group would lead to aziridines 7, whose carbonyl group
would be able to attack either the C-2 or the C-3 aziridinic
positions in a related, though different, way to that already
described for compounds 5. The resulting intramolecular ring
opening, which is known for several 2-(Boc-aminomethyl)
oxiranes,14 though to the best of our knowledge not for their
aziridine analogues,15 would pose interesting questions as
to its regio- and stereoselectivity. We disclose in this paper
our first findings regarding these intramolecular ring openings
and, moreover, exploit the presence of an aminomethyl
substituent in the resulting 1,3-oxazolidin-2-ones to report a
new synthetic approach to the antibiotic linezolid, 1.
The starting enantiopure 1-substituted aziridine-2-carboxa-
mides 2 were prepared via bacterial kinetic resolution of their
racemates as recently reported8 [(1R,2S)-2a-d], or by
Gabriel-Cromwell aziridination16 between ethyl (()-2,3-
dibromopropanoate and (S)-R-methylbenzylamine, followed
by chromatographic separation of the resulting diastereomers
and subsequent ammonolyses [(1S,1′S,2S)-2e, (1R,1′S,2R)-
2f].17 The trans relationship between the carbamoyl group
and the aryl or alkyl substituent at the nitrogen atom in all
six aziridines 2 was elucidated by NOESY experiments: the
ortho protons of 2a-c, the exocyclic methylene protons of
2d and the exocyclic methine proton of 2e,f correlate with
two protons of the aziridine ring, that of the C-2 position,
and the proton cis to the latter at the C-3 atom.
The importance of optically active 1,3-oxazolidin-2-ones
and our own interest in the reactivity of enantiopure
unactivated aziridines such as 28 converge in the possibility
of obtaining the former from the latter. In fact, ring
expansions of optically active aziridines have been employed
to prepare optically active 1,3-oxazolidin-2-ones. For in-
stance, Korean researchers have used processes of this type
in two main stereoselective ways: (a) cyclization at the N
and O atoms of aziridines 3 using either iodotrimethylsilane
and 1,1′-carbonyldiimidazole9 or sodium hydride and phos-
gene10 and (b) activation of the nitrogen atom of aziridines
4 as a carbamate by reaction with methyl chloroformate, with
subsequent ring opening by the chloride anion and ring
closure through the carbamate carbonyl.4 The latter option
is close to the ring expansion of activated N-Boc aziridines
5 to 1,3-oxazolidin-2-ones, which has been reported to occur
stereoselectively with lithium halides in the presence of
Amberlyst 1511 and also with the aid of Lewis acids.
However, the results of these Lewis acid promoted ring
expansions are known to depend strongly on the aziridine’s
substituents and stereochemistry.12 Lewis acid mediated ring
expansions of activated N-acylaziridines do not lead to 1,3-
oxazolidin-2-ones but to 4,5-dihydro-1,3-oxazoles (oxazo-
lines).13
All of the starting materials 2 were transformed into the
corresponding enantiopure 5-(aminomethyl)-1,3-oxazolidin-
2-ones 8 with a yield of 40-55% (Table 1) over the three
sequential steps shown in Scheme 1.18
Table 1. Preparation of Oxazolidinones 8 from Aziridines 2a
aziridine
N-substituent timeb (h)
product
yieldc(%)
(1R,2S)-2a
(1R,2S)-2b
(1R,2S)-2c
(1R,2S)-2d
(1S,1′S,2S)-2e (S)-PhCHMe
(1R,1′S,2R)-2f (S)-PhCHMe
Ph
6.25
5
5.25
4.5
1.5
2
(R)-8a
(R)-8b
(R)-8c
(R)-8d
(3′S,5R)-8e
(3′S,5S)-8f
45
42
40
49
55
44
4-Me-C6H4
4-MeO-C6H4
Ph-CH2
In view of the above findings, we envisaged that the
reduction of the amide moiety of our aziridines 2 and the
subsequent N-Boc protection at the resulting exocyclic amine
a See Scheme 1. b Third step, THF reflux time. c Overall yield (after
three steps); isolated yield (after column chromatography).
(7) (a) Renslo, A. R.; Luehr, G. W.; Gordeev, M. F. Bioorg. Med. Chem.
2006, 14, 4227–4240. (b) Mukhtar, T. A.; Wright, G. D. Chem. ReV. 2005,
105, 529–542. (c) Barbachyn, M. R.; Ford, C. W. Angew. Chem. Int. Ed
2003, 42, 2010–2023.
A number of side reactions were observed during the
overall process: for instance, LAH-reduction processes of
1-arylaziridine-2-carboxamides 2a-c were accompanied by
some hydride ring opening at the C-3 position; N-Boc
protection of 2-(aminomethyl)-1-arylaziridines 6a-c also
affords N,N′-diBoc 2-(arylaminomethyl)aziridines,19 whose
similar polarities to those of intermediates 7a-c resulted in
inefficient chromatographic purifications. Other side-products
observed in the NMR spectra of the intermediate and final
crude materials could not be identified, despite which we
were able to characterize several intermediates 6 and 7 as
essentially pure compounds. Nevertheless, all these problems
were overcome by performing only one chromatographic
(8) Mora´n-Ramallal, R.; Liz, R.; Gotor, V. Org. Lett. 2007, 9, 521–
524.
(9) Pyun, D. K.; Lee, C. H.; Ha, H.-J.; Park, C. S.; Chang, J.-W.; Lee,
W. K. Org. Lett. 2001, 3, 4197–4199.
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D.; Lee, W. K.; Chang, J.-W.; Ha, H.-J. J. Org. Chem. 2003, 68, 43–49.
In this case, (1′R,2R)-3 was used as the starting material.
(11) Righi, G.; Potini, C.; Bovicelli, P. Tetrahedron Lett. 2002, 43, 5867–
5869.
(12) (a) Lu, Z.; Zhang, Y.; Wulff, W. D. J. Am. Chem. Soc. 2007, 129,
7185–7194. (b) Cardillo, G.; Gentilucci, L.; Gianotti, M.; Tolomelli, A.
Synlett 2000, 1309–1311. (c) Tomasini, C.; Vecchione, A. Org. Lett. 1999,
1, 2153–2156.
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1936
Org. Lett., Vol. 10, No. 10, 2008