Copper-catalyzed cyclization of steroidal acylaminoacetylenes: Syntheses of novel 11β-Aryl-17,17-spiro[(4′H,5′-methylene)oxazol]- substituted steroids

Article abstract of DOI:10.1021/ol070447d

A variety of novel 11β-aryl-17,17-spiro[(4′H,5′-methylene) oxazol]-substituted steroids have been synthesized in moderate to good yields via copper-catalyzed cyclization of acylaminoacetylenes. The best result was obtained with a catalytic amount of Cul i

Full text of DOI:10.1021/ol070447d

ORGANIC
LETTERS
2007
Vol. 9, No. 10
1887-1890
Copper-Catalyzed Cyclization of
Steroidal Acylaminoacetylenes:
Syntheses of Novel 11
spiro[(4 H,5 -methylene)oxazol]-Substituted
Steroids
â-Aryl-17,17-
′
′
Chunyang Jin,* Jason P. Burgess, John A. Kepler,* and C. Edgar Cook†
Organic and Medicinal Chemistry, Science and Engineering Group, Research Triangle
Institute, P.O. Box 12194, Research Triangle Park, North Carolina 27709
cjin@rti.org; jak@rti.org
Received February 21, 2007
ABSTRACT
A variety of novel 11
copper-catalyzed cyclization of acylaminoacetylenes. The best result was obtained with a catalytic amount of CuI in 1:1 benzene
C for 30 min (Ar 3,4-difluorophenyl; R ethyl; 97% yield).
â
-aryl-17,17-spiro[(4
′
H,5
′
-methylene)oxazol]-substituted steroids have been synthesized in moderate to good yields via
−Et3N at 90
°
)
)
Progesterone, acting primarily via the progesterone receptor
(PR), regulates the viability of cells of several different
reproductive tissues, including the uterus, breast, cervix, and
hypothalamic-pituitary unit.1 It also has extra-reproductive
activities such as effects on the brain, the immune system,
the vascular endothelial system, and lipid metabolism. Given
the wide array of effects, it is apparent that compounds which
mimic some of the effects of progesterone (agonist), an-
tagonize these effects (antagonist), or exhibit mixed effects
(partial agonist or mixed agonist-antagonist) can be useful
in the treatment of a variety of disease states and conditions.2
Since the discovery of the first competitive progesterone
antagonist, mifepristone3 (RU 486, 1, Figure 1), hundreds
of analogues have been synthesized to optimize the anti-
progestational effect with regard to the steroid receptor
selectivity.4 It has been shown that substituents on the D-ring
Figure 1. Antiprogestins.
† Dr. C. Edgar Cook is deceased.
(1) Spitz, I. M. Steroids 2003, 68, 981.
(2) Chabbert-Buffet, N.; Meduri, G.; Bouchard, P.; Spitz, I. M. Hum.
Reprod. Update 2005, 11, 293.
(3) Teutsch, G.; Costerousse, G.; Philibert, D.; Deraedt, R. U.S. Patent
4 386 085, 1983.
of the steroid can have a marked influence on the biological
profile of these compounds. The earliest antiprogestins were
substituted with a 17â-hydroxyl group and various 17R-
10.1021/ol070447d CCC: $37.00
© 2007 American Chemical Society
Published on Web 04/17/2007

substituents.5 Replacement of these substituents with the
progesterone side chain (17â-acetyl) together with a 17R-
acetoxy substituent led to RTI-3021-012 (also known as CBD
2914) (2), which is approximately 3 times as potent as
mifepristone.6 In addition, exchange of the 17-side chain with
17,17-spirocyclic moieties characterized by a sulfur,7 nitro-
gen,8 or oxygen9 enhanced antiprogestational effects, in some
cases, with considerably reduced antiglucocorticoid activities.
In fact, one of the most active compounds in this series, ORG
33628 (3), has been claimed to be 16 times as active as RU
486 in the pregnancy interruption test in rats and about 6
times less active as an antiglucocorticoid.10
Scheme 1
Some time ago, we found that various 17â-nitro8 and
amino substituents11 (e.g., 4a; Ar ) 3,4-difluorophenyl, R
) ethyl) could also generate antiprogestational effects. To
find highly potent antiprogestins with considerably reduced
endocrine side effects, we have continued the investigation
of the C(17) modification of 4. Recently, a variety of
oxazolines,12 benzoxazines,13 quinazolin-2-ones, quinazolin-
3-ones, and indoles14 have been successfully synthesized by
the palladium-catalyzed or the copper-catalyzed14b cyclization
of alkynes having an acylamino group in close proximity to
the carbon-carbon triple bond. We now report here the
cyclization of ethynes 4 to generate novel spiro-oxazole
moieties at the C(17) position.
The key intermediate 4a for our study was prepared in
24% yield from commercially available 3,3-[1,2-ethanediyl-
bis(oxy)]estra-5(10),9(11)-dien-17-one (5) following the
reported procedure (Scheme 1).8,11 The regioselective 5,10-
epoxidation of 5 was achieved by using hexafluoroacetone
hydroperoxide generated in situ from hexafluoroacetone
trihydrate and hydrogen peroxide to give 6 in 53% yield.
The CuI-catalyzed addition of 3,4-difluorophenyl magnesium
bromide gave the corresponding Grignard adduct 7 in 92%
yield.15 Oxime formation with hydroxylamine hydrochloride
in pyridine provided 8 quantitatively. Teatment of 8 with
N-bromosuccinimide (NBS)16 gave the 17-bromo-17-nitro
compound, which was readily reduced by NaBH4 to the 17â-
nitro compound 9 as confirmed by H NMR analysis. The
1
C(17)-H presented a triplet signal at δ 4.34 with a coupling
constant of 6.1 Hz, a pattern that is consistent with the usual
finding for an R C(17) hydrogen atom.17 The 17R-ethynyl
substituent was then introduced into the nitro compound 9
by treatment of the anion of 9 in dimethyl sulfoxide (DMSO)
with ethynyllead(IV) triacetate.18 17R-Ethynyl-17â-nitro
compound 10 was isolated as a single diastereoisomer in 81%
yield. The stereochemistry at C(17) in 10 was assigned based
on comparison of its NMR spectra with that of known
compounds.8,19 Reduction of 10 with zinc dust at 0 °C gave
hydroxylamine 11, which upon treatment with sodium
tetraborate, ammonium iron(II) sulfate, and 2-mercaptoethyl
ether20 afforded an 82% yield of amine 12. Finally, acylation
with propionyl chloride followed by deketalization and
dehydration with trifluoroacetic acid (TFA) provided 11â-
(4) Teutsch, G.; Philibert, D. Hum. Reprod. 1994, 9 (1), 12.
(5) For example: (a) Wiechert, R.; Neef, G. J. Steroid Biochem. 1987,
27, 851. (b) Wehle, H.; Moll, J.; Cato, A. C. B. Steroids 1995, 60, 368. (c)
Fuhrmann, U.; Hess-Stumpp, H.; Cleve, A.; Neef, G.; Schwede, W.;
Hoffmann, J.; Fritzemeier, K. H.; Chwalisz, K. J. Med. Chem. 2000, 43,
5010.
(6) (a) Cook, C. E.; Wani, M. C.; Lee, Y.-W.; Fail, P. A.; Petrow, V.
Life Sci. 1993, 52, 155. (b) Cook, C. E.; Lee, Y.-W.; Wani, M. C.; Fail, P.
A.; Petrow, V. Hum. Reprod. 1994, 9 (1), 32.
(7) Cook, C. E.; Shetty, R. S.; Kepler, J. A.; Lee, D. Y.-W. U.S. Patent
6 043 235, 2000.
(8) Cook, C. E.; Kepler, J. A.; Shetty, R. S.; Lee, D. Y.-W. U.S. Patent
6 015 805, 2000.
(9) (a) Philibert, D.; Hardy, M.; Gaillard-Moguilewsky, M.; Nique, F.;
Tournemine, C.; Ne´de´lec, L. J. Steroid Biochem. 1989, 34, 413. (b) Nioue,
F.; Nedelec, L.; Philibert, D.; Moguilewsky, M. U.S. Patent 4 900 725, 1990.
(10) (a) Kloosterboer, H. J.; Deckers, G. H.; de Gooyer, M. E.; Dijkema,
R.; Orlemans, E. O.; Schoonen, W. G. Ann. N.Y. Acad. Sci. 1995, 761,
192. (b) Kloosterboer, H. J.; Deckers, G. H.; Schoonen, W. G.; Hanssen,
R. G.; Rose, U. M.; Verbost, P. M.; Hsiu, J. G.; Williams, R. F.; Hodgen,
G. D. Steroids 2000, 65, 733.
(15) Teutsch, G.; Klich, M.; Bouchoux, F.; Cerede, E.; Philibert, D.
Steroids 1994, 59, 22.
(11) Cook, C. E.; Kepler, J. A.; Bartley, G. S. U.S. Patent 6 262 042,
2001.
(12) Bacchi, A.; Costa, M.; Gabriele, B.; Pelizze, G.; Salerno, G. J. Org.
Chem. 2002, 67, 4450.
(13) Costa, M.; Ca`, N. D.; Gabriele, B.; Massera, C.; Salerno, G.; Soliani,
M. J. Org. Chem. 2003, 69, 2469.
(14) (a) Cacchi, S.; Fabrizi, G.; Marinelli, F.; Moro, L.; Pace, P. Synlett
1997, 1363. (b) Cacchi, S.; Fabrizi, G.; Parisi, L. M. Org. Lett. 2003, 5,
3843.
(16) Patchett, A. A.; Hoffman, F.; Giarrusso, F. F.; Schwam, H.; Arth,
G. E. J. Org. Chem. 1962, 27, 3822.
(17) Krohn, K.; Ku¨pke, J. Eur. J. Org. Chem. 1998, 679.
(18) Moloney, M. G.; Pinhey, J. T.; Roche, E. G. J. Chem. Soc., Perkin
Trans. 1 1989, 333.
(19) The stereochemistry of 10 was further confirmed based on the NMR
studies of the cyclization product 14a.
(20) Nambu, Y.; Kijima, M.; Endo, T.; Okawara, M. J. Org. Chem. 1982,
47, 3066.
1888
Org. Lett., Vol. 9, No. 10, 2007

(3,4-difluorophenyl)-17R-ethynyl-17â-[(1-oxopropyl)amino]-
estra-4,9-dien-3-one (4a) in 87% yield.
An attempt at Sonogashira-type acylation21 of the ethynyl
group of 4a with N,N-dimethylcarbamoyl chloride under
standard conditions [Pd(PPh3)2Cl2/PPh3/CuI/benzene/Et3N/
90 °C22] led to none of the coupling product. Instead, the
major product isolated in 68% yield was identified as 14a
(see below). To determine which of the reagents was essential
for this reaction to occur, the cyclization of 4a was first
carried out with 10 mol % of CuI in refluxing benzene for
24 h (eq 1). The cyclization product 14a was isolated in 30%
Figure 2. Key ROESY correlations of 14a.
these respective pairs of protons were proximal. In addition,
no correlations between vinylic protons and the C(18) methyl
group were observed. The calculated interatomic distances
of approximately 2.2 Å between vinylic Ha and C(14)-H,
and 2.6 Å between vinylic Ha and R C(16)-H are consistent
with the observation of strong ROESY correlations. On the
basis of the comparison with the known stereochemistry at
carbons C(8), C(13), and C(14), the stereochemistry at C(17)
of 14a was assigned as shown in Figure 2.
yield and a 65% yield of 4a was recovered (Table 1). The
6-membered regioisomer oxazine was not detected by H
1
Table 1. Optimization of Cyclization of Acylaminoacetylene
The CuI-catalyzed cyclization of 4a was also tried by using
dimethylformamide (DMF) or dimethyl sulfoxide (DMSO)
as the solvent, but this resulted in decomposition of 4a (Table
1). Only a small amount of desired product 14a was detected
in the reaction mixture. After further optimization, it was
found that treatment of 4a in a 1:1 mixture of benzene and
Et3N at 90 °C in the presence of 10 mol % of CuI led to
rapid cyclization (30 min) to produce 14a in 97% yield.
Lowering the temperature to 40 °C gave 14a in only 46%
yield even after 24 h of reaction time. This cyclization could
also be catalyzed by other transition metal salts such as
Pd(OAc)2 and AgNO3 with acceptable yields. However,
when HgCl2 was used as a catalyst, only a 9% yield of 14a
was realized. The optimal cyclization conditions thus far de-
veloped employ 1 equiv of the substrate 4a (0.2 mmol) and
10 mol % of CuI in 1:1 benzene-Et3N (4 mL) at 90 °C.
By employing this protocol, a number of steroidal acyl-
aminoacetylenes 4b-j23 were cyclized to give the corre-
sponding spiro-oxazoles in moderate to good yields (Table
2). Generally, the cyclization of acetyl and propionamides
was completed within 1 h to give the corresponding spiro-
oxazoles in 83-93% yields. In the case of formyl and
trifluoroacetylamides, the cyclization products were isolated
in moderate yields (40-60%) with incomplete conversion
of the starting material. Use of longer reaction times to
consume all the starting material led to decomposition and
lower yield of the cyclization product. We believe that a
reasonable mechanism for this copper-catalyzed cyclization
of terminal acetylenes involves CuI coordinating to the
carbon-carbon triple bond to form a copper-acetylene π
complex,24 followed by Et3N assisted intramolecular nucleo-
4a
temp
(°C)
time
(h)c
% isolated
yield
catalysta
solvent
benzene
DMF
DMSO
benzene-Et3N
benzene-Et3N
benzene-Et3N
benzene-Et3N
benzene-Et3N
CuI
CuI
CuI
CuI
CuI
Pd(OAc)2
AgNO3
HgCl2
80
90
90
90
40
90
90
90
24
2
2
0.5
24
1
30
traced
traced
97
46
54
84
9
b
3
3
a 10 mol % of catalyst was used. b 1.1 equiv of AgNO3 was used. c The
progress of reaction was monitored by TLC, and the reaction worked up
after approximately 100% conversion or after 24 h of reaction time.
d Determined by H NMR spectroscopy.
1
NMR analysis of the crude product mixture. The structure
of 14a was confirmed by NMR studies (Supporting Informa-
tion), particularly with the aid of 2D proton-proton (gCOSY)
and proton-carbon (gHMBC and gHSQC) correlation
spectroscopy techniques. The two terminal vinylic protons
were clearly evident at δ 4.80 and 4.20 with a coupling
constant of 2.5 Hz.
The stereochemistry of 14a was construed from analysis
of the molecular model, energy minimized with the MMFF94
force field in Spartan’04 (Wavefunction, Inc., Irvine, CA)
overlaid with key correlations observed in the two-
dimensional ROESY NMR spectrum (Figure 2). Strong
correlations were observed between vinylic Ha and C(14)-
H, and between vinylic Ha and R C(16)-H, indicating that
(21) Tohda, Y.; Sonogashira, K.; Haghiara, N. Synthesis 1977, 777.
(22) The reaction temperature was given as the temperature of the heating
bath.
(23) The steroidal acylaminoacetylenes 4b-j were prepared following
the similar synthetic route in Scheme 1.
Org. Lett., Vol. 9, No. 10, 2007
1889

h, the hydrolysis product 17R-acetyl-17â-propionylamino-
substituted steroid 15 was obtained in 96% yield (eq 2).
Table 2. Syntheses of 11â-Aryl-17,17-spiro[(4′H,5′-
methylene)oxazol]-Substituted Steroidsa
% yieldb
In conclusion, we have established an efficient copper-
catalyzed cyclization of steroidal acylaminoacetylenes to give
the corresponding 11â-aryl-17,17-spiro[(4′H,5′-methylene)-
oxazol]-substituted steroids in moderate to good yields. The
corresponding 17R-acetyl-17â-acylamino steroids were then
obtained by hydrolysis. The hormonal properties of these
novel steroids will be reported separately.
product
Ar
R
14b
14c
14d
14e
14f
14g
14h
14i
3,4-difluorophenyl
3,4-difluorophenyl
4-(N,N-dimethylamino)phenyl CH2CH3
4-(N,N-dimethylamino)phenyl CH3
4-(N,N-dimethylamino)phenyl CF3
4-(N,N-dimethylamino)phenyl
4-acetylphenyl
4-acetylphenyl
CH3
CF3
91
45
93
91
63
38
85
83
40
H
CH2CH3
CH3
Acknowledgment. This work was supported by the R.
W. Johnson Pharmaceutical Research Institute.
14j
4-acetylphenyl
H
a All reactions were carried out under the optimal conditions reported in
the text. b Isolated yield.
Supporting Information Available: Experimental pro-
cedures and characterization data for the reported reactions,
NMR assignments of 14a, and NMR spectra of 4a-j,
14a-j, and 15. This material is available free of charge via
the Internet at http://pubs.acs.org.
philic attack of the oxygen of the amide moiety on the
activated carbon-carbon triple bond.
The prepared steroidal spiro-oxazoles 14a-j are stable at
room temperature. However, they are readily hydrolyzed
upon treatment with harsher conditions (e.g., refluxed in
MeOH). When 14a was heated in refluxing MeOH for 16
OL070447D
(24) Macomber, D. W.; Rausch, M. D. J. Am. Chem. Soc. 1983, 105,
5325.
1890
Org. Lett., Vol. 9, No. 10, 2007