Stereoselective synthesis of novel (R)- and (S)-5-azidomethyl-2-oxazolidinones from (S)-epichlorohydrin: a key precursor for the oxazolidinone class of antibacterial agents

Article abstract of DOI:10.1016/j.tetlet.2008.03.061

A facile synthesis of novel (R)- and (S)-5-azidomethyl-2-oxazolidinones starting from (S)-epichlorohydrin is described. The (R)-azide was utilized for the preparation of Linezolid.

Full text of DOI:10.1016/j.tetlet.2008.03.061

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Tetrahedron Letters 49 (2008) 3060–3062
Stereoselective synthesis of novel (R)- and (S)-5-azidomethyl-
2-oxazolidinones from (S)-epichlorohydrin: a key precursor
for the oxazolidinone class of antibacterial agents q
G. Madhusudhan a,b,*, G. Om Reddy a, T. Rajesh a, J. Ramanatham a, P. K. Dubey b
a Technology Development Center, Dr. Reddy’s Laboratories Ltd, Bollaram Road, Miyapur, Hyderabad 500 049, AP, India
b Department of Chemistry, College of Engineering, J.N.T University, Kukatpally, Hyderabad 500 872, AP, India
Received 24 December 2007; revised 10 March 2008; accepted 12 March 2008
Available online 15 March 2008
Abstract
A facile synthesis of novel (R)- and (S)-5-azidomethyl-2-oxazolidinones starting from (S)-epichlorohydrin is described. The (R)-azide
was utilized for the preparation of Linezolid.
Ó 2008 Elsevier Ltd. All rights reserved.
Oxazolidinones have shown various pharmacological
activities in the areas of drug development, antibacterials,1
inhibitors of monoamine oxidase,2 cytokine modulators,3
sigma receptors,4 pschyotropics,5 antiallergy agents,6 anti-
biotics,7 intermediates in the synthesis of renin inhibitors,8
b-lactam and macrolide antibiotics,9 immunosuppres-
sants10 and in many other applications.11
Oxazolidinones are the first new class of synthetic anti-
bacterial agents introduced since the discovery of quino-
lones more than 30 years ago. Linezolid1 was the first
drug of this class possessing antibacterial activity, having
an N-aryl-5-aminomethyl-2-oxazolidinone moiety.
To access a large number of derivatives to be screened in
biological assays, we required a general and efficient
method for the synthesis of analogues containing N-aryl-
5-aminomethyl-2-oxazolidinone without using (n-BuLi),
epoxides and phenylisocyanates which are used in the clas-
sical synthesis of this class of compounds.3,4 The prepara-
tion of aryl isocyanates is cumbersome from multi-
substituted aryl amines. Moreover, these strategies require
further steps to convert the 5-hydroxymethyl group into a
5-aminomethyl functionality. The latest analogues have
common functionalities on the 5-aminomethyl group such
as acetamides carbamates, thiocarbamates, ureas and thio-
ureas.12 During the conversion of amines to carbamates,
thiocarbamates, ureas and thioureas, there is a higher
chance of obtaining the corresponding symmetrical deriva-
tives. In view of these limitations, we focused our attention
to prepare the useful chiral synthons (R)- and (S)-5-azido-
methyl-2-oxazolidinone starting from commercially avail-
able (S)-epichlorohydrin using a new methodology. These
moieties can be derivatized on both ends to develop new
oxazolidinone antibacterial analogues, as well as MAO-B
inhibitors used in the treatment of Parkinson’s disease.13
In the present synthetic strategy, we have developed facile
conditions for the one-pot synthesis of 2-oxazolidinones
from azido alcohols using Ph3P/CO2 via the generation
of an intermediate isocyanate followed by cyclization. This
is an attractive application of aza-Wittig reactions of
iminophosphoranes14 and should find general utility in
the synthesis of 2-oxazolidinones (Fig. 1).
q
DRL Publication No. 402A.
Corresponding author at present address: Inogent Laboratories Pvt.
(S)-Epichlorohydrin 1 was stereoselectively ring-opened
with NaN3 in a mixture of H2O/EtOH, whilst maintaining
mild acidic conditions using NH4Cl, to give (2S)-1-azido-3-
chloropropan-2-ol 2 without racemization. The azido
*
Ltd (A BVK BIO Company), 28A, IDA, Nacharam, Hyderabad 500 076,
India. Tel.: +91 4066281215; fax: +91 40 2715 1270.
E-mail address: madhusudhan.gutta@inogent.com (G. Madhusudhan).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.03.061

G. Madhusudhan et al. / Tetrahedron Letters 49 (2008) 3060–3062
3061
O
O
(Boc)2O
NaN3 /DMF
TBAC
OtBu
OH
OH
Pd/C-H2
R
N
O
N3
Cl
HN
80 °C, 12 h
(89%)
rt, 12 h
(71%)
N3
Cl
2
5
Fig. 1. 5-Azidomethyl-2-oxazolidinones.
O
O
Ph3P-CCl4
Et3N
OtBu
OH
alcohol 2 on treatment with Ph3P and carbon dioxide in
toluene under reflux gave (S)-5-chloromethyl-2-oxazolidi-
none 3,15 which was further treated with NaN3 under
PTC conditions to give the desired compound 4 (Scheme
1). The reaction mechanism for the formation of com-
pound 3 can be explained via an intermediate iminophos-
phorane. The iminophosphorane reacts with carbon
dioxide to generate an intermediate isocyanate, which
reacts further with the vicinal hydroxyl group to afford
the corresponding oxazolidinone (Scheme 2).
HN
O
HN
rt, 12 h
N3
SN2 Inversion
N3
(73%)
6
7
Scheme 3.
F
Br
The epimer 7 (R isomer) was obtained by converting
compound 2 into tert-butyl carbamate derivative 5 by
reductive protection with Boc using Pd/C. The specific
rotation value obtained for 5 is À21.5 (c 1, CHCl3) and this
matched with the literature result.16 Compound 5 was
further reacted with NaN3 using tetrabutylammonium
chloride (TBAC) to give azido compound 6. This azide 6
was cyclized with SN2 inversion in Ph3P–CCl4–Et3N17 to
(R)-oxazolidinone 7 (Scheme 3).
N
O
O
F
O
1,2-diaminocyclo
hexane/dioxane
HN
O
N
N
O
N3
CuI, K2CO3
110 °C, 20 h
(84%)
O
N
N3
7
8
F
O
Oxazolidinone 7 provides access for derivatization on
both nitrogens. The ring nitrogen can be alkylated and
CH3COSH
N
O
rt, 15 h
(85%)
O
H
N
CH3
Ph3P/ CO2
Toluene
NaN3/NH4Cl
H2O-EtOH
9
OH
O
O
N3
Cl
Cl
O
Scheme 4.
reflux,10 h
(90%)
0 °C- rt
1
Overnight
2
(65%)
should also be a good candidate for arylation. The azide
functionality provides the required site for preparing differ-
ent analogues of the oxazolidinone. Many established pro-
cedures are available for reductive conversion of azides to
acetamides18 and carbamates.19 The azide functionality
can also be converted to carbamates, ureas, thiocarbamates
and thioureas via iminophosphorane14 and isocyanate or
thiocyanate20 intermediates, respectively. The utility of
these intermediates has been exemplified by the synthesis
of Linezolid as shown in Scheme 4. The required aryl
bromide was coupled with azide 7 using established
conditions21 to afford compound 8 of which reductive acyl-
ation gave Linezolid 9.18b
O
O
NaN3 /DMF
TBAC
HN
HN
O
80 °C
Cl
N3
Overnight
(72%)
3
4
Scheme 1.
Ph3P
Toluene
PPh3
OH
OH
O
C O
N
N3
Cl
Cl
2
In conclusion, an efficient method has been developed
for the preparation of novel chiral synthons (R)- and (S)-
5-azidomethyl-2-oxazolidinones, which are precursors for
further transformations into potential antibacterial agents.
Iminophosphorane
O
O
C
HN
O
OH
N
Acknowledgement
Cl
Cl
Isocyanate
3
We thank Dr. Reddy’s Laboratories Ltd, for the
financial support and encouragement.
Scheme 2.

3062
G. Madhusudhan et al. / Tetrahedron Letters 49 (2008) 3060–3062
Int. Appl. WD 9320073, 1993; Chem. Abstr. 1994, 120, 106761k; (c)
Supplementary data
Afili, N. A.; Ramadan, A. Vet. Med. J. Giza. 1989, 37, 299; (d)
Ishizuka, T.; Ishibuchi, S.; Kunieda, T. Tetrahedron 1993, 49, 1841–
1852.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2008.
03.061.
12. (a) Selvakumar, N.; Srinivas, D.; Manoj Kumar, K.; Sitaram Kumar,
M.; Mamidi Rao, N. V. S.; Hemanth, S.; Chandrashekar, C.;
Srinivasa Rao, B.; Mohammed Raheem, A.; Jagattaran, D.; Javed, I.;
Raagopalan, R. J. Med. Chem. 2002, 45, 3953–3962; (b) Tokuyama,
R.; Takahashi, Y.; Tomita, Y.; Tsubouchi, M.; Yoshida, T.; Iwasaki,
N.; Kado, N.; Okezaki, E.; Nagata, O. Chem. Pharm. Bull. 2001, 49,
353–360.
13. Wouters, J. Curr. Med. Chem. 1998, 5, 137–162. and references cited
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14. (a) Molina, P.; Vilaplana, M. J. Synthesis 1994, 1197–1218; (b) Refael,
A. S.; Jose, M. Q. Tetrahedron 2001, 57, 5413–5420. and references
cited therein.
15. (a) General procedure for the one-pot conversion of azido alcohols to 2-
oxazolidinones: A solution of the azido alcohol (0.074 mol) and Ph3P
(0.081 mol) in toluene (100 mL) was taken under CO2 (pressure 2–
5 psi) at 0 °C. Then the reaction mass was slowly warmed and refluxed
for 7–12 h. The reaction mixture was concentrated and the crude
product obtained was purified by flash column chromatography using
ethylacetate in petroleum ether system as eluent, to yield the
corresponding 2-oxazolidinone. Compound 3: [a]D +16.42 (c 0.7,
CH2Cl2), IR (Neat): 3369, 1750 cmÀ1; 1H NMR (CDCl3, 200 MHz) d
6.3 (s, 1H), 4.79–4.80 (m, 1H), 3.8–3.45 (m, 4H), MS (m/z): 136, 138;
(b) Madhusudhan, G.; Om Reddy, G.; Ramanatham, J.; Dubey, P. K.
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C.; Chan, L.; Lyster, M. A.; Maloney, M. T.; Moeslein, J. A.; Greene,
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