1,3-Diaxially substituted trans-decalins: Potential nonsteroidal human progesterone receptor inhibitors

Article abstract of DOI:10.1021/jo800947m

(Chemical Equation Presented) On the basis of molecular modeling and QSAR analysis of the known human progesterone receptor (hPR) inhibitor Mifepristone (RU-486) and other hPR ligands, a new class of potential nonsteroidal hPR inhibitors was designed. The parent racemic compound 1 was synthesized through an efficient 13-step synthetic pathway. The key constructive steps are a stereoselective epoxide ring opening and the reductive Heck cyclization to form the main framework of (±)-1. The current established flexible synthetic route allows for further chemical diversification.

Full text of DOI:10.1021/jo800947m

1,3-Diaxially Substituted trans-Decalins: Potential
Nonsteroidal Human Progesterone Receptor
Inhibitors
Ze Li,† E. Blake Watkins,† Hua Liu,† Amar G. Chittiboyina,†
Paulo B. Carvalho,† and Mitchell A. Avery*,†,‡,§
Department of Medicinal Chemistry; National Center for
Natural Products Research, School of Pharmacy; and
Department of Chemistry and Biochemistry, The UniVersity
of Mississippi, P.O. Box 1848, UniVersity, Mississippi 38677
FIGURE 1. The basic framework of the RU-486 analogues; B. Overlay
of a representative compound 1 (red) with 2 (green).
maVery@olemiss.edu
ReceiVed May 9, 2008
compounds usually exhibit poor bioavailability. Thus the
development of nonsteroidal hPR antagonists is a goal worth
pursuing.
With RU-486 as a starting template, we conducted a series
of molecular modeling and QSAR studies to determine the
structure activity relationship of this drug and other ligands to
the hPR protein to discover novel nonsteroidal hPR inhibitors
with acceptable ADME profiles. These studies resulted in a class
of nonsteroidal RU-486 analogues whose general structure is
shown in Figure 1.
The designed compounds are a class of molecules mimicking
the B/C rings in the RU-486 tetracyclic backbone. The overlay
of a representative compound 1 with RU-486 indicates that this
class of compounds closely matches the RU-486 template
(Figure 1B). Modeling studies and interesting synthetic challenge
centering around the introduction of 1,3-diaxial alkyl, aryl
moiety prompted us to synthesize this class of compounds.
A probable synthetic difficulty lies in the assembly of five
chiral centers, two of which form a trans-fused decalin system
bearing a ꢀ-9-aryl functionality extending to the same face as
the 5-angular proton as well as the 7-methyl group. These
substantial challenges arise from the need to stereoselectively
assemble a ꢀ-9-aryl functionality that occupies an energetically
disfavored axial configuration. On the basis of the synthetic
difficulties mentioned above, a reasonable retrosynthetic analysis
is presented in Figure 2.
On the basis of molecular modeling and QSAR analysis of
the known human progesterone receptor (hPR) inhibitor
Mifepristone (RU-486) and other hPR ligands, a new class
of potential nonsteroidal hPR inhibitors was designed. The
parent racemic compound 1 was synthesized through an
efficient 13-step synthetic pathway. The key constructive
steps are a stereoselective epoxide ring opening and the
reductive Heck cyclization to form the main framework of
(()-1. The current established flexible synthetic route allows
for further chemical diversification.
The steroidal hormone progesterone plays a vital role in
maintaining pregnancy in animals. Disrupting or blocking
progesterone’s activity could serve as a viable method for the
management of human fertility. To date, hormone replacement
therapy has been an important tool in birth control and in the
treatment of hormone-dependent diseases. Among the known
human progesterone receptor (hPR) antagonists, Mifepristone
(RU-486) 2 is a successful example of their potential use as
birth control agents. This drug also has potential as an adjuvant
treatment tool in the management of hormone-dependent tumors
and disorders of the female reproductive system that are
refractory to chemotherapy.1,2 All currently available anti-
progestins are steroidal compounds. One of the difficulties in
using steroid-like agents is that these highly hydrophobic
An aspect of the current synthetic plan involved an axial
sulfide tether set to deliver the phenyl ring to the 9-position
from the ꢀ-face, ensuring the axial configuration of the 9-aryl
functionality. Critical to the success of this approach was the
clean epoxidation of 4 to R-epoxide 5a, which is itself a suitable
electrophile for diaxial opening by a nucleophilic aryl sulfide,
leading to formation of a C6 axial phenyl sulfide such as 6
(Figure 2). Practically, the epoxidation of the known compound
43 with m-CPBA sluggishly afforded a mixture of R- and
ꢀ-epoxides 5a and 5b in 55% yield with the required R-epoxide
1
predominating (R:ꢀ ) 8:2; based on H NMR). Changing the
(2) Proietti, C.; Salatino, M.; Rosemblit, C.; Carnevale, R.; Pecci, A.;
Kornblihtt, A. R.; Molinolo, A. A.; Frahm, I.; Charreau, E. H.; Schillaci, R.;
Elizalde, P. V. Mol. Cell. Biol. 2005, 25, 4826–4840.
(3) Doering, W. v. E.; Kitagawa, T. J. Am. Chem. Soc. 1991, 113, 4288–
4297.
† Department of Medicinal Chemistry.
‡ National Center for Natural Products Research, School of Pharmacy.
§ Department of Chemistry and Biochemistry.
(1) Koide, S. S. J. Reprod. Med. 1998, 43, 551–560.
7764 J. Org. Chem. 2008, 73, 7764–7767
10.1021/jo800947m CCC: $40.75 2008 American Chemical Society
Published on Web 09/05/2008

FIGURE 3. Stereoelectronic controlled elaboration of the C-7 quar-
ternary center.
FIGURE 2. Retrosynthetic analysis of the basic framework of the RU-
486 analogues.
SCHEME 1. Epoxidation and Epoxide-Opening Reactions
FIGURE 4. The relative stereochemistry of the oxazine-2,4-dione 18.
SCHEME 2. The Synthesis of the Thioether 12
oxidant to 3-methyl-3-trifluoromethyl-1,2-dioxirane4 dramati-
cally reduced the reaction time to 2 h, and furnished an isolated
yield of 90% (R:ꢀ ) 7:3). Separation of the two isomers by
flash column chromatography proved quite difficult, thus the
subsequent epoxide-opening reaction with o-bromobenzenethiol5
was performed on the mixture. Interestingly, the reaction proved
to be stereospecific and provided only the wanted trans diaxial
opening alcohol 9 in 92% yield with respect to R-epoxide 5a
(Scheme 1).
The observed stereoselectivity in the epoxide opening reaction
was consistent with the well-established Fu¨rst-Plattner rule.6
Associated with the rigid “bis-chair-like” conformation of the
decalone ring system, the stereoselectivity of the epoxide
opening reaction in the current case was determined by
stereoelectronic effects. Results of ab initio calculations7 were
gratifyingly consistent with the experimentally based Fu¨rst-
Plattner rule. Accordingly, ArSH-promoted R-epoxide opening
is expected to occur more readily in this case than the ꢀ-epoxide
by a ratio greater than 95:5. This calculated “substrate selectiv-
ity” is in close agreement with the experimentally derived ratio
of 8:2, thus providing additional support for the Fu¨rst-Plattner
rule.
that in the methylation step, the stronger 1,3- and 1,5-repulsive
interaction between the bulky ester group and the axial-thioaryl
ring could prevent the ester group from being assembled in the
energetically disfavored axial position (Figure 3).9 Treatment
of 10 with LHMDS followed by addition of a molar equivalent
of methyl cyanoformate afforded the ꢀ-ketoester. Slow addition
of the starting material to base proved essential to ensure the
success of the reaction. Treatment of the ꢀ-ketoester intermediate
with MeI in the presence of NaH at 0 °C furnished methylated
ꢀ-ketoester 11 in 76% yield (Scheme 2).
Reduction of 11 to the trans-fused bicyclic intermediate 12
proved difficult as the demand for stereo- and chemoselectivity
excluded many commonly used reductive methods. Among the
tested reduction methods, including catalytic hydrogenation,10
PII-catalyst,11 and copper(I) hydride cluster ([(Ph3P)CuH]6),12,13
sodium dithionite reduction14–16 provided the best result.
Protection of 9 with MOMCl gave the MOM acetal 10. To
install an axial methyl group and an equatorial ester group both
at the 2-position, the Mander carbomethoxylation reaction8 of
10 followed by methylation of the ꢀ-ketoester enolate of 10
was investigated for its stereochemical outcome. We anticipated
(9) The bulkier ꢀ-ketoester group occupies the less congested convex face,
while the methyl group occupies the concave face. For a similar result, see:
Fairweather, K. A.; Mander, L. N. Org. Lett. 2006, 8, 3395–3398.
(10) Van Tamelen, E. E.; Proost, W. C. J. Am. Chem. Soc. 1954, 76, 3632–
3634.
(11) Kametani, T.; Toya, T.; Tsubuki, M.; Kawai, K.; Honda, T. Chem.
Pharm. Bull. (Tokyo) 1986, 34, 3169–3174.
(12) Koenig, T. M.; Daeuble, J. F.; Brestensky, D. M.; Stryker, J. M.
Tetrahedron Lett. 1990, 31, 3237–3240.
(4) Yang, D.; Wong, M.-K.; Yip, Y.-C. J. Org. Chem. 1995, 60, 3887–3889.
(5) Prestat, G.; Baylon, C.; Heck, M.-P.; Mioskowski, C. Tetrahedron Lett.
2000, 41, 3829–3831.
(6) Royals, E. E.; Leffingwell, J. C. J. Org. Chem. 1966, 31, 1937–1944.
(7) The LUMO energies of the R- and ꢀ-epoxides were determined by Spartan
(v60, Wavefunction Inc; Irvine, CA; Hartree Fock/6-31G** basis set) as 0.10199
and 0.10452 hartree, respectively. A LUMO-HOMO energy gap between the
orbitals of the epoxide isomers and the HOMO orbital of the nucleophile
(benzenethiol) was calculated and shown to favor the R-epoxide by 1.59 kcal/
M.
(13) Mahoney, W. S.; Brestensky, D. M.; Stryker, J. M. J. Am. Chem. Soc.
1988, 110, 291–293.
(14) Akamanchi, K. G.; Patel, H. C.; Meenakshi, R. Synth. Commun. 1992,
22, 1655–1660.
(15) Dhillon, R. S.; Singh, R. P.; Kaur, D. Tetrahedron Lett. 1995, 36, 1107–
1108.
(16) Fornasier, R.; Marcuzzi, F.; Tonellato, U. J. Inclusion Phenom. Mol.
Recognit. Chem. 1994, 18, 81–92.
(8) Mander, L. N.; Sethi, S. P. Tetrahedron Lett. 1983, 24, 5425–5428.
J. Org. Chem. Vol. 73, No. 19, 2008 7765

SCHEME 3. Synthesis of ꢀ,γ-Unsaturated Ester 14
SCHEME 4. Intramolecular Cyclization of Unsaturated
Ester 14
SCHEME 5. Synthesis of the Target Compound 1
The relative configuration of 12 was determined by 1D- and
2D-NMR spectroscopy and single-crystal X-ray crystallography
on its analogue, compound 18 (Figure 4; for its ORTEP drawing,
see the Supporting Information).31 The heterocycle 1,3-oxazin-
2,4-dione 18 was prepared by treatment of 17, the 5′-methoxy
derivative of 12, with 2,2,2-trichloroacetyl isocyanate followed
by in situ ring formation after hydrolysis of the 2,2,2-
trichloroacetylamide with sodium bicarbonate.
Elimination of the 3-hydroxyl group in 12 to the olefin
intermediate 14 provided a key precursor for the subsequent
ring closure. This transformation was somewhat more prob-
lematic than expected, however. The congested hydroxyl group
made activation with a bulky reagent, such as tosyl chloride,
problematic. Direct dehydration with methods including Al2O3,17
POCl3,18 DBU,19 copper(II) triflate,20 and even Burgess’
reagent21,22 proved in vain. Converting the alcohol to mesylate
and dehydration by LiCO3/LiBr in DMF23 also failed in our
hands. Xanthate pyrolysis24,25 was also tested. Although the
xanthate had been successfully synthesized, the subsequent
thermolysis did not work under 200 °C, and higher temperatures
resulted in decomposition products. Finally, by conversion of
the hydroxyl group to a triflate 1326,27 elimination occurred to
give the required olefin 14 in 75% yield (Scheme 3).
Subsequently, compound 14 was subjected to an intramo-
lecular cyclization to construct a tricyclic ring system. The
intramolecular free radical condensation occurred at 140 °C in
toluene in a sealed tube and gave the wanted cyclized product
15 in 20% yield (Conditions A). Further investigation suggested
that the low yield could be due to competitive desulfurization,
causing cleavage of the phenylsulfide tether before the cycliza-
tion. Optimized reaction conditions did not improve the reaction
yield dramatically. Furthermore, the high dilution conditions
required were unfavorable for scale-up. Next, we examined an
intramolecular reductive Heck reaction.28,29 Though the des-
ulfurization side reaction remained a problem, under the new
conditions (Conditions B), the required product 15 was formed
in 50% isolated yield (Scheme 4). Switching from TEA to the
sterically hindered base pentamethylpiperidine (PMP)-curtailed
desulfurization side reaction30 led to improvement of yield to
65%.
To this end, the basic framework of the target molecule was
successfully synthesized, which proved that the current synthetic
pathway is feasible. In accordance with the original design, we
applied the present route to synthesize 20 with an electron-rich
methoxyl group at the 4′-position. Compound 20 has been
successfully synthesized following the established synthetic
route, with some minor modifications to achieve the best results,
e.g., the epoxide-opening reaction was changed to run in a DMF/
acetonitrile system mediated by Cs2CO3 to avoid the dehydration
as a side reaction. The final steps involved cleavage of the sulfide
tether to release the phenyl ring and deprotection of the MOM
protecting group to expose the 7-hydroxyl group for further
diversification as shown in Scheme 5.
In summary, the framework of the designed target molecules
has been synthesized through an efficient 13-step stereoselective
pathway from commercially available compound 3 in an overall
yield of 6%. By applying this established synthetic route, several
diversified analogues of the target molecule have been synthe-
sized. The preliminary bioassay results of 1 and its oxalate
derivative were found to be very weakly active (<20%)
candidates for hPR ligands. However, the established synthetic
route paves a path to expand the spectra of this simple and this
novel class of nonsteroidal hPR ligands. An asymmetric variant
of the current synthesis and the diversified analogues of the
target hPR antagonists for chemical biology studies will be
reported in due course.
(17) Glotter, E.; Zviely, M. J. Chem. Soc., Perkin Trans. 1 1986, 321–325.
(18) Berbalk, H.; Eichinger, K.; Schuster, R. Synthesis 1981, 613–616.
(19) Decreau, R. A.; Marson, C. M. Synth. Commun. 2004, 34, 4369–4385.
(20) Laali, K.; Gerzina, R. J.; Flajnik, C. M.; Geric, C. M.; Dombroski, A. M.
HelV. Chim. Acta 1987, 70, 607–611.
(21) Crabbe, P.; Leon, C. J. Org. Chem. 1970, 35, 2594–2596.
(22) Khapli, S.; Dey, S.; Mal, D. J. Indian Inst. Sci. 2001, 81, 461–476.
(23) Takatsuto, S.; Ikekawa, N. Chem. Pharm. Bull. (Tokyo) 1986, 34, 4045–
4049.
(24) Hagiwara, H.; Kobayashi, K.; Miya, S.; Hoshi, T.; Suzuki, T.; Ando,
M.; Okamoto, T.; Kobayashi, M.; Yamamoto, I.; Ohtsubo, S.; Kato, M.; Uda,
H. J. Org. Chem. 2002, 67, 5969–5976.
(25) Yamada, O.; Ogasawara, K. Org. Lett. 2000, 2, 2785–2788.
(26) Rhone-Poulenc Rorer S.A., Fr., WO 9603395: Bouchard, H.; Bourzat,
J.-D.; Commercon, A. Chem. Abstr. 1996, 125, 11177.
Experimental Section
Compound 14. To a solution of ester 12 (200 mg, 0.42 mmol)
in DCM (2 mL) was added DMAP (150 mg, 1.23 mmol) at 0 °C.
The reaction mixture was stirred at 0 °C for 30 min and then
trifluoromethanesulfonyl chloride (80 mg, 0.5 mmol) was added.
The reaction mixture was stirred at 0 °C for 1 h, poured to ice
water, and extracted by DCM (3 × 5 mL). The organic layers were
combined, washed with brine, and dried over Na2SO4. After removal
of solvent under reduced pressure, the resulting residue was purified
(27) Takeda, Y.; Yoshino, T.; Uoto, K.; Terasawa, H.; Soga, T. Chem. Pharm.
Bull. (Tokyo) 2002, 50, 1398–1400.
(28) Schmidt, B.; Hoffmann, H. M. R. Tetrahedron 1991, 47, 9357–9368.
(29) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1999, 121, 3543–3544.
(30) Trost, B. M.; Thiel, O. R.; Tsui, H.-C. J. Am. Chem. Soc. 2002, 124,
11616–11617.
(31) The supplementary crystallographic data can be obtained free of charge
from The Cambridge Crystallographic Data Centre, ref. no. CCDC 678950, via
www.ccdc.cam.ac.uk/data_request/cif.
7766 J. Org. Chem. Vol. 73, No. 19, 2008

by silica gel chromatography (20% hexanes in ethyl acetate) to
provide the required triflate 13 as a colorless oil (200 mg, 80%),
which was directly used for the next dehydration step.
in ethanol (1 mL). The reaction mixture was heated to reflux for
1 h and then allowed to cool to room temperature. The reaction
mixture was filtered and concentrated under reduced pressure. The
resulting residue was purified by silica gel chromatography (30%
hexanes in ethyl acetate) to provide the required compound as a
To a solution of triflate 13 (200 mg, 0.33 mmol) in toluene (2
mL) was added DMAP (100 mg, 0.8 mmol). The reaction mixture
was stirred at 80-90 °C for 2 h, and then poured into ice water.
The reaction mixture was extracted by diethyl ether (3 × 5 mL).
The organic layers were combined, washed with brine, and dried
over Na2SO4. The organic layer was filtered and concentrated under
reduced pressure. The resulting residue was purified by silica gel
chromatography (30% hexanes in ethyl acetate) to provide the
1
colorless oil (40 mg, 83%). H NMR (500 MHz, CDCl3) δ 7.19
(d, J ) 8.0 Hz, 2 H), 6.83 (d, J ) 8.0 Hz, 2 H), 4.62 (ddd, J ) 8.0,
8.0, 8.0 Hz, 2 H), 3.88 (s, 1 H), 3.81 (s, 3 H), 3.69 (s, 3 H), 3.35
(s, 3 H), 3.10 (ddd, J ) 7.0, 7.0, 7.0 Hz, 1 H), 2.25 (dd, J ) 13.5,
6.0 Hz, 1 H), 1.90 (m, 3 H), 1.79 (m, 1 H), 1.65 (m, 3 H), 1.46 (m,
2 H), 1.30 (m, 2 H), 1.14 (s, 3 H); 13C NMR (125 MHz, CDCl3)
δ 178.7, 157.2, 136.2, 129.9 × 2, 113.2 × 2, 94.7, 72.2, 55.4 × 2,
52.1, 42.6, 41.0, 40.9, 40.3, 36.9, 34.9, 33.9, 30.6, 29.2, 25.8; IR
(CHCl3) 2918, 1730, 1039 cm-1; HRMS (TOF ES+) calcd for
C22H32O5Na 399.2147, found 399.2135.
1
wanted compound 14 as a colorless oil (110 mg, 75%). H NMR
(500 MHz, CDCl3) δ 7.59 (d, J ) 8.0 Hz, 1 H), 7.50 (d, J ) 8.0
Hz, 1 H), 7.28 (dd, J ) 8.0, 8.0 Hz, 1 H), 7.08 (dd, J ) 8.0, 8.0
Hz, 1 H), 5.82 (d, J ) 10.0 Hz, 1 H), 5.60 (d, J ) 10.0 Hz, 1 H),
4.65 (ddd, J ) 7.0, 7.0, 7.0 Hz, 2 H), 3.89 (d, J ) 2.5 Hz, 1 H),
3.74 (s, 3 H), 3.63 (br s, 1 H), 3.37 (s, 3 H), 2.75 (br s, 1 H), 2.20
(br dd, J ) 12.5, 12.5 Hz, 1 H), 1.81 (m, 2 H), 1.75 (m, 1 H), 1.49
(m, 2 H), 1.39 (s, 3 H); 13C NMR (125 MHz, CDCl3) δ 177.2,
136.8, 133.2, 131.2, 131.0, 129.5, 127.7, 127.5, 125.9, 95.8, 75.3,
55.6, 52.3, 51.9, 44.8, 39.9, 39.4, 31.1, 27.7, 26.4, 26.1; IR (CHCl3)
2925, 1731, 1578, 1463, 1237, 1101, 1034 cm-1; HRMS (TOF ES+)
calcd for C21H27O4SBrK 493.0451, found 493.0461.
Compound 1. To a solution of ester 21 (40 mg, 0.10 mmol) in
MeOH (2 mL) was added a trace amount of HCl. The reaction
mixture was heated to reflux for 1 h and then allowed to cool to
room temperature. The reaction mixture was concentrated under
reduced pressure. The resulting residue was purified by silica gel
chromatography (60% hexanes in ethyl acetate) to provide the
required compound as a colorless oil (30 mg, 79%). 1H NMR (500
MHz, CDCl3) δ 7.17 (d, J ) 8.5 Hz, 2 H), 6.83 (d, J ) 8.5 Hz, 2
H), 4.10 (s, 1 H), 3.81 (s, 3 H), 3.69 (s, 3 H), 3.10 (ddd, J ) 7.5,
7.5, 7.5 Hz, 1 H), 2.24 (dd, J ) 13.5, 6.0 Hz, 1 H), 1.94 (m, 1 H),
1.82 (m, 2 H), 1.74 (m, 1 H), 1.65 (m, 1 H), 1.54 (m, 3 H), 1.31
(m, 2 H), 1.14 (s, 3 H); 13C NMR (125 MHz, CDCl3) δ 178.7,
157.2, 136.2, 129.9 × 2, 113.2 × 2, 67.1, 55.4, 52.1, 42.6, 40.9,
40.8, 40.2, 37.0, 36.3, 34.1, 32.9, 28.6, 26.0; IR (CHCl3) 3416,
2923, 1729, 1511, 1247 cm-1; HRMS (TOF ES+) calcd for
C20H27O3 315.1960, found 315.1955.
Compound 15. To a solution of Pd(OAc)2 (10 mg, 0.045 mmol),
Ph3P (26 mg, 0.1 mmol), pentamethylpiperidine (125 mg, 0.145
mL, 0.8 mmol), and formic acid (20 mg, 0.43 mmol) in anhydrous
DMF (2 mL) was added ester 14 (100 mg, 0.22 mmol). The reaction
mixture was heated to 50 °C for 6 h, and then allowed to cool to
room temperature. The reaction mixture was poured into ice water
and extracted with ethyl acetate (3 × 5 mL). The organic layers
were combined, washed with brine, and dried over sodium sulfate.
The organic layer was filtered and concentrated under reduced
pressure. The resulting residue was purified by silica gel chroma-
tography (30% hexanes in ethyl acetate) to provide the required
Acknowledgment. The authors wish to thank Dr. Jiangnan
Peng in the Department of Pharmacognosy at the University of
Mississippi for his technical assistance.
1
compound as a colorless oil (54 mg, 65%). H NMR (400 MHz,
CDCl3) δ 7.42 (m, 2 H), 7.01 (m, 2 H), 4.62 (m, 2 H), 3.98 (s, 1
H), 3.83 (s, 1 H), 3.72 (s, 3 H), 3.35 (s, 3 H), 3.23 (br s, 1 H), 2.71
(d, J ) 13.5, 6.0 Hz, 1 H), 2.16-1.40 (m, 9 H), 1.21 (s, 3 H);
HRMS (TOF ES+) calcd for C19H23O2S [M+ - MOM] 315.1419,
found 315.1434.
Supporting Information Available: Characterization data,
crystallographic data for 18, and NMR spectra for all com-
pounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
Compound 21. To a suspension of Raney 2800 Nickel (1 mL)
in ethanol (5 mL) was added a solution of 20 (50 mg, 0.13 mmol)
JO800947M
J. Org. Chem. Vol. 73, No. 19, 2008 7767