Parallel synthesis of tamoxifen and derivatives on solid support via resin capture

Full text of DOI:10.1021/jo9711807

7076
J . Org. Chem. 1997, 62, 7076-7077
P a r a llel Syn th esis of Ta m oxifen a n d
Der iva tives on Solid Su p p or t via Resin
Ca p tu r e
S. David Brown† and Robert W. Armstrong*
Department of Chemistry and Biochemistry,
University of California, Los Angeles, California 90095
Received J une 30, 1997
Estrogen analogs can be used to prevent and treat
breast cancer, osteoporosis, and other conditions that
affect women. Since estrogen receptors are found in a
variety of tissues, there is a need for analogs that are
tissue selective.1,2 Tamoxifen (Figure 1) is used clinically
to treat estrogen dependent breast cancer because it acts
as an estrogen antagonist in breast tissue.3 However, it
acts as a partial agonist in the uterus which increases a
woman’s risk for endometrial cancer. A more selective
analog could be used to prevent breast cancer without
undesirable side effects in the uterus. Combinatorial
chemistry can facilitate the search for ligands that can
F igu r e 1. Tamoxifen and natural estrogens 17â-estradiol and
estrone.
Sch em e 1
make distinctions among a family of receptors.4
A
focused library can access many structural variants of a
particular pharmacophore in a relatively short time.
Using a combinatorial approach, it may be possible to
develop drugs that are specific for a number of estrogen-
mediated disorders.
Recently, we reported the synthesis of substituted
ethylenes on solid support via resin capture.5 In this
communication, we demonstrate how this chemistry can
be used in the parallel synthesis of triphenylethylene
derivatives based on tamoxifen where each position about
the ethylene core can be modified. We also report a novel
silicon linker with an increased rate of TFA cleavage.
The 25-member library was synthesized using 5 alkynes,
5 aryl halides, and a polymer bound aryl iodide as inputs.
The alkynes were converted into bis(boryl)alkenes A-E
in solution by a platinum-catalyzed reaction developed
by Ishiyama and co-workers6,7 (Scheme 1). The crude
intermediates A-E were used in solution Suzuki reac-
tions with an excess of aryl halide to generate 6 (Scheme
2). Since the aryl halide could react at either side of the
bis(boryl)alkene, intermediates 6 were produced as a
mixture of two possible regioisomers. When all of the
bis(boryl)alkene was consumed, the reaction mixture was
introduced to the resin 7 and the reaction continued on
solid support. Through resin capture, only 6 participated
in the second Suzuki reaction on solid support. Side
reactions such as deboration or Suzuki reactions of 6 with
the solution aryl halide gave products that remained in
solution and were washed away during workup. Suzuki
reactions are typically run at elevated temperatures.
Using our modified conditions, however, these reactions
Sch em e 2
a
Bis(boryl)alkene (10 equiv), aryl halide (15 equiv), Pd(dppf)Cl2
(0.5 equiv), 3,5-dimethoxyphenol (50 equiv), 6 M KOH (50 equiv),
b
DME, 25 °C, 18 h. 7 (1 equiv), 6 M KOH (100 equiv), 25 °C, 18
h. c For simplicity, only one of two possible regioisomers is shown.
proceeded at reasonable rates at room temperature8
which simplified the reaction setup for the library. The
products are cleaved from the polymer as amine salts of
trifluoroacetic acid. Filtering the salts through a plug
of basic alumina gave 1A-5E as free amines in >90%
purity. The yields of the products varied from 13-68%
depending upon the input as shown in Table 1.9,10
Resin capture is a versatile strategy for combinatorial
synthesis. By initiating the library in solution, there was
† Current address: Combinatorial Chemistry Group, MetaXen LLC,
3910 Trust Way, Hayward, CA 94545.
(1) Evans, G. L.; Turner, R. T. Bone 1995, 17, 181S-190S.
(2) Grese, T. A.; Cho, S.; Finley, D. R.; Godfrey, A. G.; J ones, C. D.,
III, C. W. L.; Martin, M. J .; Matsumoto, K.; Pennington, L. D.; Winter,
M. A.; Adrian, M. D.; Cole, H. W.; Magee, D. E.; Phillips, D. L.; Rowley,
E. R.; Short, L. L.; Glasebrook, A. L.; Bryant, H. U. J . Med. Chem.
1997, 40, 146-167.
(3) Higginson, J .; Gelmann, E. P. Sem. Oncol. 1997, 24, S1-1-S1-
151.
(4) Crews, C. W. Chem. Biol. 1996, 3, 961-65.
(5) Brown, S. D.; Armstrong, R. W. J . Am. Chem. Soc. 1996, 118,
6331-6332.
(8) For other room temperature Suzuki conditions on solid support,
see Guiles, J . W.; J ohnson, S. G.; Murray, W. V. J . Org. Chem. 1996,
61, 5169-5171.
(6) Ishiyama, T.; Matsuda, N.; Miyaura, N.; Suzuki, A. J . Am. Chem.
Soc. 1993, 115, 11018.
(9) For 1B, 1H NMR indicates the trans-isomer, tamoxifen, is the
major isomer. See Collins, D. J .; Hobbs, J . J .; Emmens, C. W. J . Med.
Chem. 1971, 14, 952.
(7) Ishiyama, T.; Matsuda, N.; Murata, M.; Ozawa, F.; Suzuki, A.;
Miyaura, N. Organometallics 1996, 15, 713.
S0022-3263(97)01180-8 CCC: $14.00 © 1997 American Chemical Society

Communications
J . Org. Chem., Vol. 62, No. 21, 1997 7077
Ta ble 1. Yield s a n d Isom er ic Ra tios for Tr ia r yleth ylen e
Der iva tives Obta in ed th r ou gh P a r a llel Syn th esis on
Solid Su p p or t via Resin Ca p tu r e10
Sch em e 3
a
H+: 30% TFA in CH2Cl2, 10 min; I+: ICl (3 equiv) in CH2Cl2,
b
c
30 min. Obtained in greater than 90% purity after cleavage.
Purified by preparative TLC after cleavage to remove small
amounts of 1,4-diiodobenzene that result from unreacted sites on
the polymer.
solid-supported syntheses.15-17 A drawback to these link-
ers is the relative difficulty of acid cleavage in comparison
to other linkers such as Rink or Wang. The reported
cleavage conditions require exposure of the silicon linkers
to 100% TFA for 8-24 h. To increase the rate of TFA
cleavage, we prepared resin 7.18 The linker was synthe-
sized in solution as a carboxylic acid and was coupled to
ArgoGel amine resin according to standard conditions.19
The presence of the â-amide exerts a remarkable rate
enhancement to protodesilation. Products attached to 7
were cleaved efficiently in less than 10 min upon expo-
sure to 30% TFA in CH2Cl2 (Scheme 3). In Suzuki
reactions where the coupling efficiency was less than
100%, reduced or unreacted sites on the polymer were
cleaved off as benzene or iodobenzene, which were
removed under vacuum. Therefore, products were ob-
tained in high purity even in the cases with low coupling
efficiencies. Han and co-workers16 have demonstrated
that silicon linkers are cleaved with a variety of electro-
philes including Br+ and I+. This feature can be used to
introduce additional diversity in an otherwise static input
by varying the cleavage conditions. Accordingly, we
obtained 8b upon cleavage with ICl (Scheme 3).
no need to optimize diboration (Scheme 1) for solid
support. Including solution reactions in the synthetic
scheme also prevents side products from building up on
the polymer. A major side product in the Suzuki reac-
tions was deboration.11 Since diboronates A-E and
boronate intermediates 6 were in solution, there was no
resin-bound boronate which could decompose via debo-
ration. Both of the solution reactions were performed
sequentially without the need for purification. As long
as all of the initial diboronate was consumed in the
solution Suzuki reaction (Scheme 2), none of the side
products could react with 7. After resin capture, the
advantages of solid phase synthesis were realized. The
resin was isolated by filtration and purified by washing.
At that point, we could cleave the products from the resin
or continue the synthesis on solid support. Resin capture
combines the flexibility of traditional solution synthesis
with the purity of products on solid support.
This synthetic strategy provides access to a wide
variety of triphenylethylenes. The alkyl side chain R2
and phenyl substituent R1 can be varied readily with the
appropriate choice of alkyne. Commercially available
aryl halides provide a large selection of R3 substituents.
Although the final input, resin 7, was not varied in this
synthesis, the silicon linker offers some advantages over
more traditional benzyl linkers. 7 may be cleaved in
“traceless” fashion as in the present work, or it may be
cleaved with alternative conditions to obtain more diver-
sity in the final product.
We have described a parallel synthesis of triphenyl-
ethylene derivatives on solid support. This strategy
relies upon resin capture and a novel silicon linker to
obtain products that resemble tamoxifen, an estrogen
antagonist. Using this strategy, each position about the
ethylene core can be modified by the appropriate choice
of alkyne, aryl halide, and cleavage conditions. An
investigation into the cleavage mechanism of 7 is cur-
rently in progress.
Ack n ow led gm en t. This work was supported by the
National Institutes of Health (GM-51095).
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
1
cedures and copies of H NMR and 13C NMR spectra as well
as lists of IR absorbances and results of mass spectrometric
analysis for compounds e, A-E, 1, 3, 1A-5E, 7, 8a , and 8b.
Compound d was synthesized as described previously20 (82
pages).
Plunkett and Ellman first reported the use of a
traceless linker in which no functional group in the
product remained to testify to its former attachment to
the polymer.12,13 This method relies on electrophilic ipso-
substitution of arylsilanes.14 When the electrophile is an
acid, the silyl group is replaced with hydrogen. Several
other groups have also employed silicon linkers in various
J O9711807
(14) Colvin, E. W. Silicon in Organic Synthesis; Butterworth:
London, 1981; pp 125-133.
(15) Chenera, B.; Finkelstein, J . A.; Veber, D. F. J . Am. Chem. Soc.
1995, 117, 11999.
(16) Han, Y.; Walker, S. D.; Young, R. N. Tetrahedron Lett. 1996,
37, 2703.
(10) For some products with electron rich π-systems, additional
isomers are present due to facile isomerization of the double bond. See
Murphy, C. S.; Parker, C. J .; McCague, R.; J ordan, V. C. Mol.
Pharmacol. 1991, 39, 421 and references contained within.
(11)
(17) Boehm, T. L.; Showalter, H. D. H. J . Org. Chem. 1996, 61,
6498-9.
(18) While this work was in progress,
7 was presented at a
conference, but no examples of its application or utility were given:
Veber, D. F. Presented at the Second Winter Conference on Medicinal
and Bioorganic Chemistry, Steamboat Springs, CO, J anuary 1997.
(19) The synthesis of 7 is detailed in the Supporting Information.
(20) Engler, T. A.; Combrink, K. D.; Ray, J . E. Synth. Commun.
1989, 19, 1735-1744.
(12) Plunkett, M. J .; Ellman, J . A. J . Org. Chem. 1995, 60, 6006-7.
(13) Plunkett, M. J .; Ellman, J . A. J . Org. Chem. 1997, 62, 2885-
2893.