Synthesis of cyclopropanes via organoiron methodology: Preparation of 2-(2′-carboxy-3′-ethylcyclopropyl)glycine

Article abstract of DOI:10.1016/S0040-4039(00)01915-8

A route to 1,2,3-trisubstituted cyclopropanes has been developed. The relative stereochemistry at the three cyclopropane centers is established by nucleophilic attack on the pentadienyl ligand on the face opposite to iron and subsequent oxidatively induced reductive elimination with retention of configuration. This methodology was applied to the synthesis of 2-(2′-carboxy-3′-ethylcyclopropyl)glycines. The diastereomeric glycine dimethyl esters are separable as their diphenylmethylene imines.

Full text of DOI:10.1016/S0040-4039(00)01915-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 153–154
Synthesis of cyclopropanes via organoiron methodology:
preparation of 2-(2%-carboxy-3%-ethylcyclopropyl)glycine
Kamil Godula and William A. Donaldson*
Department of Chemistry, Marquette University, PO Box 1881, Milwaukee, WI 53201-1881, USA
Received 5 October 2000; revised 20 October 2000; accepted 24 October 2000
Abstract—A route to 1,2,3-trisubstituted cyclopropanes has been developed. The relative stereochemistry at the three cyclo-
propane centers is established by nucleophilic attack on the pentadienyl ligand on the face opposite to iron and subsequent
oxidatively induced reductive elimination with retention of configuration. This methodology was applied to the synthesis of
2-(2%-carboxy-3%-ethylcyclopropyl)glycines. The diastereomeric glycine dimethyl esters are separable as their diphenylmethylene
imines. © 2000 Elsevier Science Ltd. All rights reserved.
ethylcyclopropyl)glycines,
(2R,1%S,2%S,3%R)-5b.
(2S,1%S,2%S,3%R)-5a
and
L
-Glutamic acid is the major excitatory neurotransmit-
ter for a wide variety of receptors in mammalian sys-
tems.1 The selective activation of different glutamate
receptors may depend on recognition of a particular
conformer of this flexible molecule. For this reason, the
synthesis and evaluation of conformationally restricted
2-(2%-carboxycyclopropyl)glycines has led to the discov-
ery of ligands with mGluR specificity.2 In particular the
extended conformation, as exemplified by compounds
1–4, is believed to be a requirement for binding to the
mGluR1 and mGluR2 receptors, while the presence
and electronic nature of the 3%-substituent may distin-
guish between agonist and antagonist activity.3 As part
of our overall program on the development of a novel
iron-mediated formation of substituted cyclopropanes,
we herein report on the preparation of 2-(2%-carboxy-3%-
We have previously reported that the nucleophilic at-
tack of malonate anions to (1-methoxy-carbonylpenta-
+
dienyl)Fe(CO)3 (rac-6) proceeds predominantly at an
internal carbon, on the face of the pentadienyl ligand
opposite to iron, to afford (pentenediyl)iron complexes
(rac-7) (Scheme 1).4a Furthermore, oxidatively induced-
reductive elimination of rac-7 gives the vinylcyclo-
propanecarboxylate rac-8.4b It was envisioned that this
sequence of reactions might be applicable to the synthe-
sis of 2-(3%-substituted-2%-carboxycyclopropyl)glycines.
Reaction of rac-6 with the anion derived from methyl
nitroacetate gave the (pentenediyl)iron complex rac-
Cl-
+H3N
+
H NH3 Cl-
H CO2H
H CO2H
1, R = H
2, R = CO2H
3, R = CH2OCH3
S
R
H2N
HO2C
S
S
H
R
H
H
5a
Et
5b
Et
S
R
S
3'
R
4, R = Ph
MeO2C
MeO2C
Ref. 4a
HO2C
PF6-
HO2C
HO2C
CO2Me
MeO2C
MeO2C
MeO2C
Li
CAN
MeO2C
rac-7
MeO2C
Ref. 4b
Fe
MeO2C
Fe(CO)3+
(CO)3
rac-6
rac-8
Scheme 1.
* Corresponding author.
0040-4039/01/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01915-8

154
K. Godula, W. A. Donaldson / Tetrahedron Letters 42 (2001) 153–154
1) H2/Ra-Ni
(73%)
2) Ph
2CNH
(42%)
Ph
Ph
Ph
H CO2Me
MeO2C
H
O2N
H CO2Me
H N
Ph
MeO2C
O2N
2
O2N
MeO2C
N
CAN
CN
H
'
H
H
Li
CH3
'
1'
3
rac-6
Et
Et
MeO2C
'
2
Fe
MeO2C
C
MeO2C
rac-11b
MeO2
3) separate
as above
(CO)3
rac-10a/b (78%)
rac-11a
rac-9a/b (72%)
(1R)-6
(1'S)-10a/b
(52% two steps)
(-)-11a (35%)
6N HCl/∆
(+)-11b (31%)
6N HCl/∆
1) LiCH(NO2)CO2Me; 2) CAN/CH3CN
5b (95%)
5a (97%)
Scheme 2.
1990, 31, 139–142. (d) Sagnard, I.; Sasaki, N. A.; Chia-
roni, A.; Riche, C.; Potier, P. Tetrahedron Lett. 1995, 36,
3149–3152. (e) Shimamoto, K.; Ohfune, Y. J. Med. Chem.
1996, 39, 407–423. (f) Pellicciari, R.; Marinozzi, M.; Na-
talini, B.; Costantino, G.; Luneia, R.; Giorgi, G.; Moroni,
F.; Thomsen, D. J. Med. Chem. 1996, 392, 2259–2269. (g)
Chavan, S.; Venkatraman, M. S.; Sharma, A. K.; Chitti-
boyina, A. G. Tetrahedron Lett. 1996, 37, 2857–2858. (h)
Ma, D.; Ma, Z. Tetrahedron Lett. 1997, 38, 7599–7602. (i)
Pellicciari, R.; Marinozzi, M.; Costantino, G.; Natalini, B.;
Moroni, F.; Pellegrini-Giampietro, D. J. Med. Chem.
1999, 42, 2716–2720; (j) Ma, D.; Cao, Y.; Yang, Y.;
Cheng, D. Org. Lett. 1999, 1, 285–287; (k) Mazo´n, A.;
Pedregal, C.; Prowse, W. Tetrahedron 1999, 55, 7057–
7064.
9a/b as a mixture of diastereomers (Scheme 2). Treat-
ment of rac-9a/b with CAN gave rac-10a/b. The rela-
tive stereochemistry about the cyclopropane ring in
10a/b was assigned as indicated on the basis of the
magnitude of the vicinal couplings (J1%-2%=J2%-3%=5.3
Hz).5 Reduction of 10a/b, followed by reaction with
benzophenone imine6 gave a mixture of rac-11a and
rac-11b, which were separable by column chromatogra-
phy. The structure of rac-11a was confirmed by single-
crystal X-ray analysis.7 Beginning with (1R)-6,8 this
sequence of reactions gave (−)-11a and (+)-11b. The 2S
configuration (−)-11a was assigned by comparison of
the sign of its specific rotation with that of a series of 13
N-diphenylmethylene imines of
L
-amino esters.6b–e
Both (−)-11a and (+)-11b were assessed to be >80% ee
1
3. Jullian, N.; Barbet, I.; Pin, J.-P.; Acher, F. C. J. Med.
Chem. 1999, 42, 1546–1555.
by H NMR spectroscopy in the presence of Eu(hfc)3
(CDCl3). Separate hydrolysis of (−)-11a or of (+)-11b
gave the cyclopropylglycine hydrochloride salts 5a or
5b in excellent yield.
4. (a) Donaldson, W. A.; Shang, L.; Tao, C.; Yun, Y. K.;
Ramaswamy, M.; Young, V. G. J. Organomet. Chem.
1997, 539, 87–98. (b) Yun, Y. K.; Donaldson, W. A. J.
Am. Chem. Soc. 1997, 119, 4084–4085. For other recent
syntheses of 1,2,3-trisubstituted cyclopropanes see: (c)
Taylor, R. E.; Schmitt, M. J.; Yuan, H. Org. Lett. 2000, 2,
601–603; (d) Boehm, C.; Schinnerl, M.; Bubert, C.; Zabel,
M.; Labahn, T.; Parisini, E.; Reiser, O. Eur. J. Org. Chem.
2000, 2955–2965.
In summary, a route to 2-(2%-carboxy-3%-ethylcyclo-
propyl)glycines has been developed. Attempts to pre-
pare other conformationally restricted glutamate
analogs from 10a/b will be reported in due course.
5. For cyclopropanes, typically Jcis=7–13 Hz, Jtrans=4–9
Hz. Silverstein, R. M.; Bassler, G. C.; Morrill, T. C.
Spectrometric Identification of Organic Compounds, 5th ed.;
John Wiley & Sons: New York, 1991; pp. 221.
6. (a) O’Donnell, M. J. In Encyclopedia of Reagents for
Organic Synthesis; Paquette, L. A., Ed.; John Wiley &
Sons: New York, 1995; Vol. 1, p. 293–294. (b) O’Donnell,
M. J.; Polt, R. L. J. Org. Chem. 1982, 47, 2663–2666. (c)
O’Donnell, M. J.; Cook, G. K.; Rusterholz, D. R. Synthe-
sis 1991, 989–993. (d) Polt, R.; Peterson, M. A.; De
Young, L. J. Org. Chem. 1992, 57, 5469–5480. (e) O’Don-
nell, M. J.; Zhou, C.; Chen, N. Tetrahedron: Asymmetry
1996, 7, 621–624.
Acknowledgements
Financial support for this work was provided by the
National Institutes of Health (GM-42641) and the
Petroleum Research Fund (34297-AC1). The authors
are grateful to Professor Robin Polt, University of
Arizona, for stimulating discussions.
.
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