Generation of novel, potent urotensin-II receptor antagonists by alkylation-cyclization of isoindolinone C3-carbanions

Article abstract of DOI:10.1016/j.tetlet.2009.06.025

We report a facile alkylation-cyclization reaction involving the isoindolinone C3 position, which resulted in tricyclic derivatives 2 and 10 in 48% and 32% yields, respectively. These novel compounds possess potent urotensin-II receptor antagonist activit

Full text of DOI:10.1016/j.tetlet.2009.06.025

Tetrahedron Letters 50 (2009) 4958–4961
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Generation of novel, potent urotensin-II receptor antagonists
by alkylation–cyclization of isoindolinone C3-carbanions
Diane K. Luci, Edward C. Lawson, Shyamali Ghosh, William A. Kinney, Charles E. Smith,
*
Jenson Qi, Yuanping Wang, Lisa K. Minor, Bruce E. Maryanoff
Johnson & Johnson Pharmaceutical Research & Development, Welsh & McKean Roads, Spring House, PA 19477-0776, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
We report a facile alkylation–cyclization reaction involving the isoindolinone C3 position, which resulted
in tricyclic derivatives 2 and 10 in 48% and 32% yields, respectively. These novel compounds possess
potent urotensin-II receptor antagonist activity.
Received 14 May 2009
Accepted 3 June 2009
Available online 9 June 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Urotensin-II (U-II) cyclic peptides and their cell-surface receptor
(UT) are intimately involved in cardiorenal diseases,1 such as
hypertension,2 heart failure,3 and chronic renal failure.4 The U-II
receptor is a member of the G-protein-coupled receptor (GPCR)
superfamily and is expressed in a wide range of tissues.1 Thus,
we have been vigorously pursuing U-II receptor antagonists as
potential therapeutic agents.5
with potent U-II receptor antagonist activity (e.g., 2). Herein, we re-
port on this useful chemical conversion and this novel U-II antag-
onist chemotype.
We reacted 3, obtained from 4-benzyloxybutanoic acid and
MeNHOMe, with 3,4-dimethoxyphenylmagnesium bromide and
reductively aminated the ketone product enantioselectively to give
4 (95% ee) (Scheme 1).8,9 Amine 4 was condensed with bromo ester
5 to give 6. The chloro group in 6 was displaced with N-ethylpiper-
azine and the benzyl group was removed to give 7. Compound 7
was converted to iodide 8a, which was viewed as a precursor to al-
kene 9. However, treatment of 8a with NaO-t-Bu (1 h, 60 °C) not
only provided 9 (46%), but also generated a significant amount
(33%) of another product (Scheme 2), which was identified as tricy-
cle 2 (a benzoindolizidinone) by NMR spectroscopy.10 Thus, there
was a competing reaction involving deprotonation of the C3 posi-
tion of the isoindolinone to form a transient carbanion that under-
went cyclization. Notably, we were able to completely shift the
reaction in favor of tricycle 2 by employing mesylate 8b as the sub-
strate. Thus, treatment of 8b with NaO-t-Bu under the same condi-
tions afforded 2 in 48% yield.11
We investigated the application of this chemical process to
other ring sizes. To obtain the 7-membered system, 10, by alkyl-
ation–cyclization, we synthesized mesylate 11 by the chain-exten-
sion protocol as depicted in Scheme 3.12 Treatment of 11 with
NaO-t-Bu under the same conditions afforded 10 in 32% yield.13
For the 5-membered system, 14, we synthesized precursor mesy-
late 15 by the route presented in Scheme 4.14 However, exposure
of 15 to NaO-t-Bu at reflux did not produce any of desired 14 (a
pyrroloisoindolinone); only decomposition was observed. The
same reaction at 23 °C for 24 h just gave a minor amount of alkene
18.15 The failure of 15 to undergo alkylation–cyclization may be re-
lated to ring strain that develops in the transition state for carban-
ion attack on the carbon bearing the mesylate en route to the 6,5,5
tricyclic skeleton.
Et
Et
N
OMe
OMe
N
N
N
H
N R
H
H
NR
NH
S
O
S
O
OMe
OMe
O
O
1 (JNJ-39319202)
2
Our studies led to a key series of nonpeptide U-II antagonists
containing a central isoindolinone subunit, such as 1, which exhib-
ited single-digit nanomolar potency in U-II receptor functional and
binding assays.5c Since various isoindolinone derivatives possess
diverse biological properties,6 and isoindolinones are substructures
of some natural products,7 this ring system is inherently interest-
ing. In prospecting for useful compounds analogous to 1, we
encountered a facile alkylation–cyclization reaction involving the
isoindolinone C3 position, which yielded novel tricyclic derivatives
* Corresponding author. Tel.: +1 215 6285530; fax: +1 215 5404612.
E-mail address: bmaryano@its.jnj.com (B.E. Maryanoff).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.06.025

D. K. Luci et al. / Tetrahedron Letters 50 (2009) 4958–4961
4959
O
NH
2
1) ArMgBr, THF, 5-23°C, 24 h
R
Ar
MeN
OMe
(CH ) OBn
2 3
(CH ) OBn
2 3
H
R
2) [( -Tol-Binap)RuCl2(DMF)x],
4
NH4HCO2, 2.0 M NH3 in
MeOH, ~80°C, 24 h
(49% for 2 steps)
3
MeO
MeO
Ar =
R
-Tol-Binap = (
R
p
)-(+)-2,2'-bis(di- -tolylphosphino)-1,1'-binaphthyl
Cl
Cl
Br
1) 4, Et3N, CH2Cl2, x h
Ar
N
H
2) toluene, Δ, 24 h
CO Me
2
O
(87%)
OBn
5
6
N-Et-piperazine, [(t-Bu)3P]2Pd,
(C16H33)Me3N+Br-, KOH, H2O,
H2, Pd/C
toluene, 90 °C, 24 h
(74%)
EtOH, 23 h
(86%)
Et
N
Et
N
a: Ph3P, imidazole, I2,
CH2Cl2, 1 h (85%)
N
N
Ar
Ar
b: MeSO2Cl, Et3N,
N
N
H
H
CH2Cl2 (65%)
O
O
X
OH
7
8a X = I
8b X = OMs
Ar = 3,4-dimethoxyphenyl
Scheme 1.
Et
N
Et
N
Et
N
OMe
MeO
N
(CH2)
N
H
n
N
NaOBut in THF
8a X = I
H
2 +
N
R
H
N
O
9
H
N
8b X = OMs
R
(MeOCH2)2, 1 h, 60 °C
O
OMe
OMe
O
OMe
OMe
10 n = 4
14 n = 2
18
Scheme 2.
alkylation–cyclization reactions to obtain 6,5,6 (benzoindolizidi-
none) and 6,5,5 (pyrroloisoindolinone) tricyclic systems.18b How-
ever, in their case the C3 position was substituted with a PhSO2
group, which would strongly stabilize the carbanion, and the alkyl-
A possible explanation for the high diastereocontrol in the
alkylation–cyclization relates to comparative steric interactions,
as depicted in Figure 1. The intermediate benzylic carbanion can
react via pathway A or B, but the latter is strongly disfavored be-
cause of its A(1,3)-type steric strain.16 Thus, 2 is formed exclusively
over the alternative diastereomer.
Carbon–carbon bond formation at the C3 position of isoindoli-
nones has attracted synthetic interest7a,d,17 since two early reports
were published in 1998.18 Luzzio and Zacherl were able to execute
ation electrophile was an
a
,b-unsaturated ester. Moreau et al.7d
also carried out alkylation–cyclization reactions, but with a ben-
zyne-based electrophile. As far as we are aware, our reactions rep-
resent the first indolinone C3 alkylation–cyclization involving a
simple alkyl group that bears a halide or sulfonate ester leaving
group.

4960
D. K. Luci et al. / Tetrahedron Letters 50 (2009) 4958–4961
O
Et
N
O
O
I
MeO
N
OMe
CHO
O
OH
Ph3PMe+Br-, K2CO3
N
(IBX-polystyrene)
7
18-crown-6, CH2Cl2
(34%)
H
CH2Cl2 (95%)
O
12
Et
N
Et
N
MeO
OMe
MeO
N
OMe
1) 9-BBN, THF
2) 3 N NaOH, 30% H2O2
N
N
N
H
H
3) MsCl, Et3N, CH2Cl2
(48%)
O
O
OMs
13
11
Scheme 3.
OMe
OMe
Br
Br
NH2
Et3N, toluene
MeO
MeO
Br
OBn
N
+
reflux, 6 h
(85%)
CO2Me
O
16
OBn
17
Et
1. N-Et-piperazine, KOH (45%), C16H33NMe3+Br-,
[(t-Bu)3P]2Pd, sealed tube, 90 °C, 24 h
(50-58%)
N
OMe
OMe
N
N
2. H2, Pd/C (5%), HCl (cat.), EtOH/EtOAc, 6 h
3. MsCl, Et3N (5 equiv), CH2Cl2, 0 °C, 2 h
(50%)
O
OMs
15
Scheme 4.
in a FLIPR-based assay that measures intracellular calcium flux.20,21
Thus, we obtained Ki values of 64 nM for binding and 390 nM for
functional antagonism.
In summary, we have identified a facile and useful alkylation–
cyclization reaction involving the isoindolinone C3 position, which
resulted in tricyclic derivatives 2 and 10. An attempt to synthesize
the corresponding 6,5,5-system, 14, was unsuccessful. Novel com-
pounds 2 and 10 were found to display potent U-II receptor antag-
onist activity.
Et
Et
N
N
X
X
N
OMe
OMe
N
-
-
H
N
N
H
O
O
OMe
MeO
Acknowledgment
A
B
We thank Diane Gauthier for NMR spectroscopic studies and
analyses.
Figure 1. Mechanistic proposal for diastereoselectivity.
Urotensin-II antagonist activity was assessed for 2 and 10 by
using CHO-K1 cells transfected with rat U-II receptor and a
FLIPR-based assay that measures intracellular calcium flux.5a,19
Thus, we obtained potent Ki values of 6.3 and 34 nM for 2 and
10, respectively. For comparison, alkene 13 had a rat FLIPR Ki value
of 9 nM. Compound 2 was also examined for binding to human U-II
receptors20 and for the inhibition of human U-II functional activity
References and notes
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(d) Ong, K. L.; Lam, K. S. L.; Cheung, B. M. Y. Cardiovasc. Drugs Ther. 2005, 19, 65;
(e) Carmine, Z.; Mallamaci, F. Curr. Opin. Nephrol. Hypertens. 2008, 17, 199.

D. K. Luci et al. / Tetrahedron Letters 50 (2009) 4958–4961
4961
2. (a) Matsushita, M.; Shichiri, M.; Imai, T.; Iwashina, M.; Tanaka, H.; Takasu, N.;
Hirata, Y. J. Hypertens. 2001, 19, 2185; (b) Krum, H.; Kemp, W. Curr. Hypertens.
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3. (a) Douglas, S. A.; Tayara, L.; Ohlstein, E. H.; Halawa, N.; Giaid, A. Lancet 2002,
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Leung, P. A.; Maryanoff, B. E. Angew. Chem., Int. Ed. 2002, 41, 2940; (b) Luci, D.
K.; Ghosh, S.; Smith, C. E.; Qi, J.; Wang, Y.; Haertlein, B.; Parry, T. J.; Li, J.;
Almond, H. R.; Minor, L. K.; Damiano, B. P.; Kinney, W. A.; Maryanoff, B. E.;
Lawson, E. C. Bioorg. Med. Chem. Lett. 2007, 17, 6489; (c) Lawson, E. C.; Luci, D.
L.; Ghosh, S.; Kinney, W. A.; Reynolds, C. H.; Qi, J.; Smith, C. E.; Wang, Y.; Minor,
L. K.; Haertlein, B. J.; Parry, T. J.; Damiano, B. P.; Maryanoff, B. E. J. Med. Chem.,
accepted for publication.
6. (a) Zhuang, Z.-P.; Kung, M.-P.; Mu, M.; Kung, H. F. J. Med. Chem. 1998, 41, 157;
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Assink, B. K.; Bates, R. C., Jr.; Erdman, D. T.; Fedji, V.; Jennings, S. M.; Lassig, J. A.;
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Kawakami, T.; Hirano, E.; Yokota, H.; Kitajima, H. Synlett 1996, 353; (g) Anzini,
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Tetrahedron Lett. 2005, 46, 5639. and references cited.
11. Experimental:
A
solution of mesylate 8b (112 mg, 0.211 mmol) in 1,2-
dimethoxyethane (0.80 mL) was treated with 4 M NaO-t-Bu in THF (0.5 mL).
The reaction mixture was stirred at 60 °C for 1 h and allowed to cool to room
temperature. The reaction mixture was poured into 10 mL of water and was
extracted with EtOAc (2 Â 15 mL). The combined organic layers were washed
with 10 mL of brine, dried (Na2SO4), and concentrated in vacuo. Purification of
the residue by using reverse-phase prep-HPLC (chromasil; 5–90 gradient of
water (w/0.2% CF3CO2H)/MeCN (w/0.15% CF3CO2H) yielded 45 mg (48%) of 2 as
a pale yellow solid.
12. Oxidation with PS-iodoxyl reagent: (a) Sorg, G.; Mengel, A.; Jung, G.; Rademan,
J. Angew. Chem., Int. Ed. 2001, 40, 4395; 9-BBN chemistry: (b) Chan, C. et al J.
Med. 1993, 36, 3646.
13. (a) Compound 11 in 1,2-dimethoxyethane was treated with 4 M NaO-t-Bu in
THF and the mixture was stirred at 60 °C for 1 h.11 Purification by reverse-
phase prep-HPLC (chromasil; 5–90 gradient of water (w/0.2% CF3CO2H)/MeCN
(w/0.15% CF3CO2H) gave product 10. (b) MS (ESI) m/z 450 (M+H); 1H NMR
(400 MHz, CDCl3) d 0.91 (t, J = 6.9 Hz, 3 H), 1.22–1.31 (m, 2H) 1.33–1.45 (m,
2H), 1.61–1.78 (m, 2H), 2.02–2.15 (m, 2H), 2.33–2.51 (br s, 4H), 2.87–3.01 (br
m, 2H), 3.16–3.52 (m, 4H), 3.85 (s, 3H), 3.88 (s, 3H), 4.19–4.28 (d, J = 17.0 Hz,
1H), 5.55 (t, J = 6.5 Hz, 1 H), 6.75 (d, J = 8.0 Hz, 1H), 6.83 (d, J = 1.7 Hz, 1H),
6.91–6.98 (m, 1H), 7.15 (d, J = 7.8 Hz, 1H), 7.41 (t, J = 7.7 Hz, 1H), 7.48–7.56 (m,
1H).
14. 1H NMR (300 MHz, CDCl3) d 1.13 (t, J = 7.2 Hz, 3H), 1.71–1.89 (m, 2H), 2.20–
2.27 (m, 2H), 2.47–2.71 (m, 6H), 3.01 (s, 3H), 3.08 (m, 3H), 3.61–3.65 (m, 1H),
3.85 (s, 3H), 3.88 (s, 3H), 3.96 (s, 1H), 5.57 (t, J = 8.0 Hz, 1H), 4.30–4.21 (m, 3H),
6.84–7.04 (m, 3H), 7.10 (d, J = 8.0 Hz, 1H), 7.41 (t, J = 7.7 Hz, 1H), 7.51 (d,
J = 7.5 Hz, 1H).
15. Amine 16 was prepared from 3-(3,4-dimethoxy)-3-aminopropanoic acid by the
following sequence: (1) NaBH4, I2, THF, reflux, 18 h (90%); (2) Boc2O, 1 N NaOH,
1,4-dioxane, 0 °C, 8 h (83%); (3) NaH, THF, 0 °C, then PhCH2Br, 8 h (25–50%); (4)
4 N HCl, 1,4-dioxane, 4 h (80À85%).
7. Lennoxamine: (a) Comins, D. L.; Schilling, S.; Zhang, Y. Org. Lett. 2005, 7, 95; (b)
Couty, S.; Meyer, C.; Cossy, J. Tetrahedron Lett. 2006, 47, 767; Nuevamine: (c)
Alonso, R.; Castedo, L.; Dominguez, D. Tetrahedron Lett. 1985, 26, 2925; (d)
Moreau, A.; Couture, A.; Deniau, E.; Grandclaudon, P.; Lebrun, S. Tetrahedron
2004, 60, 6169; Staurosporine: (e) Rüegg, U. T.; Burgess, G. M. Trends Pharmacol.
Sci. 1989, 29, 253; (f) Wood, J. L.; Stoltz, B. M.; Goodman, S. N. J. Am. Chem. Soc.
1996, 118, 10656.
16. Johnson, F. Chem. Rev. 1968, 68, 375; Hoffmann, R. W. Chem. Rev. 1989, 89,
1841.
17. (a) Enders, D.; Braig, V.; Raabe, G. Can. J. Chem. 2001, 79, 1528; (b) Deniau, E.;
Enders, D. Tetrahedron 2001, 57, 2581; (c) Guo, Z.; Schultz, A. C. J. Org. Chem.
2001, 66, 2154; (d) Pérard-Viret, J.; Prangé, T.; Tomas, A.; Royer, J. Tetrahedron
2002, 58, 5103; (e) Couture, A.; Deniau, E.; Grandclaudon, P.; Hoarau, C.; Rys, V.
Tetrahedron Lett. 2002, 43, 2207; (f) Comins, D. L.; Hiebel, A.-C. Tetrahedron Lett.
2005, 46, 5639; (g) Lamblin, M.; Couture, A.; Deniau, E.; Grandclaudon, P.
Tetrahedron: Asymmetry 2008, 19, 111.
18. (a) Couture, A.; Deniau, E.; Ionescu, D.; Grandclaudon, P. Tetrahedron Lett. 1998,
39, 2319; (b) Luzzio, F. A.; Zacherl, D. P. Tetrahedron Lett. 1998, 39, 2285.
19. FLIPR, Fluorescence Imaging Plate Reader.
20. Binding measurements were performed with cultured human rhabdomyo-
sarcoma cells (RMS13) and [125I]U-II (Qi, J.-S.; Minor, L. K.; Smith, C.; Hu, B.;
Yang, J.; Andrade-Gordon, P.; Damiano, B. Peptides 2005, 26, 683).
21. By using cultured human rhabdomyosarcoma (RMS13) cells (Xin, H.; Wang, Y.;
Todd, M. J.; Qi, J.; Minor, L. K. J. Biomol. Screening 2007, 12, 705).
8. Nahm, S.; Weinreb, S. M. Tetrahedron. Lett. 1981, 22, 3815.
9. Kadyrov, R.; Riermeier, T. H. Angew. Chem., Int. Ed. 2003, 42, 5472.
10. Compound 2: MS (ESI) 436.4 (M+H); 1H NMR (500 MHz, CDCl3) d 1.15 (d,
J = 12.5 Hz, 1H), 1.40 (t, J = 7.3 Hz, 3H), 1.79–1.88 (m, 2H), 2.54 (dd, J = 23.8,
2.7 Hz, 1H), 2.52 (d, J = 18.3 Hz, 1H), 2.89 (t, J = 12.0 Hz, 1H), 3.17 (dd, J = 7.3,
1.5 Hz, 2H), 3.23 (d, J = 12.5 Hz, 1H), 3.29 (d, J = 6.4 Hz, 2H), 3.57 (t, J = 11.3 Hz,
1H), 3.68 (d, J = 11.0 Hz, 1H), 3.76 (d, J = 11.3 Hz, 1H), 3.85 (d, J = 20.7 Hz, 6H),
4.34 (dd, J = 12.0, 3.8 Hz, 1H), 5.78 (d, J = 2.7 Hz, 1H), 6.79–6.85 (m, 2H), 7.29 (d,
J = 7.6 Hz, 1H), 7.50 (t, J = 7.8 Hz, 1H), 7.74 (d, J = 7.3 Hz, 1H); 13C NMR
(500 MHz, CDCl3) d 166.8, 149.4, 148.2, 146.1, 139.1, 133.7, 131.9, 129.9, 123.0,
120.6, 118.8, 111.2, 110.6, 56.1, 55.9, 55.6, 52.2, 51.7, 49.4, 48.0, 30.4, 27.5,
19.8, 9.1. The 24 carbon resonances are consistent with a single diastereomer.
The stereochemistry was assigned from a 1H NOESY experiment that showed a
strong interaction between protons Ha and Hc, but not between protons Ha and
Hb (see diagram below).
Et
N
N
Ha
Hb
Hc
N
Hc
OMe
OMe
O