Expeditious synthesis of tri-substituted cyclopentane derivatives

Article abstract of DOI:10.1016/S0040-4039(02)00901-2

An efficient preparation of the cyclopentane scaffold 2, a key precursor to the potent human NK1 antagonist 1 having three contiguous chiral centers is described.

Full text of DOI:10.1016/S0040-4039(02)00901-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4569–4570
Expeditious synthesis of tri-substituted cyclopentane derivatives
Ranjit C. Desai,* Peter Cicala, Laura C. Meurer and Paul E. Finke
Department of Medicinal Chemistry, Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065, USA
Received 16 April 2002; accepted 10 May 2002
Abstract—An efficient preparation of the cyclopentane scaffold 2, a key precursor to the potent human NK1 antagonist 1 having
three contiguous chiral centers is described. © 2002 Published by Elsevier Science Ltd.
Human neurokinin-1 (hNK1) is a member of the G-
protein coupled family of receptors. The endogenous
ligand for this receptor is the tachykinin peptide Sub-
stance P (SP), which has been implicated in the patho-
physiology of a diverse range of conditions, including
asthma, inflammatory bowel disease, pain, migraine,
emesis, anxiety/depression, and schizophrenia.1 This
profile has stimulated an intense search for potent,
non-peptide antagonists of hNK1.2 Recently, we have
reported a series of potent, orally active antagonists of
hNK1 having a cyclopentane core structure as illus-
trated in structure 1.3 Compound 1 was derived from
the cyclopentane 2 which has three contiguous chiral
centers in an all trans relationship.
sponding acid derivatives. Hydrolysis of 5 followed by
the resolution of the acid using (S) or (R)-a-methylben-
zylamine furnished chiral acids 2 and 3.
The absolute stereochemistry of the trans derivative 3
was unequivocally established using the X-ray crystal-
lography. While this approach met our initial objective
of synthesizing intermediate 2, it became apparent that
for a larger scale (>50 g) preparation required for the
SAR development of this class, there was a need for an
alternative process. This was due to the length of the
Our initial approach for the synthesis of compound 2 is
shown in Scheme 1. The key intermediate ( )-trans-3-
oxo-2-(4-fluorophenyl)cyclopentane carboxylic acid
methyl ester 4 was synthesized based on the literature
procedure of Baker and Leeds.4 Reduction of ketone 4
with L-Selectride produced only the 1,2-cis diastereo-
mer 6, while use of NaBH4 resulted in a separable
4:1 mixture in which the trans isomer 5 now pre-
dominated. The assignments for isomers 5 and 6
were confirmed by NOE experiments on the corre-
* Corresponding author. E-mail: ranjit desai@merck.com
–
Scheme 1.
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)00901-2

4570
R. C. Desai et al. / Tetrahedron Letters 43 (2002) 4569–4570
Scheme 2.
synthesis (10 steps to 2) and the need to handle a large
amount of concentrated hydrochloric acid in the prepa-
ration of the starting keto derivative 4. Herein, we
describe an efficient synthesis of the cyclopentane scaf-
fold 2 (Scheme 2).
Acknowledgements
We thank Dr. George Doss for his help with the NOE
studies and Dr. Peter Meinke for reviewing the
manuscript.
The starting 2-bromo-2-cyclopenten-1-one 8 was conve-
niently prepared from cyclopenten-1-one 7 as described
by Smith et al.5 The Suzuki coupling of 8 and 4-
fluorophenylboronic acid was achieved using Pd(PPh3)4
as the catalyst to furnish compound 9 in 67% yield.6
The stage was now set for the introduction of the
desired carboxylic acid functionality at C-3. Towards
this end, the conjugate addition of cyanide to 9 was
carried out with aqueous KCN in methanol at 0°C to
provide 10 in 71% yield after chromatography. Subject-
ing compound 10 to sodium borohydride reduction at
−78°C gave a mixture of 11 and 12. Separation of this
mixture by silica gel chromatography furnished the
desired intermediate 11 in 72% yield.
References
1. (a) Quatara, L.; Maggi, C. A. Neuropeptides 1998, 32, 1;
(b) Rupniak, N. M. J.; Kramer, M. S. Trends Pharmacol.
Sci. 1999, 20, 485.
2. Hale, J. J.; Mills, S. G.; MacCoss, M.; Finke, P. E.;
Cascieri, M. A.; Sadowski, S.; Ber, E.; Chicchi, G. G.;
Kurtz, M.; Metzger, J.; Eiermann, G.; Tsou, N. N.; Tat-
tersall, F. D.; Rupniak, N. M. J.; Williams, A. R.;
Rycroft, W.; Hargreaves, R.; MacIntyre, D. E. J. Med.
Chem. 1998, 41, 4607.
3. Meurer, L.; Finke, P. E.; MacCoss, M.; Mills, S. G.;
Sadowski, S.; Cascieri, M. A.; Metzger, J.; Eiermann, G.;
MacIntyre, D. E.; Rupniak, N. M. J.; Williams, A.; Harg-
reaves, R. Development of potent, orally active cyclopen-
tane based human NK1 antagonists. Presented at the
American Chemical Society 219th National Meeting, San
Francisco, CA, March 26–30, 2000; Abstract 98.
4. Baker, W.; Leeds, W. G. J. Chem. Soc. 1948, 974.
5. Smith, A. B., III; Branca, S. J.; Guaciaro, M. A.;
Wovkulich, P. M.; Korn, A. Org. Synth. Coll. VII 1990,
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Hydrolysis of nitrile group of 11 with 5N aqueous
sodium hydroxide in methanol afforded the racemic
cyclopentane carboxylic acid 2 as a white solid in 91%
yield.7 This material was found identical to the all trans
derivative obtained via Scheme 1. Subsequent resolu-
tion as described before provided chiral 2.
In conclusion, we have developed a shorter and more
efficient five step synthesis of the key racemic cyclopen-
tane intermediate 2 having three contiguous chiral cen-
ters. This process employs a Suzuki coupling as the key
step to install the substituted phenyl functionality onto
a cyclopentene ring with a subsequent conjugate addi-
tion of the nitrile. The wide availability of substituted
phenylboronic acids makes this approach highly attrac-
tive for the synthesis of a variety of interesting targets.
We have also successfully extended this method to the
synthesis of the cyclohexane derivatives which will be
the subject of a future publication.
6. Carrera, G. M.; Sheppard, G. S. Synlett 1994, 93.
7. Selected 1H NMR data. Ester 4 1H NMR (CDCl3, 600
MHz): l 7.08 (2H, m), 6.98 (2H, m), 3.66 (1H, d, J=11.4),
3.65 (3H, s), 3.17 (1H, dt, J=6.5, 11.4), 2.59 (1H, dd,
J=8.5, 18.7), 2.41 (1H, m), 2.34 (1H, m), 2.05 (1H, m).
1
Carboxylic acid of 5 H NMR (CDCl3, 600 MHz): l 7.18
(2H, m), 6.98 (2H, m), 4.15 (1H, q, J=7.0), 3.18 (1H, dd,
J=7.7, 9.6), 2.90 (1H, m), 2.12 (3H, m), 1.79 (1H, m).
1
Carboxylic acid of 6 H NMR (CDCl3, 600 MHz): l 7.19
(2H, m), 6.97 (2H, m), 4.20 (1H, t, J=4.3), 3.27 (1H, dd,
J=4.3, 11.5), 3.24 (1H, dd, J=8.6, 11.4), 2.28 (1H, m),
2.06 (1H, m), 1.91 (1H, m), 1.80 (1H, m).