Diversity-Oriented Synthesis of Tamoxifen-type Tetrasubstituted Olefins

Article abstract of DOI:10.1021/ja037566i

A general synthetic scheme for tamoxifen-type tetrasubstituted olefins based on the novel Cu-catalyzed carbomagnesation across alkynyl(2-pyridyl)silane has been developed. A wide array of electronically and structurally diverse tetrasubstituted olefins can be prepared in a regiocontrolled, stereocontrolled, and diversity-oriented manner. Noteworthy features are that (i) the three aryl groups, which are believed to be important (essential) for anti-estrogenic activity, can be varied at will because they all stem from readily available aryl iodides, and (ii) any stereo- and regioisomers can, in principle, be prepared by simply changing the applying order of aryl iodides into the sequence. Copyright

Full text of DOI:10.1021/ja037566i

Published on Web 11/06/2003
Diversity-Oriented Synthesis of Tamoxifen-type Tetrasubstituted Olefins
Kenichiro Itami,* Toshiyuki Kamei, and Jun-ichi Yoshida*
Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto UniVersity,
Nishikyo-ku, Kyoto 615-8510, Japan
Received July 28, 2003; E-mail: itami@sbchem.kyoto-u.ac.jp; yoshida@sbchem.kyoto-u.ac.jp
Tamoxifen is the most important anti-breast cancer drug in
clinical use and has the potential to be used as a chemopreventive
breast cancer agent.1 It is a selective estrogen receptor modulator
(SERM) with anti-estrogenic properties in breast and estrogenic
effects in tissues such as bone and the cardiovascular system.
Although these aspects of tamoxifen have stimulated research for
a superior and ideal SERM, rapid and systematic screenings have
been hampered by the lack of a general and diversity-oriented2
synthetic scheme for tamoxifen-type tetrasubstituted olefins. In
addition, insufficient stereoselectivity, which is often encountered
efficiency. It was also found that the Cu-catalyzed addition did not
with the widely used dehydration reaction3 and McMurry coupling,4
occur at all with the corresponding 3-pyridyl, 4-pyridyl, and
has been a bottleneck for rapid evaluation.5 As an alternative to
phenylsilanes, which clearly implicates the strong directing effect
these procedures, Miller, Cummins, Knochel, and Armstrong have
(complex-induced proximity effect) of the 2-pyridyl group on
developed metal-mediated synthetic methods for tamoxifen.6
silicon.11
As a part of our program aimed at the development of a general
and diversity-oriented synthetic scheme for multisubstituted olefins,7
Table 1. Catalytic One-Pot Diarylation of 1
we have developed such a synthetic scheme for tamoxifen-type
tetrasubstituted olefins utilizing our removable directing 2-pyridyl-
silyl group.8,9 We envisaged that, as an initial step of our campaign,
the regio- and stereoselective addition of an arylmetal across
1-butynyldimethyl(2-pyridyl)silane (1) would afford a suitably
substituted alkenylmetal compound through the agency of a
complex-induced proximity effect of the pyridyl group on silicon.
The sequential arylations at C-M and C-Si bonds (Pd-catalyzed
cross-coupling reactions) of the resultant pyridylsilyl-substituted
alkenylmetal compound would afford the targeted tamoxifen-type
tetrasubstituted olefins. Because all aryl groups of this tetrasubsti-
tuted olefin structure stem from readily available aryl halides, the
synthesis would be sufficiently diversity-oriented.
run
Ar1
Ar2
3
yield (E/Z)
1
2
3
4
5
6
7
8
C6H5 (a)
C6H5 (a)
C6H5 (a)
C6H5 (a)
C6H5 (a)
C6H5 (a)
3-ClC6H4 (g)
3-ClC6H4 (g)
C6H5 (a)
3aa
3ab
3ac
3ad
3ae
3af
80% (92/8)
60% (92/8)
55% (88/12)
75% (95/5)
58% (94/6)
69% (94/6)
55% (92/8)
79% (92/8)
4-MeOC6H4 (b)
4-Me2N(CH2)2OC6H4 (c)
4-CF3C6H4 (d)
4-EtOCOC6H4 (e)
4-ClC6H4 (f)
4-Me2N(CH2)2OC6H4 (c)
4-MeC6H4 (h)
3gc
3gh
With the feasibility of an initial carbometalation process, we next
examined the one-pot diarylation of 1 through the catalytic
carbomagnesation/cross-coupling sequence. After extensive screen-
ing of catalyst for the cross-coupling step, Pd[P(t-Bu)3]212 was found
to effect the Kumada-Tamao-Corriu-type cross-coupling13 of the
resultant alkenylmagnesium compound and aryl iodide in good
overall yield. Thus, by simply varying Ar1MgI and Ar2I, we could
efficiently obtain various structurally and electronically diverse
alkenylsilanes 3 (Table 1).14 The two aryl groups (Ar1 and Ar2)
are introduced in a cis fashion, which is in accordance with syn
carbometalation and retention of stereochemistry during the sub-
sequent cross-coupling. The aryl group containing the basic side
chain found in tamoxifen can be installed with ease (runs 3 and 7).
Interestingly, the ester group also tolerated the conditions of this
cross-coupling reaction (run 5).
In early experiments, we found that the addition of Grignard
reagents across 1-butynyldimethyl(2-pyridyl)silane (1) does not
occur at all.10 Thus, we searched for an efficient procedure for the
initial carbometalation process across 1 (eq 1). After many trials,
it was found that the regio- and stereoselective addition of PhMgI
(1.0 equiv) to 1 proceeded smoothly in the presence of CuI catalyst
to afford 2 in 90% yield. The addition did not occur with an
equimolar amount of CuI, which indicates that organocuprate might
be the reactive species for this addition. The use of PhMgBr,
PhMgCl, or Ph2Mg in place of PhMgI resulted in lower addition
With the procedure of stereoselective one-pot diarylation of 1
in hand, we investigated the cross-coupling of 3 at the C-Si bond
(Hiyama cross-coupling)7,15 as a final step toward tamoxifen-type
tetrasubstituted olefins. However, extensive screening of catalyst
and activator to transfer these sterically condensed alkenyl groups
9
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J. AM. CHEM. SOC. 2003, 125, 14670-14671
10.1021/ja037566i CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Borodesilylation of 3
In summary, we have established a general synthetic scheme
for tamoxifen-type tetrasubstituted olefins based on the novel
Cu-catalyzed carbomagnesation across alkynyl(2-pyridyl)silane. By
using this synthetic scheme, we could prepare a wide array of
electronically and structurally diverse tetrasubstituted olefins in a
regiocontrolled, stereocontrolled, and diversity-oriented manner.
Noteworthy features are that (i) the three aryl groups, which are
believed to be important (essential) for anti-estrogenic activity, can
be varied at will because they all stem from readily available aryl
iodides, and (ii) any stereo- and regioisomers can, in principle, be
prepared by simply changing the applying order of aryl iodides
into the sequence. Although we have focused our investigation on
the synthesis of tamoxifen-type olefins in this study, our synthetic
scheme should be easily expanded to the construction of a more
general tetrasubstituted olefin structure.
run
3 (E/Z)
4
yield (Z/E)
1
3aa (94/6)
3ac (88/12)
3ad (95/5)
3ae (94/6)
3gc (92/8)
3gh (92/8)
4aa
4ac
4ad
4ae
4gc
4gh
82% (98/2)
65% (94/6)
80% (99/1)
64% (>99/1)
77% (95/5)
73% (97/3)
2a
3
4
5a
6
a 3.3 equiv of BCl3 was employed. After the treatment with pinacol, the
mixture was treated with Cs2CO3 (10 equiv) in toluene (80 °C, 11 h).
Table 3. Suzuki-Miyaura Coupling of 4 with Aryl Iodides
Acknowledgment. This work was supported by a Grant-in-Aid
for Scientific Research from the Ministry of Education, Culture,
Sports, Science, and Technology, Japan.
Supporting Information Available: Experimental procedures and
analytical and spectroscopic data of compounds (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
run
4 (Z/E)
Ar3
5
yield (E/Z)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
4aa (97/3)
4aa (97/3)
4ac (94/6)
4ac (94/6)
4ac (94/6)
4ad (99/1)
4ad (99/1)
4ad (99/1)
4ad (99/1)
4gc (95/5)
4gc (95/5)
4gc (97/3)
4gh (97/3)
4gh (99/1)
4gh (99/1)
4-Me2N(CH2)2OC6H4 (c)
4-MeC6H4 (h)
C6H5 (a)
4-MeOC6H4 (b)
3-MeOC6H4 (i)
4-MeOC6H4 (b)
4-ClC6H4 (f)
2-MeOC6H4 (j)
3-pyridyl (k)
4-MeOC6H4 (b)
3-MeC6H4 (l)
3-thienyl (m)
5aac
5aah
5aca
5acb
5aci
5adb
5adf
5adj
5adk
5gcb
5gcl
95% (99/1)
96% (99/1)
98% (5/95)
95% (5/95)
92% (95/5)
97% (>99/1)
90% (>99/1)
95% (>99/1)
67% (>99/1)
80% (4/96)
82% (98/2)
87% (99/1)
93% (>99/1)
98% (>99/1)
99% (>99/1)
References
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Si/B exchange reaction borodesilylation of 3 to achieve the
installation of a third aryl group (Ar3) by means of Suzuki-Miyaura
coupling at the resulting C-B bond.16
(8) For a review, see: Itami, K.; Mitsudo, K.; Nokami, T.; Kamei, T.; Koike,
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The stereoselective borodesilylation17 of 3 was found to occur
with BCl3 in CH2Cl2 at -41 °C, and subsequent treatment of this
mixture with pinacol and triethylamine (one-pot) afforded 4 in good
yield with retention of stereochemistry (Table 2). For compounds
bearing the tamoxifen basic side chain (Me2NCH2CH2O-) such
as 3ac and 3gc, it was necessary to treat the mixture with a base
such as Cs2CO3 to remove a boron residue coordinated to the
nitrogen. Interestingly, it was found that the isomeric purities of 4
were greater that those of the starting alkenylsilanes in all cases
examined. This may be due to the reactivity difference of isomeric
alkenylsilanes in borodesilylation.
(11) For a review on directed alkyne carbometalation, see: Fallis, A. G.;
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expense of a lower chemical yield (30-50%).
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Finally, the Suzuki-Miyaura coupling of 4 with aryl iodides
(Ar3I) afforded the targeted tamoxifen-type tetrasubstituted olefin
5. An extensive optimization of this final step revealed that the
catalyst/base/additive combination of Pd[P(t-Bu)3]2/NaOH/H2O
(5 mol %, 3.0 equiv, 3.0 equiv) effects the desired cross-coupling
in extremely high yields in THF at 60 °C (Table 3).12a A variety of
aryl groups including heteroaryl groups can be installed in the final
tetrasubstituted olefin structure. Tamoxifen (5aca) and its derivatives
can be prepared with ease. It should also be mentioned that this
final cross-coupling step also helped to increase the isomeric purities
of the final olefins 5 (>99% in most cases) presumably because of
the reactivity difference of isomeric 4 in the cross-coupling reaction.
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Tetrahedron 1998, 54, 1085.
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