Preparation of 2,3-diaminopropionate from ring opening of aziridine-2-carboxylate

Article abstract of DOI:10.1016/j.tetlet.2005.04.039

Ring opening reaction of an enantiomerically pure aziridine-2-carboxylate with an azide nucleophile under aqueous acidic media proceeded efficiently and stereoselectively to give 3-amino-2-azidopropionate which is converted to orthogonally protected 2,3-diaminopropionate.

Full text of DOI:10.1016/j.tetlet.2005.04.039

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4407–4409
Preparation of 2,3-diaminopropionate from ring opening
of aziridine-2-carboxylate
b
b
c
Yongeun Kim,a Hyun-Joon Ha,a,b, Kyusung Han, Seung Whan Ko, Hoseop Yun,
*
Hyo Jae Yoon,d Min Sung Kimd and Won Koo Leeb,d,
*
aDepartment of Chemistry, Hankuk University of Foreign Studies, Yongin 449-791, Korea
bImagene Co. Ltd, Biotechnology Incubating Center, Seoul National University, Seoul 151-742, South Korea
cDepartment of Molecular Science and Technology, Ajou University, Suwon 442-749, South Korea
dDepartment of Chemistry, Sogang University, Seoul 121-742, South Korea
Received 26 February 2005; revised 6 April 2005; accepted 11 April 2005
Available online 10 May 2005
Abstract—Ring opening reaction of an enantiomerically pure aziridine-2-carboxylate with an azide nucleophile under aqueous
acidic media proceeded efficiently and stereoselectively to give 3-amino-2-azidopropionate which is converted to orthogonally
protected 2,3-diaminopropionate.
Ó 2005 Elsevier Ltd. All rights reserved.
The importance of enantiopure 2,3-diaminopropionate
can be found as a fragment of various biologically
important molecules such as roxifiban,1 cyclotheon-
amide2 and many potential drug candidates.3 An easy
access of 2,3-diaminopropionate or its synthetic precur-
sor would therefore promote the drug discovery pro-
gram. Additional utility of 2,3-diaminopropionate was
found recently as a probe to investigate the structure
of peptide and proteins.4 Thereby its large scale prepara-
tion is absolutely necessary to carry out the solid phase
peptide synthesis cooperating 2,3-diaminopropionate as
one of unnatural amino acids. Up to now only one syn-
thetic method is available starting from aspartic acid via
Curtius rearrangement as the core reaction including
many tedious protection and deprotection steps.2,5
Herein we would like to report a simple and efficient
method forthe synthesis of enantiopuer 2,3-diamino-
propionate from the regioselective ring opening reaction
of a commercially available chiral aziridine-2-carboxyl-
ate in high yield.
Since we reported the production of aziridine-2-carbox-
ylic acid (ꢀ)-menthol esterin industiral scale, we have
been interested in the preparation of diverse nitrogen
containing chiral molecules.6 Methods we developed
include manipulation of carboxylate group, ring expan-
sion and ring opening reaction with many different
nucleophiles such as oxygen, nitrogen, sulfur and
halides.6 Even though many examples of ring opening
reaction of activated aziridine by azide nucleophiles
were reported,7 it was not possible to produce 2,3-di-
aminopropionate by direct ring opening reaction of
aziridine-2-carboxylate with benzyl substituent on the
nitrogen due to its inertness towards external nucleo-
philes. In this report we would like to describe the
first direct ring opening reaction of N-benzylaziridine-
2-carboxylate with azide as a nitrogen nucleophile
underacidic aqueous media to give 3-amino-2-
azidopropionate.
Chiral [10(R)-a-methylbenzyl]aziridine-2(R)-carboxylate
(ꢀ)-menthol ester 1a was reacted in 50% aqueous
ethanol at pH 4.0, adjusted by addition of sulfuric acid,
with sodium azide in the presence of 10 mol% of
AlCl3Æ6H2O as a catalyst to yield the ring opening pro-
duct 2-azido-3-[10(R)-a-methylbenzylamino]-propionate
2a in 95% yield (Scheme 1).
Keywords: Ring opening; Azide; Aziridine-2-carboxylate; 2,3-Diamino-
propionate.
*
Corresponding authors. Tel.: +82 31 3304369 (H.-J.H); tel.: +82 1
705 8449 (W.K.L.); e-mail addresses: hjha@hufs.ac.kr; wonkoo@
sogang.ac.kr
The ring opening product 2a was then reacted with
methyl oxalyl chloride followed by catalytic hydrogenation
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.04.039

4408
Y. Kim et al. / Tetrahedron Letters 46 (2005) 4407–4409
Ph
Ph
CO2Et
NHY
cat. AlCl3
XHN
CO2R
Me
N
Me
N
H
H
NaN3
pH=4
N3
CO2R
4a X = (R)-Ph(CH3)CH, Y = H
4b X = Y = Boc
4c X = (R)-Ph(CH3)CH, Y = Fmoc
4d X = Boc, Y = Fmoc
1a R = (-)-Menthol
1b R = Et
2a R = (-)-Menthol
2b R = Et
Scheme 1.
Ph
O
Ph
O
cat. AlCl3
Me
NaN3
COR
Me
N
1) ClCOCO2Me
NH
N
H
2a
H
Ph
N
OMen
N3
COR
2) H2/ Pd(OH)2
pH=4
Me
O
2c R = CH(CH3)2, 75%
2d R = Ph, 64%
1c R = CH(CH3)2
1d R = Ph
3
2e R = 4-F-Ph, 82%
2f R = 4-Cl-Ph, 71%
2g R = Pyrene, 78%
1e R = 4-F-Ph
1f R = 4-Cl-Ph
1g R = Pyrene
Scheme 2.
with Pd(OH)2 to yield 2,3-dioxopiperidine-5-carboxyl-
ate 3 in 74% yield (Scheme 2). The absolute configur-
ation of C-5 of the piperazine bearing the newly
formed carbon–nitrogen bond was identified as R in
the X-ray crystalline structure shown in Figure 1.8 This
outcome shows that the ring opening reaction proceeds
with complete inversion at the reaction centre as ex-
pected. This reaction was applicable to several hundred
gram scale without any difficulties in isolation and puri-
fication. The same reaction was possible with ethyl azi-
ridine-2-carboxylate 1b in 86% yield.
Scheme 3.
orthogonally protected diaminopropionate 4d in 48%
overall yield.
This ring opening reactions of aziridine with azide in the
presence of AlCl3 were also applicable to 2-acylazir-
idines10 such as 1c–f and 1d to afford the corresponding
vicinal azido amino products 2c–f and 2d in quite good
yields (Scheme 3).
Ethyl 2-azido-3-(1-a-methylbenzylamino)-propionate 2b
was served as the starting substrate towards many differ-
ent diamine derivatives. Catalytic hydrogenation with
2 equiv of Boc2O in the presence of Pd/C provided di-
aminopropionate 4b with Boc protections on the nitro-
gens of both amines. The azido group was reduced
with Ph3P and H2O to yield 2-amino-3-[10(R)-a-meth-
ylbenzylamino]-propionate 4a in 71% yield. Subsequent
protection of the free amine with N-(9-fluorenylmeth-
oxycarbonyloxy)succinamide9 yielded compound 4c
which was further hydrogenated with Boc2O to give
In summary, ring opening reaction of enantiomerically
pure aziridine-2-carboxylate with azide under aqueous
acidic media proceeded efficiently and stereoselectively
to give 3-amino-2-azidopropionate that was served as
the starting substrate for orthogonally protected 2,3-
diaminopropionate.
Acknowledgements
We gratefully acknowledge the financial supports from
the Korea Science and Engineering Foundation (R01-
2000-000-00048-0 to H.-J.H. and R14-2002-045-01002-
0 to W.K.L.) and the Korea Research Foundation
(KRF-2002-070-C00060 to W.K.L.). The financial and
technical supports from the Center for Bioactive Molec-
ular Hybrids are also gratefully acknowledged.
References and notes
1. Batt, D. G.; Houghton, G. C.; Daneker, W. F.; Jadhav, P.
K. J. Org. Chem. 2000, 65, 8100.
2. Deng, J.; Hamada, Y.; Shioiri, T. Tetrahedron Lett. 1996,
37, 2261.
3. (a) Hayashi, K.; Nunami, K.; Kato, J.; Yoneda, N.; Kubo,
M.; Ochiai, T.; Ishida, R. J. Med. Chem. 1989, 32, 289–
297; (b) Xue, C.-B.; Rafalski, M.; Roderick, J.; Eyermann,
C. J.; Mousa, S.; Olson, R. E.; DeGrado, W. F. Bioorg.
Med. Chem. Lett. 1996, 6, 339; (c) Huanga, J.; Rebelloa, S.
Figure 1.

Y. Kim et al. / Tetrahedron Letters 46 (2005) 4407–4409
4409
S.; Rosenberga, L. A.; Kanekob, M.; Sakuramab, T.;
Lucchesia, B. R. Eur. J. Pharmacol. 1999, 366, 203.
4. (a) Groebke, K.; Renold, P.; Tsang, K. Y.; Allen, T. J.;
McClure, K. F.; Kemp, D. S. Proc. Natl. Acad. Sci. U.S.A.
1996, 93, 4025; (b) Padmanabhan, S.; York, E. J.; Stewart,
J. M.; Baldwin, R. L. J. Mol. Biol. 1996, 257, 726; (c)
Kretsinger, J. K.; Schneider, J. P. J. Am. Chem. Soc. 2003,
125, 7907.
Sabitha, G.; Satheesh Babu, R.; Rajkumar, M.; Srinivas
Reddy, C.; Yadav, J. S. Tetrahedron Lett. 2001, 42, 3955;
(g) Sabitha, G.; Babu, R. S.; Rajkumar, M.; Yadav, J. S.
Org. Lett. 2002, 4, 343.
8. Crystallographic data (excluding structure factors) for the
structures in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplemen-
tary publication numbers CCDC 263351. Copies of the
data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax:
+44(0) 1223 336033 ore-mail: deposit@ccdc.cam.ac.uk].
9. (a) Paquet, A. Can. J. Chem. 1982, 60, 976; (b) Lapatsanis,
L.; Milias, G.; Froussios, K.; Kolovos, M. Synthesis 1983,
671; (c) de L. Milton, R. C.; Becker, E.; Milton, S. C. F.;
Baxter, J. E. H.; Elsworth, J. F. Int. J. Pept. Protein Res.
1987, 30, 431.
5. Englund, E. A.; Gopi, H. N.; Appella, D. H. Org. Lett.
2004, 6, 213.
6. Lee, W.-K.; Ha, H.-J. Aldrichim. Acta 2003, 36, 57.
7. (a) Leung, W. H.; Yu, M. T.; Wu, M. C.; Yeung, L. L.
Tetrahedron Lett. 1996, 37, 891; (b) Ferraris, D.; Drury,
W. J., III; Cox, C.; Lectka, T. J. Org. Chem. 1998, 63,
4568; (c) Li, Z.; Fernandez, M.; Jacobson, E. N. Org. Lett
1999, 1, 1611; (d) Wu, J.; Hou, X. L.; Dai, L. X. J. Org.
Chem. 2000, 65, 1344; (e) Chandrasekhar, M.; Sekar, G.;
Singh, V. K. Tetrahedron Lett. 2000, 41, 10079; (f)
10. Yun, J. M.; Sim, T. B.; Hahm, H. S.; Lee, W. K.; Ha, H.-J.
J. Org. Chem. 2003, 68, 7675.