Chemoselective construction of novel steroid derivatives.

Article abstract of DOI:10.1016/S0039-128X(02)00032-6

Alpha-halo-alpha-heteroarylalkyllithiums, generated by deprotonation of the corresponding halides, when added promptly to steroids with C=O or C=NR groups, lead to epoxides and aziridines. The reactions are regio- and stereoselective; in fact, in the presence of more than one C=O group, the oxido or aziridino functions are formed uniquely at the C=O of C-17 (or C-20 depending on its position in the starting molecule), and the C-20(R) stereoisomer is often the only product isolated. Protection of the hydroxyl group present on several considered steroids was required, and it was accomplished through derivatization in acetyl, ether, or lactone.

Full text of DOI:10.1016/S0039-128X(02)00032-6

Steroids 67 (2002) 687–693
Chemoselective construction of novel steroid derivatives
Luigino Troisia,∗, Saverio Floriob, Catia Granitoa
Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali, University of Lecce, Via Prov.le Lecce, Monteroni, I- 73100 Lecce, Italy
a
b
Centro CNR M.I.S.O., Dipartimento Farmaco-Chimico, University of Bari, Via E.Orabona 4, I-70125 Bari, Italy
Received 12 February 2001; received in revised form 25 January 2002; accepted 30 January 2002
Abstract
=
␣-Halo-␣-heteroarylalkyllithiums, generated by deprotonation of the corresponding halides, when added promptly to steroids with C O
=
=
or C NR groups, lead to epoxides and aziridines. The reactions are regio- and stereoselective; in fact, in the presence of more than one C O
=
group, the oxido or aziridino functions are formed uniquely at the C O of C-17 (or C-20 depending on its position in the starting molecule),
and the C-20(R) stereoisomer is often the only product isolated. Protection of the hydroxyl group present on several considered steroids
was required, and it was accomplished through derivatization in acetyl, ether, or lactone. © 2002 Elsevier Science Inc. All rights reserved.
Keywords: ␣-Halo-␣-heteroarylalkyllithiums; Steroids; Oxiranes; Aziridines; Lactones
1. Introduction
Since many natural steroids contain one or more car-
bonylic functions, we investigated the possibility of
transforming these compounds with completely analo-
gous reactions in oxiranyl and aziridinyl derivatives. The
only example present in the literature is the synthesis of
17,20-epoxy-17-picolyl derived from the 5-␣-androstene
through oxidation of the corresponding 17-picolidene with
the complex Cr(VI) oxidepyridine prepared in situ [16].
This procedure leads to modest yields (<40%) without any
stereoselectivity. On the contrary, the method presented
here seems very promising from the point of view of stere-
oselectivity and gives more satisfactory yields.
Steroids represent an extensive and important class of bio-
logically active compounds that are widely used in the phar-
macological industry [1]. Many functional and structural
modifications of steroids have been recently investigated in
order to extend the already broad range of biological activity
shown by these compounds and to increase their selectivity
[2]. We hypothesized that the introduction of an oxido or
aziridino function could play a key role in improving the bi-
ological activity of steroids and consequently, in the devel-
opment of new, pharmacologically active compounds [3–6].
Interest towards this kind of steroid modification is due to
the intense strain present in compounds, such as oxiranes and
aziridines [7–9]. The ring strain makes them easy to open
and suitable for further reactions and then, further modifica-
tions. Oxido and aziridino functions are actually known to be
useful intermediates in the preparation of a great variety of
bioorganic molecules, such as aminoacids [10], aminosug-
ars [11], and antibiotics [12]. Moreover, in the biological
environment, they may efficiently bind the nucleophilic sites
of several biomolecules, particularly in DNA [13]. We have
recently found that ␣-halo-␣-heteroarylalkyllithiums, eas-
ily produced by deprotonation of the corresponding halides,
lead to the formation of epoxides [14] and aziridines [15]
if added to a solution of carbonylic compounds and imines
(Scheme 1).
2. Experimental section
2.1. Characterization of steroids
lH NMR spectra were recorded on Varian EM 360, EM
390, Varian XL-200, and Bruker AM 300 WB spectrome-
ters; chemical shifts were recorded in parts per million (δ)
from the internal standard using CDCl3 as solvent. IR spec-
tra were recorded on a Perkin-Elmer spectrometer Model
598. GC analyses were carried out with a Hewlett-Packard
MP-5890 series II gas chromatograph (dimethylsilicon cap-
illary column, 30 m, 0.25 mm i.d.) only for compounds for
which MS analyses are reported. GC–MS spectrometry
analyses were performed on a HP-5890 series II gas chro-
matograph equipped with HP-5971 mass selective detector
operating at 70 eV (E.I.). Melting points are uncorrected.
∗
Corresponding author. Tel.: +39-0832320701; fax: +39-0832320701.
E-mail address: luigino.troisi@unile.it (L. Troisi).
0039-128X/02/$ – see front matter © 2002 Elsevier Science Inc. All rights reserved.
PII: S0039-128X(02)00032-6

688
L. Troisi et al. / Steroids 67 (2002) 687–693
Scheme 1. Synthesis of oxiranes and aziridines through a Darzens-type reaction [8,9].
Flash chromatography was performed with Merck 230–400
mesh silica gel. All reactions were conducted in oven-dried
glassware under a nitrogen atmosphere. Microanalyses were
performed on a Carlo Erba C, H, N analyzer.
N,N-diethylaniline (10 ml) and heated to 220 ◦C. After 2 h,
the TLC control showed completion of the reaction. Then,
the mixture was cooled to room temperature, and ether was
added (100 ml). Aniline was removed by washing with 10%
HCl three times (caution, exothermic reaction). Evapora-
tion of the ether and drying over Na2SO4 under reduced
pressure left a residue: 87% of a mixture of 2-allylestrone,
and 4-allylestrone, ratio 1:2 (via GC–MS). This residue
was dissolved with 0.01 mmol of Pd(OAc)2 and 0.04 mmol
of [1-4-bis(diphenylphosphino)butane] (dppb) in 5 ml of
toluene and placed in a 45 ml autoclave. The autoclave was
purged, pressurized (600 psi of CO + H2), and heated to
110–120 ◦C. After 24 h, the reaction was cooled to room
temperature, filtered through celite, and concentrated by
rotary evaporation. Separation and purification of the lac-
tones (2c, d) (ratio 2:1) were achieved by silica gel column
chromatography (eluent: petroleum ether/ether 1/1). 4-(3ꢀ-
Carboxypropyl)estrone lactone (2c): m.p. = 67−70 ◦C
(from petroleum ether 40–70 ◦C); 1H NMR (CDCl3) δ:
0.9–2.83 (m, 24 H), 6.90 (d, 1H, J = 8.5 Hz), 7.2 (d, 1H,
J = 8.5 Hz); MS m/e (rel. int.): 338 (100, M+), 320 (8), 293
(15), 238 (90); IR (CHCl3) cm−1: 3030, 2925, 2850, 1755,
1735, 1125. El. An. Calcd. for C22H26O3: C, 78.10; H, 7.78.
Found: C, 78.03; H, 7.92. 2-(3ꢀ-Carboxypropyl)estrone
lactone (2d): m.p. = 207−209 ◦C (from petroleum ether
40–70 ◦C); 1H NMR (CDCl3) δ: 0.91–2.91 (m, 24 H), 6.80
(s, 1H), 7.08 (s, 1H); MS m/e (rel. int.): 338 (56, M+), 310
(2), 283 (100); IR (CHCl3) cm−1: 3030, 2920, 2850, 1755,
1735, 1120. El. An. Calcd. for C22H26O3: C, 78.10; H,
7.78. Found: C, 77.79; H, 8.02.
Imine (2h) was synthesized from 3-allyloxy-estrone (2b)
with a modified Westeimer [19] method. An aniline solution
(1.0 mmol) and 3-allyloxy-estrone (0.5 mmol) in dry ether
(30 ml) were added to 10 g of Sieves (5 Å). The mixture
was preserved under a nitrogen atmosphere overnight; then,
ether (20 ml) was added, and the sieves were renewed. After
5 h, the mixture was filtered and chromatographed by silica
gel column (eluent: petroleum ether/ether 1/1). Unreacted
3-allyloxy-estrone (2b) was recovered (0.2 mmol) and imine
(2h) was isolated, yield 98%; m.p. = 132−134 ◦C (from
CH2Cl2-EtOAc); 1H NMR (CDCl3) δ: 1.02 (s, 3H), 1.5–2.5
(m, 13H), 2.85–2.95 (m, 2H), 4.48–4.54 (m, 2H), 5.24–5.45
(m, 2H), 5.96–6.13 (m, 1H), 6.66–7.32 (m, 8H). 13C NMR
(CDCl3) δ: 16, 23, 26, 27, 28, 30, 34, 38, 44, 46, 52, 69,
112, 115, 117, 119, 123, 126, 129, 132, 135, 138, 152, 156;
2.2. Materials
Commercial grade tetrahydrofuran (THF) was purified by
distillation (twice) from sodium wire under a nitrogen atmo-
sphere. Petroleum ether refers to the 40–70 ◦C boiling frac-
tion. 2-Chloromethyl-pyridine, 3-chloromethyl-pyridine,
and 2-chloromethyl-quinoline were obtained from their
respective hydrochlorides (Aldrich) by treatment with
a 10% NaOH solution. 2-Chloromethyl-benzothiazole,
2-(1-chloroethyl)-benzothiazole [14], 2-chloromethyl-4,4-
dimethyl-2-oxazoline [17], and 2-(1-chloroethyl)-4,4-di-
methyl-2-oxazoline [18] were prepared as reported.
All steroids and all other chemicals were of commercial
grade (Aldrich–Fluka) and used without further purification
or eventually crystallized prior to the use. Acetyl-steroids
(2a, e, f) were obtained as follows: a solution of steroid
(1.0 g) (estrone or trans-androsterone or cis-androsterone)
and sodium acetate (1.0 g) in acetic anhydride (10.0 ml) was
warmed at 70–80 ◦C for 1 h. Water (100 ml) was added, and
the precipitate of the acetyl-steroid was isolated by filtration,
yield 95%.
3-Allyloxy-estrone (2b) was obtained by the reaction of
the estrone (1.0 g, 3.7 mmol) in acetone (20 ml) with allyl-
bromide (1.0 g) and NaOH (0.4 g, 1.0 mmol). The mixture
was warmed at 60 ◦C for 1 h, and after a TLC check (elu-
ent: petroleum ether/ether 1/1), water (150 ml) was added.
The precipitate obtained was filtered, dried, and analyzed
as 3-allyloxy-estrone (2b), yield 98%; m.p. = 105−106 ◦C
(from petroleum ether 40–70 ◦C); 1H NMR (CDCl3) δ:
0.91–2.90 (m, 18H), 4.50 (t, 1H, J = 1.4 Hz), 4.53 (t, 1H,
J = 1.4 Hz), 5.28 (dd, 1H, J = 10, 1.4 Hz), 5.40 (dd, 1H,
J = 16, 1.4 Hz), 5.96–6.13 (m, 1H), 6.60–7.3 (m, 3H); MS
m/e (rel. int.): 310 (100, M+), 225 (42), 212 (23), 186 (38);
IR (CHCl3) cm−1: 3065, 3020, 2920, 2850, 1735, 1605,
1250, 1230. El. An. Calcd. for C21H26O2: C, 81.29; H,
8.38. Found: C, 81.01; H, 8.44.
Lactones (2c, d) were obtained by intermolecular cy-
clocarbonylation of a mixture of 2-allylestrone and 4-
allylestrone after a Claisen rearrangement of 3-allyloxy-
estrone (2b). Procedure: (2b) (980 mg) was dissolved in

L. Troisi et al. / Steroids 67 (2002) 687–693
689
MS m/e (rel. int.): 385 (60, M+), 185 (23), 172 (100); IR
(CHCl3) cm−1: 3060, 3020, 2930, 2860, 1670, 1600, 1500,
1230.
17β,20(S)-Epoxy-20-(2-benzothyazolyl)-3-allyloxy-estrone:
m.p. = 164−166 ◦C (from ether–petroleum ether 40–70 ◦C);
1H NMR (CDCl3) δ: 0.85–2.9 (m, 18H), 4.4–4.7 (m, 3H),
5.2–5.5 (m, 2H), 5.95–6.15 (m, 1H), 6.6–8.1 (m, 7H); IR
(CHCl3) cm−1: 3060, 3020, 2920, 2880, 1600, 1490, 1230.
El. Anal. Calcd. for C29H31NO2S: C, 76.15; H, 6.78; N,
3.06; S, 7.00. Found: C, 75.98; H, 6.95; N, 2.95; S, 7.12.
2.3. Representative experimental procedure for the
coupling reaction
The reaction of 2-benzothiazolylchloromethyllithium
(1a) with 3-allyloxy-estrone (2b) is described as an ex-
ample. An amount of 1 ml of a 2.4 M hexane solution of
n-butyllithium (n-BuLi) was added to di-isopropylamine
(2.4 mmol) in 10 ml of THF at 0 ◦C. The resulting yel-
low solution was cooled to −78 ◦C, and solutions of (2b)
(0.620 g, 2.0 mmol) and of (1a) (0.372 g, 2.0 mmol) in 5 ml
of THF were added dropwise. After l h at −78 ◦C, the re-
action mixture was allowed to warm to room temperature
and quenched with aqueous NH4Cl after 3 h. Extraction
with ether (3 × 25 ml), drying over Na2SO4, and evapo-
ration of the solvent under reduced pressure left a residue
that was column chromatographed (silica gel, petroleum
ether/ether 7/3 as eluent) to give the following epoxides
[C-20(R)/C-20(S): 40/33]. All the other coupling reactions
were carried out in the same manner, and the ratios are
reported in Table 1.
2.3.2. 17β,20(R)-Epoxy-20-(2-quinolinyl)-
3-allyloxy-estrone (3b)
Melting point = 43−45 ◦C (from ether–petroleum ether
1
40–70 ◦C); H NMR (CDCl3.) δ: 0.85–2.8 (m, 18H), 4.50
(s, 1H), 4.52–4.56 (m, 2H), 5.20–5.45 (m, 2H), 5.95–6.15
(m, 1H), 6.6–8.3 (m, 9H); IR (CHCl3) cm−1: 3060, 3020,
2930, 2860, 1720, 1600, 1440, 1375, 1160. El. An. Calcd.
for C31H33NO2: C, 82.45; H, 7.36; N, 3.10: Found: C, 81.61;
H, 7.70; N, 2.95.
2.3.3. 17β,20(R)-Epoxy-20-(2-quinolinyl)-
3-acetoxy-estrone (3c)
Melting point = 62−65 ◦C (from ether–petroleum ether
40–70 ◦C); H NMR (CDCl3) δ: 0.85–2.8 (m, 21H), 4.85
1
(s, 1H), 6.7–8.35 (m, 9H): IR (CHCl3) cm−1: 3060, 3020,
2930, 2860, 1720, 1600, 1440, 1375, 1160. El. An. Calcd.
for C30H31NO3: C, 79.44; H, 6.89; N, 3.08. Found: C, 78.52;
H, 6.95; N, 2.95. 17β,20(S)-Epoxy-20-(2-quinolinyl)-3-
acetoxy-estrone: m.p. = 85−87 ◦C (from ether–petroleum
2.3.1. 17β,20(R)-Epoxy-20-(2-benzothyazolyl)-
3-allyloxy-estrone (3a)
ether 40–70 ◦C); H NMR (CDCl3) δ: 0.85–2.8 (m, 21H),
1
Melting point = 159−161 ◦C (from ether–petroleum
4.65 (s, 1H), 6.7–8.35 (m, 9H); IR (CHCl3) cm−1: 3060,
3020, 2930, 2860, 1720, 1600, 1440, 1375, 1160. El. An.
Calcd. for C30H31NO3: C, 79.44; H, 6.89; N, 3.08. Found:
C, 78.72; H, 6.97; N, 3.05.
1
ether 40–70 ◦C); H NMR (CDCl3) δ: 0.85–2.9 (m, 18H),
4.30 (s, 1H), 4.45–4.55 (m, 2H); 5.2–5.45 (m, 2H),
5.95–6.15 (m, 1H), 6.6–8.1 (m, 7H); IR (CHCl3) cm−1
:
3060, 3020, 2920, 2880, 1600, 1490, 1230. El. An.
Calcd. for C29H31NO2S: C, 76.15; H, 6.78; N, 3.06;
S, 7.00. Found: C, 75.90; H, 6.90; N, 2.91; S, 7.20.
2.3.4. 17β-20(R)-Epoxy-20-(2-quinolinyl)-
3β-acetoxy-5α-androstan (3d)
Melting point = 162−165 ◦C (from ether–petroleum
Table 1
Reaction of ␣-halo-␣-heteroarylalkyllithiums 1a–g with steroids 2a–h in
THF at −78 ◦C under nitrogen (1a–g) + (2a–h) → (3a–q)
1
ether 40–70 ◦C); H NMR (CDCl3) δ: 0.7–2.05 (m, 28H),
4.3 (s, 1H), 5 (s, 1H broad), 7.3–8.25 (m, 6H); IR (CHCl3)
cm−1: 3020, 2930, 2860, 1730, 1440, 1375, 1260, 1160,
1010. El. An. Calcd. for C31H39NO3: C, 78.61; H, 8.30;
N, 2.96. Found: C, 77.91; H, 8.35; N, 2.85. 17β-20(S)-
Epoxy-20-(2-quinolinyl)-3β-acetoxy-5α-androstan: m.p. =
85−88 ◦C (from ether–petroleum ether 40–70 ◦C); 1H NMR
(CDCl3) δ: 0.75–2.1 (m, 28H), 4.45 (s, 1H), 5.1 (s, 1H
broad), 7.3–8.25 (m, 6H); IR (CHCl3) cm−1: 3020, 2930,
2860, 1730, 1440, 1375, 1260, 1160, 1010. El. An. Calcd.
for C31H39NO3: C, 78.61; H, 8.30; N, 2.96. Found: C,
77.95; H, 8.25; N, 2.95.
Entry
Coupling
reaction
Product
Yield (%)
C-20(R)/C-20(S)
ratio
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
1a + 2b
1e + 2b
1e + 2a
1e + 2f
1b + 2f
1c + 2e
1a + 2e
1a + 2c
1f + 2c
1f + 2d
1g + 2c
1g + 2d
1a + 2g
1b + 2g
1d + 2g
1a + 2h
1e + 2h
3a
3b
3c
3d
3e
3f
3g
3h
3I
3j
3k
3l
3m
3n
3o
3p
3q
73
52
40
50
98
45
70
50
65
75
68
60
64
60
55
52
48
40/33
100/0
15/25
20/30
42/56
20/30
55/15
100/0
100/0
100/0
100/0
100/0
100/0a
100/0a
100/0a
100/0
100/0
2.3.5. 17β-20(R)-Epoxy-20-methyl-20-(2-benzothyazolyl)-
3β-acetoxy-5α-androstan (3e)
Melting point
=
45−47 ◦C (from petroleum ether
40–70 ◦C); 1H NMR (CDCl3) ␦: 0.7–2.5 (m, 34H), 5.1
(s, 1H broad), 7.3–8.2 (m, 4H); IR (CHCl3) cm−1: 3020,
2935, 2860, 1730, 1435, 1375, 1260, 1160, 1010. El. An.
Calcd. for C28H29NO3S: C, 73.17; H, 6.36; N, 3.05; S,
a 100 is referred to the C-20(S), C-21(R) diastereoisomer, the unique
stereoisomer isolated among the four possible.

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L. Troisi et al. / Steroids 67 (2002) 687–693
6.98. Found: C, 71.76; H, 6.80; N, 2.80; S, 6.75. 17β-
20(S)-Epoxy-20-methyl-20-(2-benzothyazolyl)-3β-acetoxy-
5α-androstan: m.p. = 197−199 ◦C (from petroleum ether
cm−1: 3030, 2910, 2850, 1730, 1610, 1500, 1250. El. An.
Calcd. for C28H35NO4: C, 74.80; H, 7.85; N, 3.10. Found:
C, 74.52; H, 7.60; N, 3.05.
1
40–70 ◦C); H NMR (CDCl3) δ: 0.7–2.2 (m, 34H), 5.1 (s,
1H broad), 7.35–8.2 (m, 4H); IR (CHCl3) cm−1: 3020,
2935, 2860, 1730, 1435, 1375, 1260, 1160, 1010. El. An.
Calcd. for C30H39NO3S: C, 73.17; H, 7.90; N, 2.81; S,
6.51. Found: C, 73.44; H, 7.20; N, 3.03; S, 6.65.
2.3.10. 2-(3ꢀ-Carboxypropyl)-17β,20(R)-epoxy-20-
[(4,4-dimethyl)-2-oxazolyl]estrone lactone (3j)
Melting point = 166−170 ◦C (with dec.) (from n-
1
hexane); H NMR (CDCl3) δ: 0.9–2.95 (m, 30H), 3.59 (s,
1H), 4.03 (s, 1H), 4.27 (s, 1H), 6.67 (s, 1H), 7.0 (s, 1H); IR
(CDCl3) cm−1: 3030, 2910, 2850, 1730, 1610, 1500, 1250.
El. An. Calcd. for C28H35NO4: C, 74.80; H, 7.85; N, 3.10.
Found: C, 74.32; H, 7.68; N, 3.09.
2.3.6. 17β,20(R)-Epoxy-20-(2-pyridinyl)-
3α-acetoxy-5α-androstan (3f )
1
Oil; H NMR (CDCl3) δ: 0.8–2.6 (m, 31H), 4.75 (s, 1H
broad), 5.32 (s, lH), 7.25–8.8 (m, 4H); IR (film) cm−1
:
2.3.11. 4-(3ꢀ-Carboxypropyl)-17β,20(R)-epoxy-20-methyl-
20-[(4,4-dimethyl)-2-oxazolyl]estrone lactone (3k)
3020, 2930, 2850, 1725, 1450, 1375, 1255, 1150, 1010.
El. An. Calcd. for C27H37NO3: C, 76.56; H, 8.80; N, 3.30.
Found: C, 75.10; H, 8.85; N, 2.95. 17β,20(S)-Epoxy-20-(2-
pyridinyl)-3α-acetoxy-5α-androstan: oil; 1H NMR (CDCl3)
δ: 0.8–2.4 (m, 31H), 4.8 (s, 1H broad), 5.55 (s, 1H), 7.1–8.8
(m, 4H); IR (film) cm−1: 3020, 2930, 2850, 1725, 1450,
1370, 1260, 1150, 1010. El. An. Calcd. for C27H37NO3:
C, 76.56; H, 8.80; N, 3.30. Found: C, 75.30; H, 8.75;
N, 2.90.
Melting point = 205−209 ◦C (from n-hexane); 1H NMR
(CDCl3) δ: 0.9–3.0 (m, 33H), 3.78–3.82 (m, 2H), 6.7 (d, 1H,
J = 8.5 Hz), 7.1 (d, 1H, J = 8.5 Hz); IR (CHCl3) cm−1
:
3060, 2960, 2850, 1750, 1660, 1600, 1450, 1230. El. An.
Calcd. for C29H37NO4: C, 75.13; H, 8.04; N, 3.02. Found:
C, 74.80; H, 8.15; N, 3.10.
2.3.12. 2-(3ꢀ-Carboxypropyl)-17β,20(R)-epoxy-20-methyl-
20-[(4,4-dimethyl)-2-oxazolyl]estrone lactone (3l)
2.3.7. 17β,20(R)-Epoxy-20-(2-benzothyazolyl)-
3α-acetoxy-5α-androstan (3g)
Melting point = 160−165 ◦C (from petroleum ether
40–70 ◦C); 1H NMR (CDCl3) δ: 0.9–3.0 (m, 33H),
3.78–3.82 (m, 2H), 6.8 (s, 1H), 7.1 (s, 1H); IR (CHCl3)
cm−1: 3060, 3020, 2960, 2850, 1750, 1660, 1600, 1520,
1450, 1230. El. An. Calcd. for C29H37NO4: C, 75.13; H,
8.04; N, 3.02. Found: C, 75.50; H, 8.25; N, 2.95.
Melting point
=
65−66 ◦C (from petroleum ether
40–70 ◦C); H NMR (CDCl3) δ: 0.7–2.1 (m, 31H), 4.6 (s,
1H), 4.75 (s, 1H broad), 7.35–8.3 (m, 4H); IR (CHCl3)
cm−1: 3060, 3020, 2930, 2850, 1725, 1440, 1375, 1260,
1020. El. An. Calcd. for C29H37NO3S: C, 72.61; H, 7.78;
N, 2.92; S, 6.68. Found: C, 71.90; H, 7.95; N, 2.75; S,
6.81. 17β,20(S)-Epoxy-20-(2-benzothyazolyl)-3α-acetoxy-
5α-androstan: m.p. = 82−83 ◦C (from petroleum ether
1
2.3.13. 20(S),21(R)-Epoxy-20-methyl-
21-(2-benzothyazolyl)-androst-4-en-3-one (3m)
Melting point = 233−234 ◦C (from petroleum ether
40–70 ◦C); 1H NMR (CDCl3) δ: 0.7–2.6 (m, 29H), 4.2
40–70 ◦C); H NMR (CDCl3) δ: 0.7–2.03 (m, 31H), 4.38
1
(s, 1H), 4.75 (s, 1H broad), 7.4–8.3 (m, 4H); IR (CHCl3)
cm−1: 3060, 3020, 2925, 2850, 1725, 1450, 1375, 1260,
1015. El. An. Calcd. for C29H37NO3S: C, 72.61; H, 7.78;
N, 2.92; S, 6.68. Found: C, 71.95; H, 7.75; N, 2.78;
S, 6.83.
(s, 1H), 5.87 (s, 1H), 7.5–8.3 (m, 4H); IR (CHCl3) cm−1
:
3020, 2980, 2940, 2880, 1660, 1520, 1435, 1380, 1105. El.
An. Calcd. for C29H35NO2S: C, 75.45; H, 7.64; N, 3.03; S,
6.94. Found: C, 75.05; H, 7.72; N, 2.92; S, 7.01.
2.3.8. 4-(3ꢀ-Carboxypropyl)-17β,
2.3.14. 20(S),21(R)-Epoxy-20,21-dimethyl-
21-(2-benzothyazolyl)-androst-4-en-3-one (3n)
20(R)-epoxy-20-(2-benzothyazolyl)estrone lactone (3h)
Melting point = 220−223 ◦C (from n-hexane); 1H NMR
(CDCl3) δ: 0.9–2.86 (m, 24H), 4.3 (s, 1H), 6.80 (d, 1H,
J = 8.5 Hz), 7.1 (d, 1H, J = 8.5 Hz), 7.50–8.10 (m,
4H); IR (CHCl3) cm−1: 3050, 3020, 2900, 2840, 1735,
1410, 1250. El. An. Calcd. for C30H31NO3S: C, 74.22; H,
6.39; N, 2.88; S, 6.59. Found: C, 74.08; H, 6.68; N, 3.10;
S, 6.81.
Melting point = 240−241 ◦C (with dec.) (from petroleum
ether 40–70 ◦C); H NMR (CDCl3) δ: 0.8–2.25 (m, 32H),
1
5.75 (s, 1H), 7.4–8.2 (m, 4H); IR (CHCl3) cm−1: 3020,
2975, 2935, 2880, 1660, 1520, 1435, 1380, 1100. El. An.
Calcd. for C30H37NO2S: C, 75.75; H, 7.84; N, 2.94; S, 6.74.
Found: C, 75.30; H, 7.89; N, 2.94; S, 6.58.
2.3.15. 20(S),21(R)-Epoxy-20-methyl-
21-(3-pyridinyl)-androst-4-en-3-one (3o)
2.3.9. 4-(3ꢀ-Carboxypropyl)-17β,20(R)-epoxy-
20-[(4,4-dimethyl)-2-oxazolyl]estrone lactone (3i)
Oil; 1H NMR (CDCl3) δ: 0.7–2.6 (m, 29H), 4.65 (s, 1H),
5.8 (s, 1H), 7.3–8.75 (m, 4H); IR (film) cm−1: 3020, 2970,
2875, 1660, 1450, 1375, 1355, 1230, 1110. El. An. Calcd.
for C27H35NO2: C, 79.96; H, 8.70; N, 3.45. Found: C, 79.58;
H, 8.20; N, 3.25.
Melting point
=
207−211 ◦C (with dec.), (from
1
petroleum ether 40–70 ◦C); H NMR (CDCl3) δ: 0.9–3.0
(m, 30H), 3.61 (s, 1H), 3.99 (s, 1H), 4.24 (s, 1H), 6.78 (d,
1H, J = 8.5 Hz), 7.8 (d, 1H, J = 8.5 Hz); IR (CHCl3)

L. Troisi et al. / Steroids 67 (2002) 687–693
691
2.3.16. 17β,20(R)-(N-Phenyl-aziridine)-
20-(2-benzothiazolyl)-3-allyloxy-estrone (3p)
Melting point = 137−139 ◦C (from ether–petroleum
ether 40–70 ◦C); 1H NMR (CDCl3) δ: 1.37–2.57 (m,
16H), 2.86–2.90 (m, 2H), 3.65 (s, 1H), 4.48–4.53 (m, 2H),
5.25–5.45 (m, 2H), 5.95–6.12 (m, 1H), 6.65–6.76 (m, 4H),
7.17–7.50 (m, 6H), 7.70–8.06 (m, 2H); IR (CHCl3) cm−1
:
3050, 3020, 2930, 2855, 1600, 1505 1230. El. An. Calcd.
for C35H36N2OS: C, 78.95; H, 6.77; N, 5.27; S, 6.01.
Found: C, 78.10; H, 6.60; N, 5.50; S, 6.12.
2.3.17. 17β,20(R)-(N-Phenyl-aziridine)-
20-(2-quinolinyl)-3-allyloxy-estrone (3q)
Melting point = 175−178 ◦C (from petroleum ether
40–70 ◦C); 1H NMR (CDCl3) δ: 1.29–2.30 (m, 16H),
2.8–2.9 (m, 2H), 3.81 (s, 1H), 4.42–4.56 (m, 2H), 5.20–5.42
(m, 2H), 5.80–6.0 (m, 2H), 6.70–8.36 (m, 14H); IR (CHCl3)
cm−1: 3060, 3020, 2930, 2855, 1605, 1500, 1240; El. An.
Calcd. for C37H38N2O: C, 84.41; H, 7.22; N, 5.32. Found:
C, 83.30; H, 7.18; N, 5.25.
Plate 2.
3. Results and discussion
For steroids also possessing an hydroxyl function, it was
necessary to protect this group because it would have not per-
mitted, for obvious reasons, the coupling with the carbanion.
Protection of the hydroxyl function was accomplished, as
more widely described in the experimental section, through
acetylation with Ac2O, by allylation with allylchloride, or
by the introduction of a lactonic function between C2–3 and
C3–4, according to Alper’s method [20], as recently reported
in one of our communications [21].
We studied the coupling reactions between the ␣-chloro-
␣-heteroarylalkyllithiums in Plate 1 (1a–g), acting as car-
banions, and the steroids in Plate 2 (2a–h), acting as
electrophiles. All the lithium-derivatives (1a–g) were pre-
pared with LDA at −78 ◦C in THF from the corresponding
chloroalkyl derivatives, synthesized by us if not commer-
cially available.
The studied reactions showed high selectivity. In fact,
notwithstanding steroids 2a, c–f, which were modified by an
acetylic or lactonic function to protect the hydroxyl group
and possessed two carbonylic functions, coupling with the
various ␣-Cl-carbanions, 1a–c, e–g, always led to the isola-
tion of an unique C-17 steroid with an oxiranyl group. The
yields were good and only sometimes modest (entry 3, 4, 6,
8), Table 1. Also, in the coupling of progesterone 2g, which
=
has two C O groups, with 1a, b, d, the oxiranyl function
was formed only on C-20 with quite a lot of yield (55–64%,
entry 13, 14, 15). No products arising from a nucleophilic
attack on C-3 were isolated.
Stereoselectivity was also found. In fact, among the var-
ious possible stereoisomers, only two and sometimes only
one were found. C-20(R)/C-20(S) ratios close to unity were
found in the reactions of ␣-Cl-heteroalkyllithium 1a–c, e
with steroids 2a, b, e, f, which had the protected hydroxyl
group (entry 1, 3, 4, 5, 6). A C-20(R)/C-20(S) ratio of 55/15
was observed in the coupling of the ␣-Cl-heteroalkyllithium
1a with the acetyl-steroid 2e (entry 7). In all the other
cases reported in Table 1, only one diastereoisomer ap-
peared as product of the reaction. In fact, high stereo-
selectivity was observed in the coupling reaction of the
Plate 1.

692
L. Troisi et al. / Steroids 67 (2002) 687–693
Scheme 2. The ␣-attack of the carbanion on C-17 gives to the heteroatom (O or N) a -␤-position in the functionalized steroid.
␣-Cl-heteroarylalkyllithiums 1a, e–g with the steroids 2b–d
(entry 2, 8–12), and of the ␣-Cl-heteroarylalkyllithiums
1a, e with the imine 2h (entry 16-17) which led to the
isolation of only the C-20(R) diastereoisomer. Again, the
C-20(S),C-21(R) diastereoisomer was the only product iso-
lated from the coupling of the ␣-Cl-heteroarylalkyllithiums
1a, b, d with the progesterone 2g (entry 13, 14, 15).
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=
and C-20(S) isomeric forms in the products with R H were
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In conclusion, in this paper we have shown that
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act as Darzens-type reagents and add cleanly and stereose-
=
=
lectively to steroids with C O or C N groups to give new
steroid derivatives having both epoxide (or aziridine) and
acetyl (or allyl or seven-membered lactone ring) functions.
Acknowledgments
This work was carried out in the framework of the
National Project “Stereoselezione in Sintesi Organica.
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dell’Università e della Ricerca Scientifica e Tecnologica
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