First synthesis of 1-phenyl-3-pyrrol-1-ylindan-2-carboxylic acid, a new scaffold of potential non-peptide endothelin receptor antagonists

Article abstract of DOI:10.1055/s-1999-2793

The first synthesis of trans, trans-1-phenyl-3-pyrrol-1-ylindan-2- carboxylic acid, a key-intermediate in the access to new potential non- peptide endothelin receptor antagonists, is reported.

Full text of DOI:10.1055/s-1999-2793

LETTER
1263
First Synthesis of 1-Phenyl-3-pyrrol-1-ylindan-2-carboxylic Acid, a New
Scaffold of Potential Non-peptide Endothelin Receptor Antagonists
Jean Guillon,a Patrick Dallemagne,b Silvia Stiebing,a Philippe R. Bovy,c Sylvain Rault,*,b
a Synthéval, 5, rue Vaubénard, 14032 Caen Cedex, France
b Centre d'Etudes et de Recherche sur le Médicament de Normandie, UFR des Sciences Pharmaceutiques, Université de Caen, 1,
rue Vaubénard, 14032 Caen Cedex, France
c Synthélabo Recherche, Département de Médecine Interne, 10, rue des Carrières, 92500 Rueil-Malmaison, France
Fax 33 (0) 2 31 93 11 88; E-mail: rault@bureau.pharmacie.unicaen.fr
Received 21 April 1999
commercial 3,3-diphenylpropionic acid (5) using poly-
phosphoric acid (PPA).5 Compound 3 was then reacted
with ethyl carbonate giving ethyl 1-oxo-3-phenylindane-
2-carboxylate (6).6 The trans structure of 6 was caracter-
ized by 1H NMR and coupling constants of 4.90 Hz were
measured for the H-2 and H-3 protons. The new enami-
noester 7 was prepared in 94% yield starting from 6 by us-
ing large excess of ammonium acetate in refluxing
ethanol. The reaction of 7 according to the Clauson-Kaas
reaction with 2,5-dimethoxytetrahydrofuran (2,5-diMe-
OTHF) in refluxing 1,4-dioxane with 4-chloropyridine
hydrochloride as catalyst yielded a mixture of the isomers
8 and 9, presumably due to a thermal [1,3] sigmatropic re-
arrangement.7 Compounds 8 and 9 have been separated by
chromatography on silica gel and the position of the in-
dene double bond was determined by 1H NMR on the ba-
sis of previous results of the indene series.8 In fact,
compound 8 showed one singlet for H-1 at 5.97 ppm,
whereas proton H-1 for derivative 9 was present at 4.94
ppm. Hydrogenation of the indenes 8 and 9 at room tem-
perature using NaBH4-NiCl2, 6H2O9 provided ethyl 1-
phenyl-3-pyrrol-1-ylindan-2-carboxylate as a mixture of
the all-cis 10 and all-trans 11 epimers. A sample of the
two diastereomers 10 and 11 was readily separated by
chromatography and their relative stereochemistry was
confirmed from NOE spectra. Irradiation of H-2 in 10 led
to an NOE with both H-1 and H-3, while similar irradia-
tion of H-2 in C-2-epi 11 failed to show an NOE with ei-
ther H-1 or H-3. These observations support the all-cis
arrangement of H-1, -2 and -3 in 10 and are in accordance
with a trans stereochemical relationship between H-2 and
H-1 and H-3 in C-2-epi 11. The crude mixture of 10 and
11, when subjected to treatment with aqueous base, under-
went epimerization at C-2 and saponification to afford the
Abstract: The first synthesis of trans,trans-1-phenyl-3-pyrrol-1-
ylindan-2-carboxylic acid, a key-intermediate in the access to new
potential non-peptide endothelin receptor antagonists, is reported.
Key words: 1-phenyl-3-pyrrol-1-ylindan-2-carboxylic acid, non-
peptide antagonist, endothelin receptor
The endothelins (ETs), discovered in 1988, are a family of
three isopeptides (ET-1, ET-2 and ET-3) encoded in the
human genome. The potent smooth muscle vasoconstric-
tor activity exerted by endothelins, through selective bind-
ing of the ETa/ETb receptors, is suggestive of an
important role in cardiovascular and pulmonary diseases.1
Thus, an intense effort has been exerted by many research
groups to prepare antagonists of the two fully character-
ized endothelin receptors.2 Recently, the 1,3-diarylindan-
2-carboxylic acid (1) motif has been described as a useful
scaffold to build new potent and selective non-peptide en-
dothelin receptor antagonists such as 3-[2-car-
boxymethoxy)-4-methoxyphenyl]-1-[3,4-(methylenedi-
oxy)phenyl]-5-(prop-1-yloxy)indan-2-carboxylic
acid
(SB 209670).3
In this paper, we reported an efficient synthesis of
trans,trans-1-phenyl-3-pyrrol-1-ylindan-2-carboxylic
acid (2), a scaffold for potential bioisosteres of 1 by re-
placement of the phenyl by a pyrrole nucleus (Scheme 1).
trans-trans
1-phenyl-3-pyrrol-1-ylindan-2-carboxylic
acid 2 (Scheme 2). Assignment of the relative configura-
tion of 2 was also made on the basis of NOE experiments.
Specifically, irradiation of H-2 in 2 led to an NOE with H-
2’and H-6’of the 1-phenyl group and H-a of the pyrrole.
These observations were consistent with a trans stere-
ochemical relationship between H-2 and the hydrogens 1
and 3 in 2 (Scheme 1).
Scheme 1
The synthesis of carboxylic acid 2 was achieved accord-
ing to the following sequence. The previously reported 3-
phenylindan-1-one (3) was prepared either by condensa-
tion between benzene and cinnamic acid (4) in the pres-
ence of aluminium chloride4 or by cyclization of
Synlett 1999, No. 8, 1263–1264 ISSN 0936-5214 © Thieme Stuttgart · New York

1264
J. Guillon et al.
LETTER
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(10) Procedure for preparation of carboxylic acid 2: to a solution of
ethyl 1-phenyl-3-pyrrol-1-ylindan-2-carboxylates (10) and
(11) (10.6 g, 32 mmol) in EtOH (110 mL) were added 85 mL
of aq NaOH (2 M) and the reaction mixture was refluxed for
4 h. The solvent was evaporated in vacuo and the residue was
dissolved in water (100 mL). The aqueous layer was washed
with diethyl ether (80 mL). Acidification with 3 N HCl
solution gave a precipitate which was extracted twice with
diethyl ether (2 x 80 mL). The organic layers were collected,
dried over MgSO4, filtered over active carbon and evaporated
to dryness under reduced pressure. The solid residue was
recrystallized from diethyl ether/petroleum ether (2/1-v/v) to
give 2 as white crystals (79%): mp 66°C. IR (KBr): n = 3250-
2500 (OH), 1715 (CO). 1H NMR (400 MHz, CDCl3): d =
10.41 (brs, 1H, OH), 7.28 (m, 2H, ArH), 7.19 (m, 5H, ArH),
7.03 (m, 1H, H-5), 6.86 (m, 1H, H-6), 6.71 (dd, 2H, J = 2.10
and 2.10 Hz, H-a), 6.14 (dd, 2H, J = 2.10 and 2.10 Hz, H-b),
5.87 (d, 1H, J = 8.50 Hz, H-3), 4.52 (d, 1H, J = 9.30 Hz, H-1),
3.39 (dd, 1H, J = 9.30 and 8.50 Hz, H-2). 13C NMR (100 MHz,
CDCl3): d = 178.7 (CO), 143.5 (C-1’), 141.8 (C-7a), 140.1 (C-
3a), 129.1 (C-3’ and C-5’), 128.8 (C-4), 128.4 (C-2’ and C-
6’), 128.0 (C-7), 127.4 (C-6), 125.1 (C-4’), 124.4 (C-5), 119.8
(C-a), 108.9 (C-b), 65.7 (C-3), 63.2 (C-2), 52.6 (C-1). MS
(EI): m/z = 304 (M+.+1, 28), 303 (M+., 100), 251 (20), 162
(33), 115 (24). Anal. Calcd. for C20H17NO2: C, 79.19; H, 5.65;
N, 4.62. Found: C, 79.20; H, 5.55; N, 4.86.
Scheme 2 Reagents: i, AlCl3, C6H6, 38%; ii, PPA, 30%; iii,
(C2H5O)2CO, Na, 82%; iv, CH3COONH4, C2H5OH, 94%; v, 2,5-di-
MeOTHF, C5H4ClN.HCl, 1,4-dioxane, 88% (8/9
: 1/1); vi,
NiCl2.6H2O, NaBH4, CH3OH, 86% (10/11 : 1/3); vii, a: NaOH,
C2H5OH, H2O; b: HCl, H2O, 79% from 10 and 11.
In conclusion, we have developed the first synthesis of the
trans,trans-1-phenyl-3-pyrrol-1-ylindan-2-carboxylic
acid (2),10 an original framework for the preparation of
new non-peptide endothelin receptor antagonists.
Acknowledgement
This work was supported by Synthélabo Recherche L.E.R.S. (Ru-
eil-Malmaison / France).
References and Notes
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Kobayashi, M.; Mitsui, Y.; Yazaki, Y.; Goto, K.; Masaki, T.
Nature 1988, 332, 411-415.
(2) Aria, H.; Hori, S.; Aramori, I.; Ohkubo, H.; Nakanishi, S.
Nature 1990, 348, 730-732; Sakurai, T.; Yanagisawa, M.;
Takuwa, Y.; Miyazaki, H.; Kimura, S.; Goto, K.; Masaki, T.
Nature 1990, 348, 732-735.
(3) Elliott, J.D.; Amparo Lago, M.; Cousins, R.D.; Gao, A.;
Leber, J.D.; Erhard, K.F.; Nambi, P.; Elshourbagy, N.A.;
Kumar, C.; Lee, J.A.; Bean, J.W.; DeBrosse, C.W.; Eggleston,
D.S.; Brooks, D.P.; Feuerstein, G.; Ruffolo, R.R.; Weinstock,
Article Identifier:
1437-2096,E;1999,0,08,1263,1264,ftx,en;G12299ST.pdf
Synlett 1999, No. 8, 1263–1264 ISSN 0936-5214 © Thieme Stuttgart · New York