New potential antibacterials: A synthetic route to N-aryloxazolidinone/3- aryltetrahydroisoquinoline hybrids

Article abstract of DOI:10.1016/j.bmcl.2005.10.053

A synthetic route to a new structural type of potential antibacterials, with a hybrid 3-aryltetrahydroisoquinoline-6,7-diol/N-aryloxazolidinone structure, is reported. The synthesis involves the successive construction of the 3-aryltetrahydroisoquinoline

Full text of DOI:10.1016/j.bmcl.2005.10.053

Bioorganic & Medicinal Chemistry Letters 16 (2006) 529–531
New potential antibacterials: A synthetic route to
N-aryloxazolidinone/3-aryltetrahydroisoquinoline hybrids
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, 08028 Barcelona, Spain
bLaboratorios Lesvi S.L., Sant Joan Despı´, 08970 Barcelona, Spain
Received 13 October 2005; accepted 18 October 2005
Available online 4 November 2005
Abstract—A synthetic route to a new structural type of potential antibacterials, with a hybrid 3-aryltetrahydroisoquinoline-6,7-diol/
N-aryloxazolidinone structure, is reported. The synthesis involves the successive construction of the 3-aryltetrahydroisoquinoline
and 4-substituted oxazolidinone moieties, the latter taking advantage of the functionalization at the para position of the aryl group.
Ó 2005 Elsevier Ltd. All rights reserved.
N-Aryloxazolidinones are a novel and promising class of
synthetic antibiotics that have recently emerged as
important therapeutic agents, active against numerous
multidrug-resistant Gram-positive organisms.1 DuP
721 was the first drug candidate of this family,2 whereas
linezolid was the first member of this series introduced in
the market3 (Fig. 1). N-Aryloxazolidinones are currently
the focus of intensive research, and continuous synthetic
efforts4 are necessary to develop more effective antibac-
terial agents, in particular after the appearance of lin-
ezolid-resistant strains.5
O
F
O
O
N
O
O
N
N
O
NHAc
NHAc
DuP 721
Linezolid
HO
HO
WO 03/018017
NH
Figure 1.
A recent report6 on the antibacterial activity of a series
of 3-aryl-1,2,3,4-tetrahydroisoquinoline-6,7-diol deriva-
tives against both Gram-positive and Gram-negative
organisms prompted us to design a novel type of linezo-
lid analogs, which embody both the characteristic
N-aryloxazolidinone core of this antibiotic and a 3-aryl-
tetrahydroisoquinoline-6,7-diol fragment.
functionalization at the para position of the aryl group.
For the sake of simplicity, in the exploratory studies
reported in this letter we used racemic 3-aryltetrahydro-
isoquinolines, although practical general methods for
the asymmetric synthesis of these compounds are now
available.8
The synthetic route to the target hybrid 1, which fulfills
the Lipinski rule of five parameters,7 is depicted in
Scheme 1. It involves the successive construction of
the 3-aryltetrahydroisoquinoline and 4-substituted oxa-
zolidinone moieties, the latter taking advantage of the
Alkylation of methyl p-nitrophenylacetate9 (2a) with
3,4-dimethoxybenzyl bromide10 in the presence of
LDA, followed by alkaline hydrolysis of the resulting
ester 3a, led to acid 4a, which was then converted to
carbamate 5a by a modified Curtius rearrangement
using diphenyl phosphorazidate in the presence of
triethylamine and an excess of benzyl alcohol.11
Keywords: Antibacterials; N-Aryloxazolidinones; 3-Aryltetrahydroiso-
quinolines; Linezolid.
*
The closure of the tetrahydroisoquinoline ring was satis-
factorily accomplished by Pictet–Splenger reaction with
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.2005.10.053

530
R. Griera et al. / Bioorg. Med. Chem. Lett. 16 (2006) 529–531
MeO
MeO
R
R
R
Br
R
MeO
MeO
MeO
MeO
MeO
MeO
d
c
a
N
HN
CO2Bn
CO2Bn
O
OR'
6a R = NO2
6b R = Br
CH2CO2Me
5a,b
3a,b R' = Me
4a,b R' = H
e
f
b
a R = NO2
b R = Br
2
7
R = NH2
8
R = NHCO2Bn
O
O
O
N
O
N
O
N
O
MeO
MeO
HO
HO
MeO
MeO
NHAc
g
R
j
NHAc
l
from 12
N
N
NH
HBr
R
CO2Bn
1
12 R = CO2Bn
13 R = H
9
R = OH
k
h
i
10 R = OMs
11 R = N3
Scheme 1. Reagents and conditions: (a) LDA, THF, À78 °C to rt, 60% (3a), 89% (3b); (b) 2 M NaOH, MeOH, reflux, 85% (4a), 89% (4b); (c) DPPA,
Et3N, BnOH, THF, reflux, 60% (5a), 84% (5b); (d) HCOOH, HCHO, 70 °C, 68% (6a), 56% (6b); (e) Fe, EtOH, HCl, 0 °C to rt, 92%; (f) ClCO2Bn,
Na2CO3, acetone, 0 °C to rt, 67%; (g) (R)-glycidyl butyrate, n-BuLi, THF, À78 °C to rt, 55%; (h) MsCl, Et3N, CH2Cl2, 0 °C, 90%; (i) NaN3, DMF,
80 °C, 67%; (j) CH3COSH, rt, 50%; (k) H2, Pd(OH)2, MeOH, rt, 70%; (l) BBr3, CH2Cl2, À10 °C, 90%.
formaldehyde and formic acid. Reduction of the nitro
group present in 6a with Fe and HCl gave aniline 7,
which was then converted to carbamate 8 by treatment
with benzyl chloroformate.
overall yield as in the above nitro series by alkylation
of methyl p-bromophenylacetate9 (2b) with 3,4-dimeth-
oxybenzyl bromide, followed by alkaline hydrolysis,
Curtius rearrangement of the resulting acid 4b, and
finally Pictet–Splenger cyclization from carbamate 5b.
For the construction of the 5-substituted oxazolidinone
ring we took advantage of the carbamate function pres-
ent in 8 and used the previously reported regiospecific
lithium-ion dependent alkylation-cyclization of aryl N-
lithiocarbamates with (R)-glycidyl butyrate.3,12,13 Thus,
the aryl carbamate 8 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)-(hydroxymethyl)oxazolidi-
none 914 in 55% overall yield as a mixture of two indis-
tinguishable diastereoisomers.
The synthesis of the target oxazolidinone 1 from 9 only
required functional group interconversions. Mesylation
of the hydroxy group of 9, followed by treatment of
the resulting mesylate 10 with sodium azide, and then
reductive acetylation of azide 11 using thiolacetic acid17
provided acetamide 12 in good overall yield. Finally,
removal of the carbamate function present in 12 by cat-
alytic debenzylation gave tetrahydroisoquinoline 13,
whereas treatment of 12 with boron tribromide18
brought about the cleavage of both the carbamate and
methoxy groups leading to the target hybrid 1 as the
hydrobromide.19,20
An alternative route for assembling the oxazolidinone
moiety, involving the Pd(0)-catalyzed cross coupling of
3-(p-bromophenyl)tetrahydroisoquinoline 6b with oxa-
zolidinones 14,15 was abandoned because the coupled
products 15 were formed in poor (<10%, from 14a)
or negligible yields (from 14b)16 (Scheme 2). The re-
quired aryl bromide 6b was prepared in satisfactory
Acknowledgments
Financial support from the DURSI, Generalitat de
Catalunya (Grant No. 2001SGR-0084) is gratefully
acknowledged.
O
O
N
O
References and notes
HN
O
MeO
MeO
a
R
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R
CO2Bn
O
14
15
a R = N
O
b R = OTBDPS
Scheme 2. Reagents and conditions: (a) 6b, Pd2(dba)3, BINAP,
Cs2CO3, toluene, 100 °C.

R. Griera et al. / Bioorg. Med. Chem. Lett. 16 (2006) 529–531
531
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14. Spectroscopic data for 9: H NMR (200 MHz, CDCl3): d
3.00 (m, 1 H), 3.28 (m, 1 H), 3.68 (m, 1 H), 3.82 (s, 3 H),
3.84 (s, 3 H), 3.88 (m, 3H), 4.16 (m, 1 H), 4.66 (m, 1 H),
4.81 (m, 1 H), 5.17 (s, 2 H), 6.62 (bs, 2 H), 7.13 (m, 2 H),
7.34 (m, 9 H); 13C NMR (50.3 MHz, CDCl3): d 32.8
(CH2), 43.2 (CH2), 46.3 (CH2), 52.8 (CH), 55.9 (CH3),
62.7 (CH2), 67.4 (CH2), 72.9 (CH), 108.9 (CH), 111.2
(CH), 118.0 (CH), 124.6 (C), 125.3 (C), 127.3 (CH), 127.8
(CH), 127.9 (CH), 128.4 (CH), 135.2 (C), 136.4 (C), 136.8
(C), 147.6 (C), 147.8 (C), 154.8 (C), 156.0 (C).
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(200 MHz, CD3OD): d 1.99 (s, 3 H), 3.04 (m, 1 H),3.30
(m, 2 H), 3.61 (d, J = 5 Hz, 1 H), 3.90 (m, 1 H), 4.20 (m, 1
H), 4.36 (m, 1 H), 4.64 (m, 1 H), 4.84 (m, 1 H), 5.12 (m, 1
H), 6.60 (s, 2 H), 7.60 (d, J = 9 Hz, 2 H), 7.72 (d, J = 9 Hz,
2 H); 13C NMR (50.3 MHz, CD3OD): d 20.3 (CH3), 31.6
(CH2), 41.2 (CH2), 44.7 (CH2), 45.8 (CH2), 56.7 (CH),
71.3 (CH), 111.7 (CH), 114.0 (CH), 116.8 (C), 118.0 (CH),
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144.8 (C), 154.4 (C), 171.0 (C).
´
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bacterial activity was tested against four different strains
of methicillin-susceptible Staphylococcus aureus, including
S. aureus ATCC 29213, giving in all cases MIC values
higher than 64 lg/mL. Linezolid (MIC = 2 lg/mL) was
used as the reference compound.
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