Enantioselective synthesis of oxazolidinones from N,N-dibenzylamino epoxides

Article abstract of DOI:10.1055/s-0029-1217161

Enantiomerically pure oxazolidinones are easily prepared from N,N-dibenzylamino epoxides through a one-pot procedure involving monodeprotection of the amino group and treatment with NaHCO₃. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1217161

LETTER
1471
Enantioselective Synthesis of Oxazolidinones from N,N-Dibenzylamino
Epoxides
Oxazolidinones
f
ro
a
m
A
mino
E
b
poxides riel E. Vargas, María M. Afonso, J. Antonio Palenzuela*
Instituto Universitario de Bio-Orgánica ‘Antonio González’, Departamento de Química Orgánica, Universidad de La Laguna,
38206 La Laguna, Tenerife, Spain
Fax +34(922)318442; E-mail: jpalenz@ull.es
Received 3 February 2009
Enantiomerically pure N,N-dibenzylamino epoxides are
easily obtained from amino acids following the procedure
of Barluenga and co-workers,8 and we envisaged that cou-
pling a monodeprotection procedure with the treatment
with a carbonate salt could lead to a simple synthesis of
oxazolidinones.
Abstract: Enantiomerically pure oxazolidinones are easily pre-
pared from N,N-dibenzylamino epoxides through a one-pot proce-
dure involving monodeprotection of the amino group and treatment
with NaHCO3.
Key words: amino epoxides, cyclization, oxazolidinones, hetero-
cycles
The deprotection of an N-benzyl group can be effected by
a number of methods, however, selectivity for mono- or
di-N-debenzylation is difficult to achieve,9 and very few
procedures exist to remove only one benzyl group of an
N,N-dibenzylamine.10 The procedure of Grayson and
Davis using N-iodosuccinimide10a did not work well in
our case; whereas the one published by Davies and co-
workers using cerium ammonium nitrate (CAN) in
acetonitrile10b gave a clean reaction with only one major
product as judged by TLC.
The oxazolidinones are a group of heterocycles which
have been subjected to numerous studies due to their bio-
logical properties,1 they also serve as efficient chiral
auxiliaries2 and are useful synthetic intermediates in the
preparation of other important compounds, especially
amino alcohols.3
The strategies devised for the synthesis of oxazolidinones
are quite varied; the most common being the treatment of
amino alcohols with phosgene or the intramolecular
cyclization of hydroxy carbamates.4
In this case the ammonium ion could help with the open-
ing of the epoxide as suggested by Génisson5 and the
treatment of the crude product with a carbonate salt
should result in the desired oxazolidinone. After several
trials we found that the addition of the salt was not neces-
sary, since the published protocol called for vigorous stir-
ring with sodium bicarbonate, which was enough to
produce the carboxylation of the monodeprotected amino
alcohol and the subsequent intramolecular cyclization.
Recently, Génisson and co-workers presented the synthe-
sis of oxazolidinones from N-benzylamino epoxides by
treatment with ammonium carbonate through a one-pot
carboxylation–cyclization sequence.5 According to the
authors, and based on the work of Toda and co-workers,6
the reaction takes place by the attack of the monoprotect-
ed amino group onto the carbon dioxide produced by the
carbonate followed by the regioselective intramolecular
opening of the epoxide by the thus formed carbamate, the
reaction being catalyzed by the ammonium ion.
OH
O
R
CAN
R
5
4
O
Later, Nagase and co-workers7 presented a three-compo-
nent synthesis which involved an amine, a haloepoxide,
and a metal carbonate, proposing that the mechanism pro-
ceeds through the attack of the amine on the haloepoxide
to give an intermediate amino epoxide. Attack of the car-
bonate on the epoxide followed by an intramolecular Scheme 1
cyclization gives a six-membered cyclic carbamate which
then rearranges to the oxazolidinone.
NaHCO3
BnN
Bn2N
O
1 R = Me
2 R = i-Bu
3 R = Bn
4 R = Me (85%)
5 R = i-Bu (81%)
6 R = Bn (80%)
Thus, the treatment of 1 with CAN in acetonitrile–water,
followed by the addition of an aqueous saturated solution
of NaHCO3 and vigorous stirring, furnished the oxazolid-
inone 4 in high yield (85%) and with total selectivity
(Scheme 1).11 The structure of the new compounds was
established by a combination of spectroscopic analyses.12
Regarding the stereochemistry of the ring, the value of the
coupling constant between H-4 and H-5 (8.3 Hz) clearly
indicates a cis-substituted system.13
Thus it seems clear that the treatment of amino epoxides
with a carbonate salt is an excellent route towards the oxa-
zolidinone moiety, although the mechanism of formation
can be different depending on the reaction conditions.
SYNLETT 2009, No. 9, pp 1471–1473
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Advanced online publication: 13.05.2009
DOI: 10.1055/s-0029-1217161; Art ID: D03909ST
© Georg Thieme Verlag Stuttgart · New York

1472
G. E. Vargas et al.
LETTER
The reaction also worked well when the amino epoxides reaction conditions for the formation of oxazolidinones.
derived from other amino acids, such as 2 and 3 were sub- The anti-amino epoxide 16 gave the expected oxazolidi-
jected to the same reaction conditions as shown in none 17 as a single compound in a 91% yield (Scheme 4).
Scheme 1, yielding the oxazolidinones 5 and 6 in good The syn-amino epoxide 18 in contrast showed poor reac-
yields as a single isomer in each case.
tivity, giving a complex mixture in low yield from which
no oxazolidinone could be isolated.
Diastereomeric epoxides 7–9, prepared following Barlu-
enga’s procedure from 1–3,8 were also tested and the cor- These results indicate that the groups involved in the reac-
responding oxazolidinones 10–12 isolated (Scheme 2). tion, the epoxide and the intermediate carbamate, need to
The value of the coupling constant between H-4 and H-5 adopt a precise relative disposition for the success of the
(<5.5 Hz in all cases) allowed us to establish that the process.
trans-oxazolidinones were formed, indicating a total se-
lectivity in this process.
O
NBn2
BnN
O
OH
CAN
O
O
R
CAN
NaHCO3
91%
R
OH
O
NaHCO3
BnN
( )-16
( )-17
Bn2N
O
NBn2
7 R = Me
8 R = i-Bu
9 R = Bn
10 R = Me (83%)
11 R = i-Bu (82%)
12 R = Bn (88%)
O
Scheme 2
( )-18
Scheme 4
To extend the scope of the reaction, a disubstituted amino
epoxide was prepared by first transforming 1 into the al-
lylamine 13 with n-butyllithium.14 Compound 13 was
then subjected to the epoxidation conditions for amino
alkene compounds15 giving 14 in 82% yield. The treat-
ment of 14 with CAN followed by vigorous stirring with
NaHCO3 gave the oxazolidinone 15 in good yield, again
as a single isomer (Scheme 3).
The structure and relative stereochemistry of the oxazoli-
dinones obtained in this work indicate that the mechanism
operating here is the one postulated in the works of Toda6
and Genisson;5 that is, the attack of the nitrogen onto the
CO2 liberated by the carbonate salt and the intramolecular
cyclization of the intermediate formed. This results in the
inversion of configuration at the carbon atom of the ep-
oxide closer to the nitrogen and in the retention at the oth-
er epoxide carbon (Scheme 5).
O
n-BuLi
( )2
THF, 0 °C
Bn2N
Bn2N
13
1
82%
O
O
R
R
CAN
1. MCPBA
TsOH (75%)
2. DBU (74%)
BnNH
Bn2N
OH
( )3
O
O
C O
BnN
CAN
( )2
O
NaHCO3
75%
Bn2N
OH
O
O
R
15
14
R
BnN
O–
O
Scheme 3
BnN
O
O
The relative stereochemistry of the oxazolidinone ring in
15 was assigned as cis on the basis of the value of the H-
4–H-5 coupling constant (6.8 Hz) but the relative stere-
ochemistry of the hydroxyl group was more difficult to es-
tablish, and so it was deduced from the analysis of the
coupling constants of the relevant protons. Comparing the
experimental values with the computed ones16 for all pos-
sible isomers allowed us to establish the stereochemistry
of 15 as shown in Scheme 3.
Scheme 5
The simple, one-pot procedure outlined in this communi-
cation permits the easy preparation of enantiomerically
pure oxazolidinones with different degrees of substitution
from amino epoxides, which in turn can be efficiently pre-
pared from commercial amino acids.
To study the stereoelectronic requirements of the reaction, Acknowledgment
the cyclic N,N-dibenzylamino epoxides 16 and 18 were
G.E.V. thanks the Gobierno de Canarias for an Antonio González
Fellowship.
prepared in racemic form,15 and were subjected to the
Synlett 2009, No. 9, 1471–1473 © Thieme Stuttgart · New York

LETTER
Oxazolidinones from Amino Epoxides
1473
was vigorously stirred for 10 min. After extraction with
Et2O, drying over Na2SO4 and concentration, the crude
reaction mixture was purified by chromatography to give the
pure oxazolidinone.
References and Notes
(1) Zappia, G.; Menendez, P.; Delle Monache, G.; Misiti, D.;
Nevola, L.; Botta, B. Mini Rev. Med. Chem. 2007, 7, 389.
(2) (a) Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. Rev. 1996,
96, 835. (b) Evans, D. A. Aldrichimica Acta 1982, 2, 23.
(3) Bergmeier, S. C. Tetrahedron 2000, 56, 2561; and
references therein.
(4) Zappia, G.; Gacs-Baitz, E.; Delle Monache, G.; Misiti, D.;
Nevola, L.; Botta, B. Curr. Org. Synth. 2007, 4, 81.
(5) Ayad, T.; Faugeroux, V.; Génisson, Y.; André, C.; Baltas,
M.; Gorrichon, L. J. Org. Chem. 2004, 69, 8775.
(6) Yoshida, M.; Ohshima, M.; Toda, T. Heterocycles 1993, 35,
623.
(7) Osa, Y.; Hikima, Y.; Sato, Y.; Takino, K.; Ida, Y.; Hirono,
S.; Nagase, H. J. Org. Chem. 2005, 70, 5737.
(8) Barluenga, J.; Baragaña, B.; Concellón, J. M. J. Org. Chem.
1995, 60, 6696.
(9) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 3rd ed.; Wiley: New York, 1999.
(10) (a) Grayson, E. J.; Davis, B. G. Org. Lett. 2005, 7, 2361.
(b) Bull, S. D.; Davies, S. G.; Fenton, G.; Mulvaney, A. W.;
Prasad, R. S.; Smith, A. D. J. Chem. Soc., Perkin Trans. 1
2000, 3765.
(12) Representative Data
Oxazolidinone 4: [a]D20 –67.9 (c 1.2, CHCl3). IR: nmax
=
3415, 2927, 1731, 1424, 1052 cm–1. 1H NMR (400 MHz,
C6D6): d = 7.27 (m, 5 H), 4.75 (d, J = 15.3 Hz, 1 H), 3.91 (dt,
J = 5.0, 8.3 Hz, 1 H), 3.80 (d, J = 15.3 Hz, 1 H), 3.37 (d,
J = 5.0 Hz, 2 H), 3.16 (dq, J = 6.6, 8.3 Hz, 1 H), 0.68 (d,
J = 6.6 Hz, 1 H). 13C NMR (100 MHz, CDCl3): d = 157.7 (s),
135.7 (s), 128.8 (d), 128.0 (d), 127.9 (d), 76.7 (d), 60.8 (t),
51.8 (d), 45.6 (t), 12.5 (c). LRMS (EI): m/z (%) = 221
(29)[M+], 91 (100). HRMS (EI): m/z calcd for C12H15NO3:
221.1052; found: 221.1043.
(13) Zappia, G.; Cancelliere, G.; Gacs-Baitz, E.; Delle Monache,
G.; Misiti, D.; Nevola, L.; Botta, B. Curr. Org. Synth. 2007,
4, 238.
(14) Concellón, J. M.; Suárez, J. R.; Del Solar, V. Org. Lett.
2006, 8, 349.
(15) Davies, S. G.; Long, M. J. C.; Smith, A. D. Chem. Commun.
2005, 4536.
(16) Each possible isomer was subjected to a conformational
search using Molecular Mechanics (PCMODEL v7, Serena
Software, Bloomington, IN). The coupling constants in each
conformer were calculated and the Boltzmann weighted
average was used for the comparison with the experimental
values.
(11) General Experimental Procedure for the Preparation of
Oxazolidinones from N,N-Dibenzyl Amino Epoxides
To a 0.05 M solution of the amino epoxide in MeCN–H2O
(5:1) was added CAN (2.1 equiv) and the reaction was
stirred at r.t., following the progress by TLC (approx. 12 h).
Then a sat. aq soln of NaHCO3 was added, and the mixture
Synlett 2009, No. 9, 1471–1473 © Thieme Stuttgart · New York

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