 25, 26% of 26, 89% of 27, 85% of 28); (b) i—BBr₃, CH₂Cl₂, ꢀ78 ꢁC, 2 h (94% from 25, 89% from 26, 92% from 27, 95% from 28); ii—

NaH, ClCH₂CH₂NMe₂ÆHCl, DMF, 50 ꢁC, 8–13 h (82% of 29 [46% of (E)-29, 36% of (Z)-29]), (75% of 30 [37% of (E)-30, 38% of (Z)-30]), (88% of 31

[45% of (E)-31, 43% of (Z)-31]), (95% of 32 [44% of (E)-32, 51% of (Z)-32]); (c) TfOH, CH₂Cl₂, 0 ꢁC, 3 h (88% of 29 [44% of (E)-29, 44% of (Z)-29]

from (Z)-29), (75% of 30 [38% of (E)-30, 37% of (Z)-30] from (Z)-30), (89% of 31 [46% of (E)-31, 43% of (Z)-31] from (Z)-31), (87% of 32 [42% of (E)-

32, 45% of (Z)-32] from (Z)-32).

for the eﬀective production of novel tamoxifen-type

SERMs.

by the reaction of 3-pivaloyloxybenzaldehyde with cinn-

amyltrimethylsilane in the b-chlorophenetole solvent to

optimize the suitable ratio of TMSOTf to HfCl₄. When

no co-catalyst was added to the reaction system, a large

amount of the starting 3-pivaloyloxybenzaldehyde was

recovered and the corresponding homoallyl alcohol

derived from the intermediate alkyl silyl ether was

The results of the three-component coupling reaction

among 3-pivaloyloxybenzaldehyde, cinnamyltrimeth-

ylsilane, and b-chlorophenetole are summarized in Ta-

ble 2. First, amount of the co-catalyst was investigated

7606

I. Shiina et al. / Bioorg. Med. Chem. 15 (2007) 7599–7617

Scheme 10. Preliminary synthetic route for the preparation of droloxifene using the three-component coupling reaction.²⁹

Scheme 11. Retrosynthetic route to the basic skeleton of tamoxifen via allylation.

Table 2. The three-component coupling reaction among 3-pivaloyloxybenzaldehyde, cinnamyltrimethylsilane, and b-chlorophenetole using HfCl₄

and TMSOTf as the catalysts

Entry

x

y

Yield of 34/%

Yield of 35/%

1

2

3

4

5

6

7

8

1.0

1.5

2.0

0

12

26

Trace

21

15

0.05

0.1

0.2

0.3

0.5

0.1

27

21

23

26

19

Trace

38

43

30

5

18

mainly obtained (Entry 1). In Entries 5 and 6, a large

amount of triarylmethanes 35, which were produced

from a 1 M amount of 3-pivaloyloxybenzaldehyde and

2 M amounts of b-chlorophenetole, was preferentially

produced by the addition of 30–50 mol% of the co-cata-

lyst to the reaction mixture because the aldehyde was

over-activated by TMSOTf. On the other hand, the de-

sired three-component coupling product 34 was ob-

tained in a better yield when 10 mol% of TMSOTf was

additionally used with a stoichiometric amount of HfCl₄

as shown in Entry 3. The yield of the desired three-com-

ponent coupling product was ﬁnally improved up to

43% using a twofold amount of cinnamyltrimethylsilane

to 3-pivaloyloxybenzaldehyde (Entry 8). It was also re-

vealed that all of the reactions aﬀorded nearly equal

amounts of the syn- and anti-diastereomers of the

3,4,4-trisubstituted butenes by the careful analysis using

HPLC-MS. Furthermore, the formation of a trace

amount of o-isomers that originated from the nucleo-

philic substitution of b-chlorophenetole with intermedi-

ary homoallyl silyl ethers was also detected by the

HPLC-MS analysis ((o-)/(p-) = 2:98).

I. Shiina et al. / Bioorg. Med. Chem. 15 (2007) 7599–7617

7607

Next, the N,N-dimethylamination was successfully

accomplished by heating the three-component coupling

product 34 with 30% dimethylamine in ethanol at

110 ꢁC in a sealed vessel for 8 h to produce a mixture

of syn- and anti-3,4,4-trisubstituted butenes 36 having

the side-chain in good yield (Scheme 12). The pivaloyl

protective group was simultaneously removed under

these reaction conditions. The syn- and anti-isomers

are separable at this stage by silica gel column chroma-

tography, however, no further puriﬁcation was carried

out since it is unnecessary to separate these compounds

for preparing the identical 1,1,2-trisubstituted butene 2

by the double-bond migration in the next step.

in Scheme 13. The three-component coupling reaction

among benzaldehyde, cinnamyltrimethylsilane, and b-

chlorophenetole successfully proceeded in the presence

of HfCl₄without a co-catalyst to aﬀord the key interme-

diate 37 in 43% yield. Successive transformations similar

to the method for the preparation of 2 were successfully

carried out by way of two steps via 38, and the total syn-

thesis of 1 was then accomplished through a very short

pathway (three steps).

2.2. Biological evaluations of the coupling products

against HL-60 promyelocytic leukemia

The potency of the anti-tumor activities of tamoxifen

derivatives was assessed in this study. In order to evalu-

ate the anti-tumor activities of our compounds against

the HL-60 human acute promyelocytic leukemia, we

tried to determine the eﬃciency of the synthesized com-

pounds decreasing the cell viability by the MTT (3-(4,5-

dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide)

assay, a method of determining cell viability by measur-

ing the mitochondrial succinic dehydrogenase activity.

Finally, the desired (E)-2 was prepared in 49% yield

from the 3,4,4-trisubstituted butenes 36 by treatment

with an excess amount of BuOK in DMSO at 50 ꢁC

t

via the base catalyzed double-bond migration reaction

established for the synthesis of 1 (Scheme 5). Although

this oleﬁn transformation produced the desired com-

pound (E)-2 together with a nearly amount of (Z)-2,

the isomers are easily separable by silica gel chromatog-

raphy or fractional crystallization of the corresponding

acid salts. Furthermore, each isomer could be facilely

transformed into a mixture of (E)-2 and (Z)-2 again

by the treatment with triﬂuoromethanesulfonic acid in

CH₂Cl₂, therefore, the combined yield of (E)-2 could

be increased to nearly 70% by involving this isomeriza-

tion procedure.

The eﬀects of tamoxifen, 4-bromotamoxifen, 3-iodotam-

oxifen, and idoxifene on growth of the HL-60 human

cell line were ﬁrst measured by the MTT assay after a

4-h incubation (Table 3). A treatment of the HL-60 cells

with 5 lg/mL of tamoxifen gave ca. 50% of the ﬁnal via-

bility of the inhibited cells compared with the cell viabil-

ity at 0 h. A similar result was obtained when 5 lg/mL of

4-bromotamoxifen was used under the same conditions

for the inhibition of the cell viability. On the other hand,

5 lg/mL of 3-iodotamoxifen showed no aﬀect on the

viability of the HL-60 cells after 4 h.

2.1.4. Synthesis of tamoxifen through improved three-

component coupling reaction. As a ﬁnal study, the im-

proved method for the preparation of droloxifene (2)

was applied to the synthesis of tamoxifen (1) as shown

Scheme 12. Synthesis of droloxifene (2) through improved three-component coupling reaction. Reagents and conditions: (a) HfCl₄, TMSOTf, rt, 2 h

t

(43%, (o-)/(p-) = 2:98); (b) 30% dimethylamine, EtOH, 110 ꢁC, 8 h (81%); (c) BuOK, DMSO, 50 ꢁC, 2 h (49% of (E)-2, 38% of (Z)-2); (d) TfOH,

CH₂Cl₂, 0 ꢁC, 2 h, (73% of 2 [37% of (E)-2, 36% of (Z)-2] from (Z)-2).

7608

I. Shiina et al. / Bioorg. Med. Chem. 15 (2007) 7599–7617

Scheme 13. Synthesis of tamoxifen (1) through improved three-component coupling reaction. Reagents and conditions: (a) HfCl₄, rt, 4 h (43%); (b)

30% dimethylamine, 110 ꢁC, 8 h (93%); (c) ^tBuOK, DMSO, rt, 1 h (39% of (Z)-1, 37% of (E)-1); (d) TfOH, CH₂Cl₂, 0 ꢁC, 3 h, (97% of 1 [51% of (Z)-

1, 46% of (E)-1] from (E)-1).

Table 3. Inhibition of the cell viability of the HL-60 cell lines at various concentrations

Concentration (lg/mL)

0

1

5

10

20

5.4447

Tamoxifen (line a)

100

96.1704

99.9285

53.5425

59.2228

15.9127

13.1845

97.2073

25.4653

4-Bromotamoxifen (line b)

3-Iodotamoxifen (line c)

Idoxifene (line d)

7.01505

36.055

8.71871

108.523

105.706

103.916

82.701

nal concentrations of 5, 10, and 20 lg/mL decreased the

cell viability in a dose-dependent manner. A 4-h incuba-

tion with 10 lg/mL ﬁnal concentration of tamoxifen and

4-bromotamoxifen inhibited the cell viability more than

80% as measured by the MTT assay. Idoxifene in 10 lg/

mL concentration inhibited the cell viability more than

70% after a 4-h treatment, whereas 3-iodotamoxifen in

5 and 10 lg/mL concentrations did not inhibit the cell

viability at all under the same conditions. Among them,

tamoxifen, 4-bromotamoxifen, and idoxifene clearly in-

duced, dose-dependently, cell death to a greater extent

than 3-iodotamoxifen as shown in Figure 2. The median

growth-inhibitory concentrations (IC₅₀) against the HL-

60 cells after a 4-h incubation with tamoxifen, 4-bromo-

tamoxifen, and idoxifene were calculated as 5.9, 6.0, and

7.7 lg/mL, respectively. Although tamoxifen, 4-bromo-

tamoxifen, and idoxifene have strong cytotoxic activities

inducing apoptosis of the HL-60 cells, 3-iodotamoxifen

shows very low activity on the same cells

(IC₅₀= 19.0 lg/mL).

Figure 2. Eﬀects of tamoxifen (line a), 4-bromotamoxifen (line b), 3-

iodotamoxifen (line c), and idoxifene (line d) on the cell viability after a

4-h incubation. The dose-dependent eﬀects of tamoxifen derivatives to

HL-60 cells were measured by the MTT assay. The cell viability

obtained from the absorbance of formazan at 0 h was 100%.

We next investigated the eﬀects on the dose-dependent

viability of the HL-60 cells treated with tamoxifen, 4-

bromotamoxifen, 3-iodotamoxifen, and idoxifene at

various concentrations after a 4-h treatment (Table 3

and Fig. 2). Tamoxifen and 4-bromotamoxifen in the ﬁ-

3. Conclusions

We have developed new protocols to prepare tamoxifen

and its derivatives. The ﬁrst route involved the aldol

I. Shiina et al. / Bioorg. Med. Chem. 15 (2007) 7599–7617

7609

reaction of benzyl phenyl ketone with acetaldehyde fol-

lowed by the Friedel–Crafts substitution with anisole in

the presence of Cl₂Si(OTf)₂to produce 1,1,2-triaryl-3-

acetoxybutane, a precursor of the tamoxifen derivatives.

The alternative approach utilized the novel three-com-

ponent coupling reaction among aromatic aldehydes,

cinnamyltrimethylsilane, and aromatic nucleophiles

using HfCl₄as a Lewis acid catalyst to produce 3,4,4-tri-

arylbutene, that is also a valuable intermediate of

tamoxifen derivatives. The latter synthesis needs only

three or four steps to produce the basic skeleton of SER-

Ms including the installation of the side-chain moiety

and the double-bond migration to form the tetra-substi-

tuted oleﬁn structure. Although 3-iodotamoxifen has

very low biological activity during the MTT assay,

tamoxifen, 4-bromotamoxifen, and idoxifene showed

signiﬁcant anti-tumor activities against the HL-60 hu-

man acute promyelocytic leukemia. This synthetic strat-

egy seems to serve as a new and practical pathway to

prepare not only the tamoxifen derivatives, but also

other SERMs including estrogen-dependent breast can-

cer, leukemia, and osteoporosis agents.

n-butyllithium in hexane (1.56 M, 25.1 mL, 39.2 mmol).

After the reaction mixture had been stirred for 30 min at

0 ꢁC, a solution of 1,2-diphenylbutanone (3) (7.00 g,

35.6 mmol) in THF (50 mL) was added at ꢀ78 ꢁC.

The reaction mixture was stirred for 1 h at ꢀ78 ꢁC and

then a solution of acetaldehyde (2.40 mL, 42.7 mmol)

in THF (50 mL) was added. After the reaction mixture

had been stirred for 1 h at ꢀ78 ꢁC, saturated aqueous

ammonium chloride was added. The mixture was ex-

tracted with diethyl ether, and the organic layer was

washed with brine, dried over sodium sulfate. After ﬁl-

tration of the mixture and evaporation of the solvent,

the crude product was puriﬁed by column chromatogra-

phy to aﬀord a mixture of diastereomers of 4 (8.00 g,

94%, anti/syn = 73:27) as a colorless oil; IR (neat):

1

3487, 3433, 1674 cm^ꢀ1; H NMR (CDCl₃): d 7.93–7.87

(m, 2H, Ph), 7.48–7.14 (m, 8H, Ph), 4.56–4.42 (m, 2H,

2-H, 3-H), 2.70 (br s, 1H, OH), 1.19, 1.14 (d, J = 6.1,

5.8 Hz, 3H, 4-H).

4.2. (E)- and (Z)-1,2-Diphenylbut-2-eneone (5)

To a solution of 4 (7.36 g, 30.6 mmol) in benzene

(60 mL) at room temperature were added p-toluenesul-

fonic acid monohydrate (263 mg, 1.53 mmol) and so-

dium sulfate (2.18 g, 15.3 mmol). The reaction mixture

was reﬂuxed for 1 h and then saturated aqueous sodium

hydrogencarbonate was added at 0 ꢁC. The mixture was

extracted with diethyl ether, and the organic layer was

washed with brine, dried over sodium sulfate. After ﬁl-

tration of the mixture and evaporation of the solvent,

the crude product was puriﬁed by column chromatogra-

phy to aﬀord a mixture of geometric isomers of 5

(5.85 g, 86%, E/Z = 1:1) as a colorless oil; ¹H NMR

(CDCl₃): d 7.90–7.63 (m, 2H, Ph), 7.46–7.12 (m, 8H,

Ph), 6.34, 6.24 (q, J = 7.3 Hz, 1H, 3-H), 1.78, 1.67 (d,

J = 7.3 Hz, 3H, 4-H).

4. Experimental

All melting points were measured on a Yanaco MP-S3

micro-melting point apparatus. IR spectra were re-

corded on a Horiba FT-300 infrared spectrometer or a

Perkin Elmer spectrum One FT-IR spectrometer.

¹H and ¹³C NMR spectra were recorded on a JEOL

JNM-EX270L, a JEOL JNM-AL300, or a JEOL JNM-

LA500 spectrometer with tetramethylsilane (TMS) or

chloroform (in chloroform-d) as internal standards.

High-resolution mass spectra were recorded on a JEOL

JMS-SX102A instrument using 4-nitrobenzyl alcohol as

a matrix or an Applied Biosystems Mariner system 5055

or Bruker Daltonics micro TOF focus instrument.

HPLC was carried out using a Hitachi L-4000 UV detec-

tor, L-6200 Intelligent Pump, and D-2500 Chromato-

Integrator with a Senshu Pak Pegasil ODS-II (4.6 mm

ID · 250 mm L).

4.3. (E)-1,2-Diphenylbut-2-enol (6)

To a solution of 5 (6.44 g, 31.4 mmol) in methanol

(80 mL) at 0 ꢁC were added cerium trichloride (11.7 g,

31.4 mmol) and sodium borohydride (1.18 g, 31.4 mmol).

The reaction mixture was stirred for 15 min at 0 ꢁC and

then saturated aqueous sodium hydrogencarbonate was

added. The mixture was extracted with diethyl

ether, and the organic layer was washed with brine, dried

over sodium sulfate. After ﬁltration of the mixture

and evaporation of the solvent, the crude product was

puriﬁed by column chromatography to aﬀord the titled

compound 6 (880 mg, 15%), its geometric isomer

(2.92 g, 50%), and the unreacted (E)-5 (2.25 g, 35%

recovery).

Column chromatography was performed on Silica gel 60

(Merck) or Wakogel B5F. Thin layer chromatography

was performed on Wakogel B5F. All reactions were car-

ried out under an argon atmosphere in dried glassware,

unless otherwise noted. Dichloromethane was distilled

from diphosphorus pentoxide, then calcium hydride,

and dried over MS 4A, toluene and DMF were distilled

from diphosphorus pentoxide, and dried over MS 4A,

and THF was distilled from sodium/benzophenone

immediately prior to use. Other reagents and solvents

were purchased from Tokyo Kasei Kogyo Co., Ltd;

Kanto Chemical Co., Inc.; or Aldrich Chemical Co.,

Inc., and used without further puriﬁcation unless other-

wise noted.

To a solution of (E)-5 (2.00 g, 9.00 mmol) in methanol

(36 mL) at 0 ꢁC were added cerium trichloride (3.35 g,

9.00 mmol) and sodium borohydride (341 mg, 9.00 mmol).

The reaction mixture was stirred for 12 h at room

temperature and then saturated aqueous sodium

hydrogencarbonate was added at 0 ꢁC. The mixture

was extracted with diethyl ether, and the organic layer

was washed with brine, dried over sodium sulfate. After

ﬁltration of the mixture and evaporation of the solvent,

4.1. (2RS,3RS)/(2RS,3SR)-3-Hydroxy-1,2-diphenylbuta-

none (4)

To a solution of diisopropylamine (6.00 mL, 42.7 mmol)

in THF (250 mL) at 0 ꢁC was added a solution of

7610

I. Shiina et al. / Bioorg. Med. Chem. 15 (2007) 7599–7617

the crude product was puriﬁed by column chromatogra-

phy to aﬀord the titled compound 6 (646 mg, 30%) as a

colorless oil; IR (neat): 3410 cm^ꢀ1; ¹H NMR (CDCl₃): d

7.30–6.98 (m, 10H, Ph), 5.87 (s, 1H, 1-H), 5.79 (q,

J = 7.1 Hz, 1H, 3-H), 2.18 (br s, 1H, OH), 1.79 (d,

J = 7.1 Hz, 3H, 4-H); ¹³C NMR (CDCl₃): d 142.5,

142.3, 140.0, 128.2, 128.2, 127.9, 127.9, 126.8, 126.7,

125.6, 70.9, 14.1.

colorless solid and 10b (451 mg, 22%) as a colorless oil.

1

10a; mp 134–136 ꢁC; IR (KBr): 3433 cm^ꢀ1; H NMR

(CDCl₃):

d

7.24–6.95 (m, 10H, Ph), 5.29 (d,

J = 4.3 Hz, 1H, 1-H), 4.30 (dq, J = 8.6, 6.3 Hz, 1H, 3-

H), 2.91 (dd, J = 4.3, 8.6 Hz, 1H, 2-H), 1.09 (d,

J = 6.3 Hz, 3H, 4-H); ¹³C NMR (CDCl₃): d 141.4,

138.1, 129.7, 128.0, 127.9, 127.3, 126.8, 126.6, 75.1,

1

68.7, 60.1, 22.3. 10b; IR (neat): 3356 cm^ꢀ1; H NMR

(CDCl₃):

d

7.19–7.13 (m, 10H, Ph), 5.10 (d,

4.4. (E)-4-Acetoxy-3,4-diphenylbut-2-ene (7)

J = 6.9 Hz, 1H, 1-H), 3.88 (dq, J = 3.6, 6.4 Hz, 1H, 3-

H), 2.61 (dd, J = 3.6, 6.9 Hz, 1H, 2-H), 2.27 (br s, 2H,

OH), 0.85 (d, J = 6.4 Hz, 3H, 4-H); ¹³C NMR (CDCl₃):

d 142.6, 136.6, 130.4, 128.0, 127.7, 127.4, 127.0, 126.5,

76.1, 68.6, 59.9, 22.0.

To a solution of 6 (300 mg, 1.34 mmol) in dichlorometh-

ane (3 mL) at 0 ꢁC were added triethylamine (0.28 mL,

2.0 mmol), acetic anhydride (0.18 mL, 1.6 mmol), and

DMAP (32.7 mg, 0.268 mmol). The reaction mixture

was stirred for 15 min at room temperature and then

saturated aqueous sodium hydrogencarbonate was

added at 0 ꢁC. The mixture was extracted with dichloro-

methane, and the organic layer was washed with brine,

dried over sodium sulfate. After ﬁltration of the mixture

and evaporation of the solvent, the crude product was

puriﬁed by column chromatography to aﬀord the titled

compound 7 (279 mg, 78%) as a colorless oil; IR (neat):

4.7. (1RS,2SR,3SR)-1,3-Diacetoxy-1,2-diphenylbutane

(11a)

To a solution of 10a (2.05 g, 8.47 mmol) in dichlorometh-

ane (33 mL) at 0 ꢁC were added triethylamine (4.1 mL,

30 mmol), acetic anhydride (2.60 mL, 27.6 mmol), and

DMAP (207 mg, 1.69 mmol). The reaction mixture was

stirred for 1 h at room temperature and then saturated

aqueous ammonium chloride was added at 0 ꢁC. The mix-

ture was extracted with dichloromethane, and the organic

layer was washed with brine, dried over sodium sulfate.

After ﬁltration of the mixture and evaporation of the sol-

vent, the crude product was puriﬁed by column chroma-

tography to aﬀord the titled compound 11a (2.72 g,

99%) as a colorless solid; mp 103–106 ꢁC; IR (KBr):

1743 cm^ꢀ^{1 1}H NMR (CDCl₃): d 7.23–7.10 (m, 10H,

;

Ph), 6.95 (s, 1H, 4-H), 5.90 (q, J = 7.1 Hz, 1H, 2-H),

2.00 (s, 3H, Ac), 1.90 (d, J = 7.1 Hz, 3H, 1-H); ¹³C

NMR (CDCl₃): d 170.1, 140.5, 139.1, 138.7, 128.3,

128.1, 127.9, 127.9, 127.4, 126.8, 126.2, 73.3, 21.1, 14.1.

4.5. (Z)-3-(4-Methoxyphenyl)-1,2-diphenylbut-1-ene (8)

1705 cm^ꢀ^{1 1}H NMR (CDCl₃): d 7.20–6.28 (m, 10H,

;

To a solution of 7 (79.9 mg, 0.300 mmol) in anisole

(1.2 mL) at room temperature was added a solution of

[Mo(CO)₄Br₂]₂(9.4 mg, 0.013 mmol) in anisole

(0.3 mL). The reaction mixture was stirred for 5 min at

room temperature and then saturated aqueous sodium

hydrogencarbonate was added at 0 ꢁC. The mixture was

extracted with diethyl ether, and the organic layer was

washed with brine, dried over sodium sulfate. After ﬁltra-

tion of the mixture and evaporation of the solvent, the

crude product was puriﬁed by column chromatography

to aﬀord the titled compound 8 (91.5 mg, 97%) as a color-

less oil; IR (neat): 1250 cm^ꢀ1; ¹H NMR (CDCl₃): d 7.21–

6.70 (m, 14H, Ph), 6.40 (s, 1H, 1-H), 3.78 (q, J = 7.1 Hz,

1H, 3-H), 3.70 (s, 3H, OMe), 1.38 (d, J = 7.1 Hz, 3H, 4-

H); ¹³C NMR (CDCl₃): d 158.0, 147.5, 140.8, 137.3,

136.2, 129.0, 129.0, 128.9, 128.1, 127.8, 126.7, 126.1,

126.1, 113.5, 55.1, 47.9, 22.0; HR MS (FAB) calcd for

C₂₃H₂₂O [M⁺] 314.1670, found 314.1672.

Ph), 6.27 (d, J = 4.5 Hz, 1H, l-H), 5.38 (dq, J = 6.3,

10.2 Hz, 1H, 3-H), 3.08 (dd, J = 4.5, 10.2 Hz, 1H, 2-H),

2.05 (s, 3H, Ac), 2.04 (s, 3H, Ac), 1.01 (d, J = 6.3 Hz,

3H, 4-H); ¹³C NMR (CDCl₃): d 171.5, 171.5, 142.2,

136.7, 129.8, 127.9, 127.9, 127.7, 126.9, 125.9, 72.7, 71.1,

58.8, 21.1, 21.1, 19.1; Anal. calcd for C₂₀H₂₂O₄, C

73.60; H, 6.79, found: C, 73.61; H, 6.84.

4.8. (1RS,2SR,3RS)-1,3-Diacetoxy-1,2-diphenylbutane

(11b)

To a solution of 10b (1.00 g, 4.13 mmol) in dichloro-

methane (16.5 mL) at 0 ꢁC were added triethylamine

(1.74 mL, 12.5 mmol), acetic anhydride (1.10 mL,

11.7 mmol), and DMAP (102 mg, 0.835 mmol). The

reaction mixture was stirred for 1 h at room temperature

and then saturated aqueous ammonium chloride was

added at 0 ꢁC. The mixture was extracted with dichloro-

methane, and the organic layer was washed with brine,

dried over sodium sulfate. After ﬁltration of the mixture

and evaporation of the solvent, the crude product was

puriﬁed by column chromatography to aﬀord the titled

compound 11b (1.11 g, 82%) as a colorless solid; mp

4.6. (1RS,2SR,3SR)-1,2-Diphenylbutane-1,3-diol (10a)

and (1RS,2SR,3RS)-1,2-diphenylbutane-1,3-diol (10b)

To a solution of 4 (2.00 g, 8.32 mmol) in THF (33 mL)

at ꢀ78 ꢁC was added a solution of lithium borohydride

in THF (2.0 M, 4.37 mL, 8.74 mmol). The reaction mix-

ture was stirred for 30 min at ꢀ78 ꢁC and then saturated

aqueous ammonium chloride was added. The mixture

was extracted with diethyl ether, and the organic layer

was washed with brine, dried over sodium sulfate. After

ﬁltration of the mixture and evaporation of the solvent,

the crude product was puriﬁed by column chromatogra-

phy to aﬀord the titled compound 10a (1.32 g, 66%) as a

1

103–104 ꢁC; IR (KBr): 1736 cm^ꢀ1; H NMR (CDCl₃):

d 7.23–7.17 (m, 10H, Ph), 6.12 (d, J = 9.4 Hz, 1H, 1-

H), 4.73 (dq, J = 6.3, 4.3 Hz, 1H, 3-H), 3.06 (dd,

J = 4.3, 9.4 Hz, 1H, 2-H), 2.00 (s, 3H, Ac), 1.71 (s,

3H, Ac), 0.97 (d, J = 6.3 Hz, 3H, 4-H); ¹³C NMR

(CDCl₃): d 170.1, 170.0, 138.7, 137.2, 129.8, 128.6,

128.5, 127.9, 127.0, 127.0, 76.0, 70.1, 56.4, 21.2, 20.8,

18.5; Anal. calcd for C₂₀H₂₂O₄: C, 73.60; H, 6.79, found:

C, 73.56; H, 6.76.

I. Shiina et al. / Bioorg. Med. Chem. 15 (2007) 7599–7617

7611

4.9. (1RS,2SR,3SR)-3-Acetoxy-1-(4-methoxyphenyl)-

1,2-diphenylbutane (13a)

was washed with brine, dried over sodium sulfate.

After ﬁltration of the mixture and evaporation of the

solvent, the crude product was puriﬁed by thin layer

chromatography to aﬀord the titled compound 13a⁰

(47.0 mg, 81%) as a colorless solid; mp 97–101 ꢁC; IR

To

a solution of silver triﬂuoromethanesulfonate

(257 mg, 1.00 mmol) in anisole (2.5 mL) at 0 ꢁC was

added tetrachlorosilane (0.059 mL, 0.51 mmol). After

the reaction mixture had been stirred for 15 min at

0 ꢁC, a solution of 11a (160 mg, 0.49 mmol) in anisole

(2 mL) was added. The reaction mixture was stirred

for 4 h at room temperature and then saturated aqueous

sodium hydrogencarbonate was added at 0 ꢁC. The mix-

ture was extracted with diethyl ether, and the organic

layer was washed with brine, dried over sodium sulfate.

After ﬁltration of the mixture and evaporation of the

solvent, the crude product was puriﬁed by thin layer

chromatography to aﬀord the titled compound 13a

(179 mg, 98%) as a colorless solid; mp 126–128 ꢁC; IR

1

(KBr): 3433 cm^ꢀ1; H NMR (CDCl₃): d 7.36–7.01 (m,

12H, Ar), 6.55 (d, J = 8.7 Hz, 2H, Ar), 4.27 (br d,

J = 11.9 Hz, 1H, 4-H), 3.80–3.75 (m, 2H, 2-H, 3-H),

3.57 (s, 3H, OMe), 1.29 (br s, 1H, OH), 0.94 (d,

J = 6.3 Hz, 3H, 1-H); ¹³C NMR (CDCl₃): d 157.4,

143.9, 138.0, 135.4, 130.1, 129.0, 128.9, 127.9, 127.7,

126.4, 126.4, 113.5, 68.4, 55.7, 54.9, 52.5, 18.4; HR

MS (FAB) calcd for C₂₃H₂₄O₂Na [M+Na]⁺355.1674,

found 355.1673.

4.12. (2RS,3SR,4RS)-4-(4-Methoxyphenyl)-3,4-diphe-

nylbutan-2-ol (13b⁰)

1

(KBr): 1728 cm^ꢀ1; H NMR (CDCl₃): d 7.37–6.94 (m,

12H, Ar), 6.50 (d, J = 8.7 Hz, 2H, Ar), 5.00 (dq,

J = 6.4, 5.6 Hz, 1H, 3-H), 4.21 (d, J = 12.0 Hz, 1H, 1-

H), 3.92 (dd, J = 5.6, 12.0 Hz, 1H, 2-H), 3.53 (s, 3H,

OMe), 1.70 (s, 3H, Ac), 0.96 (d, J = 6.4 Hz, 3H, 4-H);

¹³C NMR (CDCl₃): d 170.5, 157.3, 143.6, 138.6, 135.5,

129.9, 128.9, 128.7, 127.7, 127.7, 126.4, 126.4, 113.5,

72.1, 54.9, 53.1, 52.1, 21.0, 15.8; Anal. calcd for

C₂₅H₂₆O₃: C, 80.18; H, 7.00, found: C, 80.28; H, 7.03.

To a solution of 13b (2.20 g, 5.86 mmol) in methanol

(60 mL) at room temperature was added sodium

hydroxide (269 mg, 6.73 mmol). The reaction mixture

was stirred for 5 h at 50 ꢁC and then saturated aqueous

ammonium chloride was added at 0 ꢁC. The mixture was

extracted with diethyl ether, and the organic layer was

washed with brine, dried over sodium sulfate. After ﬁl-

tration of the mixture and evaporation of the solvent,

the crude product was puriﬁed by column chromatogra-

phy to aﬀord the titled compound 13b⁰(1.92 g, 99%) as a

colorless solid; mp 101–103 ꢁC; IR (KBr): 3541,

4.10. (1RS,2SR,3RS)-3-Acetoxy-1-(4-methoxyphenyl)-

1,2-diphenylbutane (13b)

3471 cm^ꢀ^{1 1}H NMR (CDCl₃): d 7.45–7.10 (m, 12H,

;

To

a

solution of silver triﬂuoromethanesulfonate

Ar), 6.51 (d, J = 8.7 Hz, 2H, Ar), 4.64 (d, J = 12.3 Hz,

1H, 4-H), 3.79 (dq, J = 2.3, 6.4 Hz, 1H, 2-H), 3.61 (s,

3H, OMe), 3.37 (dd, J = 2.3, 12.3 Hz, 1H, 3-H), 1.26

(br s, 1H, OH), 0.90 (d, J = 6.4 Hz, 3H, 1-H); ¹³C

NMR (CDCl₃): d 157.2, 144.6, 138.5, 135.7, 130.0,

129.3, 128.7, 128.1, 127.9, 126.3, 126.2, 113.4, 66.6,

56.0, 54.9, 52.2, 22.7; HR MS (FAB) calcd for

C₂₈H₂₄O₂Na [M+Na]⁺355.1674, found 355.1667.

(257 mg, 1.00 mmol) in anisole (2.5 mL) at 0 ꢁC was

added tetrachlorosilane (0.059 mL, 0.51 mmol). After

the reaction mixture had been stirred for 15 min at

0 ꢁC, a solution of 11b (150 mg, 0.458 mmol) in anisole

(2 mL) was added. The reaction mixture was stirred

for 4 h at room temperature and then saturated aqueous

sodium hydrogencarbonate was added at 0 ꢁC. The mix-

ture was extracted with diethyl ether, and the organic

layer was washed with brine, dried over sodium sulfate.

After ﬁltration of the mixture and evaporation of the

solvent, the crude product was puriﬁed by thin layer

chromatography to aﬀord the titled compound 13b

(158 mg, 92%) as a colorless solid; mp 131–132 ꢁC; IR

4.13. (1RS,2SR,3SR)-3-Methanesulfonyl-1-(4-methoxy-

phenyl)-1,2-diphenylbutane (14a)

To a solution of 13a⁰(5.71 g, 15.2 mmol) in dichloro-

methane (15 mL) at 0 ꢁC were added triethylamine

(3.45 mL, 36.6 mmol), methanesulfonyl chloride (2.36

mL, 30.5 mmol), and DMAP (372 mg, 3.05 mmol).

The reaction mixture was stirred for 1 h at room temper-

ature and then saturated aqueous sodium hydrogencar-

bonate was added at 0 ꢁC. The mixture was extracted

with dichloromethane, and the organic layer was

washed with brine, dried over sodium sulfate. After ﬁl-

tration of the mixture and evaporation of the solvent,

the crude product was puriﬁed by column chromatogra-

phy to aﬀord the titled compound 14a (6.25 g, quant.) as

a colorless solid; mp 52–54 ꢁC; IR (KBr): 1350 cm^ꢀ1; ¹H

NMR (CDCl₃): d 7.38–7.00 (m, 12H, Ar), 6.52 (d,

J = 8.7 Hz, 2H, Ar), 4.82 (dd, J = 4.0, 6.4 Hz, 1H,

3-H), 4.22–4.10 (m, 2H, l-H, 2-H), 3.54 (s, 3H, OMe),

2.70 (s, 3H, Ms), 1.15 (d, J = 6.4 Hz, 3H, 4-H); ¹³C

NMR (CDCl₃): d 157.5, 142.6, 136.4, 134.6, 130.3,

129.1, 128.8, 127.9, 127.6, 126.9, 126.8, 113.6, 79.5,

54.9, 53.2, 52.0, 38.0, 15.9; Anal. calcd for C₂₄H₂₆O₄S:

C, 70.22; H, 6.38, found: C, 70.33; H, 6.55.

(KBr): 1728 cm^ꢀ1; H NMR (CDCl₃): d 7.24–6.96 (m,

1

12H, Ar), 6.51 (d, J = 8.7 Hz, 2H, Ar), 4.79 (dq,

J = 6.4, 2.8 Hz, 1H, 3-H), 4.32 (d, J = 12.3 Hz, 1H,

l-H), 3.54 (s, 3H, OMe), 3.40 (dd, J = 2.8, 12.3 Hz,

1H, 2-H), 2.00 (s, 3H, Ac), 0.87 (d, J = 6.4 Hz, 3H,

4-H); ¹³C NMR (CDCl₃): d 170.0, 157.4, 143.5, 139.0,

135.2, 130.1, 129.0, 128.8, 127.7, 127.7, 126.6, 126.4,

113.5, 70.7, 54.9, 54.5, 53.2, 21.2, 18.7; Anal. calcd for

C₂₅H₂₆O₃: C, 80.18; H, 7.00, found: C, 80.09; H, 6.99.

4.11. (2RS,3RS,4SR)-4-(4-Methoxyphenyl)-3,4-diphe-

nylbutan-2-ol (13a⁰)

To a solution of 13a (65.8 mg, 0.176 mmol) in metha-

nol (1.8 mL) at room temperature was added sodium

hydroxide (8.1 mg, 0.20 mmol). The reaction mixture

was stirred for 5 h at 50 ꢁC and then saturated aqueous

ammonium chloride was added at 0 ꢁC. The mixture

was extracted with diethyl ether, and the organic layer

7612

I. Shiina et al. / Bioorg. Med. Chem. 15 (2007) 7599–7617

4.14. (1RS,2SR,3RS)-3-Methanesulfonyl-1-(4-methoxy-

phenyl)-1,2- diphenylbutane (14b)

(neat): 1605, 1504, 1250 cm^ꢀ^{1 1}H NMR (CDCl₃): d

;

7.28–6.69 (m, 12H, Ar), 6.47 (d, J = 8.6 Hz, 2H, Ar),

3.76 and 3.74 (s, 3H, OMe), 2.43 and 2.38 (q, J = 7.4 Hz,

2H, 3-H), 0.87 and 0.85 (t, J = 7.4 Hz, 3H, 4-H); ¹³C

NMR (CDCl₃): d 158.3, 157.4, 143.8, 143.3, 142.4,

142.3, 141.8, 141.3, 138.4, 138.2, 136.0, 135.4, 131.8,

130.8, 130.6, 129.7, 129.4, 128.1, 127.8, 127.7, 127.3,

126.5, 126.0, 125.6, 113.4, 112.7, 55.1, 54.9, 29.0, 13.6.

To a solution of 13b⁰(1.00 g, 3.01 mmol) in dichlorometh-

ane (3 mL) at 0 ꢁC were added triethylamine (0.681 mL,

7.22 mmol), methanesulfonyl chloride (0.521 mL, 6.62

mmol), and DMAP (80.7 mg, 0.662 mmol). The reaction

mixture was stirred for 1 h at room temperature and then

saturated aqueous sodium hydrogencarbonate was added

at 0 ꢁC. The mixture was extracted with dichloromethane,

and the organic layer was washed with brine, dried over

sodium sulfate. After ﬁltration of the mixture and evapo-

ration of the solvent, the crude product was puriﬁed by

column chromatography to aﬀord the titled compound

14b (1.24 g, quant.) as a colorless solid; mp 60–62 ꢁC;

4.17. (E)- and (Z)-1-(4-Hydroxyphenyl)-1,2-diphenylbut-

1-ene (17)

To a solution of 16 (2.54 g, 8.08 mmol) in dichlorometh-

ane (80 mL) at ꢀ78 ꢁC was added boron tribromide

(13.0 mL, 4.06 mmol). The reaction mixture was stirred

for 2 h at ꢀ78 ꢁC and then saturated aqueous sodium

hydrogencarbonate was added. The mixture was

extracted with dichloromethane, and the organic layer

was washed with brine, dried over sodium sulfate. After

ﬁltration of the mixture and evaporation of the solvent,

the crude product was puriﬁed by column chromatogra-

phy to aﬀord a mixture of geometric isomers of 17

(2.42 g, quant.) as a colorless oil; IR (neat): 3518,

1

IR (KBr): 1342 cm^ꢀ1; H NMR (CDCl₃): d 7.40–6.91

(m, 12H, Ar), 6.60 (d, J = 8.6 Hz, 2H, Ar), 4.90 (dq,

J = 6.3, 2.8 Hz, 1H, 3-H), 4.45 (d, J = 12.1 Hz, 1H,

1-H), 3.54 (s, 3H, OMe), 3.45 (dd, J = 2.8, 12.1 Hz, 1H,

2-H), 2.71 (s, 3H, Ms), 1.14 (d, J = 6.3 Hz, 3H, 4-H);

¹³C NMR (CDCl₃): d 157.4, 142.8, 136.4, 134.6, 130.3,

129.1, 128.8, 127.8, 127.6, 126.9, 126.8, 113.6, 79.5, 55.1,

54.9, 52.5, 39.1, 20.2; Anal. calcd for C₂₄H₁₆O₄S: C,

70.22; H, 6.38, found: C, 70.14; H, 6.49.

3386 cm^ꢀ^{1 1}H NMR (CDCl₃): d 7.30–6.65 (m, 12H,

;

Ar), 6.39 (d, J = 8.5 Hz, 2H, Ar), 2.44 and 2.35 (q,

J = 7.6 Hz, 2H, 3-H), 0.88 and 0.83 (t, J = 7.6 Hz, 3H,

4-H); ¹³C NMR (CDCl₃): d 154.3, 153.4, 143.7, 143.3,

142.3, 141.9, 141.3, 138.3, 138.1, 136.0, 135.5, 132.0,

130.8, 130.7, 129.6, 129.4, 128.1, 127.8, 127.7, 127.2,

126.5, 126.0, 125.6, 115.0, 114.3, 28.9, 13.6.

4.15. (3RS,4RS)-4-(4-Methoxyphenyl)-3,4-diphenylbut-

1-ene (syn-15)

To a solution of 14a (300 mg, 731 mmol) in methanol

(2.9 mL) at room temperature was added sodium

hydroxide (2.9 mg, 0.073 mmol). The reaction mixture

was stirred for 4 h at 75 ꢁC and then saturated aqueous

ammonium chloride was added at 0 ꢁC. The mixture was

extracted with diethyl ether, and the organic layer was

washed with brine, dried over sodium sulfate. After ﬁl-

tration of the mixture and evaporation of the solvent,

the crude product was puriﬁed by column chromatogra-

phy to aﬀord syn-15 (218 mg, 95%) as a colorless solid;

4.18. 1-(4-[2-Dimethylaminoethoxy]phenyl)-1,2-diphenyl-

but-1-ene (1, tamoxifen)

To a suspension of sodium hydride (60%, 333 mg,

8.33 mmol) in DMF (7.3 mL) at 0 ꢁC was added a solu-

tion of 17 (1.00 g, 3.33 mmol) in DMF (3 mL). After the

reaction mixture had been stirred for 30 min at 0 ꢁC, a

solution of N,N-dimethylaminoethylchloride (1.07 g,

9.95 mmol) in DMF (3 mL) was added. The reaction

mixture was stirred for 30 min at 50 ꢁC and then satu-

rated aqueous ammonium chloride was added at 0 ꢁC.

The mixture was extracted with diethyl ether, and the

organic layer was washed with brine, dried over sodium

sulfate. After ﬁltration of the mixture and evaporation

of the solvent, the crude product was puriﬁed by column

chromatography to aﬀord a mixture of geometric iso-

mers of tamoxifen (1) as a colorless solid (1.22 g, 95%,

E/Z = 46:54). Each compound was isolated by prepara-

mp 84–86 ꢁC; IR (KBr): 1728, 1504, 1257 cm^ꢀ1

;

¹H

NMR (CDCl₃): d 7.29–6.93 (m, 12H, Ar), 6.54 (d,

J = 8.7 Hz, 2H, Ar), 5.83 (ddd, J = 7.7, 10.0, 14.8 Hz,

1H, 2-H), 4.87 (d, J = 10.0 Hz, 1H, 1-H), 4.83 (d,

J = 14.8 Hz, 1H, 1-H), 4.19 (d, J = 11.5 Hz, 1H, 4-H),

4.05 (dd, J = 7.7, 11.5 Hz, 1H, 3-H), 3.56 (s, 3H,

OMe); ¹³C NMR (CDCl₃): d 157.3, 143.8, 142.8,

141.0, 135.4, 129.1, 128.5, 128.3, 128.2, 128.2, 126.1,

126.0, 115.8, 113.5, 56.1, 55.0, 54.6; Anal. calcd for

C₂₃H₂₂O: C, 87.86; H, 7.05, found: C, 87.76; H, 7.02.

4.16. (E)- and (Z)-1-(4-Methoxyphenyl)-1,2-diphenylbut-

1-ene (16)

tive

reversed-phase

HPLC

(methanol–0.01 M

HCl = 7:3) or thin layer chromatography (benzene–tri-

ethylamine = 19:1) using preparative TLC plates

(Merck, Silica gel 60 F₂₅₄). [The plate was developed

To a solution of 15 (197 mg, 0.627 mmol) in DMSO

(1.6 mL) at room temperature was added potassium

tert-butoxide (123 mg, 1.10 mmol). The reaction mixture

was stirred for 15 min at room temperature and then sat-

urated aqueous ammonium chloride was added at 0 ꢁC.

The mixture was extracted with diethyl ether, and the or-

ganic layer was washed with brine, dried over sodium sul-

fate. After ﬁltration of the mixture and evaporation of the

solvent, the crude product was puriﬁed by thin layer chro-

matography to aﬀord a mixture of geometric isomers of

16 (191 mg, 97%, E/Z = ca. 1:1) as a colorless oil; IR

1

twice in the dark.] (Z)-1; H NMR (CDCl₃): d 7.29–

6.82 (m, 10H, Ar), 6.69 (d, J = 8.7 Hz, 2H, Ar), 6.48

(d, J = 8.7 Hz, 2H, Ar), 3.87 (t, J = 5.7 Hz, 2H,

OCH₂), 2.60 (t, J = 5.7 Hz, 2H, NCH₂), 2.38 (q,

J = 7.5 Hz, 2H, 3-H), 2.23 (s, 6H, NMe₂), 0.85 (t,

J = 7.5 Hz, 3H, 4-H). (E)-1; ¹H NMR (CDCl₃): d

7.19–6.77 (m, 14H, Ar), 4.01 (t, J = 6.0 Hz, 2H,

OCH₂), 2.68 (t, J = 6.0 Hz, 2H, NCH₂), 2.43 (q,

J = 7.5 Hz, 2H, 3-H), 2.28 (s, 6H, NMe₂), 0.87 (t,

J = 7.5 Hz, 3H, 4-H).

I. Shiina et al. / Bioorg. Med. Chem. 15 (2007) 7599–7617

7613

4.19. Isomerization of (E)-tamoxifen to (Z)-tamoxifen

4.23. (3RS,4RS)/(3RS,4SR)-4-(4-Bromophenyl)-4-(4-

methoxyphenyl)-3-phenylbut-1-ene (21)

To

8.8 lmol) in dichloromethane (0.3 mL) at 0 ꢁC was

added triﬂuoromethanesulfonic acid (12 lL,

a

solution of (E)-tamoxifen ((E)-1, 3.3 mg,

To a suspension of hafnium tetrachloride (1.73 g,

5.40 mmol) in anisole (26 mL) at 0 ꢁC was added a

solution of cinnamyltrimethylsilane (1.23 g, 6.46 mmol)

in anisole (28 mL) and 4-bromobenzaldehyde (1.00 g,

5.40 mmol). The reaction mixture was stirred for 2 h

at room temperature and then saturated aqueous so-

dium hydrogencarbonate was added at 0 ꢁC. The mix-

ture was extracted with diethyl ether, and the organic

layer was washed with brine, dried over sodium sul-

fate. After ﬁltration of the mixture and evaporation

of the solvent, the crude product was puriﬁed by col-

umn chromatography to aﬀord a mixture of diastereo-

mers of p-21 (1.37 g, 64%, (3RS,4RS)/(3RS,4SR) = 85/

15) and a mixture of diastereomers of o-21 (131 mg,

6%, (3RS,4SR)/(3RS,4RS) = 61/39) as colorless oils.

A mixture of syn- and anti-isomers of p-21; ¹H

NMR (CDCl₃): d 7.33–6.52 (m, 13H, Ar), 5.88–5.71

(m, 1H, 2-H), 4.86–4.71 (m, 2H, 1-H), 4.16–4.10 (m,

1H, 4-H), 4.05–3.95 (m, 1H, 3-H), 3.67 and 3.56 (s,

3H, OMe).

0.135 mmol). The reaction mixture was stirred for 3 h

at 0 ꢁC and then saturated aqueous sodium hydrogen-

carbonate was added. The mixture was extracted with

dichloromethane, and the organic layer was washed

with brine, dried over sodium sulfate. After ﬁltration

of the mixture and evaporation of the solvent, the

crude product was puriﬁed by thin layer chromatogra-

phy (dichloromethane–methanol = 9:1) to aﬀord a mix-

ture of geometric isomers of 1 (3.2 mg, 97%, E/

Z = 47:53) as a colorless oil.

4.20. (3RS,4RS)/(3RS,4SR)-4-(4-Methoxyphenyl)-3,4-

diphenylbut-1-ene (15)

To a suspension of hafnium tetrachloride (75.6 mg,

0.236 mmol) and trimethylsilyl triﬂuoromethanesulfo-

nate (26.2 mg, 0.118 mmol) in anisole (1.2 mL) at

0 ꢁC was added a solution of cinnamyltrimethylsilane

(57.9 mg, 0.283 mmol) and benzaldehyde (25.0 mg,

0.236 mmol) in anisole (1.2 mL). The reaction mix-

ture was stirred for 2 h at room temperature and

then saturated aqueous sodium hydrogencarbonate

was added at 0 ꢁC. The mixture was extracted with

diethyl ether, and the organic layer was washed with

brine, dried over sodium sulfate. After ﬁltration of

the mixture and evaporation of the solvent, the

crude product was puriﬁed by thin layer chromatog-

raphy (hexane–ethyl acetate = 17:1) [developed twice]

4.24. (3RS,4RS)/(3RS,4SR)-4-(4-Iodophenyl)-4-(4-meth-

oxyphenyl)-3-phenylbut-1-ene (22)

The title compound was prepared according to the

similar procedure for Section 4.23. H NMR (CDCl₃):

1

d 7.32–6.51 (m, 13H, Ar), 5.84–5.75 (m, 1H, 2-H),

4.85–4.73 (m, 2H, 1-H), 4.12 (d, J = 11.7 Hz, 1H, 4-

H), 3.99–3.95 (m, 1H, 3-H), 3.67 and 3.55 (s, 3H,

OMe).

to aﬀord

a

mixture of diastereomers of p-15

4.25. (3RS,4RS)/(3RS,4SR)-4-(4-Methoxyphenyl)-3-phe-

nyl-4-(3-pivaloyloxyphenyl)but-1-ene (23)

(29.7 mg, 40%, (3RS,4SR)/(3RS,4RS) = ca. 6:4) and

a mixture of diastereomers of o-15 (12.7 mg, 17%,

(3RS,4SR)/(3RS,4RS) = ca. 1:1) as colorless oils. A

mixture of syn- and anti-isomers of p-15; ¹H NMR

(CDCl₃): d 7.28–6.74 (m, 12H, Ar), 6.55–6.53 (m,

2H, Ar), 5.90–5.79 (m, 1H, 2-H), 4.86–4.74 (m,

2H, 1-H), 4.18 (d, J = 11.6 Hz, 1H, 4-H), 4.05 (dd,

J = 8.0, 11.2 Hz, 1H, 3-H), 3.68 and 3.56 (s, 3H,

OMe).

The title compound was prepared according to the

similar procedure for Section 4.20. H NMR (CDCl₃):

1

d 7.32–6.60 (m, 13H, Ar), 5.94–5.83 (m, 1H, 2-H),

4.95–4.82 (m, 2H, 1-H), 4.27–4.04 (m, 2H, 3-H, 4-

H), 3.72 and 3.62 (s, 3H, OMe), 1.33 and 1.32 (s,

9H, t-Bu).

4.26. (3RS,4RS)/(3RS,4SR)-4-(4-Methoxyphenyl)-3-phe-

nyl-4-(4-pivaloyloxyphenyl)but-1-ene (24)

4.21. (3RS,4RS)/(3RS,4SR)-4-(3-Bromophenyl)-4-(4-

methoxyphenyl)-3-phenylbut-1-ene (19)

The title compound was prepared according to the sim-

ilar procedure for Section 4.23. H NMR (CDCl₃): d

7.32–6.75 (m, 11H, Ar), 6.57 (d, J = 8.6 Hz, 2H, Ar),

5.94–5.84 (m, 1H, 2-H), 4.90–4.80 (m, 2H, 1-H), 4.25

(d, J = 11.6 Hz, 1H, 4-H), 4.06 (dd, J = 7.1, 9.6 Hz,

1H, 3-H), 3.66 (s, 3H, OMe), 1.31 (s, 9H, t-Bu).

1

The title compound was prepared according to the sim-

ilar procedure for Section 4.23. H NMR (CDCl₃): d

7.33–6.81 (m, 11H, Ar), 6.63 (d, J = 8.7 Hz, 2H, Ar),

5.95–5.82 (m, 1H, 2-H), 4.97–4.81 (m, 2H, 1-H), 4.20

(d, J = 11.0 Hz, 1H, 4-H), 4.08 (dd, J = 7.6, 11.6 Hz,

1H, 3-H), 3.75 and 3.67 (s, 3H, OMe).

1

4.27. (E)- and (Z)-1-(3-Bromophenyl)-1-(4-methoxyphe-

nyl)-2-phenylbut-1-ene (25)

4.22. (3RS,4RS)/(3RS,4SR)-4-(3-Iodophenyl)-4-(4-meth-

oxyphenyl)-3-phenylbut-1-ene (20)

The title compound was prepared according to the sim-

1

The title compound was prepared according to the sim-

ilar procedure for Section 4.23. H NMR (CDCl₃): d

7.38–6.47 (m, 13H, Ar), 5.82–5.66 (m, 1H, 2-H), 4.83–

4.69 (m, 2H, 1-H), 4.08–3.89 (m, 2H, 3-H, 4-H), 3.61

and 3.52 (s, 3H, OMe).

ilar procedure for Section 4.29. H NMR (CDCl₃): d

1

7.33–6.76 (m, 11H, Ar), 6.53 (d, J = 7.9 Hz, 2H, Ar),

3.80 and 3.65 (s, 3H, OMe), 2.48 and 2.45 (q,

J = 7.0 Hz, 2H, 3-H), 0.95 and 0.92 (t, J = 7.0 Hz, 3H,

4-H).

7614

I. Shiina et al. / Bioorg. Med. Chem. 15 (2007) 7599–7617

4.28. (E)- and (Z)-1-(3-Iodophenyl)-1-(4-methoxyphenyl)-

2-phenylbut-1-ene (26)

organic layer was washed with brine, dried over sodium

sulfate. After ﬁltration of the mixture and evaporation

of the solvent, the crude product was puriﬁed by column

chromatography to aﬀord a mixture of geometric iso-

mers of the title compound 27⁰(331 mg, 92%) as a col-

orless oil; ¹H NMR (CDCl₃): d 7.45–6.68 (m, 11H,

Ar), 6.45 (d, J = 6.8 Hz, 2H, Ar), 2.47 and 2.43 (q,

J = 7.2 Hz, 2H, 3-H), 0.92 and 0.91 (t, J = 7.2 Hz, 3H,

4-H).

The title compound was prepared according to the sim-

1

ilar procedure for Section 4.29. H NMR (CDCl₃): d

7.36–6.53 (m, 13H, Ar), 3.81 and 3.69 (s, 3H, OMe),

2.48 and 2.45 (q, J = 7.8 Hz, 2H, 3-H), 0.95 and 0.92

(t, J = 7.8 Hz, 3H, 4-H).

4.29. (E)- and (Z)-1-(4-Bromophenyl)-1-(4-methoxyphe-

nyl)-2-phenylbut-1-ene (27)

4.34. (E)- and (Z)-1-(4-Hydroxyphenyl)-1-(4-iodophenyl)-

2-phenylbut-1-ene (28⁰)

To a solution of 21 (121 mg, 0.307 mmol) in DMSO

(0.75 mL) at 0 ꢁC was added potassium tert-butoxide

(103 mg, 0.921 mmol). The reaction mixture was stirred

for 15 min at room temperature and then saturated

aqueous ammonium chloride was added at 0 ꢁC. The

mixture was extracted with diethyl ether, and the organ-

ic layer was washed with brine, dried over sodium sul-

fate. After ﬁltration of the mixture and evaporation of

the solvent, the crude product was puriﬁed by thin layer

chromatography to aﬀord a mixture of geometric iso-

The title compound was prepared according to the sim-

1

ilar procedure for Section 4.33. H NMR (CDCl₃): d

7.29–6.38 (m, 13H, Ar), 2.42 and 2.39 (q, J = 7.4 Hz,

2H, 3-H), 0.87 and 0.85 (t, J = 7.4 Hz, 3H, 4-H).

4.35. 1-(3-Bromophenyl)-1-(4-[2-dimethylaminoeth-

oxy]phenyl)-2-phenylbut-1-ene (29)

The title compound was prepared according to the sim-

ilar procedure for Section 4.37. (E)-29; ¹H NMR

(CDCl₃): d 7.37–6.54 (m, 13H, Ar), 3.93 (t, J = 5.9 Hz,

2H, OCH₂), 2.67 (t, J = 5.9 Hz, 2H, NCH₂), 2.45 (q,

J = 7.3 Hz, 2H, 3-H), 2.30 (s, 6H, NMe₂), 0.92 (t,

J = 7.3 Hz, 3H, 4-H). (Z)-29; ¹H NMR (CDCl₃): d

7.37–6.54 (m, 13H, Ar), 4.09 (t, J = 5.9 Hz, 2H,

OCH₂), 2.76 (t, J = 5.9 Hz, 2H, NCH₂), 2.48 (q,

J = 7.3 Hz, 2H, 3-H), 2.36 (s, 6H, NMe₂), 0.94 (t,

J = 7.3 Hz, 3H, 4-H).

1

mers of 27 (108 mg, 89%) as a colorless oil; H NMR

(CDCl₃):

d

7.42–6.76 (m, 11H, Ar), 6.52 (d,

J = 6.7 Hz, 2H, Ar), 3.78 and 3.62 (s, 3H, OMe), 2.51

and 2.45 (q, J = 7.6 Hz, 2H, 3-H), 0.94 and 0.92 (t,

J = 7.6 Hz, 3H, 4-H).

4.30. (E)- and (Z)-1-(4-Iodophenyl)-1-(4-methoxyphenyl)-

2-phenylbut-1-ene (28)

The title compound was prepared according to the sim-

1

ilar procedure for Section 4.29. H NMR (CDCl₃): d

4.36. 1-(3-Iodophenyl)-1-(4-[2-dimethylaminoeth-

oxy]phenyl)-2-phenylbut-1-ene (30)

7.28–6.45 (m, 13H, Ar), 3.75 and 3.74 (s, 3H, OMe),

2.42 and 2.39 (q, J = 7.4 Hz, 2H, 3-H), 0.87 and 0.85

(t, J = 7.4 Hz, 3H, 4-H).

The title compound was prepared according to the sim-

ilar procedure for Section 4.37. (E)-30; ¹H NMR

(CDCl₃): d 7.61–7.59 (m, 2H, Ar), 7.34–6.54 (m, 11H,

Ar), 3.94 (t, J = 5.9 Hz, 2H, OCH₂), 2.66 (t,

J = 5.9 Hz, 2H, NCH₂), 2.45 (q, J = 6.2 Hz, 2H, 3-H),

2.30 (s, 6H, NMe₂), 0.91 (t, J = 6.2 Hz, 3H, 4-H). (Z)-

4.31. (E)- and (Z)-1-(3-Bromophenyl)-1-(4-hydroxyphe-

nyl)-2-phenylbut-1-ene (25⁰)

The title compound was prepared according to the sim-

1

ilar procedure for Section 4.33. H NMR (CDCl₃): d

30; H NMR (CDCl₃): d 7.61–7.59 (m, 2H, Ar), 7.34–

7.33–6.70 (m, 11H, Ar), 6.47 (d, J = 7.4 Hz, 2H, Ar),

2.48 and 2.46 (q, J = 7.0 Hz, 2H, 3-H), 0.93 and 0.91

(t, J = 7.0 Hz, 3H, 4-H).

6.54 (m, 11H, Ar), 4.10 (t, J = 5.9 Hz, 2H, OCH₂),

2.77 (t, J = 5.9 Hz, 2H, NCH₂), 2.50 (q, J = 6.2 Hz,

2H, 3-H), 2.36 (s, 6H, NMe₂), 0.95 (t, J = 6.2 Hz, 3H,

4-H).

4.32. (E)- and (Z)-1-(4-Hydroxyphenyl)-1-(3-iodophenyl)-

2-phenylbut-1-ene (26⁰)

4.37. 1-(4-Bromophenyl)-1-(4-[2-dimethylaminoeth-

oxy]phenyl)-2-phenylbut-1-ene (31)

The title compound was prepared according to the sim-

1

ilar procedure for Section 4.33. H NMR (CDCl₃): d

7.34–6.45 (m, 13H, Ar), 2.47 and 2.45 (q, J = 7.3 Hz,

2H, 3-H), 0.96–0.89 (m, 3H, 4-H).

To a suspension of sodium hydride (60%, 204 mg,

5.10 mmol) in DMF (3.5 mL) at 0 ꢁC was added a solu-

tion of 27⁰(194 mg, 0.510 mmol) in DMF (1.5 mL).

After the reaction mixture had been stirred for 15 min

at room temperature, N,N-dimethylaminoethylchloride

hydrochloride (294 mg, 2.04 mmol) was added in por-

tions at room temperature. The reaction mixture was

stirred for 12 h at 50 ꢁC and then saturated aqueous

ammonium chloride was added at 0 ꢁC. The mixture

was extracted with ethyl acetate, and the organic layer

was washed with brine, dried over sodium sulfate. After

ﬁltration of the mixture and evaporation of the solvent,

the crude product was puriﬁed by silica gel column

4.33. (E)- and (Z)-1-(4-Bromophenyl)-1-(4-hydroxyphe-

nyl)-2-phenylbut-1-ene (27⁰)

To a solution of 27 (373 mg, 0.949 mmol) in dichloro-

methane (5 mL) at ꢀ78 ꢁC was added boron tribromide

in heptane (1.0 M, 9.50 mL, 9.50 mmol). The reaction

mixture was stirred for 2 h at ꢀ78 ꢁC and then saturated

aqueous sodium hydrogencarbonate was added. The

mixture was extracted with dichloromethane, and the

I. Shiina et al. / Bioorg. Med. Chem. 15 (2007) 7599–7617

7615

chromatography (dichloromethane–methanol = 19:1) to

4.40. (3RS,4RS)/(3RS,4SR)-4-(4-[2-Dimethylaminoeth-

oxy]phenyl)-4-(3-hydroxyphenyl)-3-phenylbut-1-ene (36)

aﬀord a mixture of geometric isomers of 31 (201 mg,

88%, E/Z = 51/49) as a colorless solid. Each compound

was isolated by thin layer chromatography (benzene–tri-

ethylamine = 19:1) using preparative TLC plates

(Merck, Silica gel 60 F₂₅₄). [The plate was developed

The coupling product 34 (421 mg, 0.909 mmol) was dis-

solved in a solution of dimethylamine in ethanol (30%,

3 mL). After the reaction mixture had been stirred for

8 h at 110 ꢁC in a sealed vessel, it was cooled down to

room temperature. The residue was diluted with ethyl

acetate and then the solvent was removed by evapora-

tion. The crude product was puriﬁed by thin layer chro-

matography (chloroform–methanol = 9:1) to aﬀord a

mixture of diastereomers of 36 (285 mg, 81%) as a color-

less oil; IR (neat): 3402, 3028, 2953, 1599, 1511, 1454,

1

twice in the dark.] (E)-31; H NMR (CDCl₃): d 7.34–

6.54 (m, 13H, Ar), 3.92 (t, J = 5.8 Hz, 2H, OCH₂),

2.63 (t, J = 5.8 Hz, 2H, NCH₂), 2.45 (q, J = 7.0 Hz,

2H, 3-H), 2.34 (s, 6H, NMe₂), 0.93 (t, J = 7.0 Hz, 3H,

1

4-H). (Z)-31; H NMR (CDCl₃): d 7.34–6.54 (m, 13H,

Ar), 4.08 (t, J = 5.8 Hz, 2H, OCH₂), 2.74 (t,

J = 5.8 Hz, 2H, NCH₂), 2.48 (q, J = 7.0 Hz, 2H, 3-H),

2.39 (s, 6H, NMe₂), 0.93 (t, J = 7.0 Hz, 3H, 4-H).

1244, 1180, 1031, 915, 775, 700 cm^ꢀ1

;

¹H NMR

(CDCl₃): d 7.31–6.47 (m, 13H, Ar), 5.91–5.78 (m, 1H,

2-H), 4.89–4.80 (m, 2H, 1-H), 4.20 (d, J = 11.5 Hz,

1H, 4-H), 4.06 and 3.87 (t, J = 5.5 and 5.3 Hz, 2H,

OCH₂), 4.02 (dd, J = 7.9, 11.5 Hz, 1H, 3-H), 2.83 and

2.77 (t, J = 5.5 and 5.3 Hz, 2H, NCH₂), 2.40 and 2.37

(s, 6H, NMe₂); ¹³C NMR (CDCl₃): d 156.7, 156.5,

156.3, 156.0, 144.6, 143.8, 143.5, 140.9, 136.1, 129.6,

129.3, 128.6, 128.4, 128.3, 128.1, 126.2, 125.8, 120.3,

120.0, 115.9, 115.6, 114.4, 114.2, 113.4, 64.9, 64.2,

57.8, 57.4, 56.0, 54.5, 45.2, 44.8; HR MS (ESI) calcd

for C₂₆H₃₀NO₂[M+H]⁺, 388.2271, found 388.2267.

4.38. 1-(4-Iodophenyl)-1-(4-[2-dimethylaminoeth-

oxy]phenyl)-2-phenylbut-1-ene (32)

The title compound was prepared according to the sim-

ilar procedure for Section 4.37. (E)-32; ¹H NMR

(CDCl₃): d 7.27–6.47 (m, 13H, Ar), 3.86 (t, J = 5.7 Hz,

2H, OCH₂), 2.58 (t, J = 5.7 Hz, 2H, NCH₂), 2.37 (q,

J = 7.0 Hz, 2H, 3-H), 2.22 (s, 6H, NMe₂), 0.85 (t,

J = 7.0 Hz, 3H, 4-H). (Z)-32; ¹H NMR (CDCl₃): d

7.27–6.47 (m, 13H, Ar), 4.02 (t, J = 5.7 Hz, 2H,

OCH₂), 2.68 (t, J = 5.7 Hz, 2H, NCH₂), 2.40 (q,

J = 7.0 Hz, 2H, 3-H), 2.28 (s, 6H, NMe₂), 0.85

(t, J = 7.0 Hz, 3H, 4-H).

4.41. 1-(4-[2-Dimethylaminoethoxy]phenyl)-1-(3-

hydroxyphenyl)-2-phenylbut-1-ene (2, droloxifene)

4.39. (3RS,4RS)/(3RS,4SR)-4-[4-(2-Chloroeth-

oxy)phenyl]-4-[3-(pivaloyloxy)phenyl]-3-phenylbut-1-ene

(34)

To a solution of potassium tert-butoxide (373 mg,

3.32 mmol) in DMSO (1 mL) at room temperature was

added a solution of 36 (199 mg, 0.512 mmol) in DMSO

(1 mL). The reaction mixture was stirred for 2 h at 50 ꢁC

and then poured into saturated aqueous ammonium

chloride at 0 ꢁC. The mixture was extracted with diethyl

ether, and the organic layer was washed with brine,

dried over sodium sulfate. After ﬁltration of the mixture

and evaporation of the solvent, the crude product was

puriﬁed by thin layer chromatography (ammoniacal

chloroform–methanol = 19:1) to aﬀord (E)-droloxifene

((E)-2) (97.4 mg, 49%) and (Z)-droloxifene ((Z)-2)

(74.5 mg, 38%) as colorless solids, respectively. (E)-2;

mp 161–162 ꢁC; IR (KBr): 3422, 2979, 1608, 1592,

To a suspension of hafnium tetrachloride (490 mg,

1.53 mmol) and trimethylsilyl triﬂuoromethanesulfonate

(34.0 mg, 0.153 mmol) in b-chlorophenetole (1 mL) at

room temperature with cooling by a water bath to main-

tain the settled temperature was added a mixture of

cinnamyltrimethylsilane (583 mg, 3.06 mmol) and 3-

pivaloyloxybenzaldehyde (316 mg, 1.53 mmol) in b-

chlorophenetole (1 mL). The reaction mixture was stirred

for 2 h at room temperature and then poured into satu-

rated aqueous sodium hydrogencarbonate at 0 ꢁC. The

mixture was extracted with diethyl ether, and the organic

layer was washed with brine, dried over sodium sulfate.

After ﬁltration of the mixture and evaporation of the sol-

vent, the crude product was puriﬁed by column chroma-

tography (hexane–ethyl acetate = 9:1) followed by thin

layer chromatography (toluene–hexane = 17:3) to aﬀord

a mixture of isomers of 34 (308 mg, 43%, (o-)/

(p-) = 2:98, (3RS,4RS)/(3RS,4SR) = ca. 55:45) as a color-

less oil; IR (neat): 2974, 1750, 1609, 1587, 1511, 1480,

1509, 1470, 1444, 1287, 1243, 1173, 1116, 785 cm^ꢀ1

;

¹H NMR (CDCl₃): d 7.36–6.54 (m, 13H, Ar), 3.98 (t,

J = 5.5 Hz, 2H, OCH₂), 2.74 (t, J = 5.5 Hz, 2H,

NCH₂), 2.41 (q, J = 7.3 Hz, 2H, 3-H), 2.34 (s, 6H,

NMe₂), 0.92 (t, J = 7.3 Hz, 3H, 4-H); ¹³C NMR

(CDCl₃): d 157.3, 157.2, 144.7, 144.5, 142.1, 138.8,

136.6, 132.4, 130.0, 129.4, 128.7, 127.1, 122.1, 117.1,

114.0, 113.7, 65.7, 58.5, 45.6, 29.6, 13.7; HR MS (ESI)

calcd for C₂₆H₃₀NO₂[M+H]⁺, 388.2271, found

388.2269. (Z)-2; mp 146–149 ꢁC; IR (KBr): 3422, 2953,

1664, 1606, 1591, 1508, 1445, 1286, 1236, 1174, 1022,

1

1453, 1244, 1146, 1116, 1032, 914, 698 cm^ꢀ1; H NMR

(CDCl₃): d 7.31–6.63 (m, 13H, Ar), 5.93–5.86 (m, 1H,

2-H), 4.94–4.90 (m, 2H, 1-H), 4.24–4.05 (m, 2H, 3-H, 4-

H), 4.18 and 4.07 (t, J = 6.0 Hz, 2H, OCH₂), 3.77 and

3.69 (t, J = 6.0 Hz, 2H, ClCH₂), 1.34 and 1.33 (s, 9H,

t-Bu); ¹³C NMR (CDCl₃): d 176.9, 176.8, 156.6, 156.2,

151.0, 144.4, 140.3, 140.2, 136.1, 136.0, 129.8, 129.7,

129.4, 129.3, 129.0, 128.6, 128.4, 128.2, 125.7, 125.6,

121.4, 119.1, 119.0, 116.5, 114.6, 114.4, 68.0, 67.9, 56.1,

54.3, 41.9, 39.0, 27.2, 27.1; HR MS (ESI) calcd for

C₂₉H₃₂ClO₃[M+H]⁺, 463.2035, found 463.2038.

770 cm^ꢀ^{1 1}H NMR (CDCl₃): d 7.22–6.55 (m, 13H,

;

Ar), 5.70 (br, 1H, OH), 4.08 (t, J = 5.7 Hz, 2H,

OCH₂), 2.76 (t, J = 5.7 Hz, 2H, NCH₂), 2.43 (q,

J = 7.3 Hz, 2H, 3-H), 2.33 (s, 6H, NMe₂), 0.92 (t,

J = 7.3 Hz, 3H, 4-H); ¹³C NMR (CDCl₃): d 157.3,

156.2, 143.9, 143.3, 141.8, 138.0, 136.1, 130.6, 130.5,

128.8, 127.2, 125.6, 121.5, 116.7, 114.0, 113.4, 65.5,

58.0, 45.5, 29.0, 13.5; HR MS (ESI) calcd for

C₂₆H₃₀NO₂[M+H]⁺, 388.2271, found 388.2280.

7616

I. Shiina et al. / Bioorg. Med. Chem. 15 (2007) 7599–7617

4.42. Isomerization of (Z)-droloxifene to (E)-droloxifene

(CDCl₃): d 7.29–6.90 (m, 10H, Ar), 7.19 and 6.95 (d,

J = 9.3 and 9.6 Hz, 2H, Ar), 6.78 and 6.57 (d, J = 9.3

and 9.6 Hz, 2H, Ar), 5.93–5.80 (m, 1H, 2-H), 4.87–

4.75 (m, 2H, 1-H), 4.19 (d, J = 12.6 Hz, 1H, 4-H), 4.05

(dd, J = 8.4, 12.6 Hz, 1H, 3-H), 3.97 and 3.84 (t,

J = 6.3 Hz, 2H, OCH₂), 2.65 and 2.57 (t, J = 6.3 Hz,

2H, NCH₂), 2.26 and 2.21 (s, 6H, NMe₂); ¹³C NMR

(CDCl₃): d 157.5, 157.1, 144.2, 143.9, 143.2, 141.4,

136.1, 135.9, 129.9, 129.5, 128.9, 128.7, 128.6, 128.5,

128.4, 126.5, 126.4, 126.1, 116.2, 114.7, 114.5, 66.1,

66.0, 58.6, 56.5, 46.2; HR MS (ESI) calcd for

C₂₆H₃₀NO [M+H]⁺372.2322, found 372.2319.

To a solution of (Z)-droloxifene (73.0 mg, 0.158 mmol)

in dichloromethane (2 mL) at 0 ꢁC was added triﬂuo-

romethanesulfonic acid (140 lL, 1.58 mmol). The reac-

tion mixture was stirred for 2 h at 0 ꢁC and then

saturated aqueous sodium hydrogencarbonate was

added. The mixture was extracted with dichlorometh-

ane, and the organic layer was washed with brine, dried

over sodium sulfate. After ﬁltration of the mixture and

evaporation of the solvent, the crude product was puri-

ﬁed by thin layer chromatography (ammoniacal chloro-

form–methanol = 19:1) to aﬀord (E)-droloxifene ((E)-2)

(26.7 mg, 37%) and (Z)-droloxifene ((Z)-2) (26.4 mg,

36%) as colorless solids, respectively.

4.45. 1-(4-[2-Dimethylaminoethoxy]phenyl)-1,2-diphenyl-

but-1-ene (1, tamoxifen)

4.43. (3RS,4RS)/(3RS,4SR)-4-[4-(2-Chloroeth-

oxy)phenyl]-3,4-diphenylbut-1-ene (37)

To a solution of potassium tert-butoxide (257 mg,

2.29 mmol) in DMSO (1 mL) at room temperature was

added a solution of 38 (83.7 mg, 0.225 mmol) in DMSO

(1 mL). The reaction mixture was stirred for 1 h at room

temperature and then saturated aqueous ammonium

chloride was added at 0 ꢁC. The mixture was extracted

with diethyl ether, and the organic layer was washed

with brine, dried over sodium sulfate. After ﬁltration

of the mixture and evaporation of the solvent, the crude

product was puriﬁed by thin layer chromatography

(dichloromethane–methanol = 9:1) to aﬀord a mixture

of geometric isomers of 1 (63.3 mg, 76%, E/Z = 49:51)

as a colorless oil. Each compound was isolated by pre-

parative reversed-phase HPLC (methanol–0.01 M

HCl = 7:3) or thin layer chromatography (benzene–tri-

ethylamine = 19:1) using preparative TLC plates

(Merck, Silica gel 60F₂₅₄). [The plate was developed

twice in the dark.] (Z)-1; mp 94–95 ꢁC; IR (KBr):

To a suspension of hafnium tetrachloride (401 mg,

1.25 mmol) in b-chlorophenetole (4.25 mL) at room

temperature with cooling by a water bath to maintain

the settled temperature was added a mixture of benzal-

dehyde (133 mg, 1.25 mmol) and cinnamyltrimethylsi-

lane (286 mg, 1.50 mmol) in b-chlorophenetole (2 mL).

The reaction mixture was stirred for 4 h at room temper-

ature and then poured into saturated aqueous sodium

hydrogencarbonate at 0 ꢁC. The mixture was extracted

with diethyl ether, and the organic layer was washed

with brine, dried over sodium sulfate. After ﬁltration

of the mixture and evaporation of the solvent, the crude

product was puriﬁed by column chromatography (hex-

ane–ethyl acetate = 10:1) to aﬀord a mixture of diaste-

reomers of p-37 (193 mg, 43%, (3RS,4SR)/

(3RS,4RS) = ca. 55:45) as a colorless oil; IR (neat):

3027, 2915, 1610, 1509, 1494, 1453, 1302, 1244, 1178,

1

1458, 1250, 1034 cm^ꢀ1; H NMR (CDCl₃): d 7.29–6.82

(m, 10H, Ar), 6.69 (d, J = 8.7 Hz, 2H, Ar), 6.48 (d,

J = 8.7 Hz, 2H, Ar), 3.87 (t, J = 5.7 Hz, 2H, OCH₂),

2.60 (t, J = 5.7 Hz, 2H, NCH₂), 2.38 (q, J = 7.5 Hz,

2H, 3-H), 2.23 (s, 6H, NMe₂), 0.85 (t, J = 7.5 Hz, 3H,

4-H); ¹³C NMR (CDCl₃): d 156.6, 143.8, 142.4, 141.3,

138.2, 135.6, 131.2, 129.7, 129.4, 128.1, 127.8, 126.5,

126.0, 113.3, 65.5, 58.2, 45.8, 28.9, 13.5.

1041, 699 cm^ꢀ^{1 1}H NMR (CDCl₃): d 7.32–6.94 (m,

;

10H, Ar), 7.24 and 7.00 (d, J = 8.4 and 9.0 Hz, 2H,

Ar), 6.81 and 6.59 (d, J = 8.4 and 9.0 Hz, 2H, Ar),

5.92–5.83 (m, 1H, 2-H), 4.91–4.79 (m, 2H, 1-H), 4.24

(d, J = 11.7 Hz, 1H, 4-H), 4.15 and 4.02 (t, J = 6.0 Hz,

2H, OCH₂), 4.09 (dd, J = 7.8, 11.7 Hz, 1H, 3-H), 3.74

and 3.66 (t, J = 6.0 Hz, 2H, ClCH₂); ¹³C NMR (CDCl₃):

d 156.5, 156.1, 143.7, 143.4, 142.7, 140.9, 136.4, 136.2,

129.6, 129.3, 128.5, 128.3, 128.2, 128.1, 126.2, 126.0,

125.7, 116.0, 115.9, 114.5, 114.3, 67.9, 67.7, 56.1, 54.5,

41.9; HR MS (ESI) calcd for C₂₄H₂₇ClNO [M+NH₄]⁺

380.1776, found 380.1768.

4.46. HL-60 human acute promyelocytic leukemia

The HL-60 cells were supplied by the Cell Resource

Center for Biomedical Research, Tohoku University

(Sendai, Japan). The cells were maintained at 37 ꢁC with

5% CO₂in RPMI 1640 medium supplemented with

kanamycin sulfate (64 mg/L), 2-mercaptoethanol

(3.5 lL/L), sodium bicarbonate (2 g/L), and heat-inacti-

vated 10% (v/v) fetal bovine serum. The cells were di-

luted with the medium to the constant concentrations

of 4.0 · 10⁵cells/mL.

4.44. (3RS,4RS)/(3RS,4SR)-4-(4-[2-Dimethylaminoeth-

oxy]phenyl)-3,4-diphenylbut-1-ene (38)

The coupling product 37 (113 mg, 0.310 mmol) was dis-

solved in a solution of dimethylamine in ethanol (30%,

2 mL). After the reaction mixture had been stirred for

8 h at 110 ꢁC in a sealed vessel, it was cooled down to

room temperature. The residue was diluted with ethyl

acetate and then the solvent was removed by evapora-

tion. The crude product was puriﬁed by thin layer chro-

matography (chloroform–methanol = 9:1) to aﬀord a

mixture of diastereomers of 38 (107 mg, 93%) as a color-

less oil; IR (neat): 3027, 2942, 2821, 2772, 1610, 1509,

4.47. MTT assay

HL-60 cells were incubated in 96-well plates at 37 ꢁC, and

then, 11 lL of 20 mg/mL 3-(4,5-dimethylthiazol-2-yl)-

2,5-diphenyl tetrazolium bromide (MTT; Sigma) in phos-

phate-buﬀered saline (PBS) was added to each well. The

plates were incubated at 37 ꢁC for 1 h. The plates were

centrifuged at 350g for 5 min, the supernatants were

1494, 1453, 1249, 1177, 1032, 914, 699 cm^ꢀ1; H NMR

1

I. Shiina et al. / Bioorg. Med. Chem. 15 (2007) 7599–7617

7617

McCague, R.; Leclercq, G.; Devleeschouwer, N. J. Med.

Chem. 1985, 28, 1491–1497.

18. Coe, P. L.; Scriven, C. E. J. Chem. Soc., Perkin Trans. 1

1986, 475–477.

19. Some syntheses of tamoxifen derivatives including dro-

loxifene. (a) Gauthier, S.; Mailhot, J.; Labrie, F. J. Org.

discarded, and 100 lL of DMSO was added to dissolve

the MTT formazan. The absorbance of each well was

measured using a microplate reader at 570 nm. The per-

centage of cell viability was taken as the percent absor-

bance at 570 nm for the SERMs-treated cells and control.

´

Chem. 1996, 61, 3890–3893; (b) Gauthier, S.; Sanceau, J.-

Y.; Mailhot, J.; Caron, B.; Cloutier, J. Tetrahedron 2000,

56, 703–709.

Acknowledgments

20. (a) Miller, R. B.; Al-Hassan, M. I. J. Org. Chem. 1985, 50,

2121–2123; (b) Al-Hassan, M. I. Synth. Commun. 1987, 17,

1247–1251; (c) Al-Hassan, M. I. Synthesis 1987, 816–817.

21. Potter, G. A.; McCague, R. J. Org. Chem. 1990, 55, 6184–

6187.

This work was partially supported by Grants-in-Aid for

Scientiﬁc Research from the Ministry of Education, Sci-

ence, Sports and Culture, Japan, the Science Research

Promotion Fund from the Promotion and Mutual Aid

Corporation for Private Schools of Japan, and a Re-

search Grant from the Center for Green Photo-Science

and Technology. The author thanks the Shin-Etsu

Chemical Co., Ltd (Japan), for kindly providing orga-

nosilane compounds as bulk samples.

22. (a) Studemann, T.; Knochel, P. Angew. Chem., Int. Ed.

¨

1997, 36, 93–95; (b) Studemann, T.; Ibrahim-Ouali, M.;

Knochel, P. Tetrahedron 1998, 54, 1299–1316.

23. Brown, S. D.; Armstrong, R. W. J. Org. Chem. 1997, 62,

7076–7077.

24. (a) Itami, K.; Kamei, T.; Yoshida, J. J. Am. Chem. Soc.

2003, 125, 14670–14671; see also (b) Itami, K.; Yoshida, J.

Bull. Chem. Soc. Jpn. 2006, 79, 811–824.

25. Tessier, P. E.; Penwell, A. J.; Souza, F. E. S.; Fallis, A. G.

Org. Lett. 2003, 5, 2989–2992.

References and notes

26. Zhou, C.; Larock, R. C. J. Org. Chem. 2005, 70, 3765–

3777.

1. McDonnell, D. P. Trends Endocrinol. Metab. 1999, 10,

301–311.

27. Shao, L.-X.; Shi, M. Org. Biomol. Chem. 2005, 3, 1828–

1831.

28. Preliminary communication Shiina, I.; Suzuki, M.;

Yokoyama, K. Tetrahedron Lett. 2004, 45, 965–967.

29. Preliminary communication Sano, Y.; Shiina, I. Tetrahe-

dron Lett. 2006, 47, 1631–1635.

2. Lonard, D. M.; Smith, C. L. Steroids 2002, 67, 15–24.

3. Jordan, V. C. J. Med. Chem. 2003, 46, 1081–1111.

4. Ke, H. Z.; Chen, H. K.; Simmons, H. A.; Qi, H.;

Crawford, D. T.; Pirie, C. M.; Chidsey-Frink, K. L.;

Ma, Y. F.; Jee, W. S. S.; Thompson, D. D. Bone 1997, 20,

31–39.

ˇ

´

30. Malkov, A. V.; Spoor, P.; Vinader, V.; Kocovsky, P. J.

5. Evans, G. L.; Turner, R. T. Bone 1995, 17, 181S–190S.

6. Hasmann, M.; Lo¨ser, R.; Kohr, A.; Seibel, K. Onkologie

1994, 17, 22–26.

7. Biedermann, E.; Lo¨ser, R.; Hasmann, M. Onkologie 1994,

17, 17–21.

8. Rauschning, W.; Pritchard, K. I. Breast Cancer Res.

Treat. 1994, 31, 83–94.

9. Gradishar, W. J.; Jordan, V. C. J. Clin. Oncol. 1997, 15,

840–852.

10. Ke, H. Z.; Chen, H. K.; Qi, H.; Pirie, C.; Simmons, H. A.;

Ma, Y. F.; Jee, W. S. S.; Thompson, D. D. Bone 1995, 17,

491–496.

11. Chen, H. K.; Ke, H. Z.; Jee, W. S. S.; Ma, Y. F.; Pirie, C.

M.; Simmons, H. A.; Thompson, D. D. J. Bone Miner.

Res. 1995, 10, 1256–1262.

12. Chen, H. K.; Ke, H. Z.; Lin, C. H.; Ma, Y. F.; Qi, H.;

Crawford, D. T.; Pirie, C. M.; Simmons, H. A.; Jee, W. S.

S.; Thompson, D. D. Bone 1995, 17, 175S–179S.

13. (a) Harper, M. J. K.; Walpole, A. L. Nature 1966, 212, 87;

(b) Bedford, G. R.; Richardson, D. N. Nature 1966, 212,

733–734; for a review of the pharmacology, see: (c) Heel,

R. C.; Brogdon, R. N.; Speight, T. M.; Avery, G. S. Drugs

1978, 16, 1–24.

14. Harper, M. J. K.; Richardson, D. N.; Walpole, A. L.

GB1013907, 1965, Imperial Chemical Industries, Ltd.

15. Robertson, D. W.; Katzenellenbogen, J. A. J. Org. Chem.

1982, 47, 2387–2393.

Org. Chem. 1999, 64, 5308–5311.

31. Shiina, I.; Suzuki, M. Tetrahedron Lett. 2002, 43, 6391–

6394.

32. Shiina, I.; Suzuki, M.; Yokoyama, K. Tetrahedron Lett.

2002, 43, 6395–6398.

33. Bank, S.; Rowe, C. A., Jr.; Schriesheim, A.; Naslund, L.

A. J. Org. Chem. 1968, 33, 221–223.

34. Cinnamyltrimethylsilane was purchased from Junsei

Chemical Co., Ltd (Japan) or synthesized according to

the literature method.³⁵

35. Andreini, B. P.; Carpita, A.; Rossi, R.; Scamuzzi, B.

Tetrahedron 1989, 45, 5621–5640.

36. (a) Sano, Y.; Nakata, K.; Otoyama, T.; Umeda, S.; Shiina,

I. Chem. Lett. 2007, 36, 40–41; (b) Shiina, I.; Sano, Y.;

Nakata, K.; Kikuchi, T.; Sasaki, A.; Ikekita, M.; Hasome,

T. Bioorg. Med. Chem. Lett. 2007, 17, 2421–2424.

37. (a) Shiina, I.; Miyoshi, S.; Miyashita, M.; Mukaiyama, T.

Chem. Lett. 1994, 515–518; (b) Shiina, I.; Mukaiyama, T.

Chem. Lett. 1994, 677–680.

38. (a) For the large-scale puriﬁcation, recrystallization of the

corresponding hydrochloric or hydrobromic acid salt is

recommended. See: (a) White, D. A. EP127128, 1984,

Bristol-Myers Co;; (b) Shinozaki, F.; Nagasawa, H.;

Maruhashi, K. WO9511879, 1995, Taiho Pharmaceutical

Co., Ltd.

39. Some other methods for the Z–E isomerization have been

reported. See: Refs. 20b,c and 38. See also Winkler, V. W.;

Nyman, M. A.; Egan, R. S. Steroids 1971, 17, 197–207.

40. McCague, R.; Leclercq, G.; Legros, N.; Goodman, J.;

Blackburn, G. M.; Jarman, M.; Foster, A. B. J. Med.

Chem. 1989, 32, 2527–2533.

16. McCague, R. J. Chem. Soc., Perkin Trans. 1 1987, 1011–

1015.

17. Some syntheses of tamoxifen derivatives (a) Ruenitz, P.

C.; Bagley, J. R.; Mokler, C. M. J. Med. Chem. 1982, 25,

1056–1060; (b) Foster, A. B.; Jarman, M.; Leung, O.-T.;

Article Doi

An expeditious synthesis of tamoxifen, a representative SERM (selective estrogen receptor modulator), via the three-component coupling reaction among aromatic aldehyde, cinnamyltrimethylsilane, and β-chlorophenetole

DOI: 10.1016/j.bmc.2007.09.008

Source and publish data:

Authors:

Article abstract of DOI:10.1016/j.bmc.2007.09.008

Full text of DOI:10.1016/j.bmc.2007.09.008

Products guided by the article

R&D Labs maybe for 693818-58-5

Relevant to this article

Hot Product