Pd(PPh3)4/AgOAc-catalyzed coupling of 17-steroidal triflates and alkynes: Highly efficient synthesis of D-ring unsaturated 17-alkynylsteroids

Article abstract of DOI:10.1016/j.steroids.2010.05.018

A novel and practical procedure was developed for the preparation of D-ring unsaturated 17-alkynyl steroids by Pd(PPh₃)₄/AgOAc- catalyzed coupling of steroidal 17-triflates and alkynes. Firstly treatment of the steroid-17-ones with PhN(Tf)₂ and KHMDS in dried THF at -78 °C for 2 h gives the corresponding steroidal 17-triflates products in high yields (97-98%), following the coupling of steroidal 17-triflates and various 1-alkynes by Pd(PPh₃)₄/AgOAc-catalyzed in the presence of DIPEA for 24 h to yield the desired D-ring unsaturated 17-alkynyl steroids (86-97%). Moreover, it was found that the coupling reaction catalyzed by Pd[(C₆H₅)₃P]₄/AgOAc system is selective for aryl triflates or vinyl triflates. By optimizing the reaction conditions, the sole C17-coupling products from steroidal bistriflates were obtained in satisfactory yields. Since D-ring unsaturated 17-alkynyl steroids with conjugated double and triplet bond can be subsequently converted into pentacyclic steroids and 17-oxosteroid derivatives at the side chain of D-ring, this general method provides a highly efficient route to these biologically important compounds.

Full text of DOI:10.1016/j.steroids.2010.05.018

Steroids 75 (2010) 936–943
Contents lists available at ScienceDirect
Steroids
journal homepage: www.elsevier.com/locate/steroids
Pd(PPh3)4/AgOAc-catalyzed coupling of 17-steroidal triflates and alkynes:
Highly efficient synthesis of D-ring unsaturated 17-alkynylsteroids
Qian Sun, Chenggang Jiang, Hangxian Xu, Zonglei Zhang, Lanhai Liu, Cunde Wang∗
School of Chemistry and Chemical Engineering, Yangzhou University, Siwangting Road, Yangzhou 225002, Jiangsu, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel and practical procedure was developed for the preparation of D-ring unsaturated 17-alkynyl
steroids by Pd(PPh3)4/AgOAc-catalyzed coupling of steroidal 17-triflates and alkynes. Firstly treatment
of the steroid-17-ones with PhN(Tf)2 and KHMDS in dried THF at −78 ◦C for 2 h gives the corresponding
steroidal 17-triflates products in high yields (97–98%), following the coupling of steroidal 17-triflates and
various 1-alkynes by Pd(PPh3)4/AgOAc-catalyzed in the presence of DIPEA for 24 h to yield the desired
D-ring unsaturated 17-alkynyl steroids (86–97%). Moreover, it was found that the coupling reaction cat-
alyzed by Pd[(C6H5)3P]4/AgOAc system is selective for aryl triflates or vinyl triflates. By optimizing the
reaction conditions, the sole C17-coupling products from steroidal bistriflates were obtained in satisfac-
tory yields. Since D-ring unsaturated 17-alkynyl steroids with conjugated double and triplet bond can
be subsequently converted into pentacyclic steroids and 17-oxosteroid derivatives at the side chain of
D-ring, this general method provides a highly efficient route to these biologically important compounds.
Received 10 April 2010
Received in revised form 19 May 2010
Accepted 22 May 2010
Available online 1 June 2010
Keywords:
Palladium catalyst
Silver acetate
17-Ketosteroid
Steroidal triflate
17-Alkynylsteroid
© 2010 Elsevier Inc. All rights reserved.
1. Introduction
way to alter the functional groups, sizes, and stereochemistry of
the D-ring, and numerous structure–activity relationships have
Steroids are a class of important multi-cyclic compounds
because of their special biological activities. Except for the natu-
rally occurring substances, most of steroidal pharmaceuticals were
semi-synthetic compounds. The development of new compounds
to improve the selectivity and to minimize side effects of steroidal
drugs has been a challenge for a long time [1]. For many years,
the modification of 3-hydroxysteroids has attracted considerable
attention from medicinal and synthetic organic chemists. Vari-
ous derivatives of steroids by modified at 17-postion side chain
with antibacterial, anticancer activity and cytotoxic activity have
been reported [2]. Other examples showed that isoxazoline deriva-
tives of 17-oxoandrostane at the side chain of D-ring can inhibit
Na/K-ATPase [3]. Moreover, some studies found that pentacyclic
steroids obtained by fusion of a carbocyclic ring such as benzene
or cyclohexane or cyclopentane to the steroid nucleus or pen-
tacyclic steroids derived by the fusion of a carbocyclic ring to
a heterosteroid skeleton exhibit interesting and diverse biologi-
cal properties [4]. And it is proved that a number of biologically
important properties of modified steroids are dependent upon
structural features of the steroid D-ring and side chain [5]. Chem-
ical modification of the steroid D-ring and side chain provides a
been established by such synthetic alterations. As an example
on the modification of steroidal 17-postion side chain, 3␣,5␣-
17-phenylandrost-16-en-3-ol is a neurosteroid antagonist [6].
3␣,5␣-17-Phenylandrost-16-en-3-ol antagonizes selectively the
GABA-modulatory and GABA-mimetic effects of 3␣,5␣-THPROG
and related 5␣-pregnane steroids [6,7].
In our recent research, several analogues of steroidal-ynenes
(Fig. 1) have been designed as key precursors for the preparation
of 23-substituted corticosteroids and for the synthesis of a series
of pentacyclic steroids fused with benzene, pyridine, furan and
oxirane. In particular, methods for the preparation of the noncom-
mercially available and modified 17-side chain and D-ring steroids
have received considerable attention. Among of reported methods,
the two main routes were described that steroidal alkenyl iodides
(17-iodo-androsta-16-ene and 17-iodo-4-methyl-4-aza-androsta-
16-ene-3-one) were reacted with conjugated unsaturated esters in
Heck reaction and 17-carbonyl group of steroids was reacted with
organolithium, organomagnesium, organotin or 1-alkynes under
a strong base condition in nucleophile addition [6,8]. However, a
major drawback to this otherwise efficient synthetic approach to
modified 17-side chain and D-ring steroids has been the relatively
poor yields obtained. Thus, to overcome the low yields associated
with Heck reaction and addition reaction of steroid 17-carbonyl we
undertook this study. We report here coupling reaction conditions
that accomplish this goal.
∗
Corresponding author. Tel.: +86 514 8797 5568; fax: +86 514 8797 5244.
E-mail addresses: wangcd@yzu.edu.cn, cundeyz@hotmail.com (C. Wang).
0039-128X/$ – see front matter © 2010 Elsevier Inc. All rights reserved.
doi:10.1016/j.steroids.2010.05.018

Q. Sun et al. / Steroids 75 (2010) 936–943
937
2.2.1.3. (3R,5S,8R,9S,10S,13S,14S)-3-(Methoxymethoxy)-10,13-
dimethyl-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetradecahydro-1H-
cyclopenta[a]phenanthren-17-yl trifluoromethanesulfonate (2c).
Following the general procedure, the title compound 2c was
obtained as a white solid; mp 48–50 ◦C (hexanes); 97% in yield;
[˛]D20 = +15.82◦ (c = 0.158, CHCl3); 1H NMR (300 MHz, CDCl3) 5.56
(m, 1H), 4.66 (m, 2H), 3.83 (m, 1H), 3.37 (s, 3H), 2.20 (m, 1H),
1.95 (m, 1H), 0.96 (s, 3H), 0.82 (s, 3H); 13C NMR (75 MHz, CDCl3):
159.56, 118.73 (q, J = 319 Hz), 114.51, 94.72, 71.65, 55.22, 54.89,
54.50, 45.01, 40.06, 36.22, 33.76, 33.62, 32.88, 32.73, 30.89, 28.62,
28.40, 26.43, 20.22, 15.38, 11.42; IR (KBr): 3081, 1628, 1423, 1142,
1050, 601 cm−1; Anal. Calcd. for C22H33F3O5S: C, 56.64; H, 7.13;
Found C, 56.34; H, 7.00.
Fig. 1. Structures of 17-alkynylsteroids and their derivatives.
2. Experimental
2.2.2. General procedure for the coupling reaction from triflates
and 1-alkynes
2.1. General remarks
To the mixture of compound 2a–c (0.5 mmol), AgOAc
(17 mg, 0.10 mmol), Pd[(C6H5)3P]4 (30 mg, 0.026 mmol) and DIPEA
(200 mg, 1.55 mmol) in DMF (8 mL) was added 1-alkyne (0.6 mmol)
by syringe at room temperature under nitrogen. The resultant mix-
ture was stirred under nitrogen at room temperature for 30 min.
After the mixture was diluted with DCM (15 mL) and the solid
was removed by filtered, the residue was purified by flash chro-
matography (silica gel, EtOAc/hexanes, 1/10–1/4) to give product
3aa–ce.
All melting points were determined on a Yanaco melting point
apparatus and are uncorrected. IR spectra were recorded on a Nico-
let FT-IR 5DX spectrometer as KBr pellets. The 1H NMR and 13C
NMR spectra were recorded on a Bruker ACF-300 spectrometer
with TMS as internal reference. The J values are given in hertz. Opti-
cal rotations were determined on a Perkin-Elmer 343 polarimeter.
The elemental analyses were performed on a Perkin-Elmer 240C
instrument.
2.2. Organic synthesis
2.2.2.1. 4-((8S,9S,13S,14S)-3-Methoxy-13-methyl-
7,8,9,11,12,13,14,15-octahydro-6H-cyclopenta[a]phenanthren-
17-yl)but-3-yn-1-ol (3aa). Following the general procedure, the
title compound 3aa was obtained as a white solid, 97% in yield,
mp 56–58 ◦C (hexanes); [˛]D20 = +46.04◦ (c = 0.202, CHCl3); 1H
NMR (300 MHz, CDCl3): 7.19 (d, J = 8.4 Hz, 1H), 6.72 (m, 1H), 6.64
(m, 1H), 5.97 (m, 1H), 3.77 (s, 3H), 3.75 (t, J = 6.3 Hz, 2H), 2.87 (m,
2H), 2.64 (t, J = 6.3 Hz, 2H), 0.85 (s, 3H); 13C NMR (75 MHz, CDCl3):
157.66, 138.02, 137.61, 134.93, 132.97, 126.17, 114.04, 111.60,
89.74, 78.14, 61.43, 55.57, 55.34, 48.25, 44.49, 37.74, 34.81, 31.83,
29.86, 27.93, 26.66, 24.17, 16.36; IR (film, cm−1): 3391, 3050, 2977,
2246, 1608, 1576, 1499, 1048, 813, 730; Anal. Calcd. for C23H28O2:
C, 82.10; H, 8.39; Found C, 82.16; H, 8.27.
2.2.1. General procedure for the synthesis of triflates 2a–c from
steroid-17-ones 1a–c
To a mixture of steroid-17-ones (1a–c) (0.5 mmol) and PhN(Tf)2
(268 mg, 0.75 mmol) in dried THF (15 mL) was added KHMDS (0.5 M
in toluene, 3 mL, 1.5 mmol) at −78 ◦C and the resultant mixture
was stirred at the same temperature for 2 h. After the reaction was
quenched by adding sat. NH4Cl (aq), the mixture was extracted
with DCM (2× 15 mL), the organic phase was washed with water
and brine, dried over Na2SO4. Removal of solvent, the residue was
purified by flash chromatography (silica gel, EtOAc/hexanes, 1/20)
to give product 2a–c.
2.2.1.1. (8R,9S,13S,14S)-3-Methoxy-13-methyl-
2.2.2.2. 4-((8S,9S,13S,14S)-3-Methoxy-13-methyl-
7,8,9,11,12,13,14,15-octahydro-6H-cyclopenta[a]phenanthren-17-yl
trifluoromethanesulfonate (2a). Following the general procedure,
the title compound 2a (98%) was obtained as an oil; [˛]D20 = +67.00◦
(c = 0.784, CHCl3); 1H NMR (300 MHz, CDCl3) 7.09 (m, 1H), 6.65 (m,
1H), 6.57 (m, 1H), 5.54 (m, 1H), 3.69 (s, 3H), 2.80 (m, 2H), 2.32 (m,
3H), 2.01 (m, 1H), 0.92 (s, 3H); 13C NMR (75 MHz, CDCl3): 159.55,
157.88, 137.82, 132.33, 126.11, 118.88 (q, J = 319 Hz), 114.65,
114.15, 111.7, 55.33, 53.79, 45.28, 44.40, 36.93, 32.95, 29.61, 28.54,
26.93, 26.02, 15.50; IR (KBr): 3082, 1630, 1601, 1499, 1408, 1143,
1040, 684 cm−1; Anal. Calcd. for C20H23F3O4S: C, 57.68; H, 5.57;
Found C, 57.56; H, 5.27.
7,8,9,11,12,13,14,15-octahydro-6H-cyclopenta[a]phenanthren-
17-yl)but-3-yn-2-ol (3ab). Following the general procedure, the
title compound 3ab was obtained as a white solid, 97% in yield;
mp 110–112 ◦C (hexanes); [˛]D20 = +45.41◦ (c = 0.540, CHCl3); 1H
NMR (300 MHz, CDCl3): 7.19 (d, J = 8.4 Hz, 1H), 6.72 (m, 1H), 6.64
(m, 1H), 6.04 (m, 1H), 4.70 (m, 1H), 3.77 (s, 3H), 2.87 (m, 2H), 1.50
(d, J = 6.6 Hz, 3H), 0.86 (s, 3H); 13C NMR (75 MHz, CDCl3): 157.67,
138.02, 137.00, 136.09, 132.95, 126.18, 114.07, 111.63, 94.81,
79.67, 59.09, 55.62, 55.36, 48.36, 44.51, 37.74, 34.73, 31.97, 29.86,
27.94, 26.64, 24.80, 16.36; IR (film, cm−1): 3391, 3050, 2977, 2211,
1609, 1576, 1499, 815; Anal. Calcd. for C23H28O2: C, 82.10; H, 8.39;
Found C, 82.02; H, 8.18.
2.2.1.2. (3S,8R,9S,10R,13S,14S)-3-(Methoxymethoxy)-10,13-
dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-
cyclopenta[a]phenanthren-17-yl trifluoromethanesulfonate (2b).
Following the general procedure, the title compound 2b was
obtained as a white solid, mp 70–72 ◦C (hexanes); 98% in yield;
[˛]D20 = −43.55◦ (c = 0.671, CHCl3); 1H NMR (CDCl3) 5.58 (m, 1H),
5.36 (d, J = 5.1 Hz, 1H), 4.70 (s, 2H), 3.43 (m, 1H), 3.38 (s, 3H), 1.04
(s, 3H), 0.99 (s, 3H); 13C NMR (75 MHz, CDCl3): 159.40, 141.32,
121.02, 118.85(q, J = 327 Hz), 114.63, 94.83, 76.98, 55.28, 54.45,
50.66, 44.80, 39.65, 37.22, 37.06, 32.84, 30.70, 30.09, 28.95, 28.72,
20.27, 19.33, 15.21; IR (KBr, cm−1): 3085, 1629, 1599, 1496, 1421,
1143, 1043, 603 cm−1; Anal. Calcd. for C22H31F3O5S: C, 56.88; H,
6.73; Found C, 57.00; H, 6.64.
2.2.2.3. 4-((8S,9S,13S,14S)-3-Methoxy-13-methyl-
7,8,9,11,12,13,14,15-octahydro-6H-cyclopenta[a]phenanthren-17-
yl)-2-methylbut-3-yn-2-ol (3ac). Following the general procedure,
the title compound 3ac was obtained as a white solid, 96% in yield;
mp 118–119 ◦C (hexanes); [˛]D20 = +53.55◦ (c = 0.310, CHCl3); 1H
NMR (300 MHz, CDCl3): 7.19 (d, J = 8.7 Hz, 1H), 6.72 (m, 1H), 6.64
(m, 1H), 6.01 (m, 1H), 3.77 (s, 3H), 2.88 (m, 2H), 1.57 (s, 6H), 0.86
(s, 3H); 13C NMR (75 MHz, CDCl3): 157.71, 138.07, 137.13, 135.56,
133.00, 126.21, 114.10, 111.66, 97.78, 77.73, 65.86, 55.63, 55.39,
48.39, 44.55, 37.78, 34.76, 31.98, 31.88(2C), 29.89, 27.99, 26.69,
16.38; IR (film, cm−1): 3233, 3051, 2981, 2214, 1611, 1574, 1495,

938
Q. Sun et al. / Steroids 75 (2010) 936–943
1257, 813; Anal. Calcd. for C24H30O2: C, 82.24; H, 8.63; Found C,
82.09; H, 8.48.
(300 MHz, CDCl3): 6.00 (m, 1H), 5.36 (d, J = 5.1 Hz, 1H), 4.70 (m,
3H), 3.39 (m, 1H), 3.37 (s, 3H), 1.49 (d, J = 6.6 Hz, 3H), 1.05 (s, 3H),
0.86 (s, 3H); 13C NMR (75 MHz, CDCl3): 141.32, 136.82, 136.15,
121.46, 94.85, 79.61, 77.11, 58.97, 56.37, 55.33, 50.83, 47.95, 39.75,
37.34, 37.14, 34.64, 32.26, 31.74, 30.84, 29.07, 24.80, 20.92, 19.44,
16.12; IR (film, cm−1): 3433, 3049, 2246, 1667, 1590, 1452, 1036,
733; Anal. Calcd. for C25H36O3: C, 78.08; H, 9.44; Found C, 78.02;
H, 9.18.
2.2.2.4. (8S,9S,13S,14S)-3-methoxy-13-methyl-17-(4-
methylpent-1-ynyl)-7,8,9,11,12,13,14,15-octahydro-6H-
cyclopenta[a]phenanthrene (3ad). Following the general procedure,
the title compound 3ad was obtained as a white solid, 95% in yield,
mp 95–96 ◦C (hexanes); [˛]D20 = +49.38◦ (c = 0.282, CHCl3); 1H
NMR (300 MHz, CDCl3): 7.19 (d, J = 8.4 Hz, 1H), 6.72 (m, 1H), 6.64
(m, 1H), 5.92 (m, 1H), 3.77 (s, 3H), 2.88 (m, 2H), 2.26 (d, J = 6.3 Hz,
2H), 1.00 (d, J = 6.6 Hz, 6H), 0.86 (s, 3H); 13C NMR (75 MHz, CDCl3):
157.69, 138.28, 138.10, 133.51, 133.10, 126.21, 114.07, 111.63,
92.82, 77.05, 55.60, 55. 36, 48.35, 44.58, 37.82, 34.93, 31.80, 29.93,
28.96, 28.45, 27.99, 26.76, 22.16(2C), 16.41; IR (film, cm−1): 3051,
2956, 2215, 1608, 1579, 1500, 1239, 814 cm−1; Anal. Calcd. for
2.2.2.9. 4-((3S,8R,9S,10R,13S,14S)-3-(Methoxymethoxy)-
10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-
cyclopenta[a]phenanthren-17-yl)-2-methylbut-3-yn-2-ol
(3bc).
Following the general procedure, the title compound 3bc was
obtained as needles, mp 115–117 ◦C (hexanes), 97% in yield,
[˛]D20 = −46.86◦ (c = 0.406, CHCl3); 1H NMR (300 MHz, CDCl3):
5.96 (s, 1H), 5.36 (d, J = 5.1 Hz, 1H), 4.69 (s, 2H), 3.42 (m, 1H), 3.37
(s, 3H), 1.55 (s, 6H), 1.05 (s, 3H), 0.85 (s, 3H); 13C NMR (75 MHz,
CDCl3): 141.32, 136.91, 135.58, 121.46, 97.72, 94.85, 77.66, 77.09,
65.71, 56.37, 55.31, 50.86, 47.95, 39.75, 37.34, 37.14, 34.62, 32.23,
31.85 (2C), 31.74, 30.86, 29.08, 20.92, 19.44, 16.11; IR (film, cm−1):
3434, 3049, 2245, 1667, 1591, 1452, 1437, 1370, 1149, 1105, 1037,
733; Anal. Calcd. for C26H38O3: C, 78.35; H, 9.61; Found C, 78.20;
H, 9.41.
C25H32O: C, 86.15; H, 9.25; Found C, 86.19; H, 9.16.
2.2.2.5. (8S,9S,13S,14S)-3-methoxy-17-((4-
methoxyphenyl)ethynyl)-13-methyl-7,8,9,11,12,13,14,15-octahydro-
6H-cyclopenta[a]phenanthrene (3ae). Following the general
procedure, the title compound 3ae was obtained as a white solid,
86% in yield, mp 101–103 ◦C (hexanes); [˛]D20 = +24.61◦ (c = 1.633,
CHCl3); 1H NMR (300 MHz, CDCl3): 7.39 (d, J = 8.7 Hz, 2H), 7.21 (d,
J = 8.7 Hz, 1H), 6.84 (d, J = 8.7 Hz, 2H), 6.73 (m, 1H), 6.65 (m, 1H),
6.08 (m, 1H), 3.80 (s, 3H), 3.77 (s, 3H), 2.88 (m, 2H), 0.93 (s, 3H);
13C NMR (75 MHz, CDCl3): 159.39, 157.49, 137.85, 137.64, 134.74,
132.96(2C), 132.83, 126.00, 115.84, 113.90(2C), 113.85, 111.41,
92.83, 83.63, 55.46, 55.23, 55.14, 48.40, 44.34, 37.60, 34.68, 31.87,
29.69, 27.78, 26.52, 16.33; IR (film, cm−1): 3047, 2994, 2195, 1608,
1580, 1507, 1287, 1247, 1034, 831; Anal. Calcd. for C28H30O2: C,
84.36; H, 7.59; Found C, 84.20; H, 7.43.
2.2.2.10. (3S,8R,9S,10S,13S,14S)-3-(Methoxymethoxy)-10,13-
dimethyl-17-(4-methylpent-1-ynyl)-2,3,4,7,8,9,10,11,12,13,14,15-
dodecahydro-1H-cyclopenta[a]phenanthrene (3bd). Following the
general procedure, the title compound 3bd was obtained as
needles, mp 103–105 ◦C (hexanes), 96% in yield, [˛]D20 = −41.95◦
(c = 0.677, CHCl3); 1H NMR (300 MHz, CDCl3): 5.88 (s, 1H), 5.36
(d, J = 4.8 Hz, 1H), 4.69 (s, 2H), 3.42 (m, 1H), 3.37 (s, 3H), 2.24 (d,
J = 6.6 Hz, 2H), 1.05 (s, 3H), 0.99 (d, J = 6.6 Hz, 6H), 0.86 (s, 3H);
13C NMR (75 MHz, CDCl3): 141.30, 138.04, 133.59, 121.55, 94.90,
92.65, 77.09 (2C), 56.34, 55.30, 50.91, 47.92, 39.78, 37.37, 37.16,
34.79, 32.07, 31.77, 30.89, 29.11, 28.90, 28.40, 22.12 (2C), 20.99,
19.46, 16.14; IR (film, cm−1): 3046, 2245, 1632, 1589, 1451, 1437,
1368, 1146, 1103, 1041; Anal. Calcd. for C27H40O2: C, 81.77; H,
10.17; Found C, 81.59; H, 10.40.
2.2.2.6. 1-(((8S,9S,13S,14S)-3-Methoxy-13-methyl-
7,8,9,11,12,13,14,15-octahydro-6H-cyclopenta[a]phenanthren-17-
yl) ethynyl)cyclohexanol (3af). Following the general procedure,
the title compound 3af was obtained as a white solid, 92% in yield;
mp 144–146 ◦C (hexanes); [˛]D20 = +36.88◦ (c = 0.892, CHCl3); 1H
NMR (300 MHz, CDCl3): 7.20 (d, J = 8.7 Hz, 1H), 6.73 (m, 1H), 6.64
(m, 1H), 6.01 (m, 1H), 3.78 (s, 3H), 2.88 (m, 2H), 0.87 (s, 3H); 13C
NMR (75 MHz, CDCl3): 157.74, 138.11, 137.21, 135.37, 133.03,
126.23, 114.13, 111.69, 97.58, 80.16, 69.52, 55.65, 55.42, 48.51,
44.60, 40.48 (2C), 37.80, 34.90, 32.01, 29.93, 28.00, 26.75, 25.47,
23.82 (2C), 16.49; IR (film, cm−1): 3282, 3050, 2998, 2214, 1611,
1574, 1496, 1257, 1071, 815; Anal. Calcd. for C27H34O2: C, 83.03;
H, 8.77; Found C, 82.89; H, 8.58.
2.2.2.11. (3S,8R,9S,10R,13S,14S)-3-(Methoxymethoxy)-
17-((4-methoxyphenyl)ethynyl)-10,13-dimethyl-
2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-
cyclopenta[a]phenanthrene (3be). Following the general procedure,
the title compound 3be was obtained as needles, 97% in yield, mp
130–132 ◦C (hexanes); [˛]D20 = −17.73◦ (c = 0.615, CHCl3); 1H NMR
(300 MHz, CDCl3): 7.37 (d, J = 8.4 Hz, 2H), 6.83 (d, J = 9.0 Hz, 2H),
6.05 (s, 1H), 5.37 (d, J = 4.5 Hz, 1H), 4.69 (s, 2H), 3.80 (s, 3H), 3.43
(m, 1H), 3.37 (s, 3H), 1.06 (s, 3H), 0.92 (s, 3H); 13C NMR (75 MHz,
CDCl3): 159.58, 141.35, 137.63, 135.11, 133.15(2C), 121.54, 116.07,
114.08(2C), 94.91, 92.94, 83.89, 77.11, 56.44, 55.43, 55.34, 50.90,
48.22, 39.80, 37.37, 37.19, 34.81, 32.41, 31.79, 30.94, 29.13, 21.01,
19.48, 16.32; IR (film): 3047, 2192, 1665, 1607, 1508, 1440, 1248,
1038, 830; Anal. Calcd. for C30H38O3: C, 80.68; H, 8.58; Found C,
80.54; H, 8.42.
2.2.2.7. 4-((3S,8R,9S,10R,13S,14S)-3-(Methoxymethoxy)-
10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-
cyclopenta[a]phenanthren-17-yl)but-3-yn-1-ol
(3ba). Following
the general procedure, the title compound 3ba was obtained as
needles, 96% in yield, mp 105–107 ◦C (hexanes); [˛]D20 = −48.18◦
(c = 0.343, CHCl3); 1H NMR (300 MHz, CDCl3): 6.95 (s, 1H), 5.36 (d,
J = 4.8 Hz, 1H), 4.69 (s, 2H), 3.73 (m, 2H), 3.42 (m, 1H), 3.37 (s, 3H),
2.63 (t, J = 6.3 Hz, 2H), 1.05 (s, 3H), 0.85 (s, 3H); 13C NMR (75 MHz,
CDCl3): 141.32, 137.41, 135.03, 121.49, 94.88, 89.65, 78.16, 77.09,
61.41, 56.36, 55.31, 50.86, 47.87, 39.75, 37.34, 37.16, 34.71, 32.13,
31.74, 30.86, 29.08, 24.18, 20.93, 19.44, 16.14; IR (film, cm−1):
3392, 3040, 2245, 1667, 1589, 1461, 1449, 1440, 1147, 1101, 1042,
730; Anal. Calcd. for C25H36O3: C, 78.08; H, 9.44; Found C, 78.22;
H, 9.35.
2.2.2.12. 1-(((3S,8R,9S,10S,13S,14S)-3-(Methoxymethoxy)-
10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-
cyclopenta[a]phenanthren-17-yl)ethynyl)cyclohexanol
(3bf).
Following the general procedure, the title compound 3bf was
obtained as needles, mp 139–140 ◦C (hexanes); 96% in yield,
[˛]D20 = −39.82◦ (c = 0.445, CHCl3); 1H NMR (300 MHz, CDCl3):
5.97 (m, 1H), 5.36 (d, J = 5.1 Hz, 1H), 4.69 (s, 2H), 3.43 (m, 1H),
3.37 (s, 3H), 1.05 (s, 3H), 0.86 (s, 3H); 13C NMR (75 MHz, CDCl3):
141.35, 137.00, 135.35, 121.51, 96.51, 94.88, 80.11, 77.11, 69.38,
56.39, 55.34, 50.91, 48.09, 40.44 (2C), 39.78, 37.37, 37.17, 34.76,
32.26, 31.75, 30.87, 29.11, 25.44, 23.77 (2C), 20.99, 19.48, 16.20;
2.2.2.8. 4-((3S,8R,9S,10R,13S,14S)-3-(Methoxymethoxy)-
10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-
cyclopenta[a]phenanthren-17-yl)but-3-yn-2-ol
(3bb). Following
the general procedure, the title compound 3bb was obtained as
an oil, 94% in yield, [˛]D20 = −42.60◦ (c = 1.22, CHCl3); 1H NMR

Q. Sun et al. / Steroids 75 (2010) 936–943
939
IR (film, cm−1): 3434, 3049, 2209, 1666, 1591, 1462, 1445, 1370,
1148, 1105, 1037, 731; Anal. Calcd. for C29H42O3: C, 79.41; H, 9.65;
Found C, 79.22; H, 9.44.
was purified by flash chromatography (silica gel, CH2Cl2/hexanes,
1/5) to give product 6a–e.
2.2.3.1. (8S,9S,13S,14S)-17-(3-Hydroxybut-1-yn-1-yl)-13-methyl-
7,8,9,11,12,13,14,15-octahydro-6H-cyclopenta[a]phenanthren-3-yl
trifluoromethanesulfonate (6a). Following the general proce-
dure, the title compound 6a was obtained as an oil; 94% in
yield; [˛]D20 = +29.29◦ (c = 1.81, CHCl3); 1H NMR (CDCl3) 7.33 (d,
J = 8.7 Hz, 1H), 7.03 (m, 2H), 6.04 (s, 1H), 4.71 (m, 1H), 2.91 (m,
2H), 1.50 (d, J = 6.6 Hz, 3H), 0.87 (s, 3H); 13C NMR (75 MHz, CDCl3):
147.46, 140.90, 139.36, 136.58, 135.79, 126.83, 121.08, 118.74
(q, J = 318.75 Hz), 118.08, 94.73, 79.23, 58.85, 55.28, 47.98, 44.37,
36.85, 34.38, 31.69, 29.34, 27.23, 26.14, 24.56, 16.06; IR (film):
3367, 3055, 1605, 1490, 1420, 1214, 1142, 917 cm−1; Anal. Calcd.
for C23H25F3O4S: C, 60.78; H, 5.54; Found C, 60.50; H, 5.60.
2.2.2.13. 4-((3R,5S,8R,9S,10S,13S,14S)-3-(Methoxymethoxy)-10,13-
dimethyl-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetradecahydro-1H-
cyclopenta[a]phenanthren-17-yl)but-3-yn-2-ol
(3cb). Following
the general procedure, the title compound 3cb was obtained as
an oil; 98% in yield, [˛]D20 = +37.10◦ (c = 0.593, CHCl3); 1H NMR
(300 MHz, CDCl3) 5.99 (m, 1H), 4.66 (m, 3H), 3.83 (m, 1H), 3.37
(s, 3H), 2.22–2.12 (m, 1H), 2.09 (d, J = 5.1 Hz, 1H), 2.00–1.90 (m,
1H), 1.48 (d, J = 5.1 Hz, 3H), 0.82 (s, 6H); 13C NMR (75 MHz, CDCl3):
137.00, 136.29, 94.75(2C), 79.83, 71.86, 59.08, 56.45, 55.33, 55.08,
48.21, 40.16, 36.32, 34.78, 34.52, 33.86, 32.91, 32.19, 32.06, 28.72,
26.56, 24.83, 20.84, 16.38, 11.57; IR (film, cm−1): 3429, 3050, 2213,
1590, 1446, 1095, 1040 cm−1; Anal. Calcd. for C25H38O3: C, 77.68;
H, 9.91; Found C, 77.54; H, 10.02.
2.2.3.2. (8S,9S,13S,14S)-17-(3-Hydroxy-3-methylbut-1-
yn-1-yl)-13-methyl-7,8,9,11,12,13,14,15-octahydro-6H-
cyclopenta[a]phenanthren-3-yl
trifluoromethanesulfonate
(6b).
2.2.2.14. (3R,5S,8R,9S,10S,13S,14S)-3-(Methoxymethoxy)-
Following the general procedure, the title compound 6b was
obtained as an oil; 96% in yield; [˛]D20 = +28.87◦ (c = 1.16, CHCl3);
1H NMR (CDCl3) 7.33 (d, J = 8.7 Hz, 1H), 7.04 (m, 2H), 6.01 (dd,
J = 3.0, 1.8 Hz, 1H), 2.92 (m, 2H), 2.22 (s, 1H), 1.58 (s, 6H), 0.87 (s,
3H); 13C NMR (75 MHz, CDCl3): 147.45, 140.90, 139.36, 136.64,
135.21, 126.82, 121.06, 118.74 (q, J = 318.75 Hz), 118.06, 97.64,
77.24, 65.59, 55.25, 47.95, 44.38, 36.85, 34.35, 31.65, 31.57 (2C),
29.32, 27.21, 26.12, 16.03; IR (film): 3368, 3054, 1606, 1490, 1423,
1212, 1142, 918 cm−1; Anal. Calcd. for C24H27F3O4S: C, 61.52; H,
5.81; Found C, 61.48; H, 5.66.
17-((4-methoxyphenyl)ethynyl)
2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetradecahydro-1H-
-10,13-dimethyl-
cyclopenta[a]phenanthrene (3ce). Following the general procedure,
the title compound 3ce was obtained as a white solid, mp
118–120 ◦C (hexanes), 96% in yield, [˛]D20 = +77.93◦ (c = 0.415,
CHCl3); 1H NMR (300 MHz, CDCl3) 7.36 (d, J = 9.0 Hz, 2H), 6.81 (d,
J = 9.0 Hz, 2H), 6.02 (t, J = 2.4 Hz, 1H), 4.65 (m, 3H), 3.83 (s, 1H), 3.79
(s, 3H), 3.36 (s, 3H), 2.20–2.17 (m, 1H), 0.89 (s, 3H), 0.83 (s, 3H);
13C NMR (75 MHz, CDCl3): 159.51, 137.78, 135.10, 133.10 (2C),
116.12, 114.05 (2C), 94.73, 92.83, 83.97, 71.80, 56.45, 55.39, 55.27,
55.08, 48.41, 40.13, 36.29, 34.88, 34.55, 33.85, 32.88, 32.27, 32.04,
28.72, 26.55, 20.89, 16.52, 11.54; IR (film, cm−1): 3049, 2248, 1608,
1577, 1508, 1447, 1032, 834, 734 cm−1; Anal. Calcd. for C30H40O3:
C, 80.31; H, 8.99; Found C, 80.16; H, 9.22.
2.2.3.3. (8S,9S,13S,14S)-17-((4-Methoxyphenyl)ethynyl)-13-methyl-
7,8,9,11,12,13,14,15-octahydro-6H-cyclopenta[a]phenanthren-3-yl
trifluoromethanesulfonate (6c). Following the general procedure,
the title compound 6c was obtained as an oil; 93% in yields;
[˛]D20 = +2.88◦ (c = 3.06, CHCl3); 1H NMR (CDCl3) 7.39 (dm,
J = 9.0 Hz, 2H), 7.33 (d, J = 8.7 Hz, 1H), 7.04 (m, 2H), 6.84 (dm,
J = 9.0 Hz, 2H), 6.07 (dd, J = 3.0, 1.8 Hz, 1H), 3.80 (s, 3H), 2.92 (m,
2H), 2.41–2.29 (m, 3H), 2.17–1.94 (m, 3H), 1.69–1.63 (m, 4H),
1.62–1.46 (m, 1H), 0.93 (s, 3H); 13C NMR (75 MHz, CDCl3): 159.44,
147.48, 141.02, 139.42, 137.43, 134.65, 132.69 (2C), 126.88, 121.08,
118.74 (q, J = 318.75 Hz), 118.07, 115.68, 113.90 (2C), 92.98, 83.44,
55.34, 55.20, 48.22, 44.41, 36.93, 34.55, 31.83, 29.38, 27.26, 26.23,
16.25; IR (film): 1607, 1585, 1568, 1508, 1489, 1422, 1212, 1141,
921 cm−1; Anal. Calcd. for C28H27F3O4S: C, 65.10; H, 5.27; Found
C, 64.88; H, 5.12.
2.2.2.15. (8R,9S,13S,14S)-13-Methyl-7,8,9,11,12,13,14,15-
octahydro-6H-cyclopenta[a]phenanthrene-3,17-diyl
bis(trifluoromethanesulfonate)
(5). To
a
mixture
of
3-
hydroxyestrone (1.00 g, 3.7 mmol), triethylamine (1.125 g,
4
11.1 mmol) and catalyst DMAP (80 mg) in dichloromethylene
(15 mL) was added trifluoromethanesulfonic anhydride (3.13 g,
11.1 mmol) dropwise at 0 ◦C under nitrogen. Then the mixture
was stirred for 10 h from 0 ◦C up to room temperature. After
water (10 mL) was added to the reaction mixture, the mixture
was extracted with methylene chloride (DCM, 2× 20 mL) and
the organic phase was washed with water and brine, dried over
Na2SO4. Removal of solvent, the residue was purified by flash
chromatography (silica gel, DCM/hexanes, 1/1.5) to give product 5
(1.67 g, 86%) as an oil; [˛]D20 = +50.00◦ (c = 1.55, CHCl3); 1H NMR
(CDCl3) 7.32 (d, J = 8.7 Hz, 1H), 7.04 (m, 2H), 2.94 (dd, J = 4.5 Hz,
2H), 1.02 (s, 3H); 13C NMR (75 MHz, CDCl3): 159.04, 147.61,
140.34, 139.20, 126.77, 121.19, 118.74 (q, J = 318.75 Hz), 118.59
(q, J = 318.75 Hz), 118.23, 114.51, 53.47, 44.93, 44.24, 36.08, 32.62,
29.10, 28.26, 26.21, 25.51, 15.18; IR (film): 1629, 1606, 1490, 1422,
1210, 1142, 921 cm−1; Anal. Calcd. for C20H20F6O6S2: C, 44.94; H,
3.77; Found C, 44.68; H, 3.62.
2.2.3.4. (8S,9S,13S,14S)-17-((1-Hydroxycyclohexyl)ethynyl)-
13-methyl-7,8,9,11,12,13,14,15-octahydro-6H-
cyclopenta[a]phenanthren-3-yl
trifluoromethanesulfonate
(6d).
Following the general procedure, the title compound 6d was
obtained as an oil; 96% in yield; [˛]D20 = +27.97◦ (c = 0.36, CHCl3);
1H NMR (300 MHz, CDCl3) 7.33 (d, J = 8.7 Hz, 1H), 7.04 (m, 2H), 6.01
(dd, J = 3.0, 1.8 Hz, 1H), 2.91 (m, 2H), 2.39–2.27 (m, 4H), 2.14–1.39
(m, 16H), 1.28–1.23 (m, 2H), 0.88 (s, 3H); 13C NMR (75 MHz,
CDCl3): 147.45, 140.92, 139.36, 136.74, 134.92, 126.80, 121.06,
118.74 (q, J = 318.75 Hz), 118.06, 96.46, 79.66, 69.21, 55.26, 48.05,
44.40, 40.15 (2C), 36.85, 34.47, 31.66, 29.32, 27.21, 26.18, 25.16,
23.53 (2C), 16.10; IR (film): 3399, 3054, 1606, 1584, 1489, 1423,
1212, 1142, 919 cm−1; Anal. Calcd. for C27H31F3O4S: C, 63.76; H,
6.14; Found C, 63.57; H, 5.96.
2.2.3. General procedure for the coupling reaction from
bistriflates and 1-alkynes
The mixture of compound 5 (267 mg, 0.5 mmol), 1-alkynes
(0.55 mmol), AgOAc (20 mg, 0.1 mmol), Pd[(C6H5)3P]4 (30 mg,
0.026 mmol) and DIPEA(129 mg, 1.0 mmol) in DMF (8 mL) was
stirred at 80 ◦C for 15 min. After the reaction was quenched with
water (2 mL) and the mixture was extracted with EtOAc (25 mL),
the organic phase was washed with 10% HCl and sat. NH4Cl, dried
over Na2SO4. After the solvent was removed by vacuum, the residue
2.2.3.5. (8S,9S,13S,14S)-13-Methyl-17-(3-methylbut-3-en-1-yn-1-
yl)-7,8,9,11,12,13,14,15-octahydro-6H-cyclopenta[a]phenanthren-3-
yl trifluoromethanesulfonate (6e). Following the general procedure,
the title compound 6e was obtained as an oil; 89% in yield;
[˛]D20 = +32.29◦ (c = 1.98, CHCl3); 1H NMR (CDCl3) 7.26 (d,

940
Q. Sun et al. / Steroids 75 (2010) 936–943
phase was washed with 10% HCl and sat. NH4Cl, dried over Na2SO4.
After the solvent was removed by vacuum, the residue was purified
by flash chromatography (silica gel, CH2Cl2/hexanes, 1/5) to give
the title product 7 (187.2 mg, 93%) as an oil; [˛]D20 = +26.88◦
(c = 2.26, CHCl3); 1H NMR (CDCl3) 7.20 (s, 1H), 7.17 (d, J = 10.8 Hz,
1H), 7.16 (d, J = 10.8 Hz, 1H), 6.01 (dd, J = 3.0, 2.1 Hz, 1H), 2.85 (m,
2H), 2.34–2.26 (m, 3H), 1.60 (s, 6H), 1.57 (s, 6H), 0.86 (s, 3H); 13C
NMR (75 MHz, CDCl3): 140.92, 136.76, 136.61, 135.38, 132.04,
128.78, 124.98, 119.80, 97.55, 92.97, 82.25, 65.68, 65.62, 55.45,
48.05, 44.73, 37.11, 34.47, 31.74, 31.63 (2C), 31.52 (2C), 31.02,
29.05, 27.52, 26.08, 16.12; IR (film): 3368, 3051, 2244, 1603, 1496,
1454, 1370, 1164, 958, 910 cm−1; Anal. Calcd. for C28H34O2: C,
83.54; H, 8.51; Found C, 83.44; H, 8.42.
Scheme 1. Preparation of triflate 2a using various reaction conditions.
2.2.3.7. (8S,9S,13S,14S)-3-((4-Methoxyphenyl)ethynyl)-13-methyl-
17-(3-methylbut-3-en-1-yn-1-yl)-7,8,9,11,12,13,14,15-octahydro-
6H-cyclopenta[a]phenanthrene (8). The mixture of triflate 6e
(225 mg, 0.5 mmol), 1-ethynyl-4-methoxybenzene (72.7 mg,
0.55 mmol), CuI (19 mg, 0.1 mmol), Pd[(C6H5)3P]4 (30 mg,
0.026 mmol) and DIPEA(129 mg, 1.0 mmol) in DMF (8 mL) was
stirred at 80 ◦C for 120 min. After the reaction was quenched
with water (2 mL) and the mixture was extracted with EtOAc
(2× 15 mL), the organic phase was washed with 10% HCl and
sat. NH4Cl, dried over Na2SO4. After the solvent was removed by
vacuum, the residue was purified by flash chromatography (silica
gel, EtOAc/hexanes, 1/6) to give the title product 8 (198.7 mg, 92%)
as an oil; [˛]D20 = +22.29◦ (c = 1.65, CHCl3); 1H NMR (300 MHz,
CDCl3) 7.45 (d, J = 8.4 Hz, 2H), 7.44 (m, 3H), 6.87 (d, J = 8.7 Hz, 2H),
6.05 (q, J = 3.0, 1.8 Hz, 1H), 5.27 (d, J = 20.1 Hz, 2H), 3.82 (s, 3H),
2.90–2.87 (m, 2H), 2.38–2.29 (m, 3H), 1.95 (s, 3H), 0.89 (s, 3H);
13C NMR (75 MHz, CDCl3): 159.47, 140.70, 137.32, 136.70, 135.47,
132.98 (2C), 131.84, 128.64, 127.06, 125.09, 121.37, 120.67, 115.68,
113.96 (2C), 94.21, 88.54, 88.26, 83.92, 55.51, 55.28, 48.27, 44.82,
37.20, 34.56, 31.89, 29.16, 27.59, 26.15, 23.66, 16.27. IR (film):
1610, 1498, 1420, 1208, 1144, 919 cm−1; Anal. Calcd. for C32H32O:
C, 88.85; H, 7.46; Found C, 88.66; H, 7.60.
Scheme 2. Various Pd/Ag or Cu salt system-catalyzed cross-coupling reaction.
J = 8.7 Hz, 2H), 6.91 (m, 2H), 5.97 (m, 1H), 5.20 (d, J = 20.0 Hz, 2H),
2.86–2.83 (m, 2H), 2.28–2.20 (m, 3H), 1.87 (t, J = 1.2 Hz, 3H), 0.82
(s, 3H); 13C NMR (75 MHz, CDCl3): 147.49, 140.99, 139.40, 137.21,
135.34, 127.00, 126.88, 121.43, 121.11, 118.73 (q, J = 318.75 Hz),
118.10, 94.27, 83.76, 55.33, 48.15, 44.43, 36.93, 34.45, 31.83, 29.40,
27.27, 26.21, 23.62, 16.19. IR (film): 3055, 1600, 1490, 1426, 1200,
1150, 917 cm−1; Anal. Calcd. for C24H25F3O3S: C, 63.98; H, 5.59;
Found C, 63.76; H, 5.64.
2.2.3.6. 4,4ꢀ-((8S,9S,13S,14S)-13-Methyl-7,8,9,11,12,13,14,15-
octahydro-6H-cyclopenta[a]phenanthrene-3,17-diyl)bis(2-
methylbut-3-yn-2-ol) (7). The mixture of bistriflates 5 (267 mg,
0.5 mmol), 2-methylbut-3-yn-2-ol (92.4 mg, 1.10 mmol), CuI
(38 mg, 0.2 mmol), Pd[(C6H5)3P]4 (60 mg, 0.052 mmol) and
DIPEA(258 mg, 2.0 mmol) in DMF (8 mL) was stirred at 80 ◦C for
120 min. After the reaction was quenched with water (5 mL) and
the mixture was extracted with EtOAc (2× 15 mL), the organic
3. Results and discussion
Considering the synthesis of these complex steroids with a mod-
ified D-ring and the formation of Csp2–Csp bond, we needed an
active intermediate for sp2–sp coupling reactions. However, the
Table 1
Pd/Ag or Cu salt-catalyzed cross-coupling reaction of triflate 2a with but-3-yn-1-ol to give compound 3aa.a.
Entry
[Pd] catalyst
Co-catalyst
Base
Solvent
Yield (%)b
1
2
3
4
5
6
7
8
PdCl2(PPh3)2
Pd(PPh3)4
PdCl2(PPh3)2
PdCl2
CuI (20 mol%)
CuI (20 mol%)
AgI (20 mol%)
AgI (20 mol%)
AgI (20 mol%)
AgI (20 mol%)
AgI (20 mol%)
AgBr (20 mol%)
AgOTf (20 mol%)
Ag2CO3 (20 mol%)
AgOAc (20 mol%)
AgBF4 (20 mol%)
AgOAc (0 mol%)
AgOAc (10 mol%)
AgOAc (30 mol%)
AgOAc (20 mol%)
AgOAc (20 mol%)
AgOAc (20 mol%)
AgOAc (20 mol%)
AgOAc (20 mol%)
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
Et3N
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
THF
72
82
78
68
72
85
76
80
96
72
97
82
32
91
96
85
90
92
39
43
Pd(OAc)2
Pd(PPh3)4
Pd2(dba)3
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
9
10
11
12
13
14
15
16
17
18
19
20
MeCN
DMF
DMF
DMF
Pyridine
K2CO3
a
Reaction conditions: triflate 2a/3-butyn-1-ol/base = 1/1.2/3.0. Isolated yield based on triflate 2a.

Q. Sun et al. / Steroids 75 (2010) 936–943
941
Table 2
Pd(PPh3)4/AgOAc-catalyzed preparation of D-ring unsaturated 17-alkynylsteroids.a.
1, 2
R1
R2
R3
Yield of 2 (%)
3
R
Yield of 3 (%)
a
OMe
ꢀ
1,3,5(10)-triene
98
aa
97
ab
ac
97
95
ad
ae
95
86
af
92
b
␤-OMOM
ꢀ5(6)
Me
98
ba
bb
96
94
bc
97
bd
be
96
97
bf
92
c
␣-OMOM
␣-H
Me
97
cb
ce
98
96
a
Reaction conditions: triflate/1-alkyne (RC CH)/base = 1/1.2/3.1, Pd(PPh3)4(5 mol%)/AgOAc (20 mol%); room temperature, reaction time: 30 min, nitrogen. Isolated yield
based on triflate.
conventional Sonogashira sp2–sp coupling reaction of vinyl iodide
with terminal alkynes catalyzed by palladium in the presence of
copper salts under an Ar or N2 atmosphere has some weak points
such as the Glaser-type oxidative dimerization of terminal alkynes
and low yield. Many studies indicated that the successful imple-
mentation of vinyl and aryl triflates as the electrophilic components
in these reactions has greatly expanded the utility of these trans-
formations, as the reactive species are readily available from the
corresponding carbonyl compounds or phenolic [9].
Fortunately, the use of vinyl triflate in place of vinyl iodide as the
electrophilic component dramatically improved the Sonogashira
sp2–sp coupling reaction, and avoided Glaser-type oxidative
dimerization of terminal alkynes.
the model compound 2a. Reagents and solvents investigated for
the reaction were Tf2O/NaH/CH2Cl2 [10], Tf2O–pyridine–CH2Cl2,
PhN(Tf)2–KHMDS–THF. Although the reaction was mild at ambi-
ent temperature while using Tf2O–pyridine–CH2Cl2 as reagents
and solvent, the yield of compound 2a was just moderate
and the reaction took almost 24 h (52% in yield, Scheme 1,
entry 1). Similar result was obtained in 83% (Scheme 1, entry
2) when base reagent NaH was used as
a replacement in
dichloromethane at 0 ◦C. Compound 2a were also prepared from
3-methoxyestr-17-one by the reaction with KHMDS and PhN(Tf)2
in THF at −78 ◦C (98% in yield, Scheme 1, entry 3). The result
showed that PhN(Tf)2–KHMDS–THF reaction system gave the best
result.
Initially, the published methods which were used for the
preparation of vinyl triflates from ketones were scanned on
To achieve this goal for the formation of Csp2–Csp bond, at first
the coupling reaction palladium-catalyzed was studied with triflate

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Q. Sun et al. / Steroids 75 (2010) 936–943
Table 3
The selectively coupling reaction of estr-16-en-3,17-diyl bistriflate catalyzed by Pd(PPh3)4/AgOAc.a.
Entry
1
Product
R
Yield of 6 (%)
6a
94
2
3
6b
6c
96
93
4
6d
6e
96
94
5
a
Reaction conditions: triflate/1-alkyne (RC CH)/base = 1/1.1/3.1, Pd(PPh3)4 (5 mol%)/AgOAc (20 mol%); 80 ◦C, reaction time: 15 min, nitrogen. Isolated yield based on
triflate.
i
2a and but-3-yn-1-ol, which were selected as suitable substrates for
reaction development (Scheme 2, Table 1). At the outset, various
palladium catalysts were screened according to reported results
[11]. To our delight, we observed the reactions using various pal-
ladium catalysts worked well when the reaction was carried out
using triflate 2a and but-3-yn-1-ol (1.1 equiv.), the formation of the
desired product 3aa when the reaction was carried out using the
commercially available CuI (20 mol%) as a co-catalyst in the pres-
ence of Pd(PPh3)2Cl2 or Pd(PPh3)4 (5 mol%) and iPr2NEt (1.5 equiv.)
in DMF at room temperature for 30 min (72% yield, Table 1, entry
1 and 82% in yield, Table 1, entry 2, respectively). Considering the
replacement of copper iodide by silver halides for the efficiently
coupling of sensitive vinyl triflates and 1-alkyne [13], we firstly
tested this reaction using the above said triflate 1a and but-3-yn-
1-ol 2a in DMF under nitrogen in the presence of Pd(PPh3)2Cl2
using silver iodide as a co-catalyst. We were delighted to find that
Pd(PPh3)2Cl2/AgI catalysts in DMF gave product 3aa in 78% yield
(Table 1, entry 3). This result encouraged us to make a detailed
investigation. Therefore, we examined the reaction in the presence
of various palladium catalysts such as PdCl2, Pd(OAc)2, Pd(PPh3)4
and Pd2(dba)3 using silver iodide as a co-catalyst in the same reac-
tion conditions (Table 1, entries 4–7). It was evident that Pd(PPh3)4
(5 mol%) was the most effective catalyst for this transformation
(85% yield, Table 1, entry 6). It is known that in many reactions
catalyzed by Pd catalysts, silver salts were the better co-catalysts
such as silver triflate AgOTf [11–13], AgBF4, Ag2CO3 and AgOAc.
Next, we examined this reaction in the presence of Pd(PPh3)4
and various other silver salts such as AgBr [14], AgOTf, Ag2CO3,
and AgOAc similar reaction conditions. The results showed that
the Pd(PPh3)4/AgOTf and Pd(PPh3)4/AgOAc catalyst systems gave
product 3aa in 96% and 97% yields, respectively (Table 1, entries 9
and 11). Owing to AgOAc being inexpensive, the Pd(PPh3)4/AgOAc
catalyst system was chosen perfectly. However Pd(PPh3)4/AgBr,
Pd(PPh3)4/Ag2CO3 and Pd(PPh3)4/AgBF4 catalyst systems similar
to Pd(PPh3)4/AgI gave product 3aa in good yields (Table 1, entries
8, 10 and 12). Subsequently we examined this reaction in the pres-
ence of Pd(PPh3)4 and varied amount of AgOAc. Both decreasing and
increasing the amount of AgOAc (Table 1, entries 13–15) somewhat
decreased the product yield. The use of a further excess amount of
AgOAc (30% equiv.) did not improve the yield (Table 1, entry 15). We
also examined various solvents (DMF, THF and MeCN) and bases
(iPr2NEt, Et3N, pyridine, and K2CO3) (Table 1, entries 11, 16–20).
Among these tested conditions, Pr2NEt, Et3N could promote effi-
ciently this reaction in DMF as solvent in high yield. However, the
weak base pyridine and sodium carbonate promoted limitedly this
coupling reaction in lower yields (Table 1, entries 19, 20).
These results showed that the experimental procedure for this
coupling reaction of 17-steroidal triflates and alkynes was very sim-
ple and straightforward. A mixture of triflate compound (1 mmol),
1-alkyne (1.2 mmol) and DIPEA (3.9 mmol) in DMF (20 mL) was
stirred at room temperature in the presence of Pd[(C6H5)3P]4
(5 mol%) and AgOAc (20 mol%) for 30 min under nitrogen. The resul-
tant mixture was stirred under nitrogen at room temperature for
30 min. Then after a simple workup the product was directly puri-
fied using column chromatography. Following the general reaction
conditions, we next examined the scope of this reaction with
various 17-steroidal triflates and 1-alkynes, and the results are
summarized in Table 2. In general the reaction was proceeded
smoothly for various17-steroidal triflates and 1-alkynes to produce
the desired D-ring unsaturated 17-alkynylsteroids in excellent
yields (86–98%). As illustrated in Scheme 3 and Table 2, the yields
of 3aa–ce were not significantly affected by substituents or stere-
ochemistry at C-3, C-5, and C-10 of steroids and by substituents of
1-alkynes.
Encouraged by above investigations, subsequently, we inves-
tigated this coupling reaction with estr-16-en-3,17-diyl bistri-
fluoromethanesulfonate (5) and various 1-alkynes in DIPEA and
Scheme 3. Pd(PPh3)4/AgOAc-catalyzed preparation of 17-alkynylsteroids through
corresponding triflates.

Q. Sun et al. / Steroids 75 (2010) 936–943
943
Acknowledgements
We are grateful to the Natural Science Foundation of Jiangsu
Education Ministry of China (Grant 07KJB150135) and the NSF of
Jiangsu Province (Grant BK2008216) for financial support.
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4. Conclusion
In summary, we have successfully developed a novel and
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