The results reported in Table 1 show that high yields and
satisfactory diastereoselectivities are always achieved. The
reported trans/cis ratio may be rationalized by the intermedi-
ate R-iodo derivative undergoing a competing Filkenstein
reaction by some iodide ion prior to ring closure. This would
account for the formation of a small amount of cis aziridine.
The products are obtained pure by flash chromatography
and have been characterized by IR and NMR spectroscopy.12
Both the ring opening of N-acyl aziridines by means of
an external nucleophile and their ring expansion by means
of an internal nucleophile with formation of oxazolines are
well-known.13 The reactions proceed with high stereocontrol.
The ring expansion of N-carboxyaziridines is usually cata-
lyzed by a Lewis acid such as boron trifluoride, while the
reaction of N-Boc aziridines with Brønsted acids has been
reported in the past14 and affords mixtures of products that
also contain oxazolidin-2-ones.
Scheme 1
The treatment of N-Boc aziridines trans-2a-c and cis-
3a,b with BF3‚Et2O or BF3‚2H2O afforded the corresponding
4-carboxymethyl oxazolidin-2-ones trans-4a-c and cis-5a,b,
respectively (Scheme 2). The rearrangement proceeds with
Table 1. Chemical Yields and Diastereomeric Product Ratios
for the Cyclization of Amidoesters 1a-c
entry
R
yield (%)
trans/cis ratio
1
2
3
Me
iPr
Ph
80
90
85
87:13
90:10
98:2
Scheme 2
reoselectivity (Scheme 1 and Table 1).8 As was previously
observed by Seebach9 and by us,10 the reaction of the lithium
dianion of N-protected â-amino esters with an electrophile
affords the 2,3-anti adducts with both high yields and high
stereoselectivities. When the electrophile is a good leaving
group (as in the case of halogens), the direct formation of
the corresponding aziridine is observed, since the halogen
is substituted by the neighboring nitrogen.11
complete regio- and stereoselectivity. Indeed, only 4-car-
boxymethyl oxazolidin-2-ones are obtained, thus showing
that the oxygen always migrates away from the carboxy-
methyl group. Moreover, the rearrangement is totally stereo-
selective, because both cis and trans disubstituted N-Boc
aziridines afford exclusively cis and trans oxazolidin-2-ones,
respectively.15
(7) Although these compounds have been used in the racemic form, it is
well-known that â-amino acids can be obtained in the enantiomerically pure
form by kinetic resolution of the corresponding phenylacetylamides by
reaction with enzyme PGA, which selectively hydrolyzes amides of R- and
â-amino acids of the L series. See: (a) Rossi, D.; Lucente, G.; Romeo, A.
Experientia 1977, 33, 1557. (b) Soloshonok, V. A.; Svedas, V. K.; Kukhlar,
V. P.; Kirilenko, A. G.; Rybakova, A. V.; Solodenko, V. A.; Fokina, N.
A.; Kogut, O. V.; Galaev, I. Y.; Kozlova, E. V.; Shishkina, I. P.; Galushko,
S. V. Synlett 1993, 339. (c) Soloshonok, V. A.; Fokina, N. A.; Rybakova,
A. V.; Shishkina, I. P.; Galushko, S. V.; Sorochinsky, A. E.; Kukhlar, V.
P.; Savchenko, M. V.; Svedas, K. V.; Tetrahedron: Asymmetry 1995, 7,
1601. (d) Cardillo, G.; Tolomelli, A.; Tomasini, C. J. Org. Chem. 1996,
61, 8651. For general reviews reporting the asymmetric synthesis of â-amino
acids, see: (e) EnantioselectiVe Synthesis of â-Amino Acids; Juaristi, E.,
Ed.; Wiley-VCH: New York, 1997. (f) Cole, D. C. Tetrahedron 1989, 50,
9517. (g) Juaristi, E.; Quintana, D.; Escalante, J. Aldrichim. Acta 1994, 27,
3. (g) Cardillo, G.; Tomasini, C. Chem. Soc. ReV. 1996, 25, 117.
(8) (a) Osborn, H. M. I.; Sweeney, J. Tetrahedron: Asymmetry 1997, 8,
1693. (b) Zwanenburg, B.; Thjis, L. Pure Appl. Chem. 1196, 68, 735. (c)
Tanner, D. Angew. Chem., Int. Ed. Engl. 1994, 33, 599. (d) Fanta, P. E. In
Heterocyclic Compounds with Three- and Four-membered Rings; Weiss-
berg, A., Ed.; Wiley-Interscience: New York, 1964; Part 1, p 524.
(9) (a) Seebach, D.; Estermann, H. Tetrahedron Lett. 1987, 28, 3103.
(b) Seebach, D.; Estermann, H. HelV. Chim. Acta 1988, 71, 1824.
(10) (a) Cardillo, G.; Gentilucci, L.; Tolomelli, A.; Tomasini, C. J. Org.
Chem. 1998, 63, 2351. (b) Cardillo, G.; Tolomelli, A.; Tomasini, C. Eur.
J. Org. Chem. 1999, 155. (c) Nocioni, A. M.; Papa, C.; Tomasini, C.
Tetrahedron Lett. 1999, 40, 8453. (d) Cardillo, G.; Gentilucci, L.; Tolomelli,
A.; Tomasini, C. Synlett 1999, 1727. (e) Papa, C.; Tomasini, C. Eur. J.
Org. Chem., in press.
Satisfactory yields were obtained only by starting from
aziridine 2c (Table 2, entries 8-11). When R is a methyl or
Table 2. Chemical Yields for the Rearrangement of N-Boc
Aziridines 2a-c with BF3
entry
R
Lewis acid (amt (equiv))
yield (%)
1
2
4
5
6
7
8
9
10
11
Me
Me
Me
Me
iPr
iPr
Ph
Ph
Ph
Ph
BF3‚Et2O (3)
BF3‚H2O (3)
a
a
BF3‚Et2O (0.5)
BF3‚H2O (0.5)
BF3‚H2O (0.5)
BF3‚Et2O (0.5)
BF3‚Et2O (3)
BF3‚H2O (3)
15a
15a
10a
30a
90
90
98
92
BF3‚H2O (0.5)
BF3‚Et2O (0.5)
a The remaining starting material was transformed into a complex mixture
of products.
(11) In similar substrates, when the amine is protected with a benzoyl
group, the exclusive formation of the oxazoline is observed.10
2154
Org. Lett., Vol. 1, No. 13, 1999