Synthesis of lipidic tamoxifen

Article abstract of DOI:10.1016/S0040-4039(00)00421-4

We describe a general method for elaboration of the ethyl sidechain of tamoxifen and its primary 4-hydroxy metabolite. Novel lipidic tamoxifen and a functionalized B-ring analog were synthesized from a common stilbene oxide intermediate for potential lipo

Full text of DOI:10.1016/S0040-4039(00)00421-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 3295–3298
Synthesis of lipidic tamoxifen
Matthew R. Lashley and Michael H. Nantz ∗
Department of Chemistry, University of California, Davis, CA 95616, USA
Received 17 August 1999; accepted 7 March 2000
Abstract
We describe a general method for elaboration of the ethyl sidechain of tamoxifen and its primary 4-hydroxy
metabolite. Novel lipidic tamoxifen and a functionalized B-ring analog were synthesized from a common stilbene
oxide intermediate for potential liposomal applications including estrogen receptor targeting. © 2000 Elsevier
Science Ltd. All rights reserved.
It is estimated that approximately one in nine women will develop breast cancer, the most common
form of malignancy in women.1 Early detection and imaging is paramount to effectively staging and
treating this disease.2 Much current research to improve early detection of breast cancer seeks to utilize
radiolabeled tamoxifen (1) or radiolabeled tamoxifen analogs for imaging estrogen receptor (ER) positive
breast cancer.3 Studies have shown that tamoxifen is a highly effective antagonist of the ER and,
consequently, tamoxifen is currently the most widely used adjuvant drug therapy for the treatment of
ER-positive breast cancer.4 The prevalence of estrogen receptors in the majority of breast tumors also
provides a means of imaging these tumors. Indeed, tamoxifen-based radiopharmaceuticals containing
18F, 111In, or 131I have been employed for this task.5 Although these agents successfully image the
target tissue, the short half life of 18F and the requirement of expensive particle accelerators have
limited widespread application of this strategy. Magnetic resonance (MR) imaging using an ER-targeted
approach to improve conspicuity remains to be explored and might offer a more practical and less
expensive alternative to the use of radiopharmaceuticals. We envision that incorporation of a tamoxifen-
linked lipid into lamellae of liposomal MRI preparations6 potentially could improve imaging in ER-rich
tissues.7 We report herein a general method for attaching a lipid domain onto the ethyl sidechain of both
tamoxifen and its more active8 4-hydroxy metabolite (2). The rationale for extending the ethyl sidechain
relies on observations made by Podoloff et al.5b who demonstrated that derivatization at this site did
not significantly interfere with recognition by the ER.9 The synthesis of representative lipidic tamoxifen
derivatives 3 and 4 is conveniently achieved from the common epoxide intermediate 5, a novel substrate
for tamoxifen derivatization.
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00421-4
tetl 16701

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Alkylation of trans-4-hydroxystilbene (6) with N,N-dimethylaminoethyl chloride readily provided
amine 7 (Scheme 1). To avoid amine oxidation, the epoxidation of 7 was conducted via bromohydrin
formation10 followed by treatment with base to obtain epoxide 5.11 Introduction of the tamoxifen and
hydroxytamoxifen B-ring was achieved by copper(I)-catalyzed reaction of 5 with either PhMgBr or the
Grignard reagent derived from (methoxymethyl)-protected 4-bromophenol, respectively. As predicted,12
epoxide cleavage proceeded regioselectively at the electron rich benzylic position to deliver tamoxifen
precursor 8 and the p-(methoxymethoxy) derivative 9 in good yields. Swern oxidations of 8 and 9
proceeded smoothly to afford the corresponding phenyl ketones in 75 and 80% yield, respectively.
Treatment of the ketones with allylmagnesium chloride in THF failed to deliver 1,2-addition products,
giving instead predominantly reduction products (e.g. 8 and 9, and their diastereomers). However, a
change in solvent to Et2O facilitated addition of the Grignard reagent to give allylic alcohols 10 and 11 as
a mixture of diastereomers in 70 and 87% yield, respectively. The osmylation of alcohol 10 using standard
conditions13 gave a mixture of the corresponding diastereomeric triols, and subsequent bisacylation using
excess myristoyl chloride gave the alcohol diester 12 in 61% yield for the two steps. Treatment of 11
Scheme 1. (a) (CH3)2NCH2CH2Cl·HCl, DMF, KOH, 25°C, 12 h, 97%; (b) (i) NBS (2 equiv.), H2O (2 equiv.), DMSO, 10°C,
0.5 h; (ii) aq. KOH, rt, 0.5 h, 54%; (c) PhMgBr (4 equiv.), CuI (0.2 equiv.), −40°C, 10 min, then 5, −40°C to rt, 12 h, 84%;
(d) p-(CH3OCH2O)C6H4MgBr (4 equiv.), CuI (0.2 equiv.), −40°C, 10 min, then 5, −40°C to rt, 12 h, 82%; (e) (i) (CO)2Cl2,
DMSO, CH2Cl2, −78°C; (ii) Et3N, −78°C to 0°C; (f) CH2CHCH2MgCl (4 equiv.), Et2O, −50°C to rt, 12 h; (g) acetone:H2O
(8:1), cat. OsO4, NMO, rt; (h) ClC(O)CH2(CH2)12CH3 (2.1 equiv.), CH2Cl2, TEA, DMAP, 0°C to rt, 12 h; (i) pyridine, SOCl2,
−10°C, 3 h; (j) TFA (30 equiv.), anisole (30 equiv.), CH2Cl2, rt, 12 h, 80%

3297
under similar conditions gave the MOM-protected analog 13 in 64% yield. The tamoxifen core was
established by alcohol dehydration of 12 using thionyl chloride in pyridine to give lipidic tamoxifen 3
as a 1:1 E:Z mixture in 70% yield.14 Separation of the isomers is not critical for application in targeted
imaging since both isomers of tamoxifen exhibit the desired ER specificity.15,16 Dehydration of 13 using
identical conditions followed by MOM ether cleavage using a 1:1 trifluoroacetic acid–anisole mixture17
gave lipidic hydroxytamoxifen derivative 4 in a 64% two-step yield.18 Other methods of MOM-group
deprotection were attempted at this and earlier stages in the synthesis, but none were as effective as
the anisole-mediated method used here. By analogy to hydroxytamoxifen (2), equilibration of the E:Z
stereoisomers in lipidic analog 4 is expected to readily occur in vivo making the mixture potentially
suitable for targeted imaging applications.19
In conclusion, we have developed a general synthesis of lipidic tamoxifen and hydroxytamoxifen
analogs from a common epoxide intermediate that serves as a template for straightforward derivatization
of the B-ring and ethyl sidechain domains.20,21
Acknowledgements
This work was supported by the University of California Cancer Research Coordinating Committee.
References
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Bonn, T.; Engström, O.; Ohman, L.; Greene, G. L.; Gustafsson, J.-A.; Carlquist, M. Nature 1997, 389, 753.
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11. All new compounds gave satisfactory combustion analysis or high resolution mass spectrometry data. Compound 5: pale
orange oil; 1H NMR (CD3Cl) δ 2.26 (s, 6H), 2.65 (t, J=5.9 Hz, 2H), 3.72 (d, J=1.8 Hz, 1H), 3.77 (d, J=1.8 Hz, 1H), 3.99 (t,
J=5.9 Hz, 2H), 6.84 (d, J=8.8 Hz, 2H), 7.16–7.28 (m, 7H); 13C NMR (CD3Cl) δ 45.8, 58.2, 62.6, 62.7, 65.9, 114.6, 125.4,
126.7, 128.1, 128.4, 129.1, 137.2, 158.9.
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13. Panek, J. S.; Cirillo, P. F. J. Am. Chem. Soc. 1990, 112, 4873.
14. Compound 3: colorless oil; 1H NMR (CD3Cl) δ 0.87 (m, 6H), 1.23–1.27 (m, 40H), 1.51 (m, 4H), 1.99 (m, 1H), 2.08 (m,
1H), 2.21 (m, 4H), 2.93 (s, 6H), 3.49 (m, 2H), 3.90 (m, 1H), 4.14 (m, 1H), 4.51 (m, 2H), 5.09 (m, 1H), 6.79–7.50 (m,
14H); 13C NMR (CD3Cl) δ 14.1, 22.7, 24.8, 29.1 (2), 29.3 (3), 29.5, 29.6 (2), 29.7, 31.9, 34.0, 36.5, 43.8, 56.6, 62.8, 64.9,
70.3, 114.1 (2), 114.3, 125.6, 126.1, 126.6, 127.3, 127.4, 127.5, 128.0 (2), 129.5, 130.5, 131.0, 135.5, 136.6, 141.1, 141.5,
142.5, 155.9, 172.8, 173.4.

3298
15. Harper, M. J. K; Walpole, A. L. Nature 1966, 159, 87.
16. Tamoxifen isomers undergo facile isomerization. Separation of E- and Z-isomers is performed commercially by fractional
crystallization of the corresponding aminium citrate salts.
17. De Medeiros, E. F.; Herbert, J. M.; Taylor, R. J. K. J. Chem. Soc., Perkin Trans. 1 1991, 2725.
18. Compound 4 (1:1 E:Z mixture): colorless oil; 1H NMR (CD3Cl) δ 0.88 (m, 12H), 1.22–1.26 (m, 80H), 1.50–1.53 (m, 8H),
2.00 (m, 4H), 2.00–2.18 (m, 4H), 2.20–2.28 (m, 8H), 2.35 (s, 6H), 2.46 (s, 6H), 2.74 (m, 2H), 2.85 (m, 2H), 3.88 (m,
2H), 4.06 (m, 2H), 5.06 (m, 2H), 6.33 (d, 4H), 6.44 (d, 4H), 6.65–7.15 (m, 20H); 13C NMR (CD3Cl) δ 14.1, 22.7, 24.8,
29.1, 29.3 (2), 29.4, 29.5, 29.6, 31.9, 34.0, 44.8, 44.9, 57.6, 64.0, 64.5, 64.8, 70.5, 113.0, 113.9, 114.6, 115.4, 126.2, 128.0,
128.4, 129.6, 130.7, 130.8, 131.7, 131.9, 134.4, 141.5, 141.7, 142.5, 156.0, 172.8, 173.5.
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R. J. Org. Chem. 1990, 55, 6184. (c) Cummins, C. H. Synth. Commun. 1995, 25, 4071. (d) Olier-Reuchet, C.; Aitken, D. J.;
Bucourt, R.; Husson, H.-P. Tetrahedron Lett. 1995, 36, 8221. (e) Stüdemann, T.; Knochel, P. Angew. Chem., Int. Ed. Engl.
1997, 36, 93, and references cited therein.
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1986, 58.