Functionalization of testosterone at position 7 and synthesis of 7-(3-methoxypropyl)-4-androsten-17-ol-3-one

Article abstract of DOI:10.1080/00397910802618430

An efficient transformation of the terminal alkene function of 7-allyltestosterone is reported along with the stereospecific synthesis of 7-(3-methoxypropyl)-4-androsten-17-ol-3-one.

Full text of DOI:10.1080/00397910802618430

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Functionalization of
Testosterone at Position
7α and Synthesis of 7α-
(3-Methoxypropyl)-4-
androsten-17β-ol-3-one
Dominic Bastien a , Josée Nault a & Gervais Bérubé a
a Research Group in Molecular Oncology and
Endocrinology, Department of Chemistry and
Biology, Université du Québec à Trois-Rivières, Trois-
Rivières, Québec, Canada
Published online: 27 Apr 2009.
To cite this article: Dominic Bastien , Josée Nault & Gervais Bérubé (2009):
Functionalization of Testosterone at Position 7α and Synthesis of 7α-(3-
Methoxypropyl)-4-androsten-17β-ol-3-one, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 39:11,
1884-1892
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Synthetic Communications1, 39: 1884–1892, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802618430
Functionalization of Testosterone at Position 7a
and Synthesis of 7a-(3-Methoxypropyl)-
4-androsten-17b-ol-3-one
´
´
´
Dominic Bastien, Josee Nault, and Gervais Berube
Research Group in Molecular Oncology and Endocrinology, Department
´
´
`
of Chemistry and Biology, Universite du Quebec a Trois-Rivieres,
`
`
Trois-Rivieres, Quebec, Canada
´
Abstract: An efficient transformation of the terminal alkene function of
7a-allyltestosterone is reported along with the stereospecific synthesis of
7a-(3-methoxypropyl)-4-androsten-17b-ol-3-one.
Keywords: 7a-Allyltestosterone, hydroboration-iodation, steroids
Testosterone (1), a steroidal hormone, is mainly involved in the develop-
ment and maintenance of male sexual characteristics. Structurally, beside
the presence of a perhydrocylopentenophenantherene ring system, it has
a ketone function at position 3 and a hydroxy function at position 17 of
the steroidal nucleus Scheme 1.[1] These groups are essential for its bio-
logical activity.[2] Several structural modifications have been performed
on the testosterone nucleus to get the desired antagonistic activity for
the treatment of androgen-dependent disorders such as prostate
cancer.[2,3]
The most interesting position on the testosterone nucleus for attach-
ment of various substituents is position 7. This carbon is the position of
choice because it is located halfway between the two groups (ketone and
alcohol) that interact with the androgen receptor. These important
Received June 6, 2008.
Address correspondence to Gervais Berube, Research Group in Molecular
´
Oncology and Endocrinology, Department of Chemistry and Biology, Universite
´
´
du Quebec a Trois-Rivieres, C.P. 500, Trois-Rivieres, Quebec, Canada G9A 5H7.
´
E-mail: Gervais.Berube@uqtr.ca
`
`
`
´
1884

Functionalization of Testosterone
1885
Scheme 1. (a) AcCl, Ac2O, Pyr, reflux, 4 h; (b) 1, NBS, DMF, 0 ꢀC, 50 min; 2,
Li2CO3, LiBr, 92 ꢀC, 4 h.
pharmacophores, the 3-ketone and the 17b-alcohol groups, are the key
features for the activation of the receptor.[3] Thus, structural modification
at position 7 should not affect greatly the steroid–receptor interaction
and consequently can lead to compounds of biological importance.
However, the major drawback of this position is the absence of a use-
ful functional group to perform chemical reactions. Consequently, it has
to be introduced prior to further chemical transformations. First, the
functionalization of position 7 on the steroid was done in a two-step pro-
cess. Then, an iodoalkyl chain was introduced in a three-step reaction
sequence. Finally, two nucleophiles were used to verify the ease of displa-
cement of the terminal iodide.
As showed in Scheme 1, testosterone (1) was initially functionalized
in a known two-step reaction sequence adapted from the reported proce-
dure that used 19-nor-testosterone as the starting material.[4] For the first
reaction, testosterone was treated with acetyl chloride and acetic anhy-
dride in the presence of pyridine (Pyr). This reaction gave the diacetate
2 with 95% yield. The derivative 2 was further transformed into the
dienone acetate 3 upon treatment with N-bromosuccinimide (NBS) for
50 min followed by Li2CO3 and LiBr at reflux for 2 h in dimethylforma-
mide (DMF). Derivative 3 was obtained with 87% yield.
The next three steps led to the formation of an iodopropyl chain at 7a
of the steroid nucleus (Scheme 2). The dienone 3 dissolved in dichloro-
methane was treated with TiCl4 and allyltrimethylsilane in the presence
of pyridine using a modified version of a reported protocol that used
19-nor-testosterone as the starting material.[5] This reaction was stereo-
specific. The alkyl chain was added on position 7a of the steroid nucleus.
The 7a-allyl-enone 4 was obtained with 65% yield. Next, the ketone at
position 3 was protected as an acetal. This protection was performed
to avoid reduction of the ketone during the hydroboration step. Thus,
derivative 4 was treated with ethylene glycol in benzene in the presence
of p-toluenesulfonic acid (TsOH), which gave compound 5 in 80%
yield.[6] As shown in Scheme 2, the acetal 5 is a mixture of two regioi-
somers having the double bond either in ring A (5A) or in ring B (5B),
1
which are indicated by the dotted line. The H NMR spectrum showed

´ ´
D. Bastien, J. Nault, and G. Berube
1886
Scheme 2. (a) 1, TiCl4, Pyr, DCM, ꢁ78 ꢀC, 5 min; 2, allyltrimethylsilane, ꢁ30 ꢀC,
1.5 h; (b) benzene, ethyleneglycol, TsOH, Dean–Stark, reflux, 24 h; (c) 1, BH3-
THF, THF, 30 min; 2. AcONa, NaI, chloramine-T, 5 min.
a split of several peaks corresponding to each regioisomer. The propor-
1
tion of regioisomers evaluated by the H NMR spectrum was about
1:2 (5A:5B).
To complete the three-step reaction sequence, hydroboration–
iodation was performed.[7] Derivative 5 was treated with the borane
(BH3–THF) followed by sodium iodide in the presence of sodium acetate
and chloramine-T. This reaction gave product 6 with 58% yield. For
the characterization of that product (6), the pure regioisomer B was
separated by flash chromatography. The 1H NMR spectrum showed
the disappearance of the allyl protons. The methylene near the iodide
was expected to be a triplet. However, a multiplet was observed at
3.20 ppm instead. An electrostatic interaction between the double bond
in ring B and the iodide is possible. This interaction limits the free rota-
tion of the iodoalkyl chain. As a result, the protons near the iodide are
not equivalent, which explains the complexity of the signal. To confirm
this hypothesis, the ketal was removed with HCl 10% (data not shown)
to obtain the free enone. In that case, the double bound migrated back
into ring A. The electrostatic interaction between the iodide and the dou-
ble bound was not possible any longer, and a triplet could be observed at
3.16 ppm for the methylene protons near the iodide.
Two nucleophilic substitution reactions were attempted (Scheme 3)
on derivative 6. First, the iodide 6 was treated with the sodium acetylide
in a mixture of DMF and xylene.[8,9] The reaction was instantaneous,
but the desired substitution product was not obtained. An elimination
reaction occurred instead. The yield of this reaction was 74%. The
1H NMR spectrum showed the presence of olefinic protons (located at

Functionalization of Testosterone
1887
Scheme 3. (a) NaCꢂCH=xylene, reflux, 2 h; (b) 1, MeOH, NaOCH3, reflux, 12 h;
2, HCl 5 N, MeOH, reflux, 2 h.
5.00 and 5.68 ppm) as two doublets and a multiplet and the absence of the
acetylenic protons. The infrared (IR) spectrum also showed the absence
of the acetylenic bond. The substitution reaction with sodium monoalk-
oxide was also attempted. In this reaction, beside the nucleophilic substi-
tution of the iodide by the alkoxide ion in compound 6, deprotection at
position 17 was anticipated. The iodide 6 was treated with an excess of
sodium methoxide in methanol. The 1H NMR spectrum showed the
disappearance of the protons near the iodide (3.20 ppm). The new signals
of the protons located at each side of the ether linkage were located at
3.31 ppm and 3.34 ppm as a singlet and multiplet. As expected, the acet-
ate group on carbon 17 was removed to give compound 9 (as an acetal).
The 1H NMR spectrum showed the disappearance of the signal at
2.04 ppm (acetate). The enone was regenerated upon treatment with
HCl to give derivative 9 with 93% yield.
In conclusion, the stereospecific synthesis of 7a-(3-methoxypropyl)-
4-androsten-17b-ol-3-one (9) is reported. It was accomplished in six steps
with 23% overall yield. The synthesis was done via the successful intro-
duction of a 7a-(3-iodopropyl) side chain to the testosterone nucleus by
a hydroboration–iodation reaction on an allyl chain to give derivative
6. This reaction sequence could give access to a variety of 7a-substituted
testosterone analogs of biological importance by the use of various
nucleophiles.
EXPERIMENTAL
Anhydrous reactions were performed under an inert atmosphere; they were
set up, assembled, and cooled under nitrogen. Unless otherwise noted, the
starting material, reactant, and solvents were obtained commercially

´ ´
D. Bastien, J. Nault, and G. Berube
1888
and were used as such or purified and dried by standard means.[10]
Organic solutions were dried over magnesium sulfate (MgSO4), filtered,
and evaporated on a rotary evaporator under reduced pressure. All reac-
tions were monitored by ultraviolet (UV) fluorescence or staining with
iodine. Commercial thin-layer chromatography (TLC) plates were Sigma
˚
˚
T 6145 (polyester silica gel 60 A, 0.25 mm). Preparative TLC was per-
formed on 1-mm silica gel 60 A, 20 ꢃ 20 plates (Whatman, 4861 840).
Flash-column chromatography was performed according to the method
of Still et al.[11] on Merck grade 60 silica gel, 230–400 mesh. All solvents
used in chromatography had been distilled.
Melting points (mp) were recorded in open capillaries on an Electro-
thermal apparatus and are uncorrected. The infrared (IR) spectra were
taken on a Nicolet Impact 420 Fourier transform–infrared (FT-IR)
spectrophotometer. Mass spectral assays were obtained using a VG
Micromass 7070 HS instrument using ionization energy of 70 eV.
Nuclear magnetic resonance (NMR) spectra were recorded either on
a Bruker AMX-II-500 equipped with a reversed or QNP probe (Pharma-
cor) or (when indicated) on a Varian 200-MHz NMR apparatus. Samples
were dissolved in deuterochloroform (CDCl3) or deuteroacetone (acet-
one-d6) for data acquisition using tetramethylsilane (TMS) or chloroform
as internal standard (TMS, d 0.0 ppm for 1H NMR, and CDCl3,
d 77.0 ppm for 13C). Chemical shifts (d) are expressed in parts per million
(ppm), and the coupling constants (J) are expressed in hertz (Hz). Multi-
plicities are described by the following abbreviations: s for singlet, d for
doublet, dd for doublet of doublets, t for triplet, q for quartet, m for
multiplet, #m for several multiplets, and br s for broad singlet. Only
the most characteristic signals are described for each compound.
Synthesis of 3,5-Androstadien-3,17b-diol Diacetate (2)
Acetyl chloride (10.9 mL, 153 mmol), acetic anhydride (3.4 mL, 42 mmol),
and pyridine (1.1 mL, 13.6 mmol) were added to testosterone (3.4 g,
11.8 mmol). The solution was stirred 3.5 h at reflux and then 20 min at
room temperature. The solvents were evaporated to dryness under
vacuum. The steroid was dissolved in dichloromethane and filtered on
silica gel. The solvent were evaporated again to obtain 4.2 g of diacetate
2 (crude yield 95%). No flash chromatography was needed for that step.
The crude material was used as such for the next transformation. Mp:
143–147ꢀC; IR (cmꢁ1): 1736 (C¼O), 1666 (C¼C), 1248 (C-O); 1H
NMR (CDCl3, d ppm): 5.69 (1H, s, 4-CH), 5.39 (1H, m, 6-CH), 4.61
(1H, t, J ¼ 8.5 Hz, 17-CH), 2.13 (3H, s, CH3, C-3 acetate), 2.04 (3H, s,
CH3, C-17 acetate), 1.01 (3H, s, 19-CH3), 0.83, (3H, s, 18-CH3);

Functionalization of Testosterone
1889
13C NMR (CDCl3, d ppm): 171.2 (C¼O, C-17 acetate), 169.3 (C¼O, C-3
acetate), 147.1 (C-3), 139.5 (C-5), 123.5 (C-6), 116.9 (C-4), 82.7 (C-17).
MS (m=e): 372 (Mþ), 330 (Mþ ꢁ C2H2O). Exact mass calculated for
C23H32O4 ¼ 372.2300; found ¼ 372.2297.
Synthesis of 4,6-Androstadien-17b-ol-3-one Acetate (3)
Under a nitrogen atmosphere, DMF (3.9 mL) and water (0.08 mL) were
combined with the diacetate 2 (1.3 g, 3.5 mmol) and cooled to 0ꢀC.
N-bromosuccinimide (NBS) was added over a period of 1 h and stirred
for an additional 40 min at 0ꢀC. Li2CO3 and LiBr were added to the mix-
ture at room temperature. The mixture was heated for 3 h at 92ꢀC and
then poured in a water=ice solution containing 150 mL of water and
10 mL of acetic acid. The crude compound 3 was filtered, washed with
water, and dried. Then, the crude material was purified by flash chroma-
tography with a mixture of hexane=acetone (9:1) to give 3 in 87% yields
(1.0 g). Mp: 144–147ꢀC; IR (cmꢁ1): 1735 (C¼O, acetate), 1664 (C¼O,
1
ketone), 1613 (C¼C), 1252 (C-O); H NMR (CDCl3, d ppm): 6.11 (2H,
m, 6-CH¼CH-7), 5.68 (1H, s, 4-CH), 4.64 (1H, t, J ¼ 8.3 Hz, 17-CH),
2.06 (3H, s, CH3, acetate) 1.12 (3H, s, 19-CH3), 0.86 (3H, s, 18-CH3);
13C NMR (CDCl3, d ppm): 199.3 (C-3), 171.0 (C-O, acetate) 163.3
(C-5), 139.9 (C-7), 128.2 (C-4), 123.2 (C-6), 82.0 (C-17). MS (m=e):
328 (Mþ), 286 (Mþ ꢁ C2H2O). Exact mass calculated for C21H28O3 ¼
328.2038; found ¼ 328.2032.
Synthesis of 7a-Allyl-4-androsten-17b-ol-3-one Acetate (4)
Under an inert atmosphere of nitrogen, the steroid 3 was dissolved in dry
dichloromethane and cooled to ꢁ78ꢀC. Then, titanium(IV) chloride
(3.8 mL, 34 mmol) and pyridine (0.7 mL, 8.5 mmol) were added to the
solution. The mixture was stirred for 5 min; allyltrimethylsilane was
added, and the mixture was stirred for 1.5 h at ꢁ78ꢀC and 1.5 h at ꢁ30ꢀC.
ꢀC. The black mixture was diluted with ether and washed with a 2% HCl
solution (2 ꢃ 20 mL) and with water (4 ꢃ 20 mL). The organic phase was
dried, filtered, and concentrated to a solid. The crude steroid was purified
by flash chromatography with hexane=acetone (9:1) as the eluant. The
crystalline compound 4 was obtained in good yield (1.5 g, 65%). Mp:
148–150ꢀC; IR (cmꢁ1): 1720 (C¼O, acetate), 1670 (C¼O, ketone),
1
1630–1610 (C¼C), 1220 (C-O); H NMR (CDCl3, d ppm): 5.71 (1H, s,
4-CH), 5.65 (1H, m, CH2¼CH), 5.00–5.02 (2H, 2d, J ¼ 10.3 Hz and
J ¼ 17.3 Hz, CH2¼CH), 4.61 (1H, t, J ¼ 8.5 Hz, 17-CH), 2.05 (3H, s,
CH3, acetate), 1.21 (3H, s, 19-CH3), 0.85 (3H, s, 18-CH3); 13C NMR

´ ´
D. Bastien, J. Nault, and G. Berube
1890
(CDCl3, d ppm): 198.7 (C-3), 170.8 (C¼O, acetate), 168.9 (C-5), 136.6
(CH2¼CH), 126.0 (C-4), 116.6 (CH2¼CH), 82.2 (17-C). MS (m=e): 370
(Mþ), 312 (Mþ ꢁ C2H2O2). Exact mass: calculated for C24H34O3 ¼
370.2508; found ¼ 370.2505.
Synthesis of 7a-Allyl-5-androsten-17b-ol-3-one 3-Ethyleneketal
Acetate (5)
The enone 4 (1.3 g, 3.5 mmol) in benzene (35 mL) was combined with
ethylene glycol (0.56 g, 8.5 mmol) and p-toluenesulfonic acid (30 mg,
0.16 mmol). The mixture was heated at reflux with a Dean–Stark appara-
tus for 12 h. The compound was diluted with ether and washed with a 2%
HCl solution (1 ꢃ 20 mL) and with water (4 ꢃ 20 mL). The organic phase
was dried, filtered, and concentrated to a solid. The crude steroid was pur-
ified by flash chromatography (hexane=acetone, 85:15). The purification
gave the product 5 with 80% yield (1.2 g) as a mixture of regioisomers.
A and B indicate the position of the double bound, either in ring A or
in ring B of the steroid nucleus. IR (cmꢁ1): 1730 (C¼O, acetate), 1630–
1610 (C¼C), 1210 (C-O), 1090 (O-C-O); 1H NMR (CDCl3, d ppm):
5.68A and 5.86B (1H, 2 m, CH2¼CH), 5.19A (1H, s, 4-CH), 5.39B (1H, s,
6-CH), 5.01 (1H, m, CH2¼CH), 4.59–4.62 (1H, 2 t, J ¼ 8.6 Hz, 17-CH),
3.86–4.01 (4H, m, O-CH2-CH2-O), 2.03B and 2.04A (1H, 2s, CH3, acetate),
1.03B and 1.05A (1H, 2s, 19-CH3), 0.80B and 0.81A (1H, 2s, 18-CH3).
Synthesis of 7a-(3-Iodopropyl)-5-androsten-17b-ol-3-one 3-
Ethyleneketal Acetate (6)
Ethyleneketal 5 (1.5 g, 3.6 mmol) was dissolved in dry THF (7 mL) and
cooled to 0ꢀC. BH3-THF was added to the mixture and stirred for
30 min at 0ꢀC. Then, sodium acetate 1 M in methanol (7 mL), an aqueous
sodium iodide solution 1 M (7 mL), and chloramine-T (0.5 M) in metha-
nol (14 mL) were added consecutively to the reaction mixture. The solu-
tion was heated at room temperature and stirred for 7 min. Aqueous
sodium thiosulfate 1 M (7 mL) was added to stop the reaction. The reac-
tion mixture was diluted in ether and washed with water (1 ꢃ 20 mL). The
aqueous phase was recovered and washed with ether (2 ꢃ 20 mL). Then,
the organic phases were combined, treated with a saturated sodium
chloride aqueous solution, and washed with water (4 ꢃ 20 mL). The
organic phase was dried, filtered, and concentrated. Flash chromatogra-
phy (hexane=acetone, 9:1) gave 6 with 58% yield (1.1 g). Mp: 122–124ꢀC;
IR (cmꢁ1): 1720 (C¼O, acetate), 1240 (CH2I), 1240 (C-O, acetate), 1080
(O-C-O); 1H NMR (CDCl3, d ppm): 5.38 (1H, d, J ¼ 4.2 Hz, 6-CH), 4.63

Functionalization of Testosterone
1891
(1H, t, J ¼ 8.5 Hz, 17-CH), 3.93 (4H, m, O-CH2-CH2-O), 3.20 (2H, m,
CH2I), 2.09 and 2.58 (2H, 2d, part A and B of system AB, J ¼ 13.9 Hz,
4-CH2), 2.04 (3H, s, CH3, acetate), 1.03 (3H, s, 19-CH3), 0.80 (3H, s,
18-CH3); 13C NMR (CDCl3, d ppm): 171.1 (C-O, acetate), 140.3 (C-
5), 125.7 (C-6), 109.3 (C-3), 82.6 (C-17), 64.2 (O-CH2-CH2-O), 7.5
(CH2I). MS (m=e): 542 (Mþ), 415 (Mþ ꢁ I). Exact mass calculated for
C26H39O4I ¼542.1893; found ¼ 542.1906.
Synthesis of 7a-Allyl-5-androsten-17b-ol-3-one 3-Ethyleneketal (7)
Under a nitrogen atmosphere, the iodide 6 (0.3 g, 0.55 mmol) was
dissolved in a mixture of DMF=xylene anhydride (2:3) (3.5 mL) and
excess sodium cyanide (0.46 g of sodium cyanide in oil). The reaction
mixture was stirred for 2 h at room temperature. The product was
extracted with ether and washed with water (4 ꢃ 5 mL). The organic
phase was dried, filtered, and concentrated. The compound 7 was
obtained with 74% yield (0.15 g) as a mixture of regioisomers. A and B
indicate the position of the double bound, either in ring A or in ring B
of the steroid nucleus. IR (cmꢁ1): 3420 (O-H), 1650 and 1620 (C¼C),
1
1090 (O-C-O), 1030 (C-O, alcohol); H NMR (CDCl3, d ppm): 5.69A
and 5.87B (1H, 2 m, CH2¼CH), 5.30B and 5.45A (1H, 2s, OH), 5.39B
(1H, d, J ¼ 3.6 Hz, 6-CH), 5.18A (1H, s, 4-CH), 5.00 (2H, m, CH2¼CH),
3.93 (4H, m, O-CH2-CH2-O), 3.65 (1H, t, J ¼ 8.8 Hz, 17-CH), 1.03B and
1.06A (3H, 2s, 19-CH3), 0.75B and 0.77A (3H, 2s, 18-CH3).
Synthesis of 7a-(3-Methoxypropyl)-4-androsten-17b-ol-3-one (9)
The iodide 6 (0.10 g, 0.18 mmol) was dissolved in dry methanol (3.5 mL).
Then, sodium methoxide (0.042 g, 0.78 mmol) in excess was added to the
steroid solution. The mixture was stirred at reflux for 12 h. The com-
pound was extracted with ether and washed with water (3 ꢃ 2 mL). The
ketal group was removed upon treatment with a 10% aqueous HCl solu-
tion for 1 h. Flash chromatography was needed (hexane–acetone, 9:1).
The purification gave product 9 (0.070 g) with 93% yield. Mp:
134–135ꢀC; IR (cmꢁ1): 3460 (O-H), 1650 (C¼O), 1610 (C¼C), 1060
1
(C-O-C), 1020 (C-O, alcohol); H NMR (CDCl3, d ppm): 5.73 (1H, s,
4-CH), 3.66 (1H, t, J ¼ 8.6 Hz, 17-CH), 3.34 (2H, m, -CH2-O), 3.31
(3H, s, O-CH3), 1.21 (3H, s, 19-CH3), 0.80 (3H, s, 18-CH3); 13C NMR
(CDCl3, d ppm): 199.1 (C-3), 169.8 (C-5), 125.9 (C-4), 81.6 (C-17), 72.6
(-CH2-O), 58.4 (O-CH3). MS (m=e): 360 (Mþ), 287 (Mþ ꢁ C4H9O). Exact
mass calculated for C23H36O3 ¼ 360.2664; found ¼ 360.2667.

´ ´
D. Bastien, J. Nault, and G. Berube
1892
ACKNOWLEDGMENTS
We are grateful to the Fonds de Recherche sur la Nature et les Technol-
´
ogies du Quebec (FQRNT) for generous financial support. The authors
thank Dr. Atul Gupta for his contribution in the preparation of this
manuscript.
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