Synthesis of novel 16-spiro steroids: Spiro-7′-(aryl)tetrahydro-1H- pyrrolo[1,2-c][1,3]thiazolo-trans-androsterone hybrid heterocycles

Article abstract of DOI:10.1016/j.steroids.2012.12.017

The 1,3-dipolar cycloaddition of azomethine ylide derived in situ from the reaction of acenaphthylene-1,2-dione and 1,3-thiazolane-4-carboxylic acid to various exocyclic dipolarophiles synthesized from trans-androsterone and trans-dehydroandrosterone afforded a library of novel spiro[5′.2″] acenaphthylene-1″-one-spiro[16.6′]-(7′-aryl) -tetrahydro-1H-pyrrolo [1,2-c][1,3]thiazolo-trans-androsterone/ dehydroandrosterone hybrid heterocycles respectively. These reactions proceeded stereo-specifically affording a single isomer of the 16-spiro steroids in excellent yields.

Full text of DOI:10.1016/j.steroids.2012.12.017

Steroids 78 (2013) 409–417
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Steroids
journal homepage: www.elsevier.com/locate/steroids
Synthesis of novel 16-spiro steroids:
Spiro-70-(aryl)tetrahydro-1H-pyrrolo[1,2-c][1,3]thiazolo-trans-androsterone hybrid
heterocycles
⇑
Selvaraj Kanchithalaivan, Raju Ranjith Kumar , Subbu Perumal
Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625 021, Tamil Nadu, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The 1,3-dipolar cycloaddition of azomethine ylide derived in situ from the reaction of acenaphthylene-
1,2-dione and 1,3-thiazolane-4-carboxylic acid to various exocyclic dipolarophiles synthesized from
trans-androsterone and trans-dehydroandrosterone afforded a library of novel spiro[50.200]acenaphthyl-
ene-100-one-spiro[16.60]-(70-aryl)-tetrahydro-1H-pyrrolo [1,2-c][1,3]thiazolo-trans-androsterone/dehy-
droandrosterone hybrid heterocycles respectively. These reactions proceeded stereo-specifically
affording a single isomer of the 16-spiro steroids in excellent yields.
Received 9 November 2012
Received in revised form 24 December 2012
Accepted 30 December 2012
Available online 31 January 2013
Keywords:
Androsterone
Ó 2013 Elsevier Inc. All rights reserved.
16-Siprosteroids
1,3-Dipolar cycloaddition
Azomethine ylide
Pyrrolothiazole
1. Introduction
The best studied spiro steroids are those which contain a spiro
heterocyclic ring at C-17 [8], whereas the reports on the synthesis
Steroids are extensively available in nature and are well known
for their profound biological activities and use in traditional med-
icines [1]. Syntheses of several modified steroids have received
considerable attention in the recent years. In particular, the syn-
theses of new compounds comprising heterocyclic rings either
fused or linked to the steroid framework have gained much impor-
tance [2]. Apart from being synthons for further modifications into
more complex molecules, these steroidal heterocycles have been
reported to possess a wide range of biological activities [2].
Spiro steroids are important class of compounds that are fre-
quently found in nature, such as spirostanes, which include a spi-
roacetal moiety in the structure and show significant biological
activities [3]. Generally, spiro compounds constitute a vital group
of many naturally occurring compounds identified by their highly
noticeable biological activities [4]. For example, coerulescine,
horsfiline and elacomine exhibit anti tumor activity [5], whereas
rynchophylline and corynoxeine are used in traditional Chinese
medicine for the treatment of neurological and cardiovascular dis-
eases, respectively [6]. The pentacyclic spirotryprostatin A and B
compounds were shown to inhibit the growth of human chronic
myelogenous leukemia K562 cells and human promyelocytic leu-
kemia HL-60 cells [7].
of C-16 spiro heterocyclic steroids are scarce [9]. The known C-16
spiro steroids are the cycloalkano derivatives [10], dioxaphospho-
rinanes [11], pyrazolines [12] and pyrrolidines [13]. In this context,
we herein report the synthesis of novel C-16 spiro pyrrolo[1,2-
c][1,3]thiazole containing trans-androsterone and trans-dehydro-
androsterone hybrid heterocycles via 1,3-dipolar cycloaddition
reactions. It is pertinent to note that the compounds with spiro
pyrrolo[1,2-c][1,3]thiazole substructure are known to exhibit ace-
tylcholinesterase (AChE) inhibition [14] and anti-tubercular activ-
ities [15]. Several methods have been devised to construct such
bio-important spiro heterocycles of which 1,3-dipolar cycloaddi-
tion represents the widely investigated one [16]. In particular,
the 1,3-dipolar cycloaddition of azomethine ylides to exocyclic ole-
fins offers a versatile protocol for the synthesis of poly-functional-
ized spiro pyrrolo[1,2-c][1,3]thiazoles [14,15].
2. Experimental
The melting points were measured in open capillary tubes and
are uncorrected. The 1H, 13C and the 2D NMR spectra were re-
corded on a Bruker (Avance) 300 MHz NMR instrument using
TMS as internal standard and CDCl3 as solvent. Standard Bruker
software was used throughout. Chemical shifts are given in parts
per million (d-scale) and the coupling constants are given in Hertz.
Elemental analyses were performed on a Perkin Elmer 2400 Series
⇑
Corresponding author. Tel.: +91 9655591445.
E-mail address: raju.ranjithkumar@gmail.com (R.R. Kumar).
0039-128X/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.steroids.2012.12.017

410
S. Kanchithalaivan et al. / Steroids 78 (2013) 409–417
II Elemental CHNS analyzer. IR spectra were recorded in a Shima-
dzu FTIR-8400S using KBr pellet. The single crystal X-ray data set
for 2k and 3i were collected on Bruker Kappa APPEXII diffractom-
1.72–2.00 (m, 5H), 2.17–2.46 (m, 4H), 2.84 (dd, J = 15.8, 6.5 Hz,
1H), 3.50–3.59 (m, 1H), 5.39–5.41 (m, 1H), 7.36–7.41 (m, 3H),
7.53–7.56 (m, 2H). 13C NMR 14.2, 19.4, 20.4, 29.3, 31.0, 31.2,
31.6, 31.7, 36.7, 37.2, 42.2, 47.3, 49.8, 50.4, 71.6, 120.7, 123.4,
131.6, 131.7, 131.9, 134.6, 136.7, 141.2 and 209.6.
eter with Mo–K (k = 0.71073 Å) radiation. SHELXTL software was
a
used for structure solution and refinement. Silica gel-G plates
(Merck) were used for tlc analysis with a mixture of petroleum
ether (60–80 °C) and ethyl acetate as eluent. All the chemicals
were purchased from Aldrich and used without any further
purification.
2.1.6. (E)-16-(4-Fluorophenyl)methylidene-trans-
dehydroandrosterone (5d)
Obtained as white solid; Yield 98%; m.p. 248–250 °C; 1H NMR
0.98 (s, 3H), 1.10 (s, 3H), 1.02–1.16 (m, 2H), 1.31–1.66 (m, 4H),
1.71–2.01 (m, 7H), 2.17–2.47 (m, 4H), 2.85 (dd, J = 15.7, 5.3 Hz,
1H), 3.50–3.59 (m, 1H), 5.3–3.41 (m, 1H), 7.08–7.13 (m, 2H), 7.40
(s, 1H), 7.51–7.55 (m, 2H). 13C NMR 14.2, 19.5, 20.4, 29.2, 30.9,
31.2, 31.5, 31.6, 36.7, 37.1, 42.2, 47.3, 49.9, 50.3, 71.6, 115.7,
116.0, 120.8, 131.9, 132.1, 132.2, 135.5, 135.6, 141.2, 161.4, 164.7
and 209.5.
2.1. General procedure for the synthesis of 16-(E)-arylidene-trans-
androsterones 2 and 16-(E)-arylidene-trans-dehydroandrosterones 5
A mixture of trans-androsterone 1 or trans-dehydroandroster-
one 4 (1 mmol) and aromatic aldehyde (1 mmol) was dissolved
in ethanol (5 mL) to which an alcoholic solution of potassium
hydroxide (10%) was added drop wise. The mixture was allowed
to stir for 60 min at ambient temperature and the progress of the
reaction monitored by TLC intermittently. After completion of the
reaction, the precipitated solid was filtered and washed with eth-
anol (10 mL) to afford the product 2 or 5 as colorless solid.
2.1.7. (E)-16-(4-Methylphenyl)methylidene-trans-
dehydroandrosterone (5e)
Obtained as white solid; Yield 97%; m.p. 272–274 °C; 1H NMR
0.98 (s, 3H), 1.01–1.14 (m, 2H), 1.07 (s, 3H), 1.31–1.66 (m, 4H),
1.71–2.00 (m, 7H), 2.17–2.48 (m, 3H), 2.38 (s, 3H), 2.88 (dd,
J = 15.8, 6.1 Hz, 1H), 3.52–3.55 (m, 1H), 4.82 (brs, 1H), 5.39–5.41
(m, 1H), 7.21–7.27 (m, 2H), 7.43–7.46 (m, 3H). 13C NMR 14.3,
19.5, 20.4, 21.5, 29.4, 30.9, 31.2, 31.6, 36.7, 37.1, 42.2, 47.3, 49.9,
50.4, 71.6, 120.8, 129.5, 130.4, 132.8, 133.2, 135.0, 139.6, 141.2
and 209.9.
2.1.1. (E)-16-(2-Methylphenyl)methylidene-trans-androsterone (2h)
Obtained as white solid; Yield 97%; m.p. 180–182 °C; 1H NMR
0.72–0.76 (m, 1H), 0.86 (s, 3H), 0.97 (s, 3H), 0.93–1.04 (m, 2H),
1.13–1.47 (m, 8H), 1.56–1.95 (m, 8H), 2.41 (s, 3H), 2.33–2.43 (m,
1H), 2.74 (dd, J = 15.9, 6.3 Hz, 1H), 3.58 (m, 1H), 7.22–7.24 (m,
3H), 7.44–7.46 (m, 1H), 7.65 (s, 1H). 13C NMR 12.4, 14.5, 20.0,
20.6, 28.4, 29.2, 31.1, 31.4, 31.7, 34.7, 35.7, 36.9, 38.0, 44.9, 47.9,
49.7, 54.5, 71.1, 125.8, 128.6, 129.0, 130.6, 130.7, 134.4, 136.8,
138.7 and 209.8.
2.1.8. (E)-16-(2-Chlorophenyl)methylidene-trans-
dehydroandrosterone (5g)
Obtained as white solid; Yield 97%; m.p. 250–252 °C; 1H NMR
1.00 (s, 3H), 1.07 (s, 3H), 1.06–1.15 (m, 2H), 1.29–1.65 (m, 5H),
1.70–1.90 (m, 5H), 1.97–2.21 (m, 2H), 2.26–2.48 (m, 3H), 2.75
(dd, J = 15.9, 6.3 Hz, 1H), 3.49–3.58 (m, 1H), 5.37–5.38 (m, 1H),
7.27–7.33 (m, 2H), 7.41–7.55 (m, 2H), 7.78 (s, 1H). 13C NMR 14.2,
19.5, 20.4, 29.2, 30.9, 31.2, 31.6, 36.7, 37.1, 49.2, 47.5, 49.8, 50.3,
71.6, 120.8, 126.6, 129.2, 129.9, 130.0, 133.8, 135.7, 138.2, 141.2
and 208.9.
2.1.2. (E)-16-(2-Methoxyphenyl)methylidene-trans-androsterone (2i)
Obtained as white solid; Yield 98%; m.p. 142–144 °C; 1H NMR
0.71–0.76 (m, 1H), 0.86 (s, 3H), 0.95 (s, 3H), 0.96–1.03 (m, 1H),
1.15–1.42 (m, 7H), 1.60–1.94 (m, 8H), 2.34–2.44 (m, 1H), 2.77
(dd, J = 15.2, 5.5 Hz, 1H), 3.52–3.61 (m, 1H), 3.86 (s, 3H), 5.08
(brs, 2H), 6.89–7.00 (m, 2H), 7.31–7.50 (m, 2H), 7.84 (s, 1H). 13C
NMR 12.4, 14.5, 20.6, 28.4, 29.4, 31.1, 31.4, 31.7, 34.7, 35.7, 36.9,
38.0, 44.9, 47.7, 49.6, 54.5, 55.5, 71.1, 110.8, 120.2, 124.7, 127.7,
129.6, 130.7, 136.0, 158.7 and 209.8.
2.1.9. (E)-16-(2-Methylphenyl)methylidene-trans-
dehydroandrosterone (5h)
Obtained as white solid; Yield 98%; m.p. 215–217 °C; 1H NMR
1.00 (s, 3H), 1.07 (s, 3H), 1.06–1.14 (m, 2H), 1.26–1.89 (m, 10H),
1.97–2.17 (m, 2H), 2.26–2.36 (m, 3H), 2.41 (s, 3H), 2.76 (dd,
J = 16.1, 5.9 Hz, 1H), 3.52–3.56 (m, 1H), 5.37–5.38 (m, 1H), 7.24–
7.25 (m, 3H), 7.46–7.47 (m, 1H), 7.67 (s, 1H). 13C NMR 14.2, 19.5,
19.9, 20.4, 29.3, 30.9, 31.2, 31.6, 36.7, 37.2, 42.2, 47.6, 50.0, 50.4,
71.6, 120.8, 125.8, 126.4, 128.6, 129.0, 130.6, 130.8, 134.4, 136.6,
138.7, 141.2 and 209.4.
2.1.3. (E)-16-(3-Bromophenyl)methylidene-trans-androsterone (2h)
Obtained as white solid; Yield 96%; m.p. 176–178 °C; 1H NMR
0.72–0.78 (m, 1H), 0.87 (s, 3H), 0.95 (s, 3H), 0.95–1.03 (m, 1H),
1.15–1.43 (m, 7H), 1.57–1.95 (m, 9H), 2.35–2.46 (m, 1H), 2.83
(dd, J = 15.9, 6.3 Hz, 1H), 3.57–3.64 (m, 1H), 4.78 (brs, 1H), 7.25–
7.33 (m, 2H), 7.43–7.49 (m, 2H), 7.65 (s, 1H). 13C NMR 12.3, 14.5,
20.5, 28.4, 29.1, 31.1, 31.4, 31.6, 34.7, 35.7, 36.9, 38.0, 44.8, 47.7,
49.4, 54.5, 71.1, 122.8, 128.8, 130.2, 131.3, 132.0, 132.7, 137.5,
137.7 and 209.5.
2.1.10. (E)-16-(2-Methoxyphenyl)methylidene-trans-
dehydroandrosterone (5i)
2.1.4. (E)-16-(Naphthyl)methylidene-trans-androsterone (2k)
Obtained as white solid; Yield 96%; m.p. 128–130 °C; 1H NMR
0.99 (s, 3H), 1.07 (s, 3H), 1.08–1.14 (m, 2H), 1.28–1.90 (m, 10H),
1.96–2.20 (m, 2H), 2.26–2.48 (m, 3H), 2.80 (dd, J = 15.6, 6.3 Hz,
1H), 3.50–3.57 (m, 1H), 3.86 (s, 3H), 5.37–5.39 (m, 1H), 6.90–7.01
(m, 2H), 7.32–7.51 (m, 2H), 7.86 (s, 1H). 13C NMR 14.2, 19.5,
20.4, 29.4, 30.9, 31.2, 31.6, 36.7, 37.1, 42.2, 47.4, 50.0, 50.3, 55.5,
71.6, 110.8, 120.2, 120.9, 124.7, 127.9, 129.6, 130.7, 135.9, 141.1,
158.7 and 209.6.
Obtained as white solid; Yield 96%; m.p. 172–174 °C; 1H NMR
0.65–0.76 (m, 1H), 0.86 (s, 3H), 0.92–0.99 (m, 2H), 1.02 (s, 3H),
1.06–1.48 (m, 7H), 1.55–1.99 (m, 8H), 2.38–2.49 (m, 1H), 2.72
(dd, J = 15.9, 6.3 Hz, 1H), 3.52–3.61 (m, 1H), 5.09 (brs, 1H), 7.47–
7.63 (m, 4H), 7.85–7.89 (m, 2H), 8.13–8.17 (m, 1H), 8.19 (s, 1H).
13C NMR 12.3, 14.5, 20.6, 28.4, 29.4, 31.1, 31.4, 31.8, 34.7, 35.7,
36.9, 38.0, 44.8, 48.1, 49.5, 54.5, 71.1, 124.1, 125.1, 126.2, 126.6,
126.9, 128.7, 129.6, 129.9, 132.2, 132.5, 133.6, 138.4 and 209.5.
2.1.11. (E)-16-(3-Bromophenyl)methylidene-trans-
2.1.5. (E)-16-(4-Bromophenyl)methylidene-trans-
dehydroandrosterone (5c)
dehydroandrosterone (5j)
Obtained as white solid; Yield 97%; m.p. 222–224 °C; 1H NMR
0.98 (s, 3H), 1.08 (s, 3H), 1.02–1.15 (m, 2H), 1.31–1.67 (m, 8H),
1.72–2.01 (m, 3H), 2.18–2.50 (m, 4H), 2.86 (dd, J = 16.2, 6.3 Hz,
Obtained as white solid; Yield 96%; m.p. 254–256 °C; 1H NMR
0.98 (s, 3H), 1.08 (s, 3H), 1.04–1.15 (m, 2H), 1.24–1.67 (m, 6H),

S. Kanchithalaivan et al. / Steroids 78 (2013) 409–417
411
1H), 3.49–3.58 (m, 1H), 5.39–5.41 (m, 1H), 7.26–7.35 (m, 2H),
2.2.3. (16R, 50R, 70R, 7a0R)-Spiro[50.200]acenaphthylene-100-one-
spiro[16.60]-70-(4-bromophenyl)-tetrahydro-1H-pyrrolo[1,2-
c][1,3]thiazolo-trans-androsterone (3c)
7.44–7.50 (m, 2H), 7.66 (s, 1H). 13C NMR 14.2, 19.5, 20.4, 29.2,
30.9, 31.2, 31.5, 31.6, 36.7, 37.1, 42.2, 47.4, 49.8, 50.3, 71.6,
120.8, 122.8, 128.8, 130.2, 131.4, 132.0, 132.8, 137.3, 137.7, 141.2
and 209.3.
Obtained as pale yellow solid; Yield 81%; m.p.186–188 °C; Anal.
Calcd. for C41H44BrNO3S: C, 69.28; H, 6.24; N, 1.97; Found: C,
69.17; H, 6.26; N, 1.86. 1H NMR ꢀ0.25–(ꢀ0.07) (m, 2H), –0.05 (s,
3H), 0.40–0.48 (m, 2H), 0.58 (s, 3H), 0.68–0.73 (m, 1H), 0.83–0.90
(m, 3H), 1.02–1.26 (m, 6H), 1.42–1.54 (m, 4H), 1.68–1.71 (m,
2H), 2.46 (dd, J = 13.1, 4.3 Hz, 1H), 2.90 (dd, J = 10.5, 4.8 Hz, 1H),
3.07 (dd, J = 10.2, 6.0 Hz, 1H), 3.44–3.54 (m, 1H), 3.64 (d,
J = 8.1 Hz, 1H), 3.77–3.83 (m, 2H), 4.71–4.78 (m, 1H), 7.21–8.15
(m, 10H). 13C NMR 12.1, 14.1, 20.0, 22.6, 28.1, 29.0, 30.6, 31.2,
31.3, 31.6, 33.8, 34.6, 35.4, 36.6, 37.9, 44.6, 47.1, 48.8, 50.2, 54.6,
55.5, 71.0, 71.9, 72.1, 80.0, 120.9, 121.6, 125.5, 126.1, 127.9,
128.3, 130.5, 131.7, 132.3, 134.5, 136.1, 141.3, 205.9 and 219.0.
2.1.12. (E)-16-(Naphthyl)methylidene-trans-dehydroandrosterone
(5k)
Obtained as white solid; Yield 97%; m.p. 134–136 °C; 1H NMR
1.05 (s, 3H), 1.07 (m, 3H), 1.08–1.13 (m, 2H), 1.22–1.62 (m, 6H),
1.72–2.52 (m, 6H), 2.75 (dd, J = 15.6, 6.0 Hz, 1H), 3.49–3.55 (m,
1H), 4.85 (brs, 1H), 5.14 (m, 2H), 5.33–5.34 (m, 1H), 7.49–7.64
(m, 4H), 7.86–8.16 (m, 3H), 8.21 (s, 1H). 13C NMR 14.3, 19.5,
20.4, 29.5, 30.9, 31.2, 31.5, 31.6, 36.7, 37.1, 42.2, 47.8, 50.1, 50.3,
71.6, 120.9, 124.0, 125.1, 126.2, 126.7, 126.9, 128.7, 129.6, 130.0,
132.2, 132.4, 133.6, 138.2, 141.0 and 209.3.
2.2.4. (16R, 50R, 70R, 7a0R)-Spiro[50.200]acenaphthylene-100-one-
spiro[16.60]-70-(4-fluorophenyl)-tetrahydro-1H-pyrrolo[1,2-
c][1,3]thiazolo-trans-androsterone (3d)
2.2. General procedure for the synthesis of spiro[50.200]acenaphthylene-
100-one-spiro[16.60]-(70-aryl)-tetrahydro-1H-pyrrolo[1,2-
c][1,3]thiazolo trans-androsterones/dehydroandrosterones 3 and 6
Obtained as pale yellow solid; Yield 75%; m.p. 172–174 °C; Anal.
Calcd. for C41H44FNO3S: C, 75.78; H, 6.82; N, 2.16. Found: C, 75.73;
H, 6.86; N, 2.19. 1H NMR ꢀ0.26–(ꢀ0.15) (m, 1H), ꢀ0.04–(ꢀ0.05)
(m, 1H), ꢀ0.01 (s, 3H), 0.46–0.53 (m, 2H), 0.58 (s, 3H), 0.70–0.79
(m, 1H), 0.83–0.91 (m, 3H), 0.95–1.07 (m, 2H), 1.12–1.29 (m, 6H),
1.47–1.68 (m, 4H), 2.52 (dd, J = 13.1, 4.3 Hz, 1H), 2.92 (dd,
J = 10.7, 4.4 Hz, 1H), 3.10 (dd, J = 10.5, 6.3 Hz, 1H), 3.47–3.54 (m,
1H), 3.64 (d, J = 8.4 Hz, 1H), 3.82–3.87 (m, 2H), 4.70–4.76 (m,
1H), 7.00–8.16 (m, 10H). 13C NMR 12.0, 14.0, 20.0, 28.1, 28.8,
30.6, 31.3, 31.4, 33.9, 34.7, 35.4, 36.6, 38.0, 44.7, 47.1, 48.9, 50.4,
54.6, 55.5, 71.0, 72.0, 72.1, 80.2, 115.3, 115.6, 120.8, 125.5, 126.2,
127.8, 128.3, 130.6, 131.6, 131.8, 132.2, 132.8, 134.6, 141.2,
160.6, 163.9, 205.8 and 220.0.
A mixture of the appropriate steroid arylidine (2 or 5, 1 mmol),
acenaphthylene-1,2-dione (1 mmol) and 1,3-thiazolane-4-carbox-
ylic acid (1.2 mmol) was taken in methanol (10 mL) and refluxed
for 3–5 h. The progress of the reaction was monitored by TLC. After
completion of the reaction as evident from TLC, the reaction mix-
ture was cooled and poured into ice cooled water. The resultant
precipitate was filtered, dried and purified by filtration column
using petroleum ether: ethyl acetate (9:1) as eluting solvent to
get the product 3 or 6 as pale yellow solid.
2.2.1. (16R,50R,70R,7a0R)-Spiro[50.200]acenaphthylene-100-one-
spiro[16.60]-70-phenyl-tetrahydro-1H-pyrrolo[1,2-c][1,3]thiazolo-
trans-androsterone (3a)
2.2.5. (16R, 50R, 70R, 7a0R)-Spiro[50.200]acenaphthylene-100-one-
spiro[16.60]-70-(4-methylphenyl)-tetrahydro-1H-pyrrolo[1,2-
c][1,3]thiazolo-trans-androsterone (3e)
Obtained as pale yellow solid; Yield 87%; m.p. 181–183 °C; Anal.
Calcd. for C41H45NO3S: C, 77.93; H, 7.18; N, 2.22. Found: C, 77.89;
H, 7.22; N, 2.19. 1H NMR ꢀ0.28–(ꢀ0.21) (m, 1H), –0.06 (s, 3H),
0.53–0.54 (m, 2H), 0.57 (s, 3H), 0.71–0.78 (m, 1H), 0.85–0.88 (m,
2H), 1.02–1.06 (m, 1H), 1.11–1.26 (m, 6H), 1.47–1.60 (m, 4H),
1.68–1.71 (m, 2H), 2.56 (dd, J = 13.2, 4.5 Hz, 1H), 2.94 (dd,
J = 10.8, 4.5 Hz, 1H), 3.12 (dd, J = 10.7, 6.4 Hz, 1H), 3.47–3.55 (m,
1H), 3.64 (d, J = 8.7 Hz, 1H), 3.86 (d, J = 5.1 Hz, 1H), 3.89 (d,
J = 6.9 Hz, 1H), 4.77–4.83 (m, 2H), 7.31–8.15 (m, 11H). 13C NMR
12.1, 13.7, 20.0, 28.1, 28.3, 30.6, 31.3, 31.4, 33.9, 35.0, 35.4, 36.6,
38.0, 44.7, 47.1, 49.1, 51.2, 54.6, 56.3, 71.0, 71.7, 72.0, 80.8, 120.8,
125.4, 126.3, 127.6, 127.8, 128.3, 128.5, 130.1, 130.5, 131.7,
132.2, 134.4, 136.7, 141.0, 205.8 and 218.6.
Obtained as pale yellow solid; Yield 83%; m.p. 191–193 °C; Anal.
Calcd. for C42H47NO3S: C, 78.10; H, 7.33; N, 2.17. Found: C, 78.15;
H, 7.39; N, 2.21. 1H NMR ꢀ0.29–(ꢀ0.19) (m, 1H), ꢀ0.05 (s, 3H),
0.58 (s, 3H), 0.50–0.64 (m, 2H), 0.71–0.79 (m, 1H), 0.83–0.90 (m,
3H), 1.06–1.26 (m, 7H), 1.47–1.67 (m, 6H), 2.32 (s, 3H), 2.56 (dd,
J = 13.4, 4.3 Hz, 1H), 2.93 (dd, J = 11.0,4.0 Hz, 1H), 3.11 (dd,
J = 10.8, 6.3 Hz, 1H), 3.46–3.55 (m, 1H), 3.63 (d, J = 8.4 Hz, 1H),
3.85 (d, J = 6.3 Hz, 1H), 3.88 (d, J = 5.4 Hz, 1H), 4.73–4.80 (m, 1H),
7.14–8.14 (m, 10H). 13C NMR 12.1, 13.8, 20.0, 21.0, 28.2, 28.4,
30.6, 31.3, 31.5, 33.9, 35.0, 35.4, 36.7, 38.0, 44.7, 47.1, 49.1, 51.0,
54.7, 56.0, 71.0, 71.8, 72.1, 80.8, 120.8, 125.4, 126.3, 127.7, 128.3,
129.2, 130.0, 130.5, 131.9, 132.1, 133.6, 134.7, 137.3, 141.1, 205.7
and 218.6.
2.2.2. (16R, 50R, 70R, 7a0R)-Spiro[50.200]acenaphthylene-100-one-
spiro[16.60]-70-(4-chlorophenyl)-tetrahydro-1H-pyrrolo[1,2-
c][1,3]thiazolo-trans-androsterone (3b)
2.2.6. (16R, 50R, 70R, 7a0R)-Spiro[50.200]acenaphthylene-100-one-
spiro[16.60]-70-(4-methoxyphenyl)-tetrahydro-1H-pyrrolo[1,2-
c][1,3]thiazolo-trans-androsterone (3f)
Obtained as pale yellow solid; Yield 79%; m.p. 158–160 °C; FT-
IR: 3427, 2924, 2852, 1724, 783, 729. Anal. Calcd. for C41H44ClNO3-
S: C, 73.91; H, 6.66; N, 2.10. Found: C, 73.98; H, 6.70; N, 2.16. 1H
NMR –0.27–(–0.06) (m, 2H), 0.05 (m, 3H), 0.39–0.51 (m, 2H),
0.58 (s, 3H), 0.67–0.78 (m, 1H), 0.83–0.88 (m, 3H), 1.01–1.25 (m,
6H), 1.41–1.54 (m, 4H), 1.67–1.69 (m, 2H), 2.47 (dd, J = 13.4,
4.7 Hz, 1H), 2.91 (dd, J = 10.5, 5.1 Hz, 1H), 3.07 (dd, J = 10.5,
6.3 Hz, 1H), 3.46–3.53 (m, 1H), 3.64 (d, J = 8.1 Hz, 1H), 3.79 (d,
J = 8.1 Hz, 1H), 3.83 (d, J = 10.2 Hz, 1H), 4.71–4.78 (m, 1H), 7.30–
8.16 (m, 10H). 13C NMR 12.0, 14.1, 20.0, 28.1, 29.1, 30.6, 31.3,
33.8, 34.5, 35.4, 36.6, 38.0, 44.7, 44.9, 47.1, 48.8, 50.0, 54.6, 55.5,
71.0, 72.0, 72.3, 79.8, 120.8, 125.5, 126.1, 127.9, 128.3, 128.8,
131.4, 131.8, 132.2, 133.5, 134.6, 135.7, 141.3, 205.8 and 218.9.
Obtained as pale yellow solid; Yield 87%; m.p. 170–172 °C; Anal.
Calcd. for C42H47NO4S: C, 76.21; H, 7.16; N, 2.12. Found: C, 76.17;
H, 7.19; N, 2.21. 1H NMR ꢀ0.28–(ꢀ0.17) (m, 1H), ꢀ0.05 (s, 3H),
0.50–0.65 (m, 2H), 0.58 (s, 3H), 0.71–0.79 (m, 1H), 0.83–0.95 (m,
4H), 1.04–1.12 (m, 2H), 1.12–1.28 (m, 3H), 1.47–1.57 (m, 3H),
1.63–1.75 (m, 4H), 2.56 (dd, J = 13.2, 4.5 Hz, 1H), 2.94 (dd,
J = 10.8, 4.2 Hz, 1H), 3.12 (dd, J = 11.0, 6.4 Hz, 1H), 3.46–3.55 (m,
1H), 3.63 (d, J = 8.7 Hz, 1H), 3.79 (s, 3H), 3.77–3.86 (m, 2H), 4.70–
4.75 (m, 1H), 6.84–8.14 (m, 10H). 13C NMR 12.0, 13.8, 20.0, 28.2,
30.6, 31.3, 31.5, 33.9, 35.0, 35.4, 36.6, 38.0, 44.7, 47.1, 49.1, 51.1,
54.6, 55.2, 55.7, 71.0, 71.8, 72.0, 80.7, 113.9, 120.7, 125.4, 126.2,
127.7, 128.2, 128.7, 130.5, 131.1, 131.8, 132.1, 134.6, 141.0,
159.0, 205.8 and 218.6.

412
S. Kanchithalaivan et al. / Steroids 78 (2013) 409–417
2.2.7. (16R, 50R, 70R, 7a0R)-Spiro[50.200]acenaphthylene-100-one-
spiro[16.60]-70-(2-chlorophenyl)-tetrahydro-1H-pyrrolo[1,2-
c][1,3]thiazolo-trans-androsterone (3g)
2.2.11. (16R, 50R, 70R, 7a0R)-Spiro[50.200]acenaphthylene-100-one-
spiro[16.60]-70-naphthyl-tetra-hydro-1H-pyrrolo[1,2-c][1,3]thiazolo-
trans-androsterone (3k)
Obtained as pale yellow solid; Yield 89%; m.p. 179–181 °C; FT–
IR: 3446, 2926, 2854, 1712, 783. Anal. Calcd. for C41H44ClNO3S: C,
73.91; H, 6.66; N, 2.10. Found: C, 73.95; H, 6.76; N, 2.18. 1H NMR
ꢀ0.51 (td, J = 13.1, 5.5 Hz, 1H), ꢀ0.17–(ꢀ0.05) (m, 2H), 0.45 (s,
3H), 0.53 (s, 3H), 0.53–0.66 (m, 2H), 0.81–0.97 (m, 6H), 1.07–1.15
(m, 3H), 1.21–1.31 (m, 3H), 1.38–1.42 (m, 3 H), 2.06 (dd, J = 13.5,
4.2 Hz, 1H), 2.90–3.02 (m, 2H), 3.38–3.46 (m, 1H), 3.54 (d,
J = 6.0 Hz, 1H), 3.69 (d, J = 5.7 Hz, 1H), 4.54 (d, J = 8.4 Hz, 1H),
4.74–4.81 (m, 1H), 7.19–8.18 (m, 10H). 13C NMR 12.0, 15.2, 19.8,
27.9, 30.6, 31.2, 32.4, 33.1, 33.4, 35.2, 36.5, 37.8, 44.5, 46.7, 47.3,
48.0, 50.2, 54.4, 70.9, 72.8, 74.3, 77.4, 120.8, 125.5, 126.2, 127.2,
128.0, 128.2, 128.6, 129.4, 130.4, 131.9, 132.2, 135.2, 135.4,
136.4, 142.4, 207.1 and 220.0.
Obtained as pale yellow solid; Yield 89%, m.p. 174–176 °C; FT-
IR: 3441, 2924, 2852, 1716, 783. Anal. Calcd. for C45H47NO3S: C,
79.26; H, 6.95; N, 2.05. Found: C, 79.33; H, 7.02; N, 2.18. 1H NMR
ꢀ0.43–(ꢀ0.37) (m, 1H), ꢀ0.25–(ꢀ0.18) (m, 1H), ꢀ0.11 (s, 3H),
0.06–0.25 (m, 3H), 0.46 (s, 3H), 0.58–0.70 (m, 2H), 0.81–0.91 (m,
4H), 1.05–1.10 (m, 3H), 1.23–1.26 (m, 3H), 1.35–1.42 (m, 3H),
2.30 (dd, J = 13.7, 4.3 Hz, 1H), 2.89 (dd, J = 9.7, 6.8 Hz, 1H), 2.97
(dd, J = 9.7, 5.9 Hz, 1H), 3.39–3.47 (m, 1H), 3.70 (d, J = 6.6 Hz, 1H),
3.75 (d, J = 6.9 Hz, 1H), 4.82 (d, J = 9.3 Hz, 1H), 5.06–5.09 (m, 1H),
7.42–8.18 (m, 13H). 13C NMR 11.9, 14.7, 19.8, 26.9, 27.9, 30.5,
31.2, 33.5, 33.8, 34.6, 35.2, 36.5, 37.8, 44.5, 47.4, 48.2, 48.6, 54.4,
70.9, 73.1, 73.6, 78.6, 120.9, 123.7, 125.5, 125.7, 126.1, 126.3,
127.5, 127.7, 128.0, 128.5, 128.7, 130.5, 132.0, 132.2, 132.9,
133.9, 134.0, 135.5, 142.0, 206.4 and 220.3.
2.2.8. (16R, 50R, 70R, 7a0R)-Spiro[50.200]acenaphthylene-100-one-
spiro[16.60]-70-(2-methylphenyl)-tetrahydro-1H-pyrrolo[1,2-
c][1,3]thiazolo-trans-androsterone (3h)
2.2.12. (16R, 50R, 70R, 7a0R)-Spiro[50.200]acenaphthylene-100-one-
spiro[16.60]-70-phenyl-tetra-hydro-1H-pyrrolo[1,2-c][1,3]thiazolo-
trans-dehydroandrosterone (6a)
Obtained as pale yellow solid; Yield 91%; m.p. 171–173 °C; Anal.
Calcd. for C42H47NO3S: C, 78.10; H, 7.33; N, 2.17. Found: C, 78.21;
H, 7.38; N, 2.27. 1H NMR ꢀ0.31–(ꢀ0.153) (m, 2H) 0.14 (s, 3H),
0.22–0.29 (m, 2H), 0.55 (s, 3H), 0.62–0.73 (m, 2H), 0.83–0.87 (m,
3H), 0.95–1.15 (m, 5H), 1.42–1.69 (m, 6H), 2.27 (s, 3H), 2.40 (dd,
J = 11.9, 5.8 Hz, 1H), 2.87 (dd, J = 9.7, 6.1 Hz, 1H), 3.00 (dd, J = 9.7,
6.1 Hz, 1H), 3.42–3.49 (m, 1H), 3.70 (s, 2H), 4.28 (d, J = 9.6 Hz,
1H), 4.76–4.83 (m, 1H), 7.14–8.16 (m, 10H). 13C NMR 12.0, 14.1,
20.0, 28.1, 30.6, 30.9, 31.3, 33.8, 33.9, 35.3, 36.6, 37.9, 44.7, 47.2,
48.4, 48.8, 50.6, 54.5, 71.0, 72.5, 73.9, 79.1, 120.8, 125.4, 126.1,
126.2, 126.9, 127.9, 128.4, 130.2, 130.5, 130.6, 132.0, 132.1,
135.5, 135.8, 137.6, 141.8, 206.2 and 220.1.
Obtained as pale yellow solid; Yield 88%; m.p. 191–193 °C; Anal.
Calcd. for C41H43NO3S: C, 78.18; H, 6.88; N, 2.22. Found: C, 78.25;
H, 6.76; N, 2.29. 1H NMR ꢀ0.22–(ꢀ0.15) (m, 1H), ꢀ0.04 (s, 3H),
0.31–0.39 (m, 1H), 0.61 (td, J = 13.8, 4.8 Hz, 1H), 0.78 (s, 3H),
0.83–0.90 (m, 2H) 1.03–1.39 (m, 6H), 1.50–1.71 (m, 3H), 1.86–
1.93 (m, 1H), 2.11–2.24 (m, 2H), 2.60 (dd, J = 13.1, 4.7 Hz, 1H),
2.95 (dd, J = 11.0, 4.4 Hz, 1H), 3.13 (dd, J = 10.8, 6.6 Hz, 1H), 3.41–
3.48 (m, 1H), 3.64 (d, J = 8.7 Hz, 1H), 3.86–3.93, (m, 2H), 4.76–
4.83 (m, 1H), 5.26–5.27 (m, 1H), 7.31–8.14 (m, 11H). 13C NMR
13.3, 19.1, 19.7, 30.3, 30.4, 31.3, 31.4, 31.5, 35.1, 36.4, 36.9, 42.1,
46.8, 49.2, 50.2, 51.3, 56.4, 71.4, 71.6, 71.7, 80.9, 120.9, 121.0,
125.4, 126.3, 127.6, 127.8, 128.2, 128.5, 130.1, 130.5, 131.6,
132.2, 134.3, 136.6, 140.5, 141.0, 205.6 and 218.2.
2.2.9. (16R, 50R, 70R, 7a0R)-Spiro[50.200]acenaphthylene-100-one-
spiro[16.60]-70-(2-methoxyphenyl)-tetrahydro-1H-pyrrolo[1,2-
c][1,3]thiazolo-trans-androsterone (3i)
2.2.13. (16R, 50R, 70R, 7a0R)-Spiro[50.200]acenaphthylene-100-one-
spiro[16.60]-70-(4-chlorophenyl)-tetrahydro-1H-pyrrolo[1,2-
c][1,3]thiazolo-trans-dehydroandrosterone (6b)
Obtained as pale yellow solid; Yield 78%; m.p. 190–192 °C; Anal.
Calcd. for C42H47NO4S: C, 76.21; H, 7.16; N, 2.12. Found: C, 76.12;
H, 7.21; N, 2.19. 1H NMR ꢀ0.44–(ꢀ0.41) (m, 1H), ꢀ0.20–(ꢀ0.15)
(m, 1H), 0.01–0.07 (m, 1H), 0.33 (s, 3H), 0.54 (s, 3H), 0.64–0.67
(m, 2H), 0.82–0.95 (m, 5H), 1.04–1.12 (m, 4H), 1.22–1.39 (m,
3H), 1.42 (s, 2H), 1.53–1.68 (m, 2H), 2.91–2.96 (m, 2H), 3.43–
3.45 (m, 1H), 3.62–3.69 (m, 5H), 4.45–4.48 (m, 1H), 4.82–4.85
(m, 1H), 6.81–8.15 (m, 10H). 13C NMR 12.0, 14.4, 19.9, 22.5, 25.2,
29.0, 30.0, 30.5, 31.2, 31.3, 31.5, 33.6, 34.6, 35.3, 36.5, 37.9, 44.6,
47.1, 48.1, 54.5, 55.1, 70.8, 72.7, 110.2, 120.6, 120.7, 125.2, 126.2,
126.7, 127.8, 128.0, 128.3, 130.4, 131.9, 132.1, 135.7, 142.1,
157.9, 206.6 and 219.3.
Obtained as pale yellow solid; Yield 86%; m.p. 190–192 °C; FT-
IR: 3443, 2926, 2854, 1724, 783. Anal. Calcd. for C41H42ClNO3S: C,
74.13; H, 6.37; N, 2.11. Found: C, 74.21; H, 6.39; N, 2.21. 1H NMR
ꢀ0.17 (td, J = 12.4, 4.7 Hz, 1H), 0.05 (s, 3H), 0.25–0.32 (m, 1H),
0.47–0.55 (m, 1H), 0.78 (s, 3H), 0.88–0.93 (m, 2H), 1.01–1.29 (m,
4H), 1.34–1.39 (m, 1H), 1.49–1.54 (m, 2H), 1.71–1.75 (m, 1H),
1.83–1.88 (m, 2H), 2.10–2.25 (m, 2H), 2.50 (dd, J = 13.4, 4.7 Hz,
1H), 2.91 (dd, J = 10.7, 4.7 Hz, 1H), 3.08 (dd, J = 10.7, 6.1 Hz, 1H),
3.40–3.47 (m, 1H), 3.63 (d, J = 8.1 Hz, 1H), 3.80 (d, J = 8.1 Hz, 1H),
3.85 (d, J = 9.9 Hz, 1H), 4.71–4.78 (m, 1H), 5.22–5.24 (m, 1H),
7.30–8.14 (m, 10H). 13C NMR 13.8, 14.0, 19.1, 19.8, 29.1, 29.7,
30.4, 31.2, 31.4, 34.6, 36.5, 36.9, 42.1, 46.8, 49.1, 50.3, 50.4, 55.7,
71.4, 72.0, 80.0, 120.9, 121.0, 125.5, 126.2, 127.9, 128.3, 128.8,
130.6, 131.4, 131.7, 132.3, 133.6, 134.5, 135.6, 140.6, 141.3, 205.7
and 218.6.
2.2.10. (16R, 50R, 70R, 7a0R)-Spiro[50.200]acenaphthylene-100-one-
spiro[16.60]-70-(3-bromophenyl)-tetrahydro-1H-pyrrolo[1,2-
c][1,3]thiazolo-trans-androsterone (3j)
Obtained as pale yellow solid; Yield 80%; m.p. 180–182 °C; FT-
IR: 3479, 2920, 2852, 1716, 783. Anal. Calcd. for C41H44BrNO3S: C,
69.28; H, 6.24; N, 1.97; Found: C, 69.36; H, 6.32; N, 2.09. 1H NMR
ꢀ0.23 (td, J = 12.7, 4.0 Hz, 1H),ꢀ0.12–(ꢀ0.06) (m, 1H), 0.55 (s, 3H),
0.41–0.51 (m, 2H), 0.58 (s, 3H), 0.69–0.78 (m, 1H), 0.85–0.88 (m,
3H), 1.04–1.22 (m, 6H), 1.42–1.71 (m, 6H), 2.49 (dd, J = 13.2,
4.5 Hz, 1H), 2.92 (dd, J = 10.5, 4.8 Hz, 1H), 3.10 (dd, J = 10.5,
6.3 Hz, 1H), 3.45–3.55 (m, 1H), 3.63 (d, J = 8.1 Hz, 1H), 3.79–3.84
(m, 2H), 4.74–4.77 (m, 1H), 7.22–8.16 (m, 10H). 13C NMR 12.1,
14.1, 20.0, 28.1, 29.1, 30.6, 31.2, 31.3, 33.8, 34.5, 35.4, 36.6, 38.0,
44.7, 47.1, 48.8, 50.1, 54.6, 55.6, 70.9, 71.8, 72.3, 79.8, 120.9,
122.7, 125.5, 126.1, 127.9, 128.3, 128.5, 130.1, 130.6, 130.7,
131.8, 132.2, 133.0, 134.6, 139.6, 141.3, 205.7 and 218.9.
2.2.14. (16R, 50R, 70R, 7a0R)-Spiro[50.200]acenaphthylene-100-one-
spiro[16.60]-70-(4-bromophenyl)-tetrahydro-1H-pyrrolo[1,2-
c][1,3]thiazolo-trans-dehydroandrosterone (6c)
Obtained as pale yellow solid; Yield 89%; m.p. 187–189 °C; Anal.
Calcd. for C41H42BrNO3S: C, 69.48; H, 5.97; N, 1.98. Found: C, 69.35;
H, 5.89; N, 1.87. 1H NMR ꢀ0.16 (td, J = 13.2, 5.4 Hz, 1H), 0.06 (s,
3H), 0.24–0.32 (m, 1H), 0.47–0.53 (m, 1H), 0.79 (s, 3H), 0.83–0.90
(m, 3H), 1.07–1.43 (m, 5H), 1.57–1.61 (m, 2H), 1.81–1.86 (m,
2H), 2.11–2.24 (m, 2H), 2.50 (dd, J = 13.3, 4.6 Hz, 1H), 2.91 (dd,
J = 10.7, 4.7 Hz, 1H), 3.08 (dd, J = 10.5, 6.0 Hz, 1H), 3.40–3.48 (m,
1H), 3.63 (d, J = 8.1 Hz, 1H), 3.80 (d, J = 8.1 Hz, 1H), 3.84 (d,
J = 10.2 Hz, 1H), 4.71–4.78 (m, 1H), 5.22–5.24 (m, 1H), 7.22–8.15

S. Kanchithalaivan et al. / Steroids 78 (2013) 409–417
413
(m, 10H). 13C NMR 14.1, 19.1, 19.7, 22.6, 28.9, 30.3, 31.2, 31.3, 31.5,
34.6, 36.4, 36.8, 42.0, 46.8, 49.0, 50.1, 50.5, 55.6, 71.4, 71.8, 80.1,
120.8, 121.0, 121.7, 125.5, 126.1, 127.9, 128.2, 128.8, 130.5,
131.6, 131.7, 132.3, 134.3, 136.0, 140.5, 141.2, 205.7 and 218.6.
(m, 1H), 0.68–0.72 (m, 1H), 0.75 (s, 3H), 0.99–1.18 (m, 4H), 1.27–
1.34 (m, 2H), 1.46–1.58 (m, 5H), 2.05–2.14 (m, 3H), 2.93 (dd,
J = 9.5, 5.9 Hz, 1H), 2.98 (dd, J = 13.5, 5.5 Hz, 1H), 3.32–3.39 (m,
1H), 3.53 (d, J = 5.7 Hz, 1H), 3.69 (d, J = 6.0 Hz, 1H), 4.57 (d,
J = 8.7 Hz, 1H), 4.79 (m, 1H), 5.06–5.07 (m, 1H), 7.19–8.17 (m,
10H). 13C NMR 14.9, 19.0, 19.6, 30.1, 30.5, 31.0, 31.3, 32.5, 33.1,
36.4, 36.8, 42.0, 46.8, 47.1, 48.3, 50.0, 50.4, 72.6, 74.2, 77.3, 120.4,
120.9, 125.5, 126.3, 127.2, 128.0, 128.2, 128.6, 129.5, 130.5,
131.9, 132.0, 132.3, 132.4, 135.2, 135.4, 136.4, 140.6, 142.4, 206.9
and 219.8.
2.2.15. (16R, 50R, 70R, 7a0R)-Spiro[50.200]acenaphthylene-100-one-
spiro[16.60]-70-(4-fluorophenyl)-tetrahydro-1H-pyrrolo[1,2-
c][1,3]thiazolo-trans-dehydroandrosterone (6d)
Obtained as pale yellow solid; Yield 80%; m.p. 179–181 °C; Anal.
Calcd. for C41H42FNO3S: C, 76.01; H, 6.53; N, 2.16. Found: C, 76.08;
H, 6.48; N, 2.30. 1H NMR ꢀ0.21–(0.13) (m, 1H), 0.01 (s, 3H), 0.31–
0.35 (m, 1H), 0.51–0.58 (m, 1H), 0.79 (s, 3H), 0.83–0.90 (m, 2H),
1.08–1.30 (m, 5H), 1.35–1.40 (m, 1H), 1.58–1.62 (m, 1H), 1.72–
1.85 (m, 3H), 2.07–2.25 (m, 2H), 2.55 (dd, J = 13.4, 4.7 Hz, 1H),
2.93 (dd, J = 10.8, 4.5 Hz, 1H), 3.10 (dd, J = 10.7, 6.4 Hz, 1H), 3.40–
3.48 (m, 1H), 3.63 (d, J = 8.4 Hz, 1H), 3.84 (d, J = 8.4 Hz, 1H), 3.88
(d, J = 10.2 Hz, 1H), 4.70–4.77 (m, 1H), 5.24–5.26 (m, 1H), 7.00–
8.15 (m, 10H). 13C NMR 13.6, 19.1, 19.8, 22.6, 28.8, 30.4, 30.5,
31.3, 31.4, 34.8, 36.4, 36.9, 42.1, 46.8, 49.1, 50.3, 50.6, 55.6, 71.4,
71.9, 72.0, 80.3, 115.3, 115.6, 120.9, 125.5, 126.2, 127.9, 128.3,
130.6, 131.7, 132.2, 132.7, 134.5, 140.6, 141.2, 160.6, 163.9, 205.6
and 218.5.
2.2.19. (16R, 50R, 70R, 7a0R)-Spiro[50.200]acenaphthylene-100-one-
spiro[16.60]-70-(2-methylphenyl)-tetrahydro-1H-pyrrolo[1,2-
c][1,3]thiazolo-trans-dehydroandrosterone (6h)
Obtained as pale yellow solid; Yield 89%; m.p. 181–182 °C; Anal.
Calcd. for C42H45NO3S: C, 78.35; H, 7.04; N, 2.18. Found: C, 78.23;
H, 7.11; N, 2.32. 1H NMR ꢀ0.13 (td, J = 12.3, 4.8 Hz, 1H), 0.10–
0.21 (m, 1H), 0.15 (s, 3H), 0.27–0.37 (m, 1H), 0.76 (s, 3H), 0.78–
0.90 (m, 3H), 1.08–1.19 (m, 4H), 1.37–1.43 (m, 1H), 1.54–1.59
(m, 2H), 1.68–1.72 (m, 2H), 2.08–2.22 (m, 2H), 2.29 (s, 3H), 2.44
(dd, J = 13.8, 4.5 Hz, 1H), 2.88 (dd, J = 10.1, 5.1 Hz, 1H), 3.01 (dd,
J = 10.2, 6.0 Hz, 1H), 3.36–3.44 (m, 1H), 3.70 (s, 2H), 4.31 (d,
J = 9.9 Hz, 1H), 4.76–4.83 (m, 1H), 5.17–5.19 (m, 1H), 7.12–8.15
(m, 10H). 13C NMR 13.6, 19.0, 19.7, 19.9, 30.3, 30.4, 30.7, 31.1,
31.3, 34.0, 36.4, 36.8, 42.0, 46.9, 48.6, 49.0, 50.1, 50.7, 71.3, 72.1,
73.8, 79.2, 120.7, 120.8, 125.3, 126.0, 126.2, 126.9, 127.9, 128.3,
130.1, 130.5, 130.6, 131.8, 132.1, 135.3, 135.6, 137.6, 140.5,
141.7, 205.9 and 219.8.
2.2.16. (16R, 50R, 70R, 7a0R)-Spiro[50.200]acenaphthylene-100-one-
spiro[16.60]-70-(4-methylphenyl)-tetrahydro-1H-pyrrolo[1,2-
c][1,3]thiazolo-trans-dehydroandrosterone (6e)
Obtained as pale yellow solid; Yield 85%; m.p. 184–186 °C; Anal.
Calcd. for C42H45NO3S: C, 78.35; H, 7.04; N, 2.18. Found: C, 78.32;
H, 7.09; N, 2.24. 1H NMR ꢀ0.23–(ꢀ0.166) (m, 1H), ꢀ0.03 (m, 3H),
0.36–0.38 (m, 1H), 0.54–0.63 (m, 1H), 0.78 (s, 3H), 0.72–0.90 (m,
3H), 1.07–1.42 (m, 6H), 1.71–1.73 (m, 2H), 1.88–1.93 (m, 1H),
2.05–2.16 (m, 1H), 2.22–2.25 (m, 1H), 2.32 (s, 3H), 2.58 (dd,
J = 13.2, 4.5 Hz, 1H), 2.94 (dd, J = 10.8, 4.2 Hz, 1H), 3.12 (dd,
J = 10.7, 6.5 Hz, 1H), 3.41–3.49 (m, 1H), 3.63 (d, J = 8.7 Hz, 1H),
3.88 (d, J = 8.7 Hz, 2H), 4.73–4.80 (m, 1H), 5.28–5.30 (m, 1H),
7.11–8.13 (m, 10H). 13C NMR 13.3, 19.1, 19.7, 21.0, 28.2, 30.3,
30.4, 31.3, 31.4, 35.1, 36.4, 36.9, 42.1, 46.8, 49.2, 50.2, 51.4, 56.1,
71.4, 71.7, 80.9, 120.8, 121.0, 125.4, 126.3, 127.8, 128.2, 129.2,
129.4, 129.9, 130.5, 131.6, 132.2, 133.4, 134.4, 137.3, 140.5,
140.9, 205.6 and 218.3.
2.2.20. (16R, 50R, 70R, 7a0R)-Spiro[50.200]acenaphthylene-100-one-
spiro[16.60]-70-(2-methoxy-phenyl)-tetrahydro-1H-pyrrolo[1,2-
c][1,3]thiazolo-trans-dehydroandrosterone (6i)
Obtained as pale yellow solid; Yield 80%; m.p.177–179 °C;
Anal. Calcd. for C42H45NO4S: C, 76.45; H, 6.87; N, 2.12. Found:
C, 76.32; H, 6.76; N, 2.01. 1H NMR (ꢀ0.13)–0.18 (m, 2H), 0.35
(s, 3H), 0.52–0.74 (m, 1H), 0.75 (s, 3H), 0.83–0.87 (m, 1H),
0.95–1.14 (m, 4H), 1.26–1.67 (m, 6H), 2.01–2.12 (m, 3H), 2.90–
2.96 (m, 2H), 3.36–3.38 (m, 1H), 3.62–3.70 (m, 5H), 4.47–4.50
(m, 1H), 4.82–4.83 (m, 1H), 5.09–5.10 (m, 1H), 6.82–8.14 (m,
10H). 13C NMR 14.1, 19.1, 19.7, 30.2, 30.5, 31.2, 31.4, 33.7,
36.4, 36.8, 42.0, 46.1, 46.9, 47.7, 48.5, 50.1, 55.1, 71.4, 72.5,
72.8, 78.0, 110.3, 120.7, 120.8, 125.3, 126.3, 127.9, 128.1,
128.4, 130.4, 130.6, 132.0, 132.1, 135.6, 140.6, 142.1, 158.0,
206.6 and 219.5.
2.2.17. (16R, 50R, 70R, 7a0R)-Spiro[50.200]acenaphthylene-100-one-
spiro[16.60]-70-(4-methoxy-phenyl)-tetrahydro-1H-pyrrolo[1,2-
c][1,3]thiazolo-trans-dehydroandrosterone (6f)
Obtained as pale yellow solid; Yield 87%; m.p. 199–201 °C; Anal.
Calcd. for C42H45NO4S: C, 76.45; H, 6.87; N, 2.12. Found: C, 76.51;
H, 6.93; N, 2.18. 1H NMR ꢀ0.22–(ꢀ0.16) (m, 1H), ꢀ0.03 (s, 3H),
0.31–0.40 (m, 1H), 0.57–0.64 (m, 1H), 0.79 (s, 3H), 0.80–0.90 (m,
1H), 1.16–1.24 (m, 4H), 1.28–1.40 (m, 3H), 1.62–1.73 (m, 2H),
1.89–1.94 (m, 2H), 2.12–2.26 (m, 2H), 2.59 (dd, J = 13.2, 4.5 Hz,
1H), 2.94 (dd, J = 10.8, 4.2 Hz, 1H), 3.13 (dd, J = 10.8, 6.6 Hz, 1H),
3.41–3.54 (m, 1H), 3.63 (d, J = 8.7 Hz, 1H), 3.79 (s, 3H), 3.85–3.90
(m, 2H), 4.69–4.76 (m, 1H), 5.27–5.28 (m, 1H), 6.84–8.13 (m,
10H). 13C NMR 13.3, 19.1, 19.7, 28.0, 30.3, 30.5, 31.4, 35.2, 36.4,
36.9, 42.1, 46.8, 49.3, 50.2, 51.5, 55.2, 55.7, 71.4, 71.6, 71.7, 81.0,
113.9, 120.8, 121.0, 125.4, 126.2, 127.8, 128.2, 128.4, 130.5,
131.1, 131.6, 132.0, 132.2, 134.3, 140.5, 140.9, 159.0, 205.6 and
218.3.
2.2.21. (16R, 50R, 70R, 7a0R)-Spiro[50.200]acenaphthylene-100-one-
spiro[16.60]-70-(3-bromophenyl)-tetrahydro-1H-pyrrolo[1,2-
c][1,3]thiazolo-trans-dehydroandrosterone (6j)
Obtained as pale yellow solid; Yield 82%; m.p. 201–203 °C;
FT–IR: 3479, 2920, 2854, 1714, 781. Anal. Calcd. for C41H42-
BrNO3S: C, 69.48; H, 5.97; N, 1.98. Found: C, 69.32; H, 5.89; N,
1.92. 1H NMR ꢀ0.17 (td, J = 12.0, 4.5 Hz, 1H), 0.07 (s, 3H),
0.29–0.34 (m, 1H), 0.49–0.55 (m, 1H), 0.79 (s, 3H), 0.85–0.88
(m, 1H), 1.11–1.26 (m, 5H), 1.35–1.39 (m, 1H), 1.57–1.71 (m,
4H), 1.86–1.90 (m, 1H), 2.11–2.24 (m, 2H), 2.53 (dd, J = 13.2,
4.5 Hz, 1H), 2.93 (dd, J = 10.7, 4.6 Hz, 1H), 3.11 (dd, J = 10.7,
6.1 Hz, 1H), 3.44–3.48 (m, 1H), 3.63 (d, J = 8.1 Hz, 1H), 3.80–
3.86 (m, 2H), 4.72–4.78 (m, 1H), 5.24–5.25 (m, 1H), 7.22–8.15
(m, 10H). 13C NMR 13.6, 19.1, 19.7, 28.7, 30.4, 31.2, 31.3, 34.8,
36.4, 36.8, 42.0, 46.8, 49.1, 50.2, 50.7, 55.7, 71.4, 71.6, 71.8,
80.2, 120.9, 121.0, 122.7, 125.6, 126.2, 127.9, 128.2, 130.1,
130.5, 130.8, 131.5, 132.3, 133.0, 134.3, 139.3, 140.6, 141.1,
205.5 and 218.4.
2.2.18. (16R, 50R, 70R, 7a0R)-Spiro[50.200]acenaphthylene-100-one-
spiro[16.60]-70-(2-chlorophenyl)-tetrahydro-1H-pyrrolo[1,2-
c][1,3]thiazolo-trans-dehydroandrosterone (6g)
Obtained as pale yellow solid; Yield 91%; m.p. 182–184 °C; FT-
IR: 3429, 2931, 2860, 1708, 785. Anal. Calcd. for C41H42ClNO3S: C,
74.13; H, 6.37; N, 2.11. Found: C, 74.18; H, 6.35; N, 2.19. 1H NMR
ꢀ0.12–(ꢀ0.02) (m, 1H), 0.03–0.08 (m, 1H), 0.48 (s, 3H), 0.48–0.56

414
S. Kanchithalaivan et al. / Steroids 78 (2013) 409–417
2.2.22. (16R, 50R, 70R, 7a0R)-Spiro[50.200]acenaphthylene-100-one-
spiro[16.60]-70-naphthyl-tetrahydro-1H-pyrrolo[1,2-c][1,3]thiazolo-
trans-dehydroandrosterone (6k)
Obtained as pale yellow solid; Yield 92%; m.p. 187–189 °C; FT-
IR: 3431, 2929, 2858, 1712, 783. Anal. Calcd. for C45H45NO3S: C,
79.49; H, 6.67; N, 2.06. Found: C, 79.52; H, 6.71; N, 2.18. 1H NMR
ꢀ0.19–(ꢀ0.15) (m, 1H), ꢀ0.09 (s, 3H), 0.04–0.07 (m, 1H), 0.25
(td, J = 13.8, 4.5 Hz 1H), 0.67 (s, 3H), 0.73–0.84 (m, 2H) 0.94–1.09
(m, 4H), 1.28–1.36 (m, 2H), 1.49–1.53 (m, 4H), 2.00–2.16 (m,
2H), 2.33 (dd, J = 13.8, 4.5 Hz, 1H), 2.89 (dd, J = 9.6, 6.0 Hz, 1H),
2.99 (dd, J = 9.6, 6.0 Hz, 1H), 3.33–3.40 (m, 1H), 3.69 (d, 6.9 Hz,
1H), 3.75, (d, 6.9 Hz, 1H), 4.85, (d, J = 9.6 Hz, 1H), 5.04–5.11 (m,
2H), 7.42–8.16 (m, 13H). 13C NMR 14.2, 19.0, 19.6, 30.1, 30.4,
31.0, 31.2, 31.3, 33.9, 36.3, 36.7, 41.9, 47.1, 48.4, 48.8, 50.0, 71.3,
72.8, 73.6, 78.7, 120.6, 120.9, 123.6, 125.5, 125.6, 125.7, 126.3,
126.4, 127.5, 127.7, 128.0, 128.5, 128.7, 130.5, 131.8, 132.3,
132.9, 133.9, 134.0, 135.4, 140.5, 141.9, 206.2 and 218.4.
3. Results and discussion
In the present study, the reaction of trans-androsterone 1 or
trans-dehydroandrosterone 4 with various aromatic aldehydes in
the presence of potassium hydroxide in ethanol at ambient tem-
perature afforded (E)-16-arylmethylidene-trans-androsterones
2a–k and (E)-16-arylmethylidene-trans-dehydroandrosterones
5a–k respectively in quantitative yields (Schemes 1 and 3). A total
of twenty-two of the above steroidal 16-exocyclic olefins were pre-
pared, among which twelve (2h–k, 5c–e and 5g–5k) are new. The
structure of all these dipolarophiles 2 and 5 was elucidated with
the help of NMR spectroscopy and single crystal X-ray crystallo-
graphic studies. As a representative example, in the 1H NMR spec-
trum of 2k,
a singlet at 8.19 ppm can be assigned to the
methylidene proton whereas the naphthyl ring protons appear as
multiplets at 7.47–8.17 ppm. A broad singlet at 5.09 ppm and a
multiplet at 3.52–3.61 ppm are due to the OH and 3-CH protons
respectively. The C-10 and C-13 angular methyl protons appear
Scheme 2. Synthesis of dispiro-trans-androsterones 3.
Yielda,b (%)
Entry Comp
Ar
Yielda,b (%)
Entry Comp
Ar
1
2
5a
5b
5c
5d
5e
5f
C6H5
98 (94)[20]
1
2
C6H5
97 (98)[18]
98 (91)[19]
96 (91)[19]
98 (95)[19]
97 (91)[19]
2a
2b
2c
2d
2e
2f
p-ClC6H4
p-BrC6H4
p-FC6H4
97 (93)[20]
p-ClC6H4
p-BrC6H4
p-FC6H4
p-CH3C6H4
3
96
3
4
98
4
5
p-CH3C6H4
p-CH3OC6H4
o-ClC6H4
o-CH3C6H4
o-CH3OC6H4
m-BrC6H4
Naphthyl
97
5
6
96 (91)[20]
6
p-CH3OC6H4 96 (94)[19]
7
5g
5h
5i
97
98
96
97
97
7
o-ClC6H4
o-CH3C6H4
o-CH3OC6H4
m-BrC6H4
Naphthyl
98 (97)[18]
2g
2h
2i
8
8
97
98
96
96
9
9
10
11
5j
10
2j
5k
11
2k
aYields were quantitative except for the loss during workup
aYields were quantitative except for the loss during workup
bYield given in the parenthesis are literature report
bYield given in the parenthesis are literature report
Scheme 1. Synthesis of 16-(E)-arylidene-trans-androsterones 2. (See above-men-
Scheme 3. Synthesis of 16-(E)-arylidene-trans-dehydroandrosterones 5. (See
tioned references for further information [18,19].)
above-mentioned reference for further information [20].)

S. Kanchithalaivan et al. / Steroids 78 (2013) 409–417
415
TLC, the mixture was poured into water to get the product as pale
yellow solid. The excellent yield of 3 in conjunction with high atom
economy (>91%) renders this protocol efficient and green
(Scheme 2).
The structure of all the dispiro-trans-androsterones 3a–k was
elucidated with the help of 1H, 13C and two-dimensional NMR
spectroscopy as illustrated for an example 3b.
In the 1H NMR spectrum of 3b,
a doublet at 3.83 ppm
(J = 10.2 Hz) can be readily assigned to H-70 on the basis of its mul-
tiplicity. The H-70 shows a C,H-COSY correlation with a carbon sig-
nal at 55.5 ppm assigning it to 70-C. Further, H-70 has a H,H-COSY
Fig. 1. ORTEP diagram of 2k.
correlation with
a triplet of doublets at 4.75 ppm (J = 10.5,
5.4 Hz), which can be assigned to H-7a0. The C,H-COSY correlation
of H-7a0 assigns the carbon signal at 72.0 ppm to 7a0-C. It is evident
from the H,H-COSY correlation of H-7a0 that the doublets of dou-
blets at 2.91 and 3.07 ppm (J = 10.5, 5.1 Hz) accounting for 2 pro-
tons is due to 10-CH2 and from the C,H-COSY spectrum it is clear
that 10-CH2 carbon appears at 34.5 ppm. The two doublets at 3.64
and 3.79 ppm with J = 8.1 Hz which can be assigned to 30-CH2 pro-
tons show (i) C,H-COSY correlation with a carbon signal at
50.0 ppm due to 30-C and (ii) HMBC correlation with one of the
spiro carbons 30-C at 79.8 ppm thereby assigning the carbon signal
at 72.3 to the other spiro carbon 60-C. The H-70 proton shows HMBC
correlations with the C-17 carbonyl carbon at 218.9 ppm and
methylene carbon at 28.1 ppm due to 15-C. The C,H-COSY correla-
tion of the above carbon signal assigns the doublets of doublets at
2.47 ppm (J = 13.4, 4.7 Hz) and the multiplet at 1.01–1.05 ppm to
the 15-CH2 protons. The chemical shifts of the 15-CH2 protons dif-
fer much by 1.44 ppm suggesting that one of the protons of 15-CH2
may presumably lie in the shielding zone of the spiroacenaphthy-
len-1(2H)-one ring shifting it upfield and the other may be proxi-
mate to the carbonyl at C-17 shifting it downfield. The H,H-COSY
correlation of 15-CH2 protons disclose that the multiplet at 0.39–
0.51 ppm is due to H-14 and from the C,H-COSY correlation of H-
14, the signal at 48.8 ppm is assigned to 14-C. The protons of the
two angular methyl groups at C-10 and C-13 appear as singlets
at 0.58 and 0.05 ppm and the carbons appear at 12.0 and
14.1 ppm respectively. The distinct assignments of these two sig-
nals emerge from the fact that the singlet at 0.05 ppm shows a
HMBC correlation with the carbonyl carbon at C-17, whereas the
other singlet does not. Further, the C-13 angular methyl protons
show HMBC correlations with a quaternary carbon at 47.1 ppm
due to C-13 and a methylene carbon at 31.3 ppm which can be as-
signed to C-12. The C-10 angular methyl protons show HMBC cor-
relations with a quaternary carbon at 35.4 ppm due to C-10 and a
methylene carbon at 36.6 ppm due to C-1. The multiplet at 3.46–
3.54 ppm is assigned to 3-CH proton on the basis of substitution.
Further, the C,H-COSY correlation of this signal reveals that the car-
bon signal at 71.0 is due to C-3. Similarly, the 1H and 13C chemical
shift of all the protons and carbons of 3b were assigned unambig-
uously and are shown in Fig. 2. The selected H,H-COSY and HMBC
correlations of 3b are shown in Fig. 3. A more detailed discussion
on the structural elucidation of 3b is given in the supporting
information.
Fig. 2. 1H and 13C chemical shifts of 3b.
as singlets at 1.02 and 0.86 ppm respectively whereas the steroidal
ring protons appear as multiplets at 0.65–2.76 ppm. The structure
of 2k assigned from NMR spectroscopy was further confirmed from
single crystal X-ray studies. The ORTEP diagram of 2k [17] reveals
(E)-configuration for the D-ring 16-exocyclic alkene (Fig. 1).
Initially, the 1,3-dipolar cycloaddition of azomethine ylides
generated in situ from the reaction of 1,3-thiazolane-4-carboxylic
acid and acenaphthylene-1,2-dione to (E)-16-arylmethylidene-
trans-androsterones 2a–k was investigated (Scheme 2). The reac-
tion proceeded stereospecifically affording a single isomer of novel
spiro[50.200]acenaphthylene-100-one-spiro[16.60]-(70-aryl)-tetrahy-
dro-1H-pyrrolo[1,2-c][1,3]thiazolo-trans-androsterones 3a–k in
excellent yields (75–91%). These cycloadditions were effected by
refluxing an equimolar mixture of the reactants in methanol on a
water-bath. After completion of the reaction as evident from the
The structure of 3 elucidated from NMR spectroscopy was fur-
ther confirmed by the single crystal X-ray crystallographic studies.
Fig. 3. Selected H,H-COSY and the HMBC correlations of 3b.

416
S. Kanchithalaivan et al. / Steroids 78 (2013) 409–417
Yielda (%)
Entry Comp
Ar
mp (oC)
192–193
191–192
188–189
180–181
185–186
199–200
183–184
181–182
178–179
203–204
188–189
1
2
C6H5
88
86
89
80
85
87
91
89
80
82
92
6a
6b
6c
6d
6e
6f
p-ClC6H4
p-BrC6H4
p-FC6H4
3
Fig. 4. ORTEP diagram of 3i.
4
5
p-CH3C6H4
p-CH3OC6H4
o-ClC6H4
o-CH3C6H4
o-CH3OC6H4
m-BrC6H4
Naphthyl
6
7
6g
6h
6i
8
9
Fig. 5. The other regioisomer (not formed).
10
6j
11
6k
The ORTEP diagram of 3i [17] shown in Fig. 4 discloses the absolute
configuration of the newly formed chiral centers as 16-R, 50-R, 70-R,
7a0-R. Further, it is evident that H-70 and H-7a0 are in trans
relationship.
aIsolated yields after flash filtration column
Scheme 4. Synthesis of dispiro-trans-dehydroandrosterones 6.
The cycloaddition of azomethine ylide to the dipolarophiles 2a–
k proceeds regioselectively as the electron rich carbon of the 1,3-
dipole is added to the b-carbon, of the dipolarophiles 2 affording
a single regioisomer 3. These observations are in accord with the
polarization of the C@C bond with a more electron-deficient b-car-
bon which could preferentially react with the electron-rich site of
the approaching 1,3-dipole. The regiochemistry of the cycloadduct
is also evident form 1H NMR spectrum of the products. A doublet
and a multiplet are observed in the range of 3.5–5.0 ppm, which
are due to H-70 and H-7a0 respectively. If the other regioisomer 7
was formed (Fig. 5), a singlet would have been expected for H-70
instead of doublet.
Further, the facial selectivity involved in the above reaction
leading to the formation of 3 is explicable from the fact that the
azomethine ylide adds to the dipolarophile preferentially from
the less hindered bottom side of the exocyclic C@C bond of 2.
The angular methyl group at 13th position of 2 presumably hinders
the approach of the dipole from the top side (Fig. 6).
The 1,3-dipolar cycloaddition of azomethine ylide generated
in situ from the reaction of acenaphthylene-1,2-dione and 1,
3-thiazolane-4-carboxylic acid to (E)-16-arylmethylidene-trans-
dehydroandrosterones 5a–k proceeds similar to (E)-16-arylmeth-
ylidene-trans-androsterones
2
affording novel (16R, 50R, 70R,
Fig. 6. Facial selectivity involved in the formation of 3.

S. Kanchithalaivan et al. / Steroids 78 (2013) 409–417
417
7a0R)-spiro[50.200]acenaphthylene-100-one-spiro[16.60]-(70-aryl)-tet-
rahydro-1H-pyrrolo[1,2-c][1,3]thiazolo-trans-dehydroandroster-
ones 6a–k in excellent yields (80–92%) stereospecifically
(Scheme 4). The structure of 6 was elucidated with the help of
one and 2D NMR spectroscopic data and the assignment of proton
and carbon signals of 6 has also been done by straightforward con-
siderations as done for 3. As a representative case, the 1H and 13C
chemical shifts of 6b are shown in the supporting information.
The absolute stereochemistry of the newly formed chiral centers
of 6 was assigned in comparison with 3.
In conclusion, a library of novel 16-spiro trans-androsterone/
trans-dehydroandrosterone hybrid heterocycles 3a–k and 6a–k
were synthesized in excellent yields stereospecifically through
the 1,3-dipolar cycloaddition of azomethine ylides generated from
the decarboxylative condensation of acenaphthylene-1,2-dione
and 1,3-thiazolane-4-carboxylic acid to (E)-16-arylmethylidene-
trans-androsterones 2a–k and (E)-16-arylmethylidene-trans-dehy-
droandrosterones 5a–k respectively. The cytotoxicity, AChE inhibi-
tion studies and anti-TB activity of these novel 16-spiro steroids 3
and 6 are currently underway.
(j) Milic D, Kop T, Csanadi J, Juranic Z, Zizak Z, Gasic MJ, Solaja B. Steroids
2009;74:890–5;
(k) Abdelhalim MM, El-Saidi MMT, Rabie ST, Elmegeed GA. Steroids
2007;72:459–65;
(l) Amr A-GE, Abdulla MM. Bioorg Med Chem 2006;14:4341–52.
[3] Perron F, Albizati KF. Chem Rev 1989;89:1617–61.
[4] Pradhan R, Patra M, Behera AK, Mishra BK, Behera RK. Tetrahedron 2006;
62:779–828.
[5] (a) Anderton N, Cockrum PA, Colegate SM, Edgar JA, Flower K, Vit I, Willing RI.
Phytochemistry 1998;48:437–9;
(b) Kamisaki H, Nanjo T, Tsukano C, Takemoto Y. Chem Eur J 2011;17:626–33;
(c) Reddy VJ, Douglas CJ. Org Lett 2010;12:952–5;
(d) Deppermann N, Thomanek H, Prenzel AHGP, Maison W. J Org Chem
2010;75:5994–6000.
[6] (a) Wang K, Zhou X-Y, Wang Y-Y, Li M-M, Li Y-S, Peng L-Y, Cheng X, Li Y, Wang
Y-P, Zhao Q-S. J Nat Prod 2011;74:12–5;
(b) Viswambharan B, Selvakumar K, Madhavan S, Shanmugam P. Org Lett
2010;12:2108–11;
(c) Chou C-H, Gong C-L, Chao C-C, Lin C-H, Kwan C-Y, Hsieh C-L, Leung Y-M. J
Nat Prod 2009;72:830–4;
(d) Yuan D, Ma B, Wu C, Yang J, Zhang L, Liu S, Wu L, Kano Y. J Nat Prod
2008;71:1271–4.
[7] (a) Allous I, Comesse S, Sanselme M, Daich A. Eur
76:5303–10;
J Org Chem 2011;
(b) Marti C, Carreira EM. J Am Chem Soc 2005;127:11505–15.
[8] (a) Krstic NM, Bjelakovic MS, Pavlovic VD, Robeyns K, Juranic ZD, Matic I,
Novakovic I, Sladic DM. Steroids 2012;77:558–65;
(b) Tietze LF, Schneider C. J Org Chem 1991;56:2479–81;
Acknowledgements
(c) Pelc B. Androstanes (Spiro derivatives). In: Johns WF, editor. International
Reviews of Science Organic Chemistry Series One, vol. 8. London: Butterworth–
Heinemann; 1973. p. 89–90;
RRK thanks the Department of Science and Technology, New
Delhi for the funds under (i) DST-SERC Fast Track scheme no. SR/
FT/CS-073/2009 and (ii) IRHPA programme for providing high res-
olution NMR facility. RRK and SK thank the Sophisticated Analyti-
cal Instrument Facility, Indian Institute of Technology Madras for
single crystal X-ray diffraction studies. SK thanks the University
Grants Commission, New Delhi for the Junior Research Fellowship.
(d) Pelc B. Androstanes (Spiro derivatives). In: Johns WF, editor. International
Reviews
of
Science
Organic
Chemistry
Series
Two,
vol.
8. London: Butterworth–Heinemann; 1976. p. 95;
(e) Ginanneschi M, Chelli M, Papini A, Rapi G. Steroids 1990;55:501–6;
(f) Paryzek Z, Blaszczyk K. Liebigs Ann Chem 1990:665–70.
[9] (a) Solyom S, Szilagyi K, Toldy L. Liebigs Ann Chem 1983:1001–19;
(b) Wiechert R. Angew Chem 1970;9:237–8;
(c) Funder JW, Feldman D, Highland E, Edelman JS. Biochem Pharmacol
1974;23:1493–501.
[10] Tietze LF, Wolfling J, Schneider G, Noltemeyer M. Steroids 1994;59:305–9.
[11] Wolfling J, Penzes PK, Zupko I, Schneider G, Frank E. J Mol Struct 2012;
1013:39–44.
Appendix A. Supplementary data
[12] Mernyak E, Kozma E, Hetenyi A, Mark L, Schneider G, Wolfling J. Steroids
2009;74:520–5.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.steroids.2012.12.
017.
[13] Babu ARS, Raghunathan R. Tetrahedron Lett 2008;49:4618–20.
[14] Ali MA, Ismail R, Choon TS, Suresh Kumar R, Osman H, Arumugam N,
Almansour AI, Elumalai K, Singh A. Bioorg Med Chem 2012;22:508–11.
[15] (a) Uma Maheswari S, Balamurugan K, Perumal S, Yogeeswari P, Sriram D.
Bioorg Med Chem Lett 2010;20:7278–82;
References
(b) Karthikeyan SV, Devi Bala B, Alex Raja VP, Perumal S, Yogeeswari P, Sriram
D. Bioorg Med Chem Lett 2010;20:350–3;
Prasanna P, Balamurugan K, Perumal S, Yogeeswari P, Sriram D. Eur J Med
Chem 2010;45:5653–61;
(d) Suresh Kumar R, Michael Rajesh S, Perumal S, Banerjee D, Yogeeswari P,
Sriram D. Eur J Med Chem 2010;45:411–22;
(e) Ranjith Kumar R, Perumal S, Manju SC, Bhatt P, Yogeeswari P, Sriram D.
Bioorg Med Chem Lett 2009;19:3461–5.
[1] (a) English HF, Santen RJ, Isaacs JT. Prostate 1987;11:229–42;
(b) Arnold JT, Isaacs JT. Endocrinol Relat Cancer 2002;9:61–73;
(c) Bruchovsky N, Lesser B, Van Doorn E, Craven S. Vitam Horm 1975;33:
61–102;
(d) Hua C, Liub H, Duc J, Moa B, Qic H, Wangc X, Ye S, Li Z. J Steroid Biochem
Mol Biol 2009;113:209–16.
[2] (a) Kovacs D, Kadar Z, Motyan G, Schneider G, Wolfling J, Zupko I, Frank E.
Steroids 2012;77:1075–85;
[16] (a) Hu Y, Zou Y, Wu H, Shi D. Ultrason Sonochem 2012;19:264–9;
(b) Prasanna R, Purushothaman S, Raghunathan R. Tetrahedron Lett
2010;51:4538–42.
(b) Huang L-H, Zheng Y-F, Song C-J, Wang Y-G, Xie Z-Y, Lai Y-W, Lu Y-Z, Liu H-
M. Steroids 2012;77:367–74;
[17] Crystallographic data (excluding structure factors) for compounds 2k and 3i
have been deposited with the Cambridge Crystallographic Data Center as
supplementary publication numbers CCDC 907216 and 907215 respectively.
Copies of the data can be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK [fax: +44 (0) 1223 762911 or e-mail:
deposit@ccdc.cam.ac.uk].
[18] Safwat HM, El Gamal MH, Hussein MM, Abdullah MM. Bull Fac Pharm Cairo
Univ 2002;40:47–56.
[19] Guo H, Wu H, Yang J, Xiao Y, Altenbach H-J, Qiu G, Hu H, Wu Z, He X, Zhou D,
Hu X. Steroids 2011;76:709–23.
(c) Iványi Z, Szabó N, Huber J, Wölfling J, Zupkó I, Szécsi M, Wittmann T,
Schneider G. Steroids 2012;77:566–74;
(d) Huang L-H, Zheng Y-F, Lu Y-Z, Song C-J, Wang Y-G, Yu B, Liu H-M. Steroids
2012;77:710–5;
(e) Kadar Z, Molnar J, Schneider G, Zupko I, Frank E. Bioorg Med Chem
2012;20:1396–402;
(f) Dutta M, Gogoi J, Shekarrao K, Goswami J, Gogoi S, Boruah RC. Synthesis
2012:2614–22;
(g) Abdelhalim MM, Kamel EM, Rabie ST, Mohamed NR. Steroids
2011;76:78–84;
(h) Frank E, Molnar J, Zupko I, Kadar Z, Wolfling J. Steroids 2011;75:1141–8;
(i) El-Far M, Elmegeed GA, Eskander EF, Rady HM, Tantawy MA. Eur J Med
Chem 2009;44:3936–46;
[20] Huang L-H, Zheng Y-F, Song C-J, Wang Y-G, Xie Z-Y, Lai Y-W, Lu Y-Z, Liu H-M.
Steroids 2012;77:367–74.