PhI=NSes mediated aziridination of 11-pregnane derivatives: Synthesis of an 11,12-aziridino analogue of neuroactive steroids

Article abstract of DOI:10.1016/S0040-4020(02)01655-1

Reaction of 11-pregnene-3,20-dione (6) or 3-α-acetoxy-11-pregnen-20-one (12) with trimethylsilylethanesulfonyl ('Ses') iminoiodinane 5 in the presence of copper (I) triflate gave the corresponding α,α-11,12-aziridino steroids 7 and 13 in 53 and 45% yields, respectively. The Ses group of each compound was removed using the TASF reagent and the resulting free aziridine NH was methylated to afford the 11α,12α-N-methyl aziridinosteroids 9 and 15, respectively. The latter is a conformationally constrained analogue of the endogenous neurosteroid pregnanolone (1).

Full text of DOI:10.1016/S0040-4020(02)01655-1

Tetrahedron 59 (2003) 1009–1014
PhIvNSes mediated aziridination of 11-pregnane derivatives:
synthesis of an 11,12-aziridino analogue of neuroactive steroids
Pablo H. Di Chenna,a Philippe Dauban,b Alberto Ghini,a Ricardo Baggio,c Maria Teresa Garland,d
Gerardo Burtona and Robert H. Doddb
,
*
a
´ ´
Departamento de Quımica Organica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
bInstitut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette cedex, France
c
´
Departamento de Fısica, Comision Nacional de Energia Atomica, Av. del Libertador 8250, C1429 Buenos Aires, Argentina
Departamento de Fısica, Facultad de Ciencias Fısicas y Matematicas, Universidad de Chile, Av. Blanco Encalada 2008,
´
´
d
´
´
´
Casilla 487-3 Santiago, Chile
Received 21 October 2002; revised 12 December 2002; accepted 12 December 2002
Abstract—Reaction of 11-pregnene-3,20-dione (6) or 3-a-acetoxy-11-pregnen-20-one (12) with trimethylsilylethanesulfonyl (‘Ses’)
iminoiodinane 5 in the presence of copper (I) triflate gave the corresponding a,a-11,12-aziridino steroids 7 and 13 in 53 and 45% yields,
respectively. The Ses group of each compound was removed using the TASF reagent and the resulting free aziridine NH was methylated to
afford the 11a,12a-N-methyl aziridinosteroids 9 and 15, respectively. The latter is a conformationally constrained analogue of the
endogenous neurosteroid pregnanolone (1). q 2003 Elsevier Science Ltd. All rights reserved.
Endogenously occurring steroids such as pregnanolone (1)
and epiallopregnanolone (2) are known to interact with the
neuroinhibitory GABAA receptor of the central nervous
system.1–3 Such neurosteroids and their synthetic analogues
can, as a result, demonstrate sedative-hypnotic, anxiolytic or
anticonvulsant activities in vivo. In the search for more
active, selective or water-soluble steroid derivatives, several
aminosteroids have been developed over the years. Thus,
the 11a-(N,N-dimethylamino)pregnan-20-one, minaxolone
(3)4 and a 2-morpholinyl analogue of alfaxolone, Org 21465
(4)5 are highly effective general anesthetics. Certain amino
steroids have also been shown to demonstrate other
activities such as enzyme inhibition.6,7 An alternative way
of obtaining more potent steroid derivatives is to synthesize
conformationally restrained analogues. In this regard, the
synthesis and biological activities of 3a-hydroxyandrostan-
16,17-epoxides and oxetanes have recently been reported.8
nucleus), there are only a few reported syntheses of fused
aziridine-steroid derivatives11,12 and none of aziridines
fused at the 11,12-position. Such aziridino steroids have
generally been prepared as epimeric mixtures by lithium
aluminum hydride reduction of ketosteroid-derived
oximes,9,10,12 a method originally introduced by Tzikas
and co-workers.13 The aziridination of a bis-unsaturated
steroid using N3CO2Et under photolytic reaction conditions
has also been reported.11
As a means of combining the presence of an apparently
well-tolerated nitrogen atom at the 11 position of neuro-
steroids (i.e. as in minaxolone 3) together with a certain
level of conformational constraint to the steroid nucleus, we
thought of preparing an 11,12-aziridino analogue of
neurosteroids 1 or 2. While a number of exocyclic
aziridinosteroids have been described (i.e. in which the
aziridine moiety shares one9 or no6,10 atoms with the steroid
Keywords: steroid; aziridine; Ses group; iminoiodinane.
*
Corresponding author. Tel.: þ33-1-69-82-45-94; fax: þ33-1-69-07-72-
47; e-mail: robert.dodd@icsn.cnrs-gif.fr
A particularly attractive method for accessing such
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01655-1

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P. H. Di Chenna et al. / Tetrahedron 59 (2003) 1009–1014
aziridine hydrogens at 3.070 and 2.870 ppm (H-12 and H-
11, respectively); the H-11 resonance appeared as a double
doublet with a very small coupling (0.8 Hz) to H-9,
indicative of the a orientation of the aziridine ring which
corresponds to approach of the nitrene species from the less
hindered face of the steroid. There was no evidence in the
reaction mixture of any compound corresponding to the
11,12-b analogue of 7. The stereochemistry of 7 was further
confirmed by X-ray crystallography of the final product (see
below). We have previously shown that it is possible to
cleave the Ses group from the intact aziridine by use of
excess tris(dimethylamino)sulfonium difluorotrimethylsili-
cate (TASF) under mild conditions (acetonitrile or DMF at
room temperature).20 In the case of compound 7, heating in
DMF with TASF (5 equiv.) at 458C for 40 min was
necessary to effect complete deprotection of the aziridine,
giving 8 in 77% yield. The free amine was then methylated
at room temperature using excess methyl iodide and
potassium carbonate in acetonitrile/ethyl acetate (1:1),
affording compound 9 in 60% yield. The NOESY spectrum
of compound 9 showed strong correlations for the b-
oriented aziridine hydrogens H-11 (1.37 ppm) and H-12
(1.65 ppm) with the angular methyl protons H-19 and H-18,
respectively. The N-methyl group had strong NOE corre-
lations with both aziridine hydrogens at positions 11b and
12b and a weak correlation with the 17a-H, consistent with
an exo orientation. The structure of compound 9 and the
orientation of the N-methyl group were confirmed by X-ray
crystallography (Fig. 1), which clearly showed the a-
configuration of the 11,12-aziridine ring and the flattening
of the C-ring as a result of the presence of the fused
aziridine; interestingly, the A-ring also shows a consider-
able distortion from its expected chairlike conformation, in
the vicinity of C1 and C2.22
Scheme 1.
molecules would be application to an unsaturated steroid of
an [N-(arylsulfonyl)imino]phenyliodinane-mediated aziri-
dination. These hypervalent iodine reagents, in the presence
of a copper catalyst, generate the nitrene species which adds
to the olefin, forming an N-arylsulfonylaziridine.14–16 Both
electron-rich and electron-poor olefins can be aziridinated
using this procedure. While the stereochemical outcome of
the nitrene addition to a double bond can in some cases be
controlled by addition of chiral catalysts to the reaction
medium (e.g. bis-oxazolines),14 use of a chiral substrate
such as a steroid should in principle allow diastereoselective
aziridination.
A disadvantage of this methodology, however, is the often
troublesome removal of the stable N-arylsulfonyl group,
both in the intact aziridine as well as in the products of
nucleophilic aziridine ring opening.17–19 It was for this
reason that we developed as an alternative the trimethyl-
silylethanesulfonyl (‘Ses’) version of these reagents (i.e. 5,
Scheme 1) in order to allow facile removal of the
alkylsulfonyl group using a source of fluoride anion.20 In
this paper, then, we describe the synthesis using the Ses
iminoiodinane 5 of a minaxolone-type steroid in which
the N,N-dimethylamino group at C-11 is replaced by an
N-methyl 11,12-aziridino function.21
As a model study, it was initially decided to attempt
aziridination of 11-pregnene-3,20-dione 6. Thus, treatment
of 6 in acetonitrile with Ses reagent 5 in the presence of
10 mol% of copper (I) triflate afforded, after 24 h at room
temperature, the desired N-Ses aziridine derivative 7 in 53%
Having established that the transformation of the 11,12
double bond of steroid 6 to an N-methyl aziridine using the
Ses-iminoiodinane 5 is a viable procedure, we then set about
to prepare the 3-a-hydroxy analogue of 9 in order to target,
by analogy with 1 and minaxolone 3, a neuroactive steroid.
1
yield (Scheme 2). The H NMR spectrum of 7 showed the
Scheme 2.

P. H. Di Chenna et al. / Tetrahedron 59 (2003) 1009–1014
1011
Figure 1. Displacement ellipsoid diagram of compound 927 showing the numbering scheme used. Displacement ellipsoids drawn at a 40% probability level.
For this purpose, a more suitable starting material, the 3a-
acetoxy-11-pregnene-20-one derivative 12, was chosen.
The latter was prepared as shown in Scheme 3. Thus, the
12a-hydroxy substrate 10 (prepared from deoxycholic acid
as previously described)23 was treated with tosyl chloride in
anhydrous pyridine for 6 days at 608C, yielding 90% of the
tosyloxy derivative 11, which could be purified by flash
chromatography on silica gel. Refluxing of a solution of 11
in collidine for 6 h then provided the desired olefin 12 in
85% yield. Treatment of the latter with PhIvNSes and
catalytic copper (I) triflate in acetonitrile produced the
expected N-Ses aziridine derivative 13 in 45% yield (77%
based on recovered starting material 12). Again, only
formation of the a-aziridine derivative was evident from the
1H NMR spectra. Finally, deprotection of the amine
function of 13 with TASF in DMF gave the free amine
14. Treatment of the latter with methyl iodide and potassium
carbonate resulted in simultaneous N-methylation and O-
deacetylation, thereby providing the desired N-methylazir-
idine-3a-hydroxy steroid derivative 15, a direct structural
analogue of 1 and 3. It is interesting to note that, while this
study was in progress, a report appeared24 describing the
allylic amidation of cholesteryl acetate by PhIvNTs
catalyzed by a Ru(II)-salen complex. We observed no
such amine insertion products in the reactions of steroids 6
and 12 with PhIvNSes and of 6 with PhIvNTs.21
and a structural analogue of the synthetic general anesthetic
minaxolone (3), will be reported elsewhere.
1. Experimental
1.1. General
Mps were taken on a Fisher–Johns apparatus and are
uncorrected. IR spectra were recorded in KBr pellets on a
1
Nicolet Magna IR 550 FT-IR spectrometer. H and 13C
NMR spectra were measured on a Bruker AC-200 (200.13
and 50.32 MHz) or AM-500 (500.13 and 125.72 MHz)
NMR spectrometer for samples in deuteriochloroform
(using tetramethylsilane as internal standard). J values are
given in Hertz. Electron impact (EI) mass spectra were
measured in a GC–MS Shimadzu QP-5000 mass spectro-
meter at 70 eV by direct inlet. Chemical ionization (CI)
mass spectra were measured on a Kratos MS80 spectro-
meter. High resolution mass spectra were obtained with a
VG ZAB BEQQ (EI), a Kratos MS80 (CI) or a Finnegan
Navigator Aqua Thermoquest (ESI) mass spectrometer.
Single crystal X-ray measurements were performed on a
Bruker SMART CCD diffractometer, with graphite mono-
chromated Mo Ka radiation. The structure was solved by
direct methods with SHELXS9725 and refined by full matrix
least squares in F 2 using SHELXL97.26 Hydrogen atoms
˚
In conclusion, use of PhIvNSes has allowed the efficient
copper-catalyzed, diastereoselective aziridination of 11-
pregnene derivatives 6 and 12 and facile conversion of the
product of the latter, via TASF-mediated removal of the N-
Ses blocking group, to the N-methyl-11,12-aziridino-3a-
hydroxy-5b-pregnan-20-one (15). The pharmacological
activity of compound 15, a conformationally constrained
analogue of the endogenous neurosteroid pregnanolone (1)
were idealized at their expected positions (C–H: 0.93 A)
and allowed to ride. Molecular plots were drawn with XP, in
the SHELXLTL-PC package.27 All solvents used were
reagent grade. Solvents were evaporated at 458C under
reduced pressure. Flash chromatography was performed
on silica gel Merck 9385 (40–63m). Homogeneity of
all compounds was confirmed by TLC. Ketone 10
was synthesized in 8% yield from deoxycholic acid.23
Scheme 3.

1012
P. H. Di Chenna et al. / Tetrahedron 59 (2003) 1009–1014
11-Pregnene-3,20-dione was purchased from Sigma.
Elemental analyses were performed at the ICSN, CNRS,
Gif-sur-Yvette, France or at the UMYMFOR, CONICET-
FCEN, Buenos Aires, Argentina.
purified by preparative chromatography (silica gel, ethyl
acetate/methanol 99:1) giving the N-methyl aziridine 9
(9.9 mg, 60% yield) as a white, crystalline solid, mp 130–
1338C; [a]2D0¼þ87.38 (c¼0.1, CH2Cl2); IR (KBr) 2933,
2871, 1706, 1451, 1096 cm21; 1H NMR (500 MHz, CDCl3)
d 2.889 (t, J¼9.3 Hz, 1H, 17-H), 2.631 (t, J¼13.0 Hz, 1H,
4a-H), 2.503 (dt, J¼14.3, 5.0 Hz, 1H, 2a-H), 2.409 (s, 3H,
N–CH3), 2.204 (s, 3H, 21-H), 1.649 (d, J¼6.6 Hz, 1H, 12-
H), 1.372 (broad d, J¼6.8 Hz, 1H, 11-H), 1.083 (s, 3H, 19-
H), 0.723 (s, 3H, 18-H); 13C NMR (125 MHz, CDCl3) d
212.40 (C-3), 209.12 (C-20), 59.15 (C-17), 50.61 (C-12),
48.18 (C-14), 47.60 (N–CH3), 44.03 (C-13), 43.33 (C-5),
43.01 (C-9), 42.63 (C-4), 40.75 (C-11), 36.92 (C-2), 36.84
(C-1), 35.33 (C-10), 32.87 (C-8), 31.31 (C-21), 27.30 (C-
15), 24.98 (C-6), 22.87 (C-19), 22.71 (C-7), 22.25 (C-16),
15.06 (C-18); EIMS m/z 343 (Mþ, 12), 328 (10), 300 (23),
286 (6), 162 (8), 108 (12), 55 (32), 43 (100); HRMS (ESI)
calcd for C22H33O2NþHþ: 344.2589. Found 344.2588.
1.1.1. N-[2-(Trimethylsilyl)ethanesulfonyl]-11a12a-azir-
idino-5b-H-pregnane-3,20-dione (7). PhIvNSes (448 mg,
1.17 mmol)20 was added portionwise over a period of 5 h
˚
under argon to a mixture of 4 A molecular sieves (185 mg),
copper (I) triflate (14 mg, 0.065 mmol) and 11-pregnene-
3,20-dione (6, 200 mg, 0.65 mmol) in acetonitrile (1.6 ml).
The green reaction mixture was stirred at room temperature
for 24 h and then purified directly by flash chromatography
(heptane/ethyl acetate 8:2), aziridine 7 was first eluted
(166 mg, 53% yield, 66% yield based on unreacted 6),
followed by unreacted starting material 6 (44 mg, 22%).
The aziridine was obtained as an amorphous solid, mp 55–
608C; [a]2D0¼þ102.38 (c¼0.1, CHCl3); IR (KBr) 2952,
2361, 2342, 1707, 1321, 1251, 1144 cm21 1H NMR
;
(500 MHz, CDCl3) d 3.070 (d, J¼6.4 Hz, 1H, 12-H),
3.060 (m, 2H, SO2CH2), 2.870 (dd, J<0.8, 7.0 Hz, 1H,
11-H), 2.712 (t, J¼9.8 Hz, 1H, 17-H), 2.569 (t, J¼13.4 Hz,
1H, 4a-H), 2.429 (dt, J¼13.6, 5.0 Hz, 1H, 2a-H), 2.225 (s,
3H, 21-H), 1.106 (s, 3H, 19-H), 0.816 (s, 3H, 18-H), 0.045
(s, 9H, Si–CH3); 13C NMR (125 MHz, CDCl3) d 211.68 (C-
3), 209.69 (C-20), 58.68 (C-17), 48.59 (C–SO2), 47.89 (C-
12), 46.93 (C-14), 43.28 (C-13), 42.97 (C-5), 42.45 (C-4),
42.23 (C-9), 39.38 (C-11), 36.78 (C-2), 36.48 (C-1), 35.37
(C-10), 32.75 (C-8), 30.99 (C-21), 27.14 (C-15), 24.79 (C-
6), 22.80 (C-19), 22.69 (C-16), 22.53 (C-7), 14.39 (C-18),
9.29 (Si–CH2), 21.90 (Si–CH3); MS (CI) 494 ([MþH]þ,
70), 330 (100), 315 (80), 297 (5), 166 (52); HRMS (CI)
calcd for C26H44NO4SSi (Mþ1), 494.2760. Found
494.2789.
1.2. Crystallographic data and data collection
parameters for compound 9
Colorless prismatic crystals recrystallized from acetone: mp
130–1338C. C22H33NO2, M¼342.49, monoclinic, space
˚
group P21 (No. 4); cell constants a¼8.580(1) A,
˚
˚
b¼12.678(2) A, c¼9.255(1) A; b¼102.20(1)8; V¼
984.0(3) A , Dc(Z¼2)¼1.156 g cm23; crystal dimensions
3
˚
0.38£0.28£0.22 mm3, reflections measured: 5913, reflec-
tions unique: 3842, reflections observed (I.2s(I)): 1339;
R¼0.047 and R2w¼0.082.
1.2.1. 3a-Acetoxy-12a-tosyloxy-5b-H-pregnan-20-one
(11). Tosyl chloride (771 mg, 3.5 mmol) was added to a
stirred solution of 10 (437 mg, 1.16 mmol) in dry pyridine
(3.3 ml) at 608C under nitrogen. After 6 days the reaction
mixture was cooled to room temperature, acidified with 1N
HCl (pH ,3), transferred to a separatory funnel and
extracted with dichloromethane (4£30 ml). The organic
extracts were combined, washed with 5% aqueous NaHCO3
and water, dried with Na2SO4 and the solvent was
evaporated. The crude product was purified by flash
chromatography (hexane/ethyl acetate 8:2) to give tosylate
11 (550 mg, 90% yield) as a white, crystalline solid, mp
157–1588C (hexane/ethyl acetate); IR (KBr) 3404, 2938,
1.1.2. 11a,12a-Aziridino-5b-H-pregnane-3,20-dione (8).
A solution of TASF (206 mg, 0.75 mmol) and N-Ses-
aziridine 7 (126 mg, 0.25 mmol) in dry DMF (6 ml) was
stirred at 458C for 45 min. The solvent was evaporated
under vacuum and the crude product was purified by flash
chromatography on silica gel (ethyl acetate/methanol 95:5)
yielding the deprotected aziridine 8 (64 mg, 77% yield), mp
1848C; [a]2D0¼þ92.58 (c¼0.4, CHCl3); IR (KBr) 3436,
2925, 2874, 1703, 1446, 1356, 1261, 1096 cm21; 1H NMR
(200 MHz, CDCl3) d 2.88 (t, J¼9.2 Hz, 1H, 17-H), 2.63 (dt,
J¼13.3, 1.8 Hz, 1H, 4a-H), 2.52 (dt, J¼14.5, 5.8 Hz, 1H,
2a-H), 2.39 (d, J¼6.3 Hz, 1H, 12-H), 2.18 (s, 3H, 20-H),
2.13 (broad d, J¼6.0 Hz, 1H, 11-H), 1.09 (s, 3H, 19-H),
0.78 (s, 3H, 18-H); 13C NMR (50 MHz, CDCl3) d 212.6
(C-3), 209.6 (C-20), 59.1 (C-17), 46.5 (C-12), 44.1 (C-13),
43.5 (C-14), 43.3 (C-5), 42.7 (C-4), 39.7 (C-9), 37.2 (C-1),
36.9 (C-2), 35.6 (C-10), 33.2 (C-11), 31.2 (C-8), 30.3 (C-
21), 27.4 (C-15), 25.0 (C-6), 23.0 (C-19), 22.7 (C-16), 22.4
(C-7), 15.2 (C-18); ESIMS m/z 659 (2MþHþ, 25), 330
(MþHþ, 100), 281 (2); Anal. calcd for C21H31O2N·1/2H2O,
C, 74.52; H, 9.52; N, 4.13. Found C, 74.56; H, 9.40; N, 3.82.
2870, 1732, 1703, 1362, 1244, 1177, 1028, 897, 557 cm21
;
1H NMR (200 MHz, CDCl3) d 7.80 (d, J¼8.4 Hz, 2H, Ph–
Ho), 7.31 (d, J¼8.4 Hz, 2H, Ph–Hp), 5.00 (t, J¼2.6 Hz, 1H,
12-H), 4.64 (m, 1H, 3-H), 2.85 (t, J¼9.9 Hz, 1H, 17-H),
2.43 (s, 3H, CH3–Ph), 2.06 (s, 3H, 21-H), 2.02 (s, 3H,
CH3COO), 0.85 (s, 3H, 19-H), 0.75 (s, 3H, 18-H); 13C NMR
(50 MHz, CDCl3) d 208.6 (C-20), 170.4 (COO), 144.4 (C-
10), 134.6 (C-40), 129.7 (C-30), 127.6 (C-20), 84.2 (C-12),
73.9 (C-3), 54.8 (C-17), 47.9 (C-14), 46.2 (C-13), 41.6 (C-
5), 35.1 (C-1), 35.0 (C-4), 34.6 (C-10), 34.0 (C-8), 33.8
(C-9), 32.1 (C-21), 30.3 (C-2), 26.7 (C-6), 26.3 (C-7), 25.9
(C-11), 25.6 (C-15), 23.4 (C-19), 22.8 (C-16), 21.4
(CH3COO), 21.3 (CH3Ph), 13.5 (C-18); EIMS m/z 530
(Mþ, 1%), 375 (1), 358 (10), 298 (31), 283 (7), 255 (25), 91
(23), 43 (100). Anal. calcd for C30H42O6S: C, 67, 89; H, 7,
98. Found C, 68.22; H, 7.81.
1.1.3. N-Methyl-11a,12a-aziridino-5b-H-pregnane-
3,20-dione (9). Methyl iodide (12 ml, 0.18 mmol) was
added to a solution of 8 (15 mg, 0.046 mmol) and K2CO3
(13 mg) in acetonitrile/ethyl acetate 1:1 (1 ml) and the
mixture was stirred at room temperature under nitrogen for
18 h. After evaporation of the solvent, the crude product was
1.2.2. 3a-Acetoxy-5b-H-11-pregnen-20-one (12). A solu-
tion of 11 (490 mg, 0.92 mmol) in dry collidine (27 ml) was

P. H. Di Chenna et al. / Tetrahedron 59 (2003) 1009–1014
1013
refluxed under nitrogen for 6 h. The reaction mixture was
cooled to room temperature, acidified with 1N HCl and
extracted with dichloromethane (4£20 ml). The organic
extracts were combined, washed with 5% aqueous NaHCO3
and water and dried with Na2SO4. The residue obtained
after evaporation of the solvent was purified by flash
chromatography (hexane/ethyl acetate 9:1) to give pregnene
12 (280 mg, 85% yield), mp 123–1258C (hexane); IR
(KBr) 3397, 2936, 2868, 1736, 1705, 1449, 1362, 1242,
1028 cm21; EIMS m/z 358 (Mþ, 2%), 315 (4), 298 (32), 255
(C-20), 170.76 (COO), 73.87 (C-3), 59.18 (C-17), 46.73
(C-12), 44.14 (C-13), 42.55 (C-14), 41.18 (C-5), 39.59 (C-
9), 35.33 (C-10), 35.17 (C-1), 33.41 (C-11), 32.60 (C-4),
31.18 (C-8), 30.53 (C-21), 27.67 (C-2), 26.65 (C-15), 25.41
(C-6), 23.58 (C-19), 22.66 (C-16), 22.31 (C-7), 21.42
(CH3COO), 15.27 (C-18); EIMS m/z 373 (Mþ, 1), 358 (2),
330 (3), 314 (1), 148 (4), 69 (26), 43 (100); HRMS (ESI)
calcd for C23H35O3NþHþ: 374.2695. Found 374.2688.
1.2.5. 3a-Hydroxy-N-methyl-11a,12a-aziridino-5b-H-
pregnan-20-one (15). Methyl iodide (14 ml, 0.21 mmol)
was added to a solution of 14 (20 mg, 0.054 mmol) and
K2CO3 (15 mg, 0.11 mmol) in acetonitrile (1.5 ml) and the
mixture was stirred at room temperature under nitrogen for
6 h. After evaporation of the solvent the residue was
dissolved in a solution of K2CO3 (60 mg) in methanol/water
(9:1, 4 ml), and stirred for 1 h at room temperature. The
reaction mixture was concentrated to 1/2 of its volume,
diluted with water and extracted with dichloromethane
(4£2 ml). The combined organic phases were dried over
Na2SO4 and evaporated. The crude product was purified by
preparative chromatography (silica gel, ethyl acetate/metha-
nol 95:5) to give the N-methyl aziridine 15 (12 mg, 65%
yield) as an amorphous solid, mp 708C; [a]2D0¼þ87.38
(c¼0.1, CH2Cl2); IR (KBr) 3387, 2928, 2860, 1703, 1449,
1
(65), 228 (16), 213 (19), 43 (100); H NMR (200 MHz,
CDCl3) d 6.12 (dd, J¼10.2, 2.9 Hz, 1H, 11-H), 5.52 (d,
J¼10.0 Hz, 1H, 12-H), 4.73 (m, 1H, 3-H), 2.68 (t,
J¼8.4 Hz, 1H, 17-H), 2.17 (s, 3H, 21-H), 2.02 (s, 3H,
CH3COO), 0.89 (s, 3H, 19-H), 0.67 (s, 3H, 18-H); 13C NMR
(50 MHz, CDCl3) d 208.8 (C-20), 170.4 (COO), 135.9 (C-
12), 126.2 (C-11), 73.9 (C-3), 59.7 (C-17), 53.6 (C-14), 45.9
(C-13), 43.1 (C-5), 40.7 (C-9), 34.9 (C-10), 34.7 (C-1), 34.3
(C-8), 32.7 (C-4), 31.2 (C-21), 27.7 (C-2), 26.4 (C-6), 25.2
(C-7), 23.5 (C-19), 23.0 (C-15), 23.9 (C-16), 21.2
(CH3COO), 17.8 (C-18). Anal. calcd for C23H34O3: C,
77.05; H, 9.56. Found C, 76.85; H, 9.60.
1.2.3. 3a-Acetoxy-N-[2-(trimethylsilyl)ethanesulfonyl]-
11a,12a-aziridino-5b-H-pregnan-20-one (13). Following
the above procedure, pregnene 12 (80 mg, 0.22 mmol),
1
1358, 1081, 1038 cm21; H NMR (500 MHz, CDCl3) d
˚
PhIvNSes (153 mg, 0.40 mmol), 4 A molecular sie-
3.636 (m, 1H, 3-H), 2.892 (t, J¼9.4 Hz, 1H, 17-H), 2.387 (s,
3H, N–CH3), 2.192 (s, 3H, 21-H), 1.557 (d, J¼6.6 Hz, 12-
H), 1.302 (broad d, J¼6.6 Hz, 11-H), 0.981 (s, 3H, 19-H),
0.680 (s, 3H, 18-H); 13C NMR (125 MHz, CDCl3) d 209.36
(C-20), 71.48 (C-3), 59.19 (C-17), 50.49 (C-12), 48.44 (C-
14), 47.52 (N–CH3), 44.11 (C-13), 42.23 (C-5), 41.37 (C-
9), 40.97 (C-11), 36.97 (C-4), 35.60 (C-1), 35.01 (C-10),
33.21 (C-8), 31.33 (C-21), 30.48 (C-2), 27.79 (C-6), 25.49
(C-15), 23.54 (C-19), 22.72 (C-7), 22.16 (C-16), 15.07 (C-
18); EIMS m/z 345 (Mþ, 12), 330 (17), 302 (31), 286 (5),
246 (12), 162 (10), 108 (25), 43 (100); HRMS (ESI) calcd
for C22H35O2NþHþ: 346.2746. Found 346.2745.
ves(185 mg) and copper (I) triflate (5 mg, 0.022 mmol) in
acetonitrile(0.55 ml) gave after cromatography (silica gel,
hexane/ethyl acetate 8:2) unreacted olefin 3 (34 mg, 45%)
and aziridine 13 (53 mg, 45% yield, 77% yield based on
unreacted 12) as an amorphous solid, mp 50–548C;
[a]2D0¼þ68.38 (c¼0.2, CH2Cl2); IR (KBr) 2951, 2872,
;
1H NMR
1736, 1705, 1323, 1248, 1144, 841 cm21
(500 MHz, CDCl3) d 4.743 (m, 1H, 3-H), 3.081 (m, 2H,
SO2CH2), 3.057 (d, J¼7.1 Hz, 1H, 12-H), 2.820 (t,
J¼9.3 Hz, 1H, 17-H), 2.765 (dd, J¼0.9, 7.1 Hz, 1H, 11-
H), 2.266 (s, 3H, 21-H), 2.002 (s, 3H, CH3COO), 1.168 (m,
2H, SiCH2), 1.027 (s, 3H, 19-H), 0.782 (s, 3H, 18-H), 0.076
(s, 9H, Si–CH3); 13C NMR (125 MHz, CDCl3) d 209.23
(C-20), 170.42 (COO), 73.33 (C-3), 58.67 (C-17), 48.78
(SO2CH2), 47.27 (C-12), 46.57 (C-14), 43.30 (C-13), 41.36
(C-5), 41.23 (C-9), 40.85 (C-11), 35.11 (C-10), 34.82 (C-1),
33.04 (C-8), 32.63 (C-4), 31.31 (C-21), 27.48 (C-15), 27.03
(C-2), 25.19 (C-6), 23.44 (C-19), 22.58 (C-16), 22.39 (C-7),
21.26 (CH3COO), 14.55 (C-18), 9.29 (Si–CH2), 22.05
(Si–CH3); EIMS m/z 522 (Mþ215, 1), 372 (M2Ses, 84),
312 (35), 73 (97), 43 (100); HRMS (ESI) calcd for
C28H47O5NSSiNa: 560.2841. Found 560.2845.
Acknowledgements
We thank ECOS, France (grant A97 E06), Universidad de
´
Buenos Aires and Agencia Nacional de Promocion
Cientıfica y Tecnologica (Argentina) for financial support
´
´
´
and Fundacion Andes-C13575 and CONICYT-FONDAP
11980002 for the purchase of a CCD detector.
1.2.4. 3a-Acetoxy-11a,12a-aziridino-5b-H-pregnan-20-
one (14). Following the above procedure, a solution of
TASF (123 mg, 0.445 mmol) and Ses-aziridine 13 (48 mg,
0.089 mmol) in dry DMF (2.5 ml) gave after flash
chromatography on silica gel (ethyl acetate/methanol
95:5) the deprotected aziridine 14 (23 mg, 70% yield), mp
110–1158C (d); [a]D20¼þ94.08 (c¼1, CH2Cl2); IR (KBr)
3306, 2934, 2872, 1736, 1701, 1449, 1362, 1244,
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