Synthesis of racemic cis-1-alkyl- and 1-aryl-2-aminocyclopropanecarboxylic esters

Article abstract of DOI:10.1016/S0040-4039(03)00126-6

The title cyclic β-amino esters were synthesized stereo- and regioselectively. Starting from the corresponding 1-aryl- and 1-alkylcyclopropane-1,2-dicarboxylates, selective monosaponification and subsequent Curtius reaction leads to certain cis-1-alkyl- and 1-aryl-2-aminocyclopropanecarboxylic esters. These β-aminocyclopropanecarboxylate derivatives (β-ACCs) can be seen as useful building blocks for β-peptides.

Full text of DOI:10.1016/S0040-4039(03)00126-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 1771–1774
Synthesis of racemic cis-1-alkyl- and
1-aryl-2-aminocyclopropanecarboxylic esters
Sven Mangelinckx and Norbert De Kimpe*
Department of Organic Chemistry, Faculty of Agricultural and Applied Biological Sciences, Ghent University,
Coupure Links 653, B-9000 Gent, Belgium
Received 26 November 2002; revised 9 January 2003; accepted 13 January 2003
Abstract—The title cyclic b-amino esters were synthesized stereo- and regioselectively. Starting from the corresponding 1-aryl- and
1-alkylcyclopropane-1,2-dicarboxylates, selective monosaponification and subsequent Curtius reaction leads to certain cis-1-alkyl-
and 1-aryl-2-aminocyclopropanecarboxylic esters. These b-aminocyclopropanecarboxylate derivatives (b-ACCs) can be seen as
useful building blocks for b-peptides. © 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
In this report we wish to present our results of a
one-step Curtius reaction starting from 1-aryl- and
1-alkylcyclopropane-1,2-dicarboxylates. In general,
only few articles have appeared on the synthesis of
alkyl- and aryl-substituted b-aminocyclopropanecar-
boxylic esters.5,13,15,16,18,22,28 Most of them require car-
bene-type reactions or photolysis.
The interesting pharmacological properties of b-amino
acids and their use in the synthesis of b-peptides have,
especially in the last decade, renewed the interest of
organic chemists.1–4 The conformationally restricted b-
aminocyclopropanecarboxylates (b-ACCs) are impor-
tant building blocks in the synthesis of peptides with
improved properties and in SAR studies.5–12 Several
synthetic methods have led to these vicinally push–pull-
substituted cyclopropanes. Carbene or carbenoid addi-
tion to enamines or enaminocarbonyl compounds,7,13–21
Michael addition of amines to cyclopropenecarboxyl-
ates,22 oxidation of the corresponding hydroxymethyl-
cyclopropylamines8,9,23–27 and lithiation–substitution of
cyclopropylamines are the most important methods
described.28 These methods suffer from drawbacks such
as very low overall yield or stringent reaction condi-
tions. A quite elegant method with good yields is the
Curtius reaction applied at the corresponding cyclo-
propane-1,2-dicarboxylates.10,27,29–34 Surprisingly this
method has not been generalized towards alkyl- or
aryl-substituted cyclopropane-1,2-dicarboxylates. Only
ethyl (1R,2R)-2-(benzyloxycarbonylamino)-2-methylcy-
clopropane-1-carboxylate has been synthesized this
way.27
2. Results and discussion
The reaction between acrylates 2 and enolates derived
from a-bromo esters 1 gives a ready access to cis-cyclo-
propanedicarboxylates 3 (major products) and trans-
cyclopropanedicarboxylates
4
(d.r. >4:1) (Scheme
1).35,36 Distillation and column chromatography enables
the isolation of pure cis-1-aryl- and 1-alkylcyclo-
propane-1,2-dicarboxylates 3.
The regioselective monosaponification of the least steri-
cally hindered ester function in 3 with sodium hydrox-
Keywords: b-amino acids; b-aminocyclopropanecarboxylic acids; Cur-
tius reaction.
* Corresponding author. Tel.: +32-9-264-5951; fax: +32-9-264-6243;
e-mail: norbert.dekimpe@rug.ac.be
Scheme 1.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00126-6

1772
S. Mangelinckx, N. De Kimpe / Tetrahedron Letters 44 (2003) 1771–1774
ide in methanol leads to 2-aryl- and 2-alkyl-2-
(methoxycarbonyl)cyclopropane-1-carboxylic acids
5
(Scheme 2). This monosaponification has already been
used in our research group for the synthesis of
dimethyl-2,2-dialkylcyclopropane-1,1-dicarboxylates.37
The spectral data of the phenyl derivative 5a, which are
in correspondence with literature data,38 confirm that
only reaction occurs at the least sterically hindered
methoxycarbonyl group at position 2. The signal of the
least sterically hindered methoxy group and, as a conse-
quence, also the most deshielded signal (l 3.77 ppm
versus l 3.66 ppm of the shielded methoxycarbonyl
function on the phenyl-substituted carbon), disap-
peared completely. The same observations were made
for methyl- and ethyl-substituted cyclopropanes 5b and
5c.
Scheme 3.
A modified Curtius rearrangement on the cyclo-
propanecarboxylic acids 5 finally led to the correspond-
ing methyl 2-(alkoxycarbonylamino)-1-aryl- and
1-alkylcyclopropane-1-carboxylates 6 and 7 (Scheme 3).
When a two-step modified version of the Curtius reac-
tion was applied by treatment of 5a with triethylamine
and diphenyl phosphorazidate for 2 h reflux in toluene,
followed by addition of methanol and subsequent stir-
ring for 8–15 h, only a small amount of carbamate 6a
could be isolated from the reaction mixture with
1
column chromatography. In the H NMR spectra of
most of the impure fractions was clearly present an
aldehyde peak, probably arising from the ring-opened
product 12. The formation of this g-keto ester is ratio-
nalised by formation of the carbaminic acid 9 from the
intermediate isocyanate 8 and traces of water. This
carbaminic acid 9 opens to the iminium salt 11 which
underwent hydrolysis. This ring opening is inherent for
1,2-push–pull-substituted cyclopropanes (Scheme 4).39
In order to avoid this ring opening the modified Curtius
reaction was repeated under one-step conditions. Dry
Scheme 4.
tert-butanol was used instead of toluene, so that the
formed isocyanate 8 would react in situ to the Boc-pro-
tected b-ACC derivative 7a. Under these conditions,
cis-methyl 1-aryl- and 1-alkyl-2-(tert-butoxycarbonyl-
amino)cyclopropane-1-carboxylates 7 were isolated in
better yields after column chromatography.
The cis configuration of 7a was confirmed with DIF-
NOE-NMR experiments (Table 1, CDCl3). The fact
that after irradiation of proton Hc, the most shielded
proton exhibits the highest NOE, proves that the pro-
ton in cis position of Hc is also positioned cis to the
phenyl substituent (Fig. 1). This indicates that the
carbamate function holds a cis position to the ester
group.
Scheme 2.
Table 1. DIFNOE-NMR experiments on 7a: irradiated protons and corresponding percentages NOE of the different protons
(CDCl3).
Irradiated proton
NOE (%)
Ha
Hb
Hc
NH
OCH3
C6H5
Ha
Hb
Hc
–
24.6
8.1
20.5
–
2.2
6.5
0
6.4
1.6
1.3
8.1
6.0
7.8
Overlapa
Overlapa
0
–
a The total % NOE of Hc and OCH3 was 2.2%; the signals were however not resolved enough to make a distinction and the use of C6D6 resulted,
because of ASIS, in a better resolution of the signals of Hc and OCH3, but in a worse resolution of the signals of Hb and the tert-butyl group.

S. Mangelinckx, N. De Kimpe / Tetrahedron Letters 44 (2003) 1771–1774
1773
3. Experimental
A typical procedure for the synthesis of methyl cyclo-
propanecarboxylates 7a–c and 16 is given with cis-methyl
2-(tert-butoxycarbonylamino)-1-phenylcyclopropane-
1-carboxylate 7a as an example. To a solution of 0.5 g
(23 mmol) of cis-2-methoxycarbonyl-2-phenylcyclo-
propane-1-carboxylic acid 5a in 5 ml dry tert-butanol was
added 0.23 g (23 mmol) of triethylamine and 0.62 g (23
mmol) of diphenyl phosphorazidate. The reaction mix-
ture was heated for 5 h at 90–95°C (oil bath), the solvent
was evaporated and 5 ml of water was added. After
extraction with ethyl acetate (3×40 ml), the combined
organic phases were washed with water and brine and
dried (MgSO4). Evaporation in vacuo resulted in a brown
viscous oil which was subjected to column chromatogra-
phy to obtain the resultant products.
Figure 1.
The synthesis of the other regioisomer 16 was achieved
via a four-step sequence. Treatment of the cyclopropane
diester 3b with a large excess of potassium hydroxide
resulted in the diacid 13 which could be converted into
the corresponding anhydride 14 by heating at reflux for
a short period of time in acetyl chloride. Subsequent
heating at reflux in methanol gave quantitatively cis-2-
(methoxycarbonyl)-1-methylcyclopropane-1-carboxylic
acid 15. Also in this case, a complete regioselectivity of
the nucleophilic addition of methanol to the least steri-
cally hindered carbonyl group was observed. The final
rearrangement under the same conditions as in the
synthesis of 1-aryl- and 1-alkyl-substituted cyclopropanes
7, resulted in the isolation of methyl 2-(tert-butoxycar-
bonylamino)-2-methylcyclopropane-1-carboxylate 16,
although in low yield, after chromatography and crystalli-
sation (Scheme 5).
3.1. cis-Methyl 2-(tert-butoxycarbonylamino)-1-phenyl-
cyclopropane-1-carboxylate 7a
White crystals (253 mg, 38%), mp 97.0–98.0°C, Rf=0.30,
petroleumether/EtOAc4/1;1HNMR(CDCl3, 270MHz):
l 1.47 (s, 9H), 1.58 (dd, J=5.9, 7.9 Hz, 1H), 1.84 (dd,
J=5.9, 5.9 Hz, 1H), 3.48 (m, 1H), 3.62 (s, 3H), 5.26 (broad
s, 1H), 7.24–7.36 (m, 3H), 7.46–7.49 (m, 2H); 13C NMR
(CDCl3, 68 MHz): l 21.1, 28.3, 35.7, 39.2, 52.6, 79.9,
127.5, 128.3, 130.7, 138.4, 156.2, 172.0; IR (KBr, cm−1):
3367, 1710; MS (70 eV): m/z (%): no M+, 234 (5), 202
(6), 190 (12), 189 (7), 175 (10), 158 (100), 157 (21), 132
(26), 130 (45), 129 (42), 115 (12), 103 (31), 77 (9), 57 (82).
3.2. cis-Methyl 2-(tert-butoxycarbonylamino)-1-methyl-
cyclopropane-1-carboxylate 7b
In conclusion, this paper describes a stereo- and regiose-
lective synthesis of 1-methyl, 1-phenyl and 2-methyl
2-(alkoxycarbonylamino)cyclopropane-1-carboxylates.
This makes certain b-ACC derivatives available which are
of interest for further research in the fast-growing field
of b-peptides and peptidomimetics.
White crystals, mp 71.8–72.7°C, Rf=0.21, petroleum
ether/EtOAc 4/1; H NMR (CDCl3, 270 MHz): l 1.05
1
(dd, J=5.6, 7.9 Hz, 1H), 1.32 (s, 3H), 1.37 (m, 1H), 1.43
(s, 9H), 3.10 (m, 1H), 3.71 (s, 3H), 5.24 (broad s, 1H);
13C NMR (CDCl3, 68 MHz): l 19.0, 22.0, 24.9, 28.3, 39.0,
52.2, 79.6, 156.1, 173.7; IR (KBr, cm−1): 3359, 1714; MS
(70 eV): m/z (%): no M+, 172 (9), 155 (6), 141 (5), 128
(13), 123 (6), 113 (14), 97 (42), 70 (19), 69 (12), 57 (100).
3.3. cis-Methyl 2-(tert-butoxycarbonylamino)-1-ethylcy-
clopropane-1-carboxylate 7c
1
Colorless oil, Rf=0.24, petroleum ether/EtOAc 4/1 ; H
NMR (CDCl3, 270 MHz): l 0.98 (t, J=7.3 Hz, 3H), 1.05
(dd, J=5.8, 7.8 Hz, 1H), 1.27 (m, 1H), 1.36 (m, 1H), 1.43
(s, 9H), 1.96 (dq, J=7.3, 14.4 Hz, 1H), 3.10 (m, 1H), 3.72
(s, 3H), 5.20 (broad s, 1H); 13C NMR (CDCl3, 68 MHz):
l 11.3, 20.1, 26.4, 28.3, 31.2, 38.1, 52.0, 79.6, 156.0, 173.2;
IR (NaCl, cm−1): 3370, 1720; MS (70 eV): m/z (%): 243
(M+, 0.05), 186 (8), 142 (10), 128 (14), 111 (46), 84 (17),
83 (20), 82 (12), 57 (100).
3.4. cis-Methyl 2-(tert-butoxycarbonylamino)-2-methyl-
cyclopropane-1-carboxylate 16
White crystals, mp 82.7–83.3°C, Rf=0.20, petroleum
1
ether/EtOAc 4/1 ; H NMR (CDCl3, 270 MHz): l 1.13
Scheme 5.

1774
S. Mangelinckx, N. De Kimpe / Tetrahedron Letters 44 (2003) 1771–1774
(dd, J=5.3, 8.4 Hz, 1H), 1.40 (m, 1H), 1.42 (s, 9H),
1.46 (s, 3H), 1.84 (dd, J=6.3, 8.4 Hz, 1H), 3.67 (s, 3H),
4.98 (broad s, 1H); 13C NMR (CDCl3, 68 MHz): l 21.9,
24.1, 27.6, 28.2, 37.6, 51.8, 79.6, 155.7, 171.3; IR (KBr,
cm−1): 3371, 1729, 1695; MS (ES, 3.5kV): m/z (%): 230
(M++1, 7), 174 (32), 152 (12), 130 (100), 98 (25).
14. Tanny, S. R.; Grossman, J.; Fowler, F. W. J. Am. Chem.
Soc. 1972, 94, 6495–6501.
15. Wenkert, E.; McPherson, C. A.; Sanchez, E. L.; Webb,
R. L. Synth. Commun. 1973, 3, 255–259.
16. Wenkert, E.; Hudlicky´, T.; Showalter, H. D. H. J. Am.
Chem. Soc. 1978, 100, 4893–4894.
17. Horikawa, H.; Nishitani, T.; Iwasaki, T.; Inoue, I. Tetra-
hedron Lett. 1983, 24, 2193–2194.
18. Paulini, K.; Reissig, H. U. Liebigs Ann. Chem. 1991,
455–461.
3.5. cis-Methyl 2-(methoxycarbonylamino)-1-phenylcy-
clopropane-1-carboxylate 6a
Rf=0.25, petroleum ether/EtOAc 7/3 ; 1H NMR
(CDCl3, 270 MHz): l 1.63 (dd, J=5.9, 8.6 Hz, 1H),
1.86 (dd, J=5.9, 6.3 Hz, 1H), 3.62 (s, 3H), 3.65 (m,
1H), 3.72 (s, 3H), 5.52 (broad s, 1H), 7.28–7.38 (m,
3H), 7.43–7.48 (m, 2H); 13C NMR (CDCl3, 68 MHz): l
21.2, 35.5, 39.5, 52.4, 52.7, 127.6, 128.4, 130.6, 138.1,
157.3, 172.1; IR (NaCl, cm−1): 3350, 1726; MS (70 eV):
m/z (%): 249 (M+, 1), 248 (7), 218 (15), 217 (100), 190
(19), 189 (20), 174 (67), 159 (12), 158 (81), 144 (10), 131
(14), 130 (23), 129 (10), 115 (43), 103 (50), 86 (10), 84
(11), 77 (19), 59 (15).
19. El. Abdioui, K.; Martinez, J.; Viallefont, P.; Vidal, Y.
Bull. Soc. Chim. Belg. 1997, 106, 425–431.
20. Galardon, E.; Le Maux, P.; Simonneaux, G. Tetrahedron
2000, 56, 615–621.
21. Beumer, R.; Bubert, C.; Cabrele, C.; Vielhauer, O.; Piet-
zsch, M.; Reiser, O. J. Org. Chem. 2000, 65, 8960–8969.
22. Franck-Neumann, M.; Miesch, M.; Kempf, H. Tetra-
hedron 1988, 44, 2933–2942.
23. Jime´nez, J. M.; Rife´, J.; Ortun˜o, R. M. Tetrahedron:
Asymmetry 1996, 7, 537–558.
24. Jime´nez, J. M.; Ortun˜o, R. M. Tetrahedron: Asymmetry
1996, 7, 3203–3208.
25. Jime´nez, J. M.; Rife´, J.; Ortun˜o, R. M. Tetrahedron:
Asymmetry 1995, 6, 1849–1852.
Acknowledgements
26. Wick, L.; Tamm, C.; Boller, T. Helv. Chim. Acta 1995,
78, 403–410.
27. Mart´ın-Vila`, M.; Muray, E.; Aguado, G. P.; Alvarez-
Larena, A.; Branchadell, V.; Minguillo´n, C.; Giralt, E.;
Ortun˜o, R. M. Tetrahedron: Asymmetry 2000, 11, 3569–
3584.
This work was financially supported by the IWT, BOF,
FWO and Ghent University (GOA).
28. Park, Y. S.; Beak, P. Tetrahedron 1996, 52, 12333–12350.
29. Yamazaki, S.; Inoue, T.; Hamada, T.; Takada, T.;
Yamamoto, K. J. Org. Chem. 1999, 64, 282–286.
30. Csuk, R.; von Scholz, Y. Tetrahedron 1996, 52, 6383–
6396.
References
1. Abele, S.; Seebach, D. Eur. J. Org. Chem. 2000, 1–15.
2. Juaristi, E.; Lo´pez-Ruiz, H. Curr. Med. Chem. 1999, 6,
983–1004.
31. Csuk, R.; von Scholz, Y. Tetrahedron 1995, 51, 7193–
7206.
32. Csuk, R.; von Scholz, Y. Tetrahedron 1994, 50, 10431–
10442.
3. Cole, D. C. Tetrahedron 1994, 50, 9517–9582.
4. Fu¨lo¨p, F. Chem. Rev. 2001, 101, 2181–2204.
5. Paulini, K.; Reissig, H. U. Liebigs Ann. Chem. 1994,
549–554.
33. Cannon, J. G.; Garst, J. E. J. Org. Chem. 1975, 40,
182–184.
6. D´ıaz, M.; Ortun˜o, R. M. Tetrahedron: Asymmetry 1996,
7, 3465–3478.
34. Shroff, C. C.; Stewart, W. S.; Uhm, S. J.; Wheeler, J. W.
J. Org. Chem. 1971, 36, 3356–3361.
7. Voigt, J.; Noltemeyer, M.; Reiser, O. Synlett 1997, 202–
204.
35. Epstein, J. W.; Brabander, H. J.; Fanshawe, W. J.; Hof-
mann, C. M.; McKenzie, T. C.; Safir, S. R.; Osterberg, A.
C.; Cosulich, D. B.; Lovell, F. M. J. Med. Chem. 1981,
24, 481–490.
8. D´ıaz, M.; Jime´nez, J.; Ortun˜o, R. M. Tetrahedron: Asym-
metry 1997, 8, 2465–2471.
9. Godier-Marc, E.; Aitken, D. J.; Husson, H.-P. Tetra-
hedron Lett. 1997, 38, 4065–4068.
36. Bonavent, G.; Causse, M.; Guitard, M.; Fraisse-Jullien,
R. Bull. Soc. Chim. Fr. 1964, 2462–2471.
10. Hibbs, D. E.; Hursthouse, M. B.; Jones, I. G.; Jones, W.;
Abdul Malik, K. M.; North, M. Tetrahedron 1997, 53,
17417–17424.
11. Bubert, C.; Cabrele, C.; Reiser, O. Synlett 1997, 827–829.
12. Zorn, C.; Gnad, F.; Salmen, S.; Herpin, T.; Reiser, O.
Tetrahedron Lett. 2001, 42, 7049–7053.
13. Kunieda, T.; Witkop, B. J. Am. Chem. Soc. 1971, 93,
3478–3487.
37. Salgado, A.; Huybrechts, T.; Eeckhaut, A.; Van der
Eycken, J.; Szakonyi, Z.; Fu¨lo¨p, F.; Tkachev, A.; De
Kimpe, N. Tetrahedron 2001, 57, 2781–2786.
38. Milewska, M. J.; Gdaniec, M.; Polonski, T. Tetrahedron
Asymmetry 1996, 7, 3169–3180.
39. Reissig, H. U. Top. Curr. Chem. 1988, 144, 73–135.