Novel synthesis of 4-carboxymethyl 5-alkyl/aryl oxazolidin-2-ones by rearrangement of 2-carboxymethyl 3-alkyl/aryl N-tert-butoxycarbonyl aziridines

Article abstract of DOI:10.1021/ol991225l

(matrix presented) A two-step approach for the diastereoselective synthesis of 4-carboxymethyl 5-alkyl/aryl oxazolidin-2-ones is described, which proceeds via the intermediate formation of 2-carboxymethyl 3-alkyl/aryl N-tert-butoxycarbonyl (N-Boc) aziridines. By reaction of N-Boc β-amino methyl esters with LiHMDS and iodine, trans 2,3-disubstituted N-Boc aziridines are obtained with high stereoselectivities and yields. The final rearrangement to oxazolidin-2-ones is achieved by treatment with a catalytic amount of a Lewis acid and proceeds with high yield and complete regio- and stereoselectivity.

Full text of DOI:10.1021/ol991225l

ORGANIC
LETTERS
1999
Vol. 1, No. 13
2153-2156
Novel Synthesis of 4-Carboxymethyl
5-Alkyl/Aryl Oxazolidin-2-ones by
Rearrangement of 2-Carboxymethyl
3-Alkyl/Aryl N-tert-Butoxycarbonyl
Aziridines
Claudia Tomasini* and Andrea Vecchione
Dipartimento di Chimica “G. Ciamician”, UniVersita` degli Studi di Bologna,
Via F. Selmi 2, 40126 Bologna, Italy
tomasini@ciam.unibo.it
Received November 5, 1999
ABSTRACT
A two-step approach for the diastereoselective synthesis of 4-carboxymethyl 5-alkyl/aryl oxazolidin-2-ones is described, which proceeds via
the intermediate formation of 2-carboxymethyl 3-alkyl/aryl N-tert-butoxycarbonyl (N-Boc) aziridines. By reaction of N-Boc â-amino methyl
esters with LiHMDS and iodine, trans 2,3-disubstituted N-Boc aziridines are obtained with high stereoselectivities and yields. The final
rearrangement to oxazolidin-2-ones is achieved by treatment with a catalytic amount of a Lewis acid and proceeds with high yield and complete
regio- and stereoselectivity.
Polypeptides containing unusual amino acids are among the
new interesting compounds which show high antibacterial
or anticancer activity. In particular, â-hydroxy R-amino acids
are widely present in macrocyclic polypeptides such as
Lysobactin,1 Vancomicin,2 and Luzopeptidin E2.3
A number of elegant approaches have been described for
the synthesis of nonproteogenic syn and anti â-hydroxy
R-amino acids.4 Many of these methods involve derivatiza-
tion of glycine equivalents attached to a chiral template, a
difficult problem since they are rarely easily removable.
We propose here a novel synthesis of trans 4-alkyl/aryl
5-carboxymethyl oxazolidin-2-ones, which are the protected
forms of syn â-hydroxy R-amino acids. These heterocycles
are excellent protecting groups for amino alcohols and allow
the derivatization of the nitrogen, so that polypeptide chains
can be obtained without the hydrolysis of the heterocycle.5
The starting N-Boc â-amino methyl esters 1a-c are easily
obtained in good yields from the corresponding â-amino
acids6 by esterification with MeOH/SOCl2 and reaction with
Boc-anhydride and sodium carbonate.7 By treatment with
LiHMDS and iodine at low temperature, these substrates
undergo cyclization with the formation of the corresponding
2-carboxymethyl 3-alkyl/aryl aziridines, with high diaste-
(1) Tymiak, A. A.; McCormick, J. J.; Unger, S. E. J. Org. Chem. 1989,
54, 1149.
(2) (a) Williams, D. H. Acc. Chem. Res. 1984, 17, 364. (b) Harris, C.
M.; Kopecka, H.; Harris, T. M. J. Am. Chem. Soc. 1983, 105, 6915. (c)
Nagarajan, R.; Schabel, A. A.; Occolowitz, J. L.; Counter, F. T.; Ott, J. L.
J. Antibiot. 1988, 41, 1431.
(3) (a) Konishi, M.; Ohkuma, H.; Sakai, F.; Tsuno, T.; Koshiyama, H.;
Naito, T.; Kawaguchi, H. J. Am. Chem. Soc. 1981, 103, 1241. (b) Arnold,
E.; Clardy, J. J. Am. Chem. Soc. 1981, 103, 1243.
(4) See for example: (a) Blaskovich, M. A.; Evindar, G.; Rose, N. G.
W.; Wilkinson, S.; Luo, Y.; Lajoie, G. A. J. Org. Chem. 1998, 63, 6361
and references therein. (b) Duthaler, R. O. Tetrahedron 1994, 50, 1539.
(5) Xi, N.; Ciufolini, M. A. Tetrahedron Lett. 1995, 36, 6595.
(6) Racemic 3-aminobutanoic acid is commercially available. Racemic
3-amino-5-methylbutanoic acid was obtained according to: Lazar, L.;
Martinek, T.; Bernath, G.; Fulop, F. Synth. Commun. 1998, 28, 219. Racemic
3-amino-3-phenylpropanoic acid was obtained according to: Rodionow,
W. M.; Postovskaja, E. A. J. Am. Chem. Soc. 1929, 51, 841.
10.1021/ol991225l CCC: $18.00 © 1999 American Chemical Society
Published on Web 12/03/1999

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

an isopropyl group, complex mixtures of ring-opening
products together with small amounts of oxazolidin-2-ones
were obtained. This behavior can be explained by analyzing
the probable reaction mechanism (Figure 1). The Lewis acid
obtained with Cu(OTf)2, and the reaction rate could be greatly
accelerated by the use of a chelating solvent, such as THF/
DME, which promotes the full conversion of the aziridine
to oxazoline.
In our hands, when N-Boc aziridines 2a-c and 3a,b were
treated with a catalytic amount of Cu(OTf)2, Sn(OTf)2, and
Zn(OTf)2, they afforded the desired oxazolidin-2-ones in
good to excellent yields.17 Surprisingly, when the reaction
was carried out in a mixture of THF/DME as described by
Leckta (entry 4), only the starting material was recovered,
while high yields were obtained in methylene chloride. This
discrepancy can be attributed to the carboxymethyl group
present near the aziridine ring, which chelates the metal ion
(Figure 2).
Figure 1. Mechanism for the rearrangement of N-Boc aziridine
catalyzed by BF3.
catalyzes the formation of an incipient carbocation on C-3,
which is the driving force for the rearrangement that proceeds
with the elimination of a molecule of isobutene. This process
is certainly easier when an electron-donating group is
connected to C-3. This explains the excellent results obtained
with the phenyl group and the low yields of methyl and
isopropyl groups.
In contrast, very good results were obtained when the
reaction was performed with catalytic amounts of chelating
Lewis acids (Table 3). Recently Leckta16 highlighted the ring
Figure 2. Mechanism for the rearrangement of N-Boc aziridine
catalyzed by azaphilic Lewis acids.
The oxazolidin-2-ones 4a-c and 5a,b can be easily
transformed into the corresponding â-hydroxy R-amino
acids.18 Indeed, the hydrolysis of trans 4-carboxymethyl
5-phenyl oxazolidin-2-one 4c with LiOH in water afforded
threo phenylserine in high yield (Scheme 3).
Table 3. Chemical Yields for the Rearrangement of N-Boc
Aziridines 2a-c with Various Lewis Acids
Lewis acid
entry
R
(amt (equiv))
solvent
time (h) yield (%)
1
2
3
4
5
6
7
8
9
Me Cu(OTf)2 (0.1) CH2Cl2
Me Zn(OTf)2 (0.1) CH2Cl2
Me Sn(OTf)2 (0.1) CH2Cl2
iPr Cu(OTf)2 (0.1) DME/THF
40
40
40
6
99
90
99
a
20a
65
85
20a
98
98
98
96
Scheme 3
iPr
Cu(OTf)2 (0.1) CH2Cl2
8
iPr Cu(OTf)2 (0.1) CH2Cl2
iPr Cu(OTf)2 (0.1) CH2Cl2
iPr Zn(OTf)2 (0.1) CH2Cl2
iPr Sn(OTf)2 (0.1) CH2Cl2
40
70
40
40
40
40
40
10
11
12
Ph
Ph
Ph
Cu(OTf)2 (0.1) CH2Cl2
Zn(OTf)2 (0.1) CH2Cl2
Sn(OTf)2 (0.1) CH2Cl2
In conclusion, we have demonstrated an efficient method
for the preparation of trans 4-carboxymethyl 5-alkyl/aryl
oxazolidin-2-ones, the protected forms of â-hydroxy R-amino
acids. These substrates have been obtained by means of a
new rearrangement which allows us to transform N-Boc
aziridines into oxazolidin-2-ones by reaction with a catalytic
a The starting material was recovered.
expansion of N-benzoyl aziridines to oxazolines by reaction
with catalytic amounts of azaphilic Lewis acids, such as
Cu(OTf)2, Sn(OTf)2, and Zn(OTf)2. The best results were
(14) (a) Quinze, K.; Laurent, A.; Mison, P. J. Fluorine Chem. 1989, 44
233. (b) Alvernhe, G.; Lacombe, S.; Laurent A. Tetrahedron Lett. 1980,
21, 289.
(15) As the reaction is totally stereoselective, only the results regarding
the trans aziridines 2a-c are reported.
(16) Ferraris, D.; Drudy, W. J., III; Cox, C.; Lectka, T. J. Org. Chem.
1998, 63, 4568.
(17) As the reaction is totally stereoselective, only the results regarding
the trans aziridines 2a-c are reported.
(18) Ishizuka, T.; Kunieda, T. Tetrahedron Lett. 1987, 28, 4185.
(12) All new compounds have been fully characterized.
(13) (a) Heine, H. W.; Fetter, M. E.; Nicholson, M. J. Am. Chem. Soc.
1959, 81, 2202. (b) Heine, H. W.; King, D. C.; Portland, L. A. J. Org.
Chem. 1966, 31, 2662. (c) Nakajima, K.; Neya, M.; Yamada, S.; Okawa,
K. Bull. Chem. Soc. Jpn. 1982, 55, 3049. (d) Legters, J.; Willems, J. G. H.;
Thijs, L.; Zwanenburg, B. Recl. TraV. Chim. Pays-Bas 1992, 111, 59. (e)
Legters, J.; Thijs, L.; Zwanenburg, B. Recl. TraV. Chim. Pays-Bas 1992,
111, 16. (f) Cardillo, G.; Gentilucci, L.; Tolomelli, A. Chem. Commun.
1999, 167.
Org. Lett., Vol. 1, No. 13, 1999
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amount of Lewis acid and are efficient starting materials for
the synthesis of polypeptides.
Supporting Information Available: Experimental pro-
cedures and characterization data for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. This work was supported in part by
MURST Cofin 1998 (Rome) and by the University of
Bologna (funds for Selected Research Topics).
OL991225L
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