A synthetic route to a novel type of conformationally constrained N-aryloxazolidinones

Article abstract of DOI:10.1016/j.bmcl.2005.03.071

The synthesis of N-aryloxazolidinone 1, a conformationally constrained analog of linezolid embodying a tricyclic pyrrolo[1,2-a][4,1]benzoxazepine moiety as the N-aryl substituent, is reported. The synthetic route involves the successive construction of th

Full text of DOI:10.1016/j.bmcl.2005.03.071

Bioorganic & Medicinal Chemistry Letters 15 (2005) 2515–2517
A synthetic route to a novel type of conformationally constrained
N-aryloxazolidinones
Rosa Griera,a Carme Cantos-Llopart,a Mercedes Amat,a Joan Bosch,a,*
Juan-C. del Castillob and Joan Huguetb
aLaboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona, 0802-Barcelona, Spain
b
´
Laboratorios Lesvi S.L., 08970-Sant Joan Despı, Barcelona, Spain
Received 19 November 2004; revised 17 March 2005; accepted 17 March 2005
Available online 12 April 2005
Abstract—The synthesis of N-aryloxazolidinone 1, a conformationally constrained analog of linezolid embodying a tricyclic pyr-
rolo[1,2-a][4,1]benzoxazepine moiety as the N-aryl substituent, is reported. The synthetic route involves the successive construction
of the pyrrole, oxazepine, and oxazolidinone rings, with incorporation of the isoxazolylamino moiety in the last synthetic steps.
Ó 2005 Elsevier Ltd. All rights reserved.
The emergence of bacterial resistance to antibiotics is a
problem of ever increasing significance.1 N-aryl oxazo-
lidinones have recently attracted a great deal of atten-
of the acetamidomethyl group present at C-4 of the oxa-
zolidinone ring.8
tion as
a
new class of orally active, synthetic
We present here the synthesis of N-aryl oxazolidinone 1
as the first example of a new class of conformationally
constrained analogs of linezolid, bearing a tricyclic pyr-
rolo[1,2-a][4,1]benzoxazepine moiety as the aryl substi-
tuent on the nitrogen of the core oxazolidinone ring.
Additionally, 1 incorporates an N-(isoxazol-3-yl)amino-
methyl susbstituent at the C-4 position of the oxazolidi-
none ring instead of the acetamidomethyl group present
in linezolid. The synthetic route is depicted in Scheme 1
and involves, as the key steps, the successive construc-
tion of the pyrrole, oxazepine, and C-4 substituted
oxazolidinone rings, with incorporation of the
isoxazolylamino moiety in the last synthetic steps from
the key intermediate 12.
antibacterial agents with activity against Gram-positive
and anaerobic bacteria.2 DuP 721 was the first drug can-
didate of this family of totally synthetic antibiotics,3
whereas linezolid was the first member of this series
introduced in the market (Fig. 1).4 The novel mechanism
of action of linezolid, involving the inhibition of bacte-
rial protein synthesis at a very early stage,5 combined
with its biological activity against resistant organisms
has stimulated further synthetic work in the area.6
Among the many different approaches to modify the
chemical structure of linezolid, two different strategies
have received particular attention: the synthesis of con-
formationally constrained analogs7 and the modification
The pyrrole ring was constructed via Clauson–Kaas
reaction9 by refluxing a solution of methyl 2-amino-5-
nitrobenzoate (2)10 and 2,5-dimethoxytetrahydrofuran
in glacial acetic acid. N-arylpyrrole 3 was obtained in
82% yield.
F
O
O
O
O
N
N
O
N
O
NHAc
NHAc
DuP 721
Linezolid
The closure of the oxazepine ring was accomplished by
intramolecular dehydration of a diol, as previously re-
ported for the construction of the basic pyrrolo[1,2-a]
[4,1]benzoxazepine ring system.11 Thus, formylation
of 3 under Vilsmeier–Haack conditions occurred regio-
selectively on the 2-position of the pyrrole ring to give
2-formylpyrrole 4 (65%) as the major product. Then,
Figure 1.
Keywords: N-Aryloxazolidinones; Antibiotics; Linezolid; Constrained
analogs; Pyrrolo[1,2-a][4,1]benzoxazepine.
*
Corresponding author. Tel.: +34 93 402 45 38; fax: +34 93 402 45
39; e-mail: joanbosch@ub.edu
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.03.071

2516
R. Griera et al. / Bioorg. Med. Chem. Lett. 15 (2005) 2515–2517
CHO
d
f
b
a
N
NO2
N
R
H2N
NO2
N
R
MeO2C
MeO2C
MeO2C
2
3
OH
6 R = NH2
HO
4 R = NO2
5 R = NH2
c
e
7 R = NHCO2Bn
8 R = NO2
O
O
O
CO2CH2CCl3
R
N
N
H
N
O
N
g
N
N
O
N
O
N
R
from 10
h
OH
O
N
O
O
13 R = CO2CH2CCl3
1 R = H
12
9 R = NH2
10 R = NHCO2Bn
11 R = NO2
i
Scheme 1. Reagents and conditions: (a) 2,5-dimethoxytetrahydrofuran, AcOH, reflux; (b) POCl3, DMF, reflux; (c) H2, PtO2, MeOH, rt; (d) LiAlH4,
THF, rt; (e) ClCO2Bn, Na2CO3, acetone, 0 °C to rt; (f) P2O5, toluene, 60 °C; (g) (R)-glycidyl butyrate, n-BuLi, THF, À78 °C to rt, then MeOH,
K2CO3, rt; (h) PPh3, DIAD, THF, rt; (i) Zn, AcOH, THF/H2O, rt.
O
the nitro group of 4 was chemoselectively reduced by
N
N
O
catalytic hydrogenation over PtO2 to give aniline 5 in
90% yield. A subsequent LiAlH4 reduction of 5 brought
about the reduction of both the formyl and ester groups
to give the required aminodiol 6 in 80% yield. Although
direct P2O5-promoted cyclodehydration of 6 gave tricy-
clic aniline 9 in poor yield (17%), the closure of the oxa-
zepine ring was satisfactorily accomplished from
carbamate 7, which was easily accessible by treatment
of 6 with benzyl chloroformate. The tricyclic carbamate
10 was obtained in 60% overall yield from 6. An alterna-
tive sequence involving the initial reduction of 4 with
either LiAlH4 or Red-Al, followed by cyclodehydration
of the resulting diol 8 with P2O5 to give 11 took place in
poor yields.
OH
O
O
15
a
N
NHCO2Bn
O
O
14
N
N
O
16
OH
Scheme 2. Reagents and conditions: (a) (R)-glycidyl butyrate, n-BuLi,
THF, À78 °C to rt, then MeOH, K2CO3, rt.
the chemical shift of the oxazolidinone methine and
methylene groups.
For the construction of the 5-substituted oxazolidinone
ring we took advantage of the carbamate function pres-
ent in 10 and used the previously reported regiospecific
lithium-ion dependent alkylation–cyclization of aryl N-
lithiocarbamates with (R)-glycidyl butyrate.4,12–14 Thus,
the tricyclic aryl carbamate 10 was treated with n-BuLi,
and the resulting lithiated intermediate was allowed to
react with (R)-glycidyl butyrate to furnish, after in situ
hydrolysis of the ester function, 5(R)-(hydroxy-
methyl)oxazolidinone 1215 in 51% overall yield. Variable
amounts (<10%) of the corresponding regioisomeric 4-
substituted oxazolidinone were also formed. The forma-
tion of mixtures of 4- and 5-(hydroxymethyl)oxazolidi-
nones from (R)-glycidyl butyrate have been reported12
when using N-potassium or sodium (but not lithium)
carbamate salts. An initial nucleophilic attack of the car-
bamate anion on the substituted C-1, rather than C-2,
position of the oxirane ring accounts for the formation
of the unexpected 4-substituted isomer.
Finally, the 3-aminoisoxazole moiety was incorporated
by Mitsunobu reaction of alcohol 12 with 3-(2,2,2-tri-
chloroethoxycarbonylamino)isoxazole, followed by
deprotection of the resulting trichloroethyl carbamate
13 with zinc in acetic acid. The target oxazolidinone
117 was obtained in 52% overall yield from 12.
The efficient route reported above for the preparation of
1 can provide facile and practical access to structurally
diverse new tricyclic oxazolidinones, since the hydroxy-
methyl substituent of the key intermediate 12 can be fur-
ther elaborated into a variety of methylene O and N
linked substituents at the C-5 position of the oxazolidi-
none ring.8
Acknowledgements
Financial support from the DURSI, Generalitat de
Catalunya (Grant No. 2001SGR-0084) is gratefully
acknowledged.
It is worth mentioning that we also isolated a similar C-4
substituted oxazolidinone 16 as a by-product (5% yield),
in addition to the previously reported 5-substituted iso-
mer 157c (45%), from the reaction of tricyclic carbamate
14 with (R)-glycidyl butyrate (Scheme 2).16
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1
15. Spectroscopic data for 12: H NMR (300 MHz, CD3OD)
d 3.88 (dd, J = 12.4, 4.0 Hz, 1H), 4.03 (dd, J = 12.4,
3.4 Hz, 1H), 4.14 (dd, J = 6.4, 2.6 Hz, 1H), 4.32 (app t,
J = 8.9 Hz, 1H), 4.56 (s, 2H), 4.58 (s, 2H), 4.94–5.03 (m,
1H), 6.42–6.46 (m, 2H), 7.27–7.29 (m, 1H), 7.63 (d,
J = 8.6 Hz, 1H), 7.84 (d, J = 2.6 Hz, 1H), 7.90 (dd, J = 8.6,
2.6 Hz, 1H); 13C NMR (75 MHz, CD3OD) d 46.7 (CH2),
60.0 (CH2), 62.2 (CH2), 66.7 (CH2), 74.0 (CH), 109.4
(2CH), 119.9 (CH), 120.5 (CH), 120.6 (CH), 121.4 (CH),
130.0 (C), 130.2 (C), 136.6 (C), 136.9 (C), 156.0 (C).
16. The final treatment with K2CO3/MeOH is necessary to
complete the hydrolysis of the butyrate esters resulting
from the cyclization.
1
17. Spectroscopic data for 1: H NMR (300 MHz, CDCl3) d
3.61–3.68 (m, 1H), 3.73–3.81 (m, 1H), 3.94 (dd, J = 6.7,
2.0 Hz, 1H), 4.15 (app t, J = 8.8 Hz, 1H), 4.45 (s, 2H), 4.48
(s, 2H), 4.56 (app t, J = 6.4 Hz, 1H), 4.95–5.02 (m, 1H),
5.89 (d, J = 1.7 Hz, 1H), 6.32–6.33 (m, 2H), 7.04 (dd,
J = 2.6, 1.7 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 7.57 (d,
J = 2.6 Hz, 1H), 7.68 (dd, J = 8.8, 2.6 Hz, 1H), 8.07 (d,
J = 1.7 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 46.9
(CH2), 48.1 (CH2), 60.8 (CH2), 67.3 (CH2), 71.8 (CH),
96.8 (CH), 110.0 (2CH), 120.1 (CH), 120.8 (2CH), 121.9
(CH), 130.5 (C), 130.9 (C), 136.6 (C), 137.0 (C), 154.8 (C),
158.7 (CH), 163.9 (C).
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