Synthesis of 17α-(Iodovinyl)estradiol and analogous derivatives by iododestannylation of insoluble polymer-supported organotin precursors

Article abstract of DOI:10.1002/(sici)1099-0690(199904)1999:4<781::aid-ejoc781>3.0.co;2-f

Iodoestrogen derivatives were prepared by iododestannylation of insoluble polymer-supported organotin precursors.

Full text of DOI:10.1002/(sici)1099-0690(199904)1999:4<781::aid-ejoc781>3.0.co;2-f

FULL PAPER
Synthesis of 17α-(Iodovinyl)estradiol and Analogous Derivatives
by Iododestannylation of Insoluble Polymer-Supported Organotin Precursors
Gilles Dumartin,*[a] Jamil Kharboutli,[a] Bernard Delmond,[a] Yves Frangin,[b]
and Michel Pereyre[a]
Keywords: Polymer-supported organotin hydride / Steroids / Iodinated estrogens
Iodoestrogen derivatives were prepared by iododestannylation of insoluble polymer-supported organotin precursors.
These hydrostannation reactions were performed with the
polymer 1 (tin hydride content: 0.83 mmol/gram of poly-
mer) in the presence of AIBN in refluxing THF for 8 h.
The conversion rates (80%, 82% and 75% for 2, 3 and 4,
respectively) have been evaluated from the amounts of reco-
vered starting estrogen derivatives.
Iododestannylation reactions were performed in di-
chloromethane solution, for 15 h at room temperature, with
excess iodine (4 equiv.) because of partial adsorption on the
polymer. Under these conditions, using 17α-(tributylstan-
nylvinyl)estradiol [prepared from 17α-ethynylestradiol (2)
and tributyltin hydride], we have checked that iododestan-
nylation retains the configuration of the CϭC bond. Iodo-
steroids, easily recovered from the reaction mixture by sim-
ple filtration, were analyzed by HPLC.
The iododestannylation of the estradiol adduct 5 led to
a mixture of diastereoisomers 8a (E) and 8b (Z), (8a/8b ഠ
98:2); we have also observed the presence of a small amount
of 17α-vinylestradiol (11; Scheme 2) generated by protodes-
tannylation of 5 (Table 1).
Introduction
Radiopharmaceuticals are drugs containing unstable nu-
clei which emit nuclear particles or photons. These medical
imaging agents are of interest for diagnosis and radio-
therapy of various diseases.
Compounds bearing γ-emitting radioisotopes such as 123
I
are commonly used in SPECT (Single Photon Emission
Computerized Tomography) detection. Radioiodinated de-
rivatives are frequently prepared from organotin precur-
sors.[1][2] The iododestannylation reaction is fast, as well as
regio- and stereoselective. Furthermore, high yields can be
obtained under mild conditions.
However, the complete elimination of these precursors or
their by-products can be difficult. In order to avoid traces
of polluting organotin residues in the reaction products, the
organotin precursor can be anchored onto an insoluble
solid support;[3][4] the radiopharmaceutical will be released
into solution. Few papers report the utilization of these re-
agents.[5Ϫ8]
Studies of some breast and ovarian cancers have shown
the presence of selective estrogen receptors in the tumorous
cells. Therefore, radioiodinated estrogens like 17α-(iodovin-
yl)estradiol and analogous derivatives have been used as im-
aging agents due to their high specificity and their stability
in vivo.[9] These compounds are prepared by iododestannyl-
ation of organotin compounds. For the reasons previously
reported, we have prepared iodinated estrogens from insol-
uble polymer-supported organotin precursors.
On the other hand, the iododestannylation of adducts 6
and 7, prepared from mestranol (3) and moxestrol (4),
respectively, led to the formation of E (9a, 10a), Z (9b, 10b)
and gem (9c, 10c) (Scheme 2) isomers (Table 1). In all cases,
the E isomers were the major compounds.
The configurations of iodovinyl compounds have been
1
determined using H and 13C NMR, based on the charac-
teristic coupling constants (3JHH) between vinylic hydrogen
atoms: approximately 14 Hz for E isomers and 8.6 Hz for
Z isomers (Table 2).
Results and Discussion
In this study, we have used an insoluble polymer-sup-
ported organotin hydride, PϪ[CH2]4SnBu2H (1; P: poly-
styrene),[10] in order to perform the hydrostannation of 17α-
ethynylestradiol (2),[11][12] and its derivatives mestranol
(3)[13] and moxestrol (4)[14] (Scheme 1).
Conclusion
This report shows that polymer-supported organotin in-
termediates can be used as precursors for (iodovinyl)estra-
diol and related compounds. The iodide derivatives were
obtained directly in good yields, free of organotin groups,
[a]
´
Laboratoire de Chimie Organique et Organometallique,
´
Universite Bordeaux 1,
1
as proved by HPLC and H NMR, without later purifi-
´
´
351 cours de la Liberation, F-33405 Talence Cedex, France
Fax: (internat.) ϩ 33-5/56846994
cation. This method can be applied to the preparation of
radioiodinated compounds as described in a previous
paper.[15] Indeed, the utilization of polymer-supported re-
agents strongly improves the purification of compounds
E-mail: g.dumartin@lcoo.u-bordeaux.fr
[b]
´
Laboratoire de Biophysique Medicale et Pharmaceutique,
´
Universite F. Rabelais,
31 avenue Monge, F-37200 Tours, France
Eur. J. Org. Chem. 1999, 781Ϫ783
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
1434Ϫ193X/99/0404Ϫ0781 $ 17.50ϩ.50/0
781

G. Dumartin, J. Kharboutli, B. Delmond, Y. Frangin, M. Pereyre
FULL PAPER
Scheme 1. Hydrostannation of estrogen derivatives 2, 3 and 4 and iododestannylation of polymer-supported adducts 5, 6 and 7
Polymer-Supported Tin Hydride: Compound 1 was prepared from
Amberlite XE 305, a monofunctional macroporous polystyrene
cross-linked with divinylbenzene (Rohm and Haas).[10] The SnH
content (0.83 mmol per gram of polymer) was evaluated from the
amount of decane formed during the reduction of 1-bromodecane
by 1.
Addition of 1 to Estrogen Derivatives: In a Schlenck tube, under
nitrogen, a mixture of polymer 1 (2.10 g, 1.74 mmol SnH), 17α-
Scheme 2. By-products formed during the iododestannylation of 5,
ethynylestradiol (2; 0.43 g, 1.45 mmol), AIBN (0.014g, 0.08 mmol)
6, and 7
and dry THF (30 mL) was stirred and heated at reflux for 8 h.
After 4 h, a second portion of AIBN (0.08 mmol) was added. The
Table 1. Iododestannylation of polymer-supported organotin pre-
cursors 5, 6 and 7
polymer was filtered and washed several times with THF. After
evaporation of the solvent, the amount (0.086 g, 0.29 mmol) of
17α-ethynylestradiol recovered allows for the evaluation of the con-
Polymer-supported
organotin precursors
Yield
(%)
Isomers (%)
version yield (80%). The polymer was dried in vacuo at 60°C. Poly-
mer 5 (2.4 g) containing 1.16 mmol of the estradiol moiety was
obtained. Similar procedures were used for mestranol (3) and
moxestrol (4).
E
Z
others
5
6
7
61
40
48
8a (95%)
9a (83%)
8b (2%)
11[a] (3%)
9c[b] (3%)
9b (14%)
10a (83%) 10b (10%) 10c[b] (7%)
Preparation of 17α-(Iodovinyl)estradiol (8): In a Schlenck tube, un-
der nitrogen, in the dark, polymer 5 (2.0 g, 0.97 mmol estradiol),
iodine (0.98 g, 3.88 mmol) and dichloromethane (25 mL) were
stirred at room temperature for 15 h. After filtration, the polymer
was washed several times with dichloromethane. The organic layers
were washed with a solution (0.1 ) of sodium thiosulfate and
water and then dried with sodium sulfate. After evaporation of the
solvent, the crude 17α-(iodovinyl)estradiol (8; yield: 61%) was ana-
lyzed. HPLC: column A; eluent: MeOH (85%), H2O (15%), 1 mL/
min; retention times: 4.0 min [17α-vinylestradiol (11)], 4.4 min (E
[a]17α-Vinylestradiol. Ϫ [b]gem isomers.
Table 2. NMR data (1H and 13C) of iodoestrogen derivatives 8, 9
and 10
1
isomer 8a), 5.2 min (Z isomer 8b). Ϫ H NMR of vinylic protons:
3
δ ϭ 6.23 and 6.75, JHH ϭ 14.3 Hz for 8a; δ ϭ 6.43 and 6.73,
3JHH ϭ 8.6 Hz for 8b. Ϫ 13C NMR: δ ϭ 152.0 (C-19) and 74.8 (C-
20) for 8a; δ ϭ 145.0 (C-19) and 77.4 (C-20) for 8b; the other NMR
data are in agreement with those of the estrogen skeleton. NMR
data of 11 have been compared with those of 17α-vinylestradiol
prepared by protodestannylation of 17α-(tributylstannylvinyl)estra-
diol.
Preparation of 17α-(Iodovinyl)mestranol (9): In a similar procedure,
the crude product 9 was prepared from polymer 6 (yield: 40%).
HPLC: column B; eluent: MeOH, 1.2 mL/min; retention times: 3.3
min (gem isomer 9c), 4.0 min (E isomer 9a), 4.3 min (Z isomer 9b).
Ϫ 1H NMR of vinylic protons: δ ϭ 6.34 and 6.84, 3JHH ϭ 14.5 Hz
and leads to a very low level of tin pollution as shown by
atomic absorption and ICPϪMS.[16]
3
Experimental Section
General: NMR spectra were recorded with a Bruker AC 250 spec-
trometer operating at 250 and 62.9 MHz for 1H and 13C resonance
frequencies, respectively. Products were dissolved in [D6]DMSO.
for 9a; δ ϭ 6.42 and 6.89, JHH ϭ 8.6 Hz for 9b; δ ϭ 6.18 and
2
6.46, JHH ϭ 2.3 Hz for 9c. Ϫ 13C NMR : δ ϭ 150.4 (C-19) and
74.6 (C-20) for 9a; δ ϭ 143.3 (C-19) and 87.4 (C-20) for 9b; δ ϭ
73.3 (C-19) and 126.9 (C-20) for 9c.
Tetramethylsilane was used as internal standard. Ϫ HPLC analyses Preparation of 17α-(Iodovinyl)moxestrol (10): In a similar pro-
were performed on column A (Nucleosil phenyl, 7 µm, 250 ϫ 4.6
mm), column B (Nucleosil C 18, 5 µm, 250 ϫ 4.6 mm) or column
C (Nucleosil C 18, 10µm, 250 ϫ 4.6 mm).
cedure, the crude product 10 was prepared from polymer 7 (yield:
48%). HPLC: column C; eluent: MeOH (90%), H2O (10%), 1 mL/
min; retention times: 4.2 min (E isomer 10a), 5.1 min (gem isomer
782
Eur. J. Org. Chem. 1999, 781Ϫ783

17α-(Iodovinyl)estradiol and Analogous Derivatives
FULL PAPER
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