Diels-Alder reaction of androsta-14,16-dien-17-yl acetates with nitroethylene: Product distribution and selected adduct transformations

Article abstract of DOI:10.1016/j.steroids.2012.11.015

The Diels-Alder cycloaddition of nitroethylene to some androsta-14,16-dien- 17-yl acetates has been studied. The addition occurs stereoselectively, giving predominantly head-to-head-adduct. 14β-Cyanomethyl steroids were obtained via the reductive cleavage

Full text of DOI:10.1016/j.steroids.2012.11.015

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Steroids xxx (2012) xxx–xxx
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Contents lists available at SciVerse ScienceDirect
Steroids
journal homepage: www.elsevier.com/locate/steroids
Diels–Alder reaction of androsta-14,16-dien-17-yl acetates with nitroethylene:
Product distribution and selected adduct transformations
2
3
a
a
b
Alexander V. Baranovsky a, , Dmitry A. Bolibrukh , Vladimir A. Khripach , Bernd Schneider
⇑
4 Q1
a Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Kuprevich str. 5/2, 220143 Minsk, Belarus
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b Max Planck Institute for Chemical Ecology, Beutenberg Campus, Hans Knöll Str. 8, D-07745 Jena, Germany
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8
a r t i c l e i n f o
a b s t r a c t
1 0
2 3
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Article history:
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The Diels–Alder cycloaddition of nitroethylene to some androsta-14,16-dien-17-yl acetates has been
studied. The addition occurs stereoselectively, giving predominantly head-to-head-adduct. 14b-Cyanom-
ethyl steroids were obtained via the reductive cleavage reaction of bridged nitro compounds. The struc-
tures of the new compounds have been fully characterized by 2D NMR and tandem mass-spectrometry
methods.
Received 1 September 2012
Received in revised form 14 November 2012
Accepted 21 November 2012
Available online xxxx
Ó 2012 Published by Elsevier Inc.
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Keywords:
Bridged steroid
Diels–Alder reaction
Reductive cleavage
Transfer hydrogenation
2D NMR
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1. Introduction
use of the standard Bruker program package. Mass spectra (APCI
MS and MS2, positive mode, CID 35%) were recorded on an Accela
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We have recently described how the Diels–Alder adduct of
3-methoxyestra-1,3,5(10),14,16-pentaen-17-yl acetate with nitro-
ethylene could undergo various unusual chemical transformations
under relatively mild conditions [1,2] probably with the involve-
ment of the nitrile oxide intermediate. Here, we tried expanding
the procedures on androstane-type steroids in order to analyze
the product distribution of the Diels–Alder reaction of steroidal
dienyl acetates with nitroethylene and to verify that the method
can be applied to more functionalized steroids for exploring the ap-
proach to C-14-modified natural steroids such as brassinosteroids.
HPLC system coupled with LCQ Fleet mass-detector, mass-to-
charge ratio (m/z) and relative intensities (%) are indicated for
the significant peaks. Microanalyses were determined using a
Eurovector EA3000 CHNS-O instrument. Accurate masses (EI) were
obtained with a VG-70E mass spectrometer.
TLC was performed on precoated aluminum backed TLC sheets
(silica gel 60 F254) and visualized by UV and/or exposure to
Ce(NH4)4(SO4)4 in 8 M H2SO4. Column chromatography was con-
ducted with Merck silica gel 60: 70–230 mesh. Solvents were dried
and freshly distilled according to common practice [3]. All reac-
tions were conducted under positive nitrogen pressure.
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2. Experimental
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2.1.1. Cycloaddition of dienyl acetate 1 with nitroethylene
2.1. General
A solution of dienyl acetate 1 (0.809 g, 2.19 mmol) and nitroeth-
ylene (0.318 g, 4.35 mmol) in dry benzene (7 ml) was refluxed for
3 h and after which more nitroethylene (0.511 g, 7 mmol) was
added. Refluxing was continued for another 2 h and the solution
was cooled, diluted with dichloromethane and filtered through a
Celite plug. The filtrate was evaporated and the residue was crystal-
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Melting points were measured using a Boetius apparatus and
are uncorrected. IR spectra were recorded using a Michelson Bo-
mem 100 FTIR spectrometer. 1H NMR (500.13 MHz) and 13C NMR
(125.77 MHz) spectra were recorded on a Bruker AVANCE-500
NMR spectrometer. CDCl3 was used as a solvent and the residual
solvent signals (d 7.26 ppm for 1H NMR and 77.16 ppm for 13C
NMR) served as an internal reference standards. COSY, HSQC,
HMBC, TOCSY and NOESY experiments were carried out with the
lized from benzene to give 3b-acetoxy-14,17-etheno-16a-nitro-
androst-5-en-17b-yl acetate (5) (0.734 g, 76%): m.p. 219–221 °C
(hexane). IR (KBr, cmꢀ1) 2940, 1735 (OAc), 1730 (OAc), 1550 and
1370 (NO2), 1240, 1040. 1H NMR d: 0.98 (3H, s, 19-Me), 1.00 (3H,
s, 18-Me), 1.08 (1H, m, 12b-H), 1.14 (1H, m, 1
-H), 1.28 (1H, m, 11b-H), 1.54 (1H, m, 11 -H), 1.57 (1H, m, 8b-
H), 1.58 (1H, m, 2b-H), 1.87 (1H, m, 1b-H), 1.88 (1H, m, 2 -H),
a-H), 1.19 (1H, m,
⇑
9a
a
Corresponding author. Tel.: +375 17 267 9103; fax: +375 17 267 8761.
E-mail address: baranovsky@iboch.bas-net.by (A.V. Baranovsky).
a
0039-128X/$ - see front matter Ó 2012 Published by Elsevier Inc.
http://dx.doi.org/10.1016/j.steroids.2012.11.015
Please cite this article in press as: Baranovsky AV et al. Diels–Alder reaction of androsta-14,16-dien-17-yl acetates with nitroethylene: Product distribution
and selected adduct transformations. Steroids (2012), http://dx.doi.org/10.1016/j.steroids.2012.11.015

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1.97 (2H, m, 7-H), 1.99 (1H, m, 15
m, 15b-H), 2.14 (3H, s, 17-AcO), 2.19 (1H, m, 12
4-H), 4.61 (1H, m, 3 -H), 5.38 (1H, dd, J = 3 and 9 Hz, 16b-H), 5.42
a
-H), 2.03 (3H, s, 3-AcO), 2.13 (1H,
2.1.2. 3b-Benzoyloxy-14,17-etheno-16
acetate (8)
a
-nitroandrost-5-en-17b-yl
a-H), 2.35 (2H, m,
82
a
Following the same procedure as for compound 5, compound 2
(0.868 g, 2 mmol) was converted into steroid 8 and its two isomers.
Crystallization of the reaction mixture gave 0.531 g (53%) of nitro
compound 8: m.p. 223–225 °C (benzene). IR (KBr, cmꢀ1): 2940,
1740 (OAc), 1710 (OBz), 1560 and 1370 (NO2), 1275, 1240, 1110.
1H NMR d: 1.02 (3H, s, 18-Me), 1.03 (3H, s, 19-Me), 1.10 (1H, m,
(1H, m, 6-H), 6.19 (1H, J = 6 Hz, 171-H), 6.29 (1H, d, J = 6 Hz,
172-H); 13C NMR d: 14.92 (C-18), 19.37 (C-19), 20.90 (C-11), 21.53
(3-OC(O)CH3), 21.55 (17-OC(O)CH3), 26.41 (C-7), 27.77 (C-2),
28.65 (C-12), 31.46 (C-8), 34.96 (C-15), 36.48 (C-10), 36.84 (C-1),
38.22 (C-4), 46.08 (C-9), 55.44 (C-14), 62.12 (C-13), 73.68 (C-3),
87.34 (C-16), 96.24 (C-17), 121.53 (C-6), 129.72 (C-171), 135.13
(C-172), 139.70 (C-5), 169.74 (17-OC(O)CH3), 170.59 (3-OC(O)CH3).
LRMS m/z (I,%): 444 ([MH]+, 39), 402 ([MHꢀCH2CO]+, 21), 384
([MHꢀAcOH]+, 26), 342 ([MHꢀCH2COꢀAcOH]+, 15), 324
([MHꢀ2AcOH]+, 100), 307 (25), 283 (19). MS2 (444): 402
([MHꢀCH2CO]+, 11), 358 (13), 330 (100), 324 ([MHꢀ2AcOH]+, 20).
MS2 (324): 307 (50), 306 ([MHꢀ2AcOHꢀH2O]+, 100), 296
([MHꢀ2AcOHꢀC2H4]+ 47), 279 (24), 278 ([MHꢀ2AcOHꢀC2H4ꢀH2-
O]+,19), 265 (52), 247 (33). Anal. calcd. for C25H33NO6: C, 67.70;
H, 7.50; N, 3.16. Found. C, 67.38; H, 7.43; N, 3.40. Mother liquor res-
idues were chromatographed on a silica gel column (petroleum
ether: EtOAc = 90: 10) to give three fractions: A – 0.018 g of com-
pound 5; B – 0.163 g of mixture of adducts 5 and 6 (1:1 based on
integration curve in 1H NMR spectrum); C – 0.048 g of mixture of
adducts 6 and 7 (1:1 based on integration curve in 1H NMR
spectrum). Fraction C was repeatedly separated to afford pure 3b-
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12b-H), 1.23 (1H, m, 1
H), 1.58 (1H, m, 11 -H), 1.59 (1H, m, 8b-H), 1.73 (1H, m, 2b-H),
1.94 (1H, dt, J = 3 and 13 Hz, 1b-H), 2.01 (2H, m, 7-H), 2.01 (1H,
m, 15 -H), 2.03 (1H, m, 2 -H), 2.15 (1H, m, 15b-H), 2.15 (3H, s,
17-AcO), 2.20 (1H, m, 12 -H), 2.50 (2H, m, 4-H), 4.87 (1H, m, 3
a-H), 1.25 (1H, m, 9a-H), 1.29 (1H, m, 11b-
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90
91
a
a
92
a
a-
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H), 5.39 (1H, dd, J = 3 and 9 Hz, 16b-H), 5.48 (1H, m, 6-H), 6.20
(1H, J = 6 Hz, 171-H), 6.33 (1H, d, J = 6 Hz, 172-H), 7.44 (2H, m, m-
Ph), 7.55 (1H, m, p-Ph), 8.04 (2H, d, J = 7 Hz, o-Ph); 13C NMR d:
14.95 (C-18), 19.46 (C-19), 20.94 (C-11), 21.58 (17-OC(O)CH3),
26.47 (C-7), 27.90 (C-2), 28.68 (C-12), 31.49 (C-8), 34.99 (C-15),
36.57 (C-10), 36.90 (C-1), 38.33 (C-4), 46.11 (C-9), 55.47 (C-14),
62.15 (C-13), 74.29 (C-3), 87.36 (C-16), 96.27 (C-17), 121.68 (C-6),
128.44 (Ph C-3), 129.69 (Ph C-2), 129.75 (C-171), 130.90 (Ph C-1),
132.93 (Ph C-4), 135.18 (C-172), 139.71 (C-5), 166.11 (3-OC(O)Ph),
169.78(17-OC(O)CH3). LRMS m/z (I,%): 506 ([MH]+, 45), 464
([MHꢀCH2CO]+, 14), 384 ([MHꢀBzOH]+, 24), 342 ([MHꢀBzOHꢀCH2-
CO]+, 25), 324 ([MHꢀBzOHꢀAcOH]+, 100). MS2 (506): 392 (100),
324 ([MHꢀBzOHꢀAcOH]+, 10). MS2 (324): 307 (56), 306
([MHꢀBzOHꢀAcOHꢀH2O]+, 100), 296 ([MHꢀBzOHꢀAcOHꢀC2H4]+
40), 279 (29), 278 ([MHꢀBzOHꢀAcOHꢀC2H4ꢀH2O]+, 17), 265
(52), 247 (15). HRMS calcd for C23H29NO4 (M+ꢀBzOH): 383.2097.
Found. 383.2094. Mother liquor residues were chromatographed
on a silica gel column (petroleum ether: EtOAc = 90: 10) to give
two fractions: A – 0.147 g of compound 8, thus elevating the overall
yield of 8 to 67%; B – 0.191 g of two minor adducts.
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acetoxy-14,17-etheno-15a-nitroandrost-5-en-17b-yl acetate (6):
m.p.194–196 °C (hexane). IR (KBr, cmꢀ1) 2920, 1740 (OAc) 1730
(OAc), 1550 and 1365 (NO2), 1245, 1030. 1H NMR d: 0.99 (3H, s,
19-Me), 1.02 (3H, s, 18-Me), 1.13 (1H, m, 1
H), 1.18 (1H, m, 12b-H), 1.27 (1H, m, 11b-H), 1.52 (1H, m, 11
1.57 (1H, m, 2b-H), 1.85 (1H, m, 1b-H), 1.87 (1H, m, 2 -H), 1.87
(1H, m, 7 -H), 1.95 (1H, m, 8b-H), 2.01 (1H, m, 7b-H), 2.02 (3H, s,
3-AcO), 2.09 (1H, m, 12 -H), 2.09 (3H, s, 17-AcO), 2.33 (2H, m, 4-
H), 2.49 (1H, dd, J = 9 and 13 Hz, 16b-H), 2.61 (1H, dd, J = 4 and
13 Hz, 16 -H), 4.58 (1H, m, 3 -H), 5.04 (1H, dd, J = 4 and 9 Hz,
a
-H), 1.17 (1H, m, 9
a-
a-H),
a
a
a
a
a
15b-H), 5.31 (1H, m, 6-H), 6.05 (1H, J = 6 Hz, 172-H), 6.58 (1H, d,
J = 6 Hz, 171-H); 13C NMR d: 15.18 (C-18), 19.26 (C-19), 20.57 (C-
11), 21.33 (17-OC(O)CH3), 21.51 (3-OC(O)CH3), 25.71 (C-7), 27.79
(C-2), 28.21 (C-12), 32.7 (C-8), 36.44 (C-10), 37.02 (C-1), 37.99 (C-
4), 39.93 (C-16), 46.23 (C-9), 60.9 (C-14), 62.15 (C-13), 73.61 (C-
3), 89.52 (C-15), 92.54 (C-17), 121.52 (C-6), 129.7 (C-172), 135.49
(C-171), 138.95 (C-5), 170.6 (OC(O)CH3). LRMS m/z (I,%): 444
([MH]+, 43), 384 ([MHꢀAcOH]+, 38), 324 ([MHꢀ2AcOH]+, 100. Anal.
calcd. for C25H33NO6: C, 67.70; H, 7.50; N, 3.16. Found. C, 67.14; H,
7.35; N, 3.26. and 3b-acetoxy-14,17-etheno-15b-nitroandrost-5-
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2.1.3. 14,17-Etheno-6,6-ethylenedioxy-2
16 -nitro-5 -androstan-17b-yl acetate (9)
A solution of steroid 3 (0.066 g, 0.15 mmol) and nitroethylene
a,3a-isopropylidendioxy-
a
a
(0.54 g, 7.4 mmol) in dry benzene (7 ml) was refluxed for 10 h
and some more nitroethylene (0.27 g, 3.7 mmol) was added.
Refluxing was continued for a further 6 h and the solution was
cooled, evaporated and residue was chromatographed on a silica
gel column (petroleum ether: EtOAc = 90:10) to give steroid 9
(0.038 g, 49%): m.p.132–134 °C (hexane). IR (KBr, cmꢀ1): 2940,
1745 (OAc), 1550 and 1370 (NO2). 1H NMR d: 0.80 (3H, s, 19 Me),
en-17a-yl acetate (7): m.p.205–207 °C. (hexane, dec.). IR (KBr,
cmꢀ1) 2945, 1735 (OAc) 1730 (OAc), 1550 and 1365 (NO2), 1245,
0.98 (3H, s, 18 Me), 1.03 (1H, m, 9
(1H, m, 12b-H), 1.13 (1H, m, 11b-H), 1.34 (3H, s, b-CH3 acetonide),
1.44 (1H, m, 7 -H), 1.48 (3H, s, -CH3 acetonide), 1.58 (1H, m, 11
H), 1.59 (1H, m, 8b-H), 1.70 (1H, m, 7b-H), 1.81 (1H, m, 4b-H), 1.87
(1H, m, 5 -H), 1.93 (1H, m, 1b-H), 1.97 (1H, m, 15 -H), 2.12 (1H,
m, 12 -H), 2.13 (1H, m, 15b-H), 2.15 (3H, s, OAc), 2.23 (1H, d,
J = 15 Hz, 4 -H), 3.80 and 3.94 (2H, m, -CH2 dioxolane), 3.92
a-H), 1.08 (1H, m, 1a-H), 1.08
1040. 1H NMR d: 1.01 (3H, s 18-Me), 1.06 (3H, m, 19-Me), 1.25
(1H, m, 1
m, 2b-H), 1.61 (1H, m, 9
-H), 1.89 (1H, m, 1b-H), 1.90 (1H, m, 2
2.04 (3H, s, 3-AcO), 2.05 (1H, m, 7b-H), 2.10 (3H, s, 17-AcO), 2.35
(2H, m, 4-H), 2.58 (2H, m, 16-H), 4.62 (1H, m, 3 -H), 5.37 (1H, m,
6-H), 5.49 (1H, dd, J = 5 and 8 Hz, 15 -H), 6.10 (1H, d, J = 6 Hz,
a
-H), 1.47 (2H, m, 12-H), 1.54 (1H, m, 11b-H), 1.58 (1H,
-H), 1.69 (1H, m, 11 -H), 1.78 (1H, m,
-H), 1.98 (1H, m, 8b-H),
a
a
a-
a
a
7a
a
a
a
a
a
a
a
a
and 3.99 (2H, m, b-CH2 dioxolane), 4.08 (1H, m, 2b-H), 4.27 (1H,
m, 3b-H), 5.37 (1H, dd, J = 2 and 9 Hz, 16b-H), 6.18 (1H, d, J = 6.4,
171-H), 6.28 (1H, d, J = 6.4, 172-H). 13C NMR d: 13.43 (C-19),
15.04 (C-18), 20.41 (C-11), 21.57 (OC(O)CH3), 22.04 (C-4), 26.70
(b-CH3 acetonide), 28.64 (C-12), 28.77 (
(C-8), 34.82 (C-15), 36.61 (C-7), 38.21 (C-10), 42.69 (C-1), 45.28
(C-5), 48.68 (C-9), 55.18 (C-14), 62.13 (C-13), 64.42 ( -CH2 dioxo-
lane), 65.79 (b-CH2 dioxolane), 72.78 (C-3), 72.84 (C-2), 87.30 (C-
16), 96.02 (C-17), 107.83 (Me2C acetonide), 109.36 (C-6), 129.74
(C-171), 134.61 (C-172), 169.78 (OC(O)CH3). LRMS m/z (I,%): 518
([MH]+, 23), 460 ([MHꢀMe2CO]+, 40), 400 ([MHꢀMe2COꢀAcOH]+,
40), 382 ([MHꢀMe2COꢀAcOHꢀH2O]+, 51), 338 ([MHꢀMe2-
COꢀAcOHꢀH2OꢀCH2CH2O]+, 20). HRMS calcd for C28H39NO8:
517.2676. Found. 517.2679.
172-H), 6.50 (1H, d, J = 6 Hz, 171-H). 13C NMR d: 15.51 (C-18),
19.07 (C-11), 19.53 (C-19), 21.38 (17-OC(O)CH3), 21.52 (3-
OC(O)CH3), 26.94 (C-12), 27.21 (C-7), 27.77 (C-2), 30.49 (C-8),
37.14 (C-1), 37.48 (C-16), 37.58 (C-10), 38.11 (C-4), 43.78 (C-9),
58.88 (C-14), 61.87 (C-13), 73.62 (C-3), 86.33 (C-15), 92.49 (C-17),
122.07 (C-6), 132.05 (C-172), 135.97 (C-171), 139.18 (C-5), 170.56
(3-OC(O)CH3), 170.66 (17-OC(O)CH3). LRMS m/z (I,%): 444 ([MH]+,
100), 384 ([MHꢀAcOH]+, 35), 324 ([MHꢀ2AcOH]+, 68), 306
([MHꢀ2AcOHꢀH2O]+, 13). MS2 (444): 402 ([MHꢀCH2CO]+, 92),
384 ([MHꢀAcOH]+, 100), 324 ([MHꢀ2AcOH]+, 86). Anal. calcd. for
C25H33NO6: C, 67.70; H, 7.50; N, 3.16. Found. C, 66.84; H, 7.40; N,
3.40. Therefore, the overall yield of the adducts was 87% of com-
pound 5, 11% of compound 6 and 2% of compound 7.
a-CH3 acetonide), 32.78
a
Please cite this article in press as: Baranovsky AV et al. Diels–Alder reaction of androsta-14,16-dien-17-yl acetates with nitroethylene: Product distribution
and selected adduct transformations. Steroids (2012), http://dx.doi.org/10.1016/j.steroids.2012.11.015

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2.1.4. 2
17b-yl acetate (10)
a
,3
a
-Diacetoxy-14,17-etheno-16
a
-nitro-5
a
-androstan-6-on-
[40,50:14b,15b-androst-5-en-17-one (11) (0.060 g, 26%): m.p. 256–
258 °C (EtOAc). IR mmax (KBr), cmꢀ1: 3241 (NH), 2930, 1735 (CO
and OAc), 1700 (NC = O), 1670, 1245. 1H NMR d: 1.03 (3H, s, 19
Following the same procedure as for compound 9, compound 4
(0.016 g, 0.04 mmol) was converted into steroid 10 (0.013 g 70%):
m.p. 245–247 °C (hexane). IR (KBr, cmꢀ1): 2945, 1741 (CO), 1715
(CO), 1550 and 1370 (NO2). 1H NMR d: 0.80 (3H, s, 19 Me), 0.98
(3H, s, 18 Me), 1.15 (1H, m, 12b-H), 1.16 (1H, m, 11b-H), 1.65
(1H, m, 1
m, 8b-H), 1.88 (2H, m, 4-H), 1.79 (1H, dd, J = 5 and 12 Hz, 1b-H),
1.94 (1H, dd, J = 3 and 13 Hz, 15 -H), 1.99 (3H, s, 2-OAc), 2.11
(3H, s, 3-OAc), 2.12 (1H, m, 15b-H), 2.16 (3H, s, 17-OAc), 2.21
(1H, td, J = 5 and 14 Hz, 12 -H), 2.32 (2H, m, 7-H), 2.64 (1H, dd,
J = 5 and 11 Hz, 5 -H), 4.92 (1H, ddd, J = 3, 5 and 12 Hz, 2b-H),
5.33 (1H, dd, J = 3 and 9 Hz, 16b-H), 5.39 (1H, m, 3b-H), 6.29 (1H,
d, J = 6 Hz, 171-H), 6.38 (1H, d, J = 6 Hz, 172-H). 13C NMR d: 13.40
(C-19), 15.03 (C-18), 20.90 (C-11), 21.18 (2-OC(O)CH3), 21.32 (3-
OC(O)CH3), 21.54 (17-OC(O)CH3), 24.94 (C-4), 28.58 (C-12), 34.42
(C-15), 37.28 (C-8), 37.49 (C-1), 42.18 (C-7), 42.47 (C-10), 49.51
(C-9), 51.62 (C-5), 55.38 (C-14), 62.38 (C-13), 67.96 (C-3), 68.96
(C-2), 87.14 (C-16), 95.68 (C-17), 130.56 (C-171), 133.18 (C-172),
169.79 (17-OC(O)CH3), 170.15 (3-OC(O)CH3), 170.46 (2-OC(O)CH3),
209.34 (C-6). LRMS m/z (I,%): 518 ([MH]+, 43), 458 ([MHꢀAcOH]+,
63), 416 ([MHꢀAcOHꢀCH2CO]+, 71), 398 ([MHꢀ2AcOH]+, 59),
356 ([MHꢀ2AcOHꢀCH2CO]+, 100). MS2 (518): 476 ([MHꢀCH2CO]+,
13), 432 (10), 404 (100), 356 ([MHꢀ2AcOHꢀCH2CO]+, 17). HRMS
calcd for C27H35NO9: 517.2312. Found. 517.2301.
Me), 1.11 (3H, s, 18 Me), 1.17 (1H, m, 1
1.37 (1H, m, 12 -H), 1.41 (1H, m, 11b-H), 1.43 (1H, m, 12b-H),
1.61 (1H, m, 2b-H), 1.68 (1H, m, 11 -H), 1.69 (1H, m, 8b-H), 1.90
(1H, m, 2 -H), 1.92 (1H, dt, J = 3 and 13 Hz, 1b-H), 2.03 (2H, m,
7-H), 2.04 (3H, s, 3-OAc) 2.01 (1H, d, J = 17 Hz, 141
-H), 2.13 (1H,
dd, J = 3 and 19 Hz, 16b-H), 2.21 (1H, d, J = 17 Hz, 141b-H), 2.34
(2H, m, 4-H), 3.15 (1H, dd, J = 9 and 19 Hz, 16 -H), 4.10 (1H, ddd,
J = 1, 4, 7 Hz, 15 -H), 4.62 (1H, m, 3 -H), 5.42 (1H, m, 6-H), 5.85
a-H), 1.34 (1H, m, 9a-H),
a
a
a
a
-H), 1.65 (1H, m, 9
a
-H), 1.66 (1H, m, 11
a
-H), 1.86 (1H,
a
a
a
a
a
a
(1H, br s, NH); 13C NMR d: 15.17 (C-18), 19.65 (C-11), 19.67 (C-
19), 21.54 (3-OC(O)CH3), 26.49 (C-7), 27.64 (C-2), 32.64 (C-12),
36.98 (C-8), 37.01 (C-1), 37.30 (C-10), 37.83 (C-4), 41.15 (C-141),
43.20 (C-16), 45.25 (C-9), 51.53 (C-15), 52.86 and 53.95 (C-14
and C-13), 73.60 (C-3), 121.94 (C-6), 138.56 (C-5), 170.70 (3-
OC(O)CH3), 176.32 (C-142), 217.12 (C-17). LRMS m/z (I,%): 386
([MH]+, 100). MS2 (386): 326 ([MHꢀAcOH]+, 100). MS3 (326): 280
([MHꢀAcOHꢀH2OꢀCO]+, 100), 249 ([MHꢀAcOHꢀH2OꢀCH3-
CONH2]+, 16). Anal. calcd. for C23H31NO4: C, 71.66; H, 8.11; N,
3.63. Found. C, 70.61; H, 7.86; N, 3.93.
a
296
297
298
299
300
301
302
303
304
305
306
307
308
309
310
311
312
313
314
315
316
317
318
319
320
321
322
323
324
325
326
327
328
2.1.6. 3b-Benzoyloxy-14b-cyanomethylandrosta-5,15-dien-17-one
(13)
A mixture of nitro compound 8 (0.22 g, 0.44 mmol), NaHCO3
(0.259, 3.18 mmol), and triphenylphosphine (150 mg, 0.57 mmol)
in aq. ethanol (30 ml, 10:1) was deoxygenated by bubbling nitro-
gen for 10 min and then refluxed for 1 h. The solution was cooled,
diluted with dichloromethane and filtered. The precipitate was
washed with dichloromethane and the combined filtrate was dried
(Na2SO4) and evaporated. The concentrated solid residue was chro-
matographed on a silica gel column. Elution with ethyl acetate–tol-
uene (5:95) gave nitrile 13 (0.188 g, 99%): m.p. 201–202 °C
(MeOH). IR (KBr, cmꢀ1): 2940, 2250 (CN), 1720 (CO) 1710 (OBz),
236
237
238
239
240
241
242
243
244
245
246
247
248
249
250
251
252
253
254
255
256
257
258
259
260
261
262
263
264
265
266
267
268
269
270
271
272
273
274
2.1.5. Solvolysis of nitro compound 5
A mixture of nitro compound 5 (0.263 g, 0.59 mmol) and
NaHCO3 (0.346 g, 4.13 mmol) in aqueous ethanol (66 ml, 10:1)
was refluxed for 1 h. The yellow solution was cooled to 0 °C and
poured into a cooled 1 M HCl solution. The resulting mixture was
stirred for 10 min and extracted with chloroform. The combined
organic phase was washed with brine, dried (Na2SO4), and concen-
trated. The oily residue (0.266 g) was dissolved in pyridine (3 ml)
and benzoyl chloride (0.21 g, 1.5 mmol) was added. The resulting
mixture was stirred for 24 h, then poured out in cold water and ex-
tracted with chloroform. The combined organic phase was washed
with 1 M HCl solution, saturated NaHCO3, brine, dried (Na2SO4),
and concentrated. The residue was chromatographed on a silica
gel column with ethyl acetate as eluent to afford 3b-acetoxy-10-
benzoyloxy-20-oxopyrrolidino-[40,50:14b,15b]-androst-5-en-17-
one (12b) (0.062 g, 20%). m.p. 157–158 °C (EtOAc-hexane). IR mmax
(KBr), cmꢀ1: 2945, 1770 (OBz), 1740 (CO), 1725 (OAc and NC = O),
1245. 1H NMR d: 1.05 (3H, s, 19 Me), 1.13 (3H, s, 18 Me), 1.20 (1H,
1275, 1115. 1H NMR d: 1.07 (1H, m, 1
1.25 (1H, m, 9 -H), 1.29 (3H, s, 18-Me), 1.29 (1H, m, 11b-H),
a-H), 1.10 (3H, s, 19-Me),
a
1.40 (1H, m, 11
1.76 (1H, m, 12
a
a
-H), 1.59 (1H, m, 12b-H), 1.74 (1H, m, 2b-H),
-H), 1.84 (1H, dt, J = 3 and 13 Hz, 1b-H), 1.99
(1H, m, 2
2.34 and 2.59 (2H, two d, J = 17 Hz, 141-H), 2.42 (1H, m, 4b-H),
2.52 (1H, ddd, J = 2, 5 and 13 Hz, 4 -H), 4.83 (1H, m, 3 -H), 5.48
a-H), 2.15 and 2.25 (2H, m, 7-H), 2.25 (1H, m, 8b-H),
a
a
(1H, m, 6-H), 6.40 (1H, d, J = 6 Hz, 16-H), 7.44 (2H, m, m-Ph), 7.56
(1H, m, p-Ph), 7.64 (1H, d, J = 6 Hz, 15-H), 8.04 (2H, d, J = 7 Hz, o-
Ph); 13C NMR d:17.85 (C-19), 18.87 (C-11), 18.95 (C-18), 24.81
(C-141), 27.11 (C-7), 27.46 (C-2), 33.75 (C-8), 35.59 (C-12), 36.20
(C-1), 37.76 (C-4), 38.88 (C-10), 42.81 (C-9), 51.45 (C-13), 52.57
(C-14), 74.17 (C-3), 117.29 (CN), 120.83 (C-6), 128.45 (Ph C-3),
129.68 (Ph C-2), 130.76 (Ph C-1), 133.00 (Ph C-4), 135.25 (C-16),
140.42 (C-5), 164.14 (C-15), 166.13 (3-OC(O)Ph), 213.49 (C-17).
LRMS m/z (I,%): 430 ([MH]+, 1), 308 ([MHꢀBzOH]+, 100), 291
([MHꢀBzOHꢀOH]+, 19). MS2 (430): 412 ([MHꢀH2O]+, 31), 308
([MHꢀBzOH]+, 100), 292 ([MHꢀBzOHꢀCH4]+, 11), 228 (17). MS2
(308): 290 ([MHꢀBzOHꢀH2O]+, 100), 280 ([MHꢀBzOHꢀCO]+, 50),
267 (21). HRMS calcd for C21H25NO (M+ꢀBzOH): 307.1936. Found.
307.1924.
m, 1
11b-H), 1.49 (1H, m, 12b-H), 1.63 (1H, m, 2b-H), 1.71 (1H, m,
11 -H), 1.72 (1H, m, 8b-H), 1.91 (1H, m, 2 -H), 1.92 (1H, m, 1b-
H), 2.04 (3H, s, 3-OAc), 2.06 (1H, m, 7b-H), 2.21 (1H, d, J = 17 Hz,
141 -H), 2.30 (1H, d, J = 17 Hz, 141b-H), 2.34 (1H, m, 4b-H), 2.40
(1H, ddd, J = 1.5, 5 and 13 Hz, 4 -H), 2.52 (1H, dd, J = 3 and
19 Hz, 16b-H), 2.61 (1H, m, 7 -H), 3.02 (1H, dd, J = 9 and 19 Hz,
16 -H), 4.49 (1H, dd, J = 4 and 9 Hz, 15 -H), 4.64 (1H, m, 3 -H),
a-H), 1.38 (1H, m, 12a-H), 1.42 (1H, m, 9a-H), 1.42 (1H, m,
a
a
a
a
a
a
a
a
5.54 (1H, m, 6-H), 7.49 (2H, m, m-Ph), 7.65 (1H, m, p-Ph), 8.09
(2H, d, J = 8 Hz, o-Ph); 13C NMR d: 14.19- (C-18), 19.60 (C-11),
19.74 (C-19), 21.54 (3-OC(O)CH3), 26.23 (C-7), 27.66 (C-2), 32.84
(C-12), 36.85 (C-8) 36.95 (C-1), 37.32 (C-10), 37.86 (C-4), 38.37
(C-141), 38.72 (C-16), 45.21 (C-9), 48.44 and 54.07 (C-13 and C-
14), 57.16 (C-15), 73.61 (C-3), 122.40 (C-6), 126.49 (Ph C-1),
128.94 (Ph C-3), 130.38 (Ph C-2), 134.59 (Ph C-4), 138.01 (C-5),
163.81 (PhCO), 168.94 (C-142), 170.63 (3-OC(O)CH3), 215.82
(C-17). LRMS m/z (I,%): 506 ([MH]+, 100), 446 ([MHꢀAcOH]+, 15).
MS2 (506): 446 ([MHꢀAcOH]+, 100). MS3 (446): 324
([MHꢀAcOHꢀBzOH]+, 73), 296 ([MHꢀAcOHꢀBzOHꢀCO]+, 10),
282 ([MHꢀAcOHꢀBzOHꢀCH2CO]+, 100). Further elution with
329
330
331
332
333
334
335
336
337
338
2.1.7. 3b-Benzoyloxy-14b-cyanomethylandrost-5-en-17-one (14)
To a solution of steroid 13 (0.167 g, 0.39 mmol) and ammonium
formate (0.123 g, 1.95 mmol) in methanol (5 ml), palladium on
charcoal (10%, 75 mg) was added. The resulting mixture was stir-
red for 12 h and then the solvent was evaporated. The obtained
residue was dissolved in EtOAc, the organic phase was washed
with brine, dried (Na2SO4) and concentrated. The solid residue
was chromatographed on a silica gel column (toluene: EtOAc = 95:
5) to afford nitrile 14 (0.134 g, 80%): m.p. 227–229 °C (MeOH). IR
(KBr, cmꢀ1) 2945, 2240 (CN), 1740 (CO), 1715 (OBz), 1277, 1120.
EtOAc:
EtOH
(97:3)
gave
3b-acetoxy-20-oxopyrrolidino-
Please cite this article in press as: Baranovsky AV et al. Diels–Alder reaction of androsta-14,16-dien-17-yl acetates with nitroethylene: Product distribution
and selected adduct transformations. Steroids (2012), http://dx.doi.org/10.1016/j.steroids.2012.11.015

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1H NMR d: 1.11 (3H, s, 19 Me), 1.18 (3H, s, 18 Me), 1.26 (1H, m, 1
H), 1.31 (1H, m, 12b-H), 1.40 (1H, m, 11b-H), 1.41 (1H, m, 9 -H),
1.51 (1H, m, 12 -H), 1.71 (1H, m, 11 -H), 1.76 (1H, m, 2b-H),
1.79 (1H, m, 15b-H), 1.96 (1H, m, 8b-H), 1.98 (1H, m, 1b-H), 2.00
and 2.17 (2H, m, 7-H), 2.05 (1H, m, 2 -H), 2.27 (1H, m, 15 -H),
2.27 and 2.32 (2H, two d, J = 17 Hz, 141-H), 2.28 (1H, m, 16-H),
2.52 (2H, m, 4-H), 2.57 (1H, m, 16-H), 4.88 (1H, m, 3 -H), 5.45
(1H, m, 6-H), 7.45 (2H, m, m-Ph), 7.57 (1H, m, p-Ph), 8.05 (2H, d,
J = 7 Hz, o-Ph); 13C NMR d: 14.85 (C-18), 19.51 (C-19), 19.95 (C-
11), 25.85 and 25.88 (C-7 and C-15), 26.28 (C-141), 27.81 (C-2),
31.68 (C-12), 32.71 (C-16), 34.95 (C-8), 37.07 (C-1), 37.12 (C-10),
38.00 (C-4), 44.41 (C-9), 47.07 and 53.26 (C-13 and C-14), 74.19
(C-3), 118.19 (CN), 121.57 (C-6), 128.46 (Ph C-3), 129.70 (Ph C-
2), 130.80 (Ph C-1), 133.00 (Ph C-4), 139.12 (C-5), 166.16 (3-
OC(O)Ph), 219.57 (C-17). LRMS m/z (I,%): 432 ([MH]+, 4), 310
([MHꢀBzOH]+, 100). MS2 (432): 414 ([MHꢀH2O]+, 10), 310
([MHꢀBzOH]+, 100), 228 (15). MS2 (310): 293 ([MHꢀBzOHꢀOH]+,
100), 292 ([MHꢀBzOHꢀH2O]+, 87), 282 ([MHꢀBzOHꢀCO]+, 40),
275 (41), 267 (86), 254 ([MHꢀBzOHꢀCH2CHCHO]+, 22). Anal.
calcd. for C28H33NO3 C, 77.93; H, 7.71; N, 3.25. Found. C, 77.48;
H, 7.63; N, 3.14.
a-
2940, 2250 (CN), 1720 (CO). 1H NMR d: 0.84 (3H, s, 19 Me), 0.93
(1H, m, 1 -H), 0.94 (1H, m, 9 -H), 1.25 (3H, s, 18-Me), 1.31 (3H,
s, b-CH3 acetonide), 1.32 (2H, m, 11-H), 1.44 (3H, s, -CH3 aceto-
nide), 1.45 (1H, m, 7 -H), 1.54 (1H, ddd, J = 7, 9, 14 Hz, 12b-H),
1.66 (1H, m, 12 -H), 1.78 (1H, m, 5 -H), 1.80 (1H, dd, J = 4 and
8 Hz, 4b-H), 1.82 (1H, dd, J = 7 and 13 Hz, 1b-H), 1.97 (1H, dd,
J = 3 and 13, 7b-H), 2.17 (1H, m, 4 -H), 2.21 (1H, m, 8b-H), 2.30
(1H, d, J = 17 Hz, 141b-H), 2.57 (1H, d, J = 17 Hz, 141
-H), 3.79
and 3.98 (2H, m, -CH2 dioxolane), 3.99 and 4.04 (2H, m, b-CH2
339
340
341
342
343
344
345
346
347
348
349
350
351
352
353
354
355
356
357
358
359
365
366
367
368
369
370
371
372
373
374
375
376
377
378
379
380
381
382
383
384
385
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
dioxolane), 4.09 (1H, m, 2b-H), 4.27 (1H, m, 3b-H), 6.33 (1H, d,
J = 6 Hz, 16-H), 7.48 (1H, d, J = 6 Hz, 15-H). 13C NMR d: 12.50 (C-
19), 18.47 (C-18), 19.26 (C-11), 22.10 (C-4), 25.42 (C-141), 26.65
(b-CH3 acetonide), 28.72 (
(C-8), 36.66 (C-7), 39.16 (C-10), 42.18 (C-1), 45.28 (C-5), 45.65
(C-9), 51.49 (C-13), 52.30 (C-14), 64.60 ( -CH2 dioxolane), 65.73
a-CH3 acetonide), 35.00 (C-12), 35.37
a
(b-CH2 dioxolane), 72.71 (C-3), 72.76 (C-2), 107.84 (Me2C aceto-
nide), 109.17 (C-6), 116.90 (CN), 134.26 (C-16), 162.99 (C-15),
212.74 (C-17). LRMS m/z (I,%): 441 ([M]+, 0.1), 384 ([MHꢀMe2CO]+,
100), 322 ([MHꢀMe2COꢀCH2OꢀH2O]+, 11). MS2 (384): 340
([MHꢀMe2COꢀCH2O]+, 100), 322 ([MHꢀMe2COꢀCH2OꢀH2O]+,
45). HRMS calcd for C26H35NO5: 441.2515. Found 441.2523.
360
361
362
363
364
386
2.1.8. 14b-Cyanomethyl-6,6-ethylenedioxy-2
-androst-15-en-17-one (15)
Following the same procedure as for compound 13, compound 9
a
,3
a
-isopropylidendioxy-
3. Results and discussion
5a
387
388
389
Dienyl acetates 1–4 in this work were synthesized from appro-
priate enones [4]. The cycloaddition of nitroethylene to steroids 1
and 2 in refluxing benzene gave each of the three adducts in excel-
(0.018 g, 0.04 mmol) was converted over 4 h into steroid 15
(0.009 g, 58%): m.p.107–109 °C (EtOAc-hexane). IR (KBr, cmꢀ1):
OAc
NO2
OAc
NO2
OAc
OAc
NO2
+
i
+
AcO
AcO
RO
ii
5 R=Ac
8 R=Bz
RO
7
6
1 R=Ac
2 R=Bz
iv
O
O
H
CN
N
BzO
R
AcO
O
13 C15-C16 - double bond
14 C15-C16 - single bond
v
11 R=H
12a R=OH
12b R=OBz
iii
O
OAc
OAc
i
NO2
O
iv
O
O
O
CN
O
O
O
O
O
9
O
O
O
15
3
OAc
OAc
i
NO2
AcO
AcO
AcO
AcO
O
O
10
4
Scheme 1. Reagents and conditions: (i) nitroethylene, PhH, reflux; (ii) NaHCO3, H2O, EtOH, reflux; (iii) BzCl, Py, rt.; (iv) NaHCO3, Ph3P, H2O, EtOH, reflux; (v) HCO2NH4, Pd/C,
MeOH, rt.
Please cite this article in press as: Baranovsky AV et al. Diels–Alder reaction of androsta-14,16-dien-17-yl acetates with nitroethylene: Product distribution
and selected adduct transformations. Steroids (2012), http://dx.doi.org/10.1016/j.steroids.2012.11.015

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390
391
392
393
394
395
396
397
398
399
400
401
402
403
404
405
406
407
408
409
410
411
412
413
414
415
416
417
418
419
420
421
422
423
lent overall yield (86–99%), and the b-side head-to-head adducts 5
and 8 were predominant (about 85% of the mixture). In the case of
functionalized steroids 3 and 4, the result was less unambiguous:
we were able to isolate only compounds 9 and 10 in 49% and
70% yield due to a heavy contamination of the reaction mixtures
by degradation products. Here, a higher excess of the dienophile
was used and the reaction took 16 h to complete (See Scheme 1).
The low efficiency of the reaction with 3 can be attributed to a
steric hindrance [5] caused by substituents in the B ring as well as
to lability. Product distribution was established using the Diels–
Alder reaction with steroid 1 as an example. Products 5–7 were
separated and their structures were proven by 2D NMR spectros-
copy. Key interactions in NOESY spectra of the compounds for
structure assignment are presented in Scheme 2.
ene. Therefore, the reaction proceeded in accordance with previous
observations of steroidal 14,16-dienes [6,7]; the addition of nitro-
ethylene happens from b-face (compounds 5 and 6) and highly
selectively gives head-to-head adduct. Structures of major and
two minor products correspond to those obtained in the reaction
of 14,16-dienolacetate with phenyl vinyl sulphone [8] where three
isomers had been isolated but with different ratio.
Tandem mass-spectrometry analysis revealed an interesting
common feature of the fragmented protonated molecules of the nit-
roadducts. No ions of retro Diels–Alder reaction were found among
daughter ions. Instead, after the elimination of acetic acid, the
bridged part of the molecules lost ethylene but not nitroethylene.
Nitroadducts 5, 9 and 10 underwent several representative
reactions; these had been characteristic for the nitroadduct cleav-
age in the estrane series [1,2] in order to allow the transformations,
distribution and yields of products to be compared. The reproduc-
ibility of these procedures in the androstane series is important for
Based on obtained data, the ratio of the isomers in the cycload-
dition reaction was found to be 5:6:7 = 87:11:2. Similar data were
received in the cycloaddition reaction of steroid 2 with nitroethyl-
H
H
H
H
OAc
H
H
NO2
H
H
H
H
H
H
H
5
H
H
H
OAc
H
OAc
H
H
H
H
H
H
H
H
NO2
H
NO2
7
6
Scheme 2. Ring C/D region of cycloadducts 5–7 and interactions in NOESY spectra.
15
-
3
2
+
2
-
+
-
3
Scheme 3. Pathways of the nitroadducts’ fragmentation.
Please cite this article in press as: Baranovsky AV et al. Diels–Alder reaction of androsta-14,16-dien-17-yl acetates with nitroethylene: Product distribution
and selected adduct transformations. Steroids (2012), http://dx.doi.org/10.1016/j.steroids.2012.11.015

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425
426
427
428
429
430
431
432
433
434
435
436
437
438
439
440
441
442
443
444
445
446
447
448
449
450
451
452
453
454
455
456
457
458
459
460
461
462
463
464
465
466
467
468
469
470
471
472
473
474
475
476
477
the development of an approach to D-ring modified analogs of ste-
roidal hormones.
acetoxy group migrates to nitro group with the formation of 6-
membered cyclic mixed anhydride as the first step of the process
[1] (Scheme 3).
The obtained results prove the high selectivity of the cycloaddi-
tion of nitroethylene to the steroidal 14,16-dienyl acetates and
reproducibility of the reductive cleavage reaction of bridged nitro
compounds. Consequently, nitroadducts 5, 9 and 10 can serve as
an effective starting point for the synthesis 14b-substituted ana-
logs of natural steroids.
The solvolysis of steroid 5 in aqueous ethanol in the presence of
NaHCO3 followed by column chromatography gave an inseparable
mixture of two major products; these products were formulated as
lactam 11 and hydroxylactam 12a based on preliminary NMR
examination. The separation of components for a complete charac-
terization was accomplished by exploiting different chemical prop-
erties. In contrast to compound 11, that hydroxylactam 12a can be
easily esterified at ambient temperature. Thus, when the crude res-
idue was treated with benzoyl chloride in pyridine, only compound
12a reacted, and, upon work-up and separation, steroids 12b and
11 were isolated in 20% and 26% yield respectively. The result of
the reaction differed from that obtained in the estrane series where
the ratio of products was 1:2 and overall yield was 60%. Possibly, a
lower yield of compound 11 was connected with certain lability of
3-acetoxy group under basic condition of the reaction and, for the
synthesis of nitriles, benzoyloxy derivative 8 was used.
478
Acknowledgments
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480
The authors thank Prof. J.R. Bull for stimulation of this work and
Emily Wheeler for editorial assistance.
481
References
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Both compounds reacted to give 14-cyanomethyl derivatives as ex-
[2] Baranovsky AV, Bolibrukh DA, Bull JR, Lyakhov AS, Khripach VA. Synthesis and
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D
5-derivative 13
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The conversion of steroid 9 lasted much longer, and though minor
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can expect formation of lactam to accompany the fragmentation
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The saturation of the 15-double bond in steroid 13 was fulfilled
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A unique role played by a combination of functional groups and
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517
Please cite this article in press as: Baranovsky AV et al. Diels–Alder reaction of androsta-14,16-dien-17-yl acetates with nitroethylene: Product distribution
and selected adduct transformations. Steroids (2012), http://dx.doi.org/10.1016/j.steroids.2012.11.015