A convenient enantioselective synthesis of 3-asymmetrically substituted oxindoles as progesterone receptor antagonists

Article abstract of DOI:10.1016/j.tetlet.2011.05.120

A convenient enantioselective synthesis of 3-asymmetrically substituted oxindoles is reported. Compound (2) prepared by radical cyclisation of (1) was used for the synthesis of racemic and enantiomerically pure 3-asymmetrically substituted oxindoles. Desu

Full text of DOI:10.1016/j.tetlet.2011.05.120

Tetrahedron Letters 52 (2011) 3945–3948
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Tetrahedron Letters
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A convenient enantioselective synthesis of 3-asymmetrically substituted
oxindoles as progesterone receptor antagonists
S. Alluri a, H. Feng a, M. Livings a, L. Samp a, D. Biswas a, T. W. Lam b, E. Lobkovsky c, A. K. Ganguly a,
⇑
a Department of Chemistry and Chemical Biology, Stevens Institute of Technology, Hoboken, NJ 07030, USA
b Merck Research Laboratories, Oss, The Netherlands
c Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient enantioselective synthesis of 3-asymmetrically substituted oxindoles is reported. Com-
pound (2) prepared by radical cyclisation of (1) was used for the synthesis of racemic and enantiomeri-
cally pure 3-asymmetrically substituted oxindoles. Desulfurisation of (2) using Raney Ni yielded the
racemate (5). Addition of (S)-1-phenylethanol to compound (2) yielded the diastereoisomer (21) the
structure of which was determined using X-ray crystallography. Using a sequence of steps (21) was con-
verted to the enantiomer (8). The enantiomer (9) was similarly prepared from (2) using (R)-1-
phenylethanol.
Received 26 April 2011
Accepted 25 May 2011
Available online 1 June 2011
Keywords:
Radical cyclization
Desulfurisation
Enantioselective synthesis
Progesterone receptor antagonist
Ó 2011 Elsevier Ltd. All rights reserved.
In a previous publication1 from our laboratory we reported the
conversion of compound (1–2) using tributyltin hydride, 2,20-azob-
isisobutyronitrile (AIBN) in toluene solution at 110 °C (Scheme 1).
We repeated the reaction with (3) and obtained (4). Compounds
(1) and (3) were easily prepared by treating ortho bromoaniline
with the acid chloride derived from thiophene-3-carboxylic acid
in the presence of pyridine, followed by N-alkylation of the amides.
In this Letter we wish to report the conversion of (2–5) and (4–
6) both of which are asymmetrically substituted oxindoles
(Scheme 2), a feature present in several natural products and phar-
maceutical molecules.2,3 We have also successfully used (2) for the
enantioselective synthesis of this class of compounds. Using our
synthetic procedure described in this Letter we have synthesised4
racemic (7) and enantiomerically pure (8) and (9) (Fig. 1). These
compounds are novel and related to Wyeth 255348,5a which has
been reported to be a potent progesterone receptor antagonist.
Excepting racemic (10)5b all the compounds synthesized by Wyeth
scientists were symmetrically substituted oxindoles. We wish to
report the progesterone receptor antagonist activity of our com-
pounds. Progesterone receptor antagonist, mifepristone6a has been
in use in the clinic as an abortifacient. They are also potentially
useful for the treatment of cancer and non-malignant chronic con-
ditions such as uterine fibroids and endometriosis.6b–f
provided the desulfurised products (5) and (6), respectively. Bro-
mination of (5) and (6) using Br2/AcOH and NaOAc afforded the
5-bromooxindoles (11) and (12), respectively (Scheme 3). Palla-
dium-catalyzed Suzuki coupling of (11) with phenylboronic acid
(13) in dimethoxyethane and water (1:1) as solvent and in the
presence of sodium bicarbonate afforded (14) as a racemate. The
N-benzyl analog (15) was similarly synthesized from (12). Suzuki
coupling of (11) with 4-fluorophenylboronic acid (16) and 2-thio-
pheneboronic acid (17) yielded (7) and (18), respectively.
The synthesis of N–H analog (20) is shown in Scheme 4. Com-
pound (6) on treatment with N-bromosuccinimide and AIBN in
ethyl acetate under refluxing conditions afforded (19) wherein
the debenzylation and bromination occurred in one step.7 The bro-
mo intermediate (19) was further reacted with phenylboronic acid
(13) under Suzuki coupling conditions to yield (20).
The racemic compounds (14), (15), (7), (18), and (20) were eval-
uated for progesterone receptor antagonist activity. In this assay
compound (7) was most potent with an IC50 = 50 nM and (15)
was inactive.
R
N
R
N
O
AIBN, TBTH
O
Toluene, 1100C
Br
S
Thus the key intermediates (2) and (4) when treated with Raney
Ni in the presence of isopropyl alcohol under refluxing conditions
S
Y: 52%
Y: 51%
(1) R= -CH3
(3) R= -CH2-Ph
(2) R= -CH3;
(4) R= -CH2-Ph;
⇑
Corresponding author. Tel.: +1 201 216 5540; fax: +1 201 216 8240.
E-mail address: akganguly1@aol.com (A.K. Ganguly).
Scheme 1. Radical reaction.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.05.120

3946
S. Alluri et al. / Tetrahedron Letters 52 (2011) 3945–3948
R
H
N
Ph
N
NBS, AIBN
Raney Ni
N
O
(2)
(4)
O
O
3
EA
Y: 55%
Br
IPA, 80 0C
(19)
(5) R= -CH ;
(6) R= -CH -Ph;
Y: 57%
(6)
3
Y: 48%
2
PdII(PPh3)2Cl2
Suzuki coupling
Y: 25%
OH
OH
Ph
B
(13)
Scheme 2. 3-Unsymmetrically substituted oxindoles.
H
N
O
Cl
NC
Ph
N
Me
O
(20)
N
O
H
N
F
Scheme 4. Synthesis of (20).
H
(10)
WAY 255348
CH3
N
(S)
CH3
N
(R)
anol and THF). Hydrogenation of compound (22) in the presence of
10%Pd/C and catalytic amount of trifluoroacetic acid in methanol
gave the alcohol (23). In the literature, compound (24) was re-
ported as a key intermediate in the asymmetric synthesis of physo-
stigmine and physovenine.11 Our synthetic approach will thus
provide an alternative way of making these alkaloids.
CH3
N
O
O
O
F
F
F
(9)
(8)
(7)
Figure 1. Spiro-oxindoles.
Bromination of (23) using NBS and AIBN in refluxing ethanol
yielded (25) which underwent Suzuki coupling with 4-fluor-
ophenylboronic acid (16) to give the alcohol (26).
Compound (18) showed IC50 = 295 nM. The N-unsubstituted
compound (20) showed IC50 = 161 nM and the corresponding
N-methyl compound (14) showed IC50 = 141 nM.
Deoxygenation12 of (26–8) was achieved using the following
two steps. Compound (26) was treated with p-toluenesulfonyl
chloride and pyridine in DCM to yield (27), which upon treatment
with NaI, AIBN and TBTH using dimethoxyethane as solvent at
80 °C yielded the (R)-enantiomer (8).
We decided to use the key intermediate (2) for the enantiose-
lective synthesis of the enantiomers of (7) to determine their activ-
ities compared to the racemate. Thus treatment of spirooxindole
(2) with (S)-1-phenylethanol in the presence of p-toluenesulfonic
acid and toluene at room temperature afforded a mixture of diaste-
reoisomers. Purification by chromatographic techniques yielded
diasteroisomer (21)8 (Scheme 5). The absolute stereochemistry of
(21) was established as C3(S), C13(R), C17(S) using X-ray crystallo-
graphic analysis9 (Fig. 2).
Treatment of compound (21) with Raney Ni in isopropyl alcohol
under refluxing conditions gave the alcohol (23). The above step,
however, yielded the alcohol in variable yields. Thus we investi-
gated alternative methods for desulfurisation.
Having established the synthetic procedures for the preparation
of the (R)-enantiomer (8) we followed a similar concept for the
preparation of the corresponding (S)-enantiomer (9). Thus spiroox-
indole (2) when treated with (R)-1-phenylethanol and p-toluene-
sulfonic acid in toluene gave the diastereoisomer (28) (Scheme
6). Compound (28) was determined to be the enantiomer of (21)
the absolute stereochemistry of which was assigned based on the
X-ray crystallographic analysis. Compounds (21) and (28) were
identical in their spectroscopic properties including NMR spectros-
copy however in CD studies they showed similar rotation values
with opposite signs. Thus the absolute stereochemistry of com-
pound (28) is assigned to be C3(R), C13(S), C17(R). Following the
same sequence of steps as in Scheme 5, compound (28) afforded
the desulfurised product (29), which upon hydrogenation yielded
After several experiments desulfurisation of compound (21)
was achieved reproducibly using nickel boride.10 Compound (21)
was thus converted to (22) using nickel boride (prepared in situ
using nickel chloride/sodium borohydride in 3:1 mixture of meth-
HO OH
B
CH3
N
(13)
CH3
N
O
PdII(PPh3)2Cl2
(11)
O
Y: 99%
(14)
CH3
Suzuki coupling
Br
HO OH
B
(11) R = CH3 Y: 67%
(12) R = CH2Ph Y: 31%
N
(16)
O
F
(7)
Y: 71%
F
CH3
N
OH
B
S
(17)
OH
O
Y: 64%
S
(18)
Ph
O
(13)
PdII(PPh3)2Cl2
Suzuki coupling
N
(12)
Y: 65%
(15)
Scheme 3. Bromination and Suzuki coupling.

S. Alluri et al. / Tetrahedron Letters 52 (2011) 3945–3948
3947
CH3
N
(R)
OH
O
Me
(S)
NiCl2/NaBH4
MeOH:THF(3:1)
Y: 92%
MeO
(22)
[θ]208= -393
O
O
H
H2/ 10%Pd/C
MeOH, TFA(cat.)
Y: 99%
N
Me
H3C
(S)
O
(24)
CH3
N
CH3
N
OH
CH3
N
CH3
N
F
B
(S) 1-Phenyl ethanol
OH
Raney Ni
IPA, 800C
Y: 86%
O
NBS, AIBN
(S)
(R)
O
O
(R)
3
Toluene, RT
Y: 20%
Br
H
S
EtOH, reflux
Y: 83%
Pd(PPh3)2Cl2
NaHCO3, DME
S
13
H
(R)
(2)
(25)
H3C
(S)
HO
O
Y: 89%
17
HO
[θ]208= -682
(23)
(21)
X-RAY
[θ]288= -1034
[θ]228= +1616
CH3
CH3
N
N
(R)
CH3
N
O
p-toluene sulfonyl
chloride
O
NaI, AIBN, TBTH
(R)
O
(R)
F
DME
pyridine, DCM
Y: 55%
F
O
Y: 70%
F
(8)
SO2
(27)
(26)
HO
H3C
[θ]226= +1171
Scheme 5. Synthesis of (R)-enantiomer (8).
CH3
N
CH3
N
(S)
CH3
O
O
(R)
NiCl2/NaBH4
N
(R) 1-Phenylethanol
3
O
H
Toluene, RT
Y: 20%
MeOH:THF(3:1)
Y: 90%
S
(S)
13
H
H
S
H3C
(R)
O
H3C
(R)
O
(2)
17
(28)
(29)
[θ]288= +981
[θ]228= -1762
[θ]208= +313
CH3
N
CH3
(16)
NBS, AIBN
N
H2/ 10%Pd/C
O
O
(S)
(S)
Pd(PPh3)2Cl2
NaHCO3, DME
Y: 90%
EtOH, reflux
Y: 76%
MeOH, TFA(cat.)
Y: 99%
Br
HO
(30)
(31)
HO
[θ]208= +584
CH3
N
CH3
N
O
(S)
O
(S)
Steps
F
F
(9)
HO
(32)
[θ]226= -1104
Scheme 6. Synthesis of (S)-enantiomer (9).
In conclusion, a novel approach for the enantioselective synthe-
sis of 3-unsymmetrically substituted 5-aryl oxindoles is described.
All the compounds disclosed in this Letter are novel and represent
the first examples of chiral oxindoles as progesterone receptor
antagonists. Further work is in progress to extend our present work
toward the synthesis of the enantiomers of physostigmine
alkaloids.
Figure 2. X-ray crystal structure of compound (21).
alcohol (30). Bromination of (30) followed by Suzuki reaction with
(16) yielded (32). Deoxygenation of (32) in two steps gave the (S)-
enantiomer (9).
Acknowledgments
The progesterone receptor antagonist activities of the enantio-
mers (8) and (9) of compound (7) were evaluated in parallel. In this
experiment compound (7) showed IC50 = 247 nM. The (R)-enantio-
mer (8) showed IC50 = 111 nM and the (S)-enantiomer (9) showed
IC50 = 158 nM. We are unable to explain the differences of the IC50
values of (7) in two different experiments.
We wish to thank Stevens Institute of Technology, Hoboken, NJ
for generous financial support and Mr. Alexey Makarov, Novartis
Pharmaceuticals Corporation, East Hanover, NJ for providing CD
data.

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S. Alluri et al. / Tetrahedron Letters 52 (2011) 3945–3948
8. Typical procedure for the preparation of (21). To a solution of compound (2)
References and notes
(300 mg, 1.38 mmol) in toluene (3 mL), was added p-toluenesulfonic acid
monohydrate (315.16 mg, 1.65 mmol) followed by (S)-1-phenylethanol
(337.3 mg, 2.76 mmol) and the reaction mixture was stirred at room
temperature (rt) for overnight. Trace of starting material was present even
after prolonged reaction times. The reaction mixture was diluted with ethyl
acetate and washed with water. The organic layer was dried over anhydrous
Na2SO4, filtered and concentrated to yield the crude product, which was
purified by flash column chromatography to yield the pure diastereoisomer
(21) as crystalline compound. The fractions containing mixtures of
diastereoisomers were further purified by preparatory TLC using MeOH/
CHCl3 (0.02:99.98). Compound (21) was recrystallised from DCM and hexane
(1:4) (94 mg, 20%). mp 118–120 °C; 1H NMR (400 MHz): d ppm 7.94 (d, 1H,
J = 7.4 Hz), 7.38–7.24 (m, 6H), 7.10 (t, 1H, J = 7.5 Hz), 6.85 (d, 1H, J = 7.8 Hz),
5.32 (d, 1H, J = 5.3 Hz), 4.78 (q, 1H, J = 6.4 Hz), 3.39 (d, 1H, J = 11.1 Hz), 3.23 (s,
3H), 3.11 (d, 1H, J = 11.1 Hz), 2.62 (dd, 1H, J = 5.5 Hz, J = 13.6 Hz), 2.33 (d, 1H,
J = 13.4 Hz), 1.55 (d, 3H, J = 6.5 Hz).
1. Ganguly, A. K.; Wang, C. H.; Chan, T. M.; Ing, Y. H.; Buevich, A. V. Tetrahedron
Lett. 2004, 45, 883.
2. (a) Wearing, X. Z.; Cook, J. M. Org. Lett. 2002, 4, 4237; (b) Albrecht, B. K.;
Williams, R. M. Org. Lett. 2003, 5, 197; (c) Reisman, S. E.; Ready, J. M.; Weiss, M.
M.; Hasuoka, A.; Hirata, M.; Tamaki, K.; Ovaska, T. V.; Smith, C. J.; Wood, J. L. J.
Am. Chem. Soc. 2008, 130, 2087; (d) Abadi, A. H.; Abou-Seri, S. M.; Abdel-
Rahman, D. E.; Klein, C.; Lozach, O.; Meijer, L. Eur. J. Med. Chem. 2006, 41, 296.
3. For enantioselective synthesis, see: (a) Tian, X.; Jiang, K.; Peng, J.; Du, W.; Chen,
Y.-C. Org. Lett. 2008, 10, 3583; (b) Yasui, Y.; Kamisaki, H.; Takemoto, Y. Org. Lett.
2008, 10, 3303; (c) Trost, B. M.; Zhang, Y. J. Am. Chem. Soc. 2007, 129, 14548; (d)
Linton, E. C.; Kozlowski, M. C. J. Am. Chem. Soc. 2008, 130, 16162; (e) Chen, X.-
H.; Wei, Q.; Luo, S.-W.; Xiao, H.; Gong, L.-Z. J. Am. Chem. Soc. 2009, 131, 13819.
4. NMR and high resolution mass spectra of all the compounds described in this
Letter were consistent with the assigned structures. Assignments were further
confirmed using 2D NMR and NOE experiments. It should be noted that the
yields (represented as Y) reported in this Letter are not optimised. The purity of
the compounds was established using various chromatographic techniques.
Compounds (3–9), (11), (12), (15), (18–20), (23), (27), (30), and (31) were not
crystalline. All other compounds described in the paper were crystalline.
Crystals were obtained from DCM–hexane for compounds (1), (2), (21), (22),
(25), (26), (28), (29), and (32). The melting points of compounds (1), (2), (21),
(22), (25), (26), (28), (29), (32) were 88–90, 96–97, 118–120, 81–82, 95–97,
130–132, 117–118, 96–97, 103–104 °C, respectively.
5. (a) Fensome, A.; Adams, W. R.; Adams, A. L.; Berrodin, T. J.; Cohen, J.; Huselton,
C.; Illenberger, A.; Kern, J. C.; Hudak, V. A.; Marella, M. A.; Melenski, E. G.;
McComas, C. C.; Mugford, C. A.; Slayden, O. D.; Yudt, M.; Zhang, Z.; Zhang, P.;
Zhu, Y.; Winneker, R. C.; Wrobel, J. E. J. Med. Chem. 2008, 51, 1861; (b) Fensome,
A.; Bender, R.; Cohen, J.; Collins, M. A.; Mackener, V. A.; Miller, L. L.; Ullrich, J.
W.; Winneker, R.; Wrobel, J.; Zhang, P.; Zhang, Z.; Zhu, Y. Bioorg. Med. Chem.
Lett. 2002, 12, 3487.
6. (a) Brogden, R. N.; Goa, K. L.; Faulds, D. Drugs 1993, 45, 384; (b) Chwalisz, K.;
DeManno, D.; Garg, R.; Larsen, L.; Mattia-Goldberg, C.; Stickler, T. Semin. Reprod.
Med. 2004, 22, 113; (c) Chwalisz, K.; Larsen, L.; Mattia-Goldberg, C.; Edmonds,
A.; Elger, W.; Winkel Craig, A. Fertil. Steril. 2007, 87, 1399; (d) Fedele, L.;
Berlanda, N. Exp. Opin. Emerging Drugs 2004, 9, 167; (e) Kettel, L. M.; Murphy, A.
A.; Morales, A. J.; Yen, S. S. C. Am. J. Obstet. Gynecol. 1998, 178, 1151; (f) Kettel, L.
M. Int. Congr., Symp. Semin. Ser. 1997, 13, 334 (Endometriosis Today).
7. Baker, R. S.; Parsons, A. F.; Wilson, M. Tetrahedron Lett. 1998, 39, 331.
9. Crystals of (21) were transferred from a crystallization vessel into a drop of
viscose organic oil. Using a nylon loop, a suitable single crystal has been
chosen, mounted on a Bruker X8 APEX II diffractometer (MoK radiation) and
a
cooled to ꢀ100 °C.Data collection and reduction were done using Bruker APEX2
[1] and SAINT+ [2] software packages. An empirical absorption correction was
applied with SADABS [3]. Structures were solved by direct methods and refined
on F2 by full matrix least-squares techniques using SHELXTL [4] software
package. All non-hydrogen atoms were refined anisotropically. Hydrogen
atoms were found in a difference Fourier map and refined isotropically.
For (21) the sample size was 0.6 ꢁ 0.2 ꢁ 0.15 mm3. Overall 8434 reflections
were collected, 4020 of which were symmetry independent (Rint = 0.0217);
with 3604 ‘strong’ reflections (with Fo > 4rFo). Final R1 = 3.71% APEX2 v.1.0-22
User Manual, Bruker AXS Inc., Madison WI 53719, 2004.SAINT+v.6.02 User
Manual, Bruker AXS Inc., Madison WI 53719, 1999.G.M.Scheldrick, SADABS,
Program for Empirical Absorption Correction of Area Detector Data, University
of Göttingen, 1996.G.M.Scheldrick, SHELXTL v. 5.10 Bruker AXS Inc., Madison
WI 53719, 1999.
Crystallographic data for (21) have been deposited with the Cambridge
Crystallographic Data Centre, deposition number CCDC 821991.
10. Back, T. G.; Baron, D. L.; Yang, K. J. Org. Chem. 1993, 58, 2407.
11. Matsuura, T.; Overman, L. E.; Poon, D. J. J. Am. Chem. Soc. 1998, 120, 6500. Also
see references cited there in.
12. Ueno, Y.; Tanaka, C.; Okawara, M. Chem. Lett. 1983, 795.