Stereoselective synthesis of anti-2-oxazolidinones by Ph3P-CCl4-Et3N mediated SN2 cyclization of N-Boc-β-amino alcohols

Article abstract of DOI:10.1016/S0040-4039(03)01508-9

Ethyl anti-4-substituted phenyl-2-oxo-1,3-oxazolidine-5-carboxylates were synthesized stereoselectively in excellent yields using the Ph₃P-CCl₄-Et₃N system by S_N2 cyclization of N-Boc-β-amino alcohols. syn to an

Full text of DOI:10.1016/S0040-4039(03)01508-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6323–6325
Stereoselective synthesis of anti-2-oxazolidinones by
Ph3P–CCl4–Et3N mediated SN2 cyclization of N-Boc-b-amino
alcoholsꢀ
G. Madhusudhan,a G. Om Reddy,a,* J. Ramanathama and P. K. Dubeyb
aTechnology Development Center, Dr. Reddy’s Laboratories Ltd, Bollaram Road, Miyapur, Hyderabad 500 050, AP, India
bDepartment of Chemistry, College of Engineering, JNT University, Kukatpally, Hyderabad 500 872, AP, India
Received 31 March 2003; revised 5 June 2003; accepted 13 June 2003
Abstract—Ethyl anti-4-substituted phenyl-2-oxo-1,3-oxazolidine-5-carboxylates were synthesized stereoselectively in excellent
yields using the Ph3P–CCl4–Et3N system by SN2 cyclization of N-Boc-b-amino alcohols. syn to anti conversion of ethyl
4-substituted phenyl-2-oxo-1,3-oxazolidine-5-carboxylates using DBU as base is also described.
© 2003 Elsevier Ltd. All rights reserved.
2-Oxazolidinone moieties are present in many biologi-
cally active molecules of pharmaceutical interest. These
heterocyclic units are also useful intermediates for the
synthesis of polymers and agricultural chemicals. Chiral
2-oxazolidinones are also widely used as a powerful
tool in asymmetric synthesis.1 DUP-721,2 Linezolid3
and Cytoxazone4 are a few examples of drugs that
contain the 2-oxazolidinone ring.
2-Oxazolidinones can be prepared from a variety of
compounds such as other heterocyclic compounds (e.g.
epoxides, aziridines, oxetanes, 2-oxazolones), b-difunc-
tional compounds, hydroxy acids or esters and most
commonly from amino alcohols.5,6 Chiral oxazolidine-
2-ones have been prepared from b-hydroxy acids using
the Curtius rearrangement with intramolecular capture
of the intermediate isocyanate.7 Chiral oxazolidinones
have also been prepared from N-Boc-b-amino alcohol
derivatives by converting the hydroxy group into a
tosylate followed by cyclization via an intramolecular
SN2 displacement.8,9 Zhao et al.10 reported the prepara-
tion of chiral oxazolidinones with good yields by treat-
ing
N-Boc-b-amino
alcohol
derivatives
with
N,N-diethylaminosulfur trifluoride (DAST) under mild
conditions. Recently this approach has been used by
Benedetti et al.11 in the preparation of oxazolidinone
from mesylate derivatives of N-Boc-b-amino alcohols
via SN2 cyclization.
Scheme 1.
The condensation of carbonyl groups and other nucle-
ophiles with alcohols using Ph3P–DEAD has become
an important technique in the synthesis of many
molecules, and is known as the Mitsunobu reaction.12
The related Ph3P–CCl4–Et3N system was previously
utilized for conversion of alcohols to halides,13 b-
Keywords: anti-2-oxazolidinones; N-Boc-b-amino alcohols; SN2
cyclization; Ph3P–CCl4–Et3N.
ꢀ DRL Publication No. 300.
* Corresponding author. Tel.: +91-40-2304-3539; fax: +91-40-2304-
4044; e-mail: omreddyg@drreddys.com
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01508-9

6324
G. Madhusudhan et al. / Tetrahedron Letters 44 (2003) 6323–6325
Table 1. Conversion of N-Boc-b-amino alcohols 1 to ethyl
anti-4-substituted phenyl-2-oxo-1,3-oxazolidine-5-carboxy-
lates 5
with NaH in toluene gave the coresponding syn-2-oxa-
zolidinones 2 due to attack of the hydroxyl nucleophile
on the carbamide carbonyl group (Scheme 1). We con-
ducted the same reaction using the Ph3P–CCl4–Et3N
system18 and found that different compounds were
obtained. These were later confirmed to be anti-2-oxa-
zolidinones 5 (Table 1). This can be explained by an
SN2 process, in which nucleophilic attack of the carbon-
ate on the activated hydroxyl bearing center results in
cyclization and formation of the inverted product
514,19,20 (Scheme 2). This is a versatile and efficient
method for the stereoselective preparation of anti-oxa-
zolidinones from the corresponding N-Boc-b-amino
alcohols.
Entry
R
Yield (%)
Mp (°C)
1
2
3
4
5
H
F
OBn
OAc
OMe
92
91
88
87
90
84–86
Viscous liquid
124–126
91–93
121–122.5
hydroxy hydroxamic acids to b-lactams,14 and also for
amino alcohols to aziridines15 with complete inversion.
In continuation of our earlier work,16 we have devel-
oped a novel method for the preparation of anti oxazo-
lidinones from syn-N-Boc-b-amino alcohols using
Ph3P–CCl4–Et3N, in which O-substitution is not
required. Racemic N-Boc-b-amino alcohols 1 were pre-
pared by reductive Boc protection of the corresponding
azido alcohols,17 which were obtained from the corre-
sponding benzaldehydes by Darzen’s condensation with
ethyl chloroacetate followed by regioselective opening
of the epoxides with NaN3. Compound 1 on treatment
The Ph3P–CCl4–Et3N system has two advantages when
compared to that reported16 earlier in which the O-
tosyl derivatives of N-Boc b-amino alcohols are used; it
gives superior yields and also avoids the conversion of
the hydroxy group to the tosylate. The formation of
anti-oxazolidinones was not observed when the reaction
was carried out with ethyl carbonates or any other
carbonates. This indicates that the tertiary butyl group
is a prerequisite for the formation of the corresponding
anti-oxazolidinones.
Scheme 2.
Table 2. 1H NMR data of 2 (syn) and 5 (anti) in CDCl3
Entry
R
syn isomer 2
H5 (l)
anti isomer 5
H4 (l)
J4–5 (Hz)
H4 (l)
H5 (l)
J4–5 (Hz)
1
2
3
4
5
H
F
OBn
OAc
OMe
5.25
5.25
5.25
5.1
5.25
5.25
5.2
5.1
5.2
–
–
–
–
–
5.0
5.0
4.9
5.0
4.9
4.7
4.7
4.7
4.7
4.7
5.1
5.1
5.1
5.3
5.3
5.2

G. Madhusudhan et al. / Tetrahedron Letters 44 (2003) 6323–6325
6325
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Scheme 3.
1
In their H NMR spectra, chemical shift values for the
vicinal protons 4H and 5H in compounds 2 and 5 were
found to be at l ꢀ5.2 ppm and l 4.7–5.0 ppm,
respectively (Table 2). This is in accordance with
reported trends21 and was further supported by correla-
tion of the dihedral angle calculated by energy mini-
mization of structures 2 and 5 using Chem Draw
software (Chem3D Pro Version 3.5.1) and the Karplus
curve. According to the Karplus curve, the coupling
constant J should be ꢀ5.0 Hz for the anti-configura-
tion as observed for 5 (J=ꢀ5.0 Hz). Similarly 2 is
assigned the syn-configuration.
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All syn oxazolidinones 2 were converted to their anti
epimers 5 by epimerisation of the hydroxy center with
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)22 in toluene
at room temperature (Scheme 3). Energy minimization
data23 further support the formation of anti over syn
products (for syn-oxazolidinones 2 ꢀ29.4 kcal/mol and
for anti oxazolidinones 5 ꢀ25.2 kcal/mol).
12. Mitsunobu, O. Synthesis 1981, 1–28.
13. Appel, R. Angew. Chem. Int. Ed. Engl. 1975, 14, 801–811.
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16. Madhusudhan, G.; Om Reddy, G.; Ramanatham, J.;
Dubey, P. K. Indian J. Chem. 2003, submitted.
17. Hamersak, Z.; Ljuboric, E.; Mercep, M.; Mesic, M.;
Sunjic, V. Synthesis 2001, 13, 1989–1992.
18. To a solution of compound 1 (2 g) in acetonitrile (20 mL)
was added Ph3P (1.2 equiv.), CCl4 (2.5 equiv.), Et3N (2.5
equiv.). The resulting mixture was stirred at room tem-
perature overnight. The reaction mass was concentrated
under reduced pressure to give a residue. This residue was
purified by flash chromatography on 230–400 mesh silica
gel (ethyl acetate–petoleum ether 4:6) to afford the oxa-
zolidinone 5.
Acknowledgements
The authors are thankful to Dr. Reddy’s Group for
supporting this work. Acknowledgements are also due
to all the colleagues in Discovery Research and Tech-
nology Development Center. Discussions with Dr. J.
Moses Babu for the dihedral angle calculations and Dr.
B. Gopalakrishnan for energy calculations, of Discov-
ery Research are also gratefully acknowledged.
19. Slagle, J. D.; Huang, T. T. S.; Franzus, B. J. Org. Chem.
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