A concise and efficient stereoselective synthesis of protected (2R,1′S,2′S)-2-(carboxycyclopropyl)glycine (D-CCG-I)

Article abstract of DOI:10.1039/b105503h

The stereoselective synthesis of protected D-carboxycyclo-propylglycine (D-CCG-I) was achieved, as an extension of Taguchi's protocol for Simmons-Smith cyclopropanation to a chiral, amino-containing allyl alcohol derivative, in 8 steps (40% overall yield)

Full text of DOI:10.1039/b105503h

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A concise and efficient stereoselective synthesis of protected
(2R,1ЈS,2ЈS)-2-(carboxycyclopropyl)glycine (D-CCG-I)
Debendra K. Mohapatra
1
OCT Division, National Chemical Laboratory, Pune-411 008, India.
E-mail: dkm_77@yahoo.com; Fax: 91-020-5893614/5892456
Received (in Cambridge, UK) 22nd June 2001, Accepted 6th July 2001
First published as an Advance Article on the web 20th July 2001
The stereoselective synthesis of protected D-carboxycyclo-
propylglycine (D-CCG-I) was achieved, as an extension of
Taguchi’s protocol for Simmons–Smith cyclopropanation
to a chiral, amino-containing allyl alcohol derivative, in 8
steps (40% overall yield).
-Glutamic acid functions at many synapses in mammalian
central nervous systems (CNS) as an excitatory neurotrans-
mitter1 and is implicated in the development of memory and
early learning,2 as well as in the pathogenesis of neuron damage
to cause various neuronal diseases.3 Recent years have seen, in
particular, a growing interest in the field of the metabotropic
glutamate receptor (mGluR) family,4–6 due to the intriguing
therapeutic opportunities offered by the modulation of its
members. Indeed, mGluRs have been shown to play important
roles in spatial learning7 and the process of postaral-vinetic
integration,8 as well as in the pathogenesis of either acute
(ischemia, epilepsy, hypoxia) or chronic (e.g., Alzheimer’s
disease, Parkinsonism, AIDs-related dementia) diseases.
Among the several classes of glutamate analogs, carboxy-
cyclopropylglycines (CCGs) represent a valuable source of
potent and selective ligands for the various members of the
glutamate receptor family. (2R,1ЈS,2ЈS)-2-(Carboxycyclo-
propyl)glycine (D-CCG-I), which restricts the conformation of
-glutamate in the extended form, has received much attention
from neuroscientists because it is a potent and selective
N-methyl--aspartate (NMDA) agonist.9,10
Prompted by the above observations and by our interest in
the synthesis of bioactive natural products containing cyclo-
propyl rings,11 we undertook synthetic studies on the above
class of compounds. Herein, we would like to report a facile
and stereoselective synthesis of protected D-CCG-I, extending
Taguchi’s asymmetric cyclopropanation protocol12 to a chiral,
amino-containing allylic alcohol derivative. To our knowledge,
no analogous studies have been reported so far on such com-
pounds in which the chiral oxygen group has been replaced by a
nitrogen functionality.
For the proposed synthesis, we decided to utilize the easily
available and widely used -serine-derived Garner’s aldehyde 3
(Scheme 1) as a chiral template in which the stereodefined amine
functionality, along with a primary hydroxy group (both of
Fig. 1
which can ultimately be utilized in the α-amino acid precursor),
and the aldehyde functionality would assist in building the
cyclopropane skeleton.
Following a retrosynthetic strategy, the journey began with a
diastereoselective two-carbon Wittig reaction of Garner’s alde-
hyde with (ethoxycarbonylmethylene)triphenylphosphorane in
benzene which provided (E)-allyl ester 4 (Scheme 2) in 92%
yield. The (E)-geometry of the double bond was confirmed by
the coupling constant between the olefinic protons (J = 15.8
Hz). Compound 6 was obtained by the exposure of compound
4 to 2.5 equivalents of DIBAL-H in CH2Cl2 followed by protec-
tion with a TBDPS group.
In order to investigate the Simmons–Smith cyclopropanation
reaction on chiral, amino-containing allyl alcohol derivatives
and to synthesize the intermediate 2 with the required stereo-
chemistry, compound 6 was treated with Et2Zn and CH2I2,
following Taguchi’s protocol, to afford the disubstituted cyclo-
propane derivative 7 in 93% yield (Scheme 3). At this stage,
we could not determine the diastereomeric excess as the silyl
alcohol accompanied the product during purification by silica
gel column chromatography.
Compound 7 was then treated with tetrabutylammonium
fluoride to afford the free hydroxy compound 2, which on
HPLC analysis was found to be a mixture of diastereomers
(90 : 10). Chelation-controlled positioning of the reagent (the
complexation-induced proximity effect) has been proposed to
account for this diastereoselective addition to the allylic alco-
hol. Four models can be considered as possible transition state
models (Fig. 1). Among them conformer A is most favourable
compared to the rest in terms of steric repulsion between the
N,O-acetonide ring and the TBDPS group. Owing to the bulki-
ness of the TBDPS group, the reagent might co-ordinate to the
carbonyl oxygen of the Boc group and the methylene transfer
may then occur from the less hindered face of the double bond,
providing the major cyclopropane in the required (1S,2S)-
stereochemistry.12,13
Finally, hydrolysis of the acetonide linkage of 2 with PTSA
in methanol yielded the intermediate 8 and oxidation of the
hydroxy groups to carboxylic acids, followed by esterification
with diazomethane under standard reaction conditions,
Scheme 1
DOI: 10.1039/b105503h
J. Chem. Soc., Perkin Trans. 1, 2001, 1851–1852
This journal is © The Royal Society of Chemistry 2001
1851

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Scheme 2
Scheme 3
5 Z. A. Bortolotte, Z. I. Beshir, C. H. Davies and G. L. Collingridge,
afforded the target cyclopropylglutamic acid analogue 1 in
good overall yield. The structure of 1 was established on the
basis of 1H NMR, 13C NMR and mass spectra.14
Nature, 1994, 368, 740.
6 C. Pawloski-Dahm and F. J. Gordon, Am. J. Physiol., 1992, 262,
1611.
7 G. Riedel, W. Wetzel and K. G. Reymann, Neurosci. Lett., 1994, 167,
141.
8 A. I. Sacaan, F. P. Bymaster and D. D. Schoepp, J. Neurochem.,
1992, 59, 245.
9 (a) H. Shinozaki, Y. Ohfune, K. Watanabe, P. Li and H. Takeuchi,
Tetrahedron Lett., 1988, 29, 1181; (b) K. Shimamato, M. Ishida,
H. Shinozaki and Y. Ohfune, J. Org. Chem., 1991, 56, 4167; (c)
K. Shimamato and Y. Ohfune, Synlett, 1993, 12, 919.
10 D. Ma and Z. Ma, Tetrahedron Lett., 1997, 38, 7599.
11 (a) D. K. Mohapatra and A. Datta, J. Org. Chem., 1998, 63, 642; (b)
V. Sundararaman, D. K. Mohapatra and A. Datta, Tetrahedron
Lett., 1998, 39, 1075; (c) V. Sundararaman, D. K. Mohapatra and
A. Datta, Tetrahedron Lett., 1998, 39, 5667; (d ) D. K. Mohapatra,
Synth. Commun., 1999, 29, 4261.
In conclusion, an efficient stereoselective synthesis of pro-
tected D-CCG-I has been developed using as the key step
a
chelation-controlled Simmons–Smith cyclopropanation,
following Taguchi’s protocol, on a readily available -serine-
derived chiral template. Utilizing ent-3 and/or changing the
starting alkene geometry, it is possible to synthesize all four of
the possible isomers of CCG following the approach described
above, thereby, showing the versatility of this method. The
reported methods either involve multistep reactions or give a
poor overall yield. Following our protocol, it is, however,
possible to prepare large amounts of the carboxycyclopropyl-
glycine, which is important for pharmacological applications.
The synthesis of other cyclopropyl-containing bioactive mole-
cules is in progress and will be reported in due course.
12 T. Morikawa, H. Sasaki, A. Shibuya and T. Taguchi, J. Org. Chem.,
1994, 59, 103.
13 A. B. Charette, S. Prescott and C. Brochu, J. Org. Chem., 1995, 60,
1081 and references therein.
Acknowledgements
14 Compound 4: [α]D: Ϫ63.8 (c = 2.0, CHCl3); IR (neat): 1742, 1698
cmϪ1; 1H NMR (CDCl3): δ 1.30 (t, J = 6.98 Hz, 3H, CH3), 1.38–1.70
(m, 15H, 2 × CH3 and t-Bu), 3.80 (dd, J = 3.68, 9.2 Hz, 1H, OCH2),
4.07 (dd, J = 5.00, 9.20 Hz, 1H, OCH2), 4.20 (q, J = 6.80 Hz, 1H,
OCH2CH3), 4.32–4.60 (br m, 1H, NCH), 5.87 (br d, J = 15.80 Hz,
I thank Dr M. K. Gurjar, Dr A. Datta and Dr B. V. Rao for
their support and fruitful discussions.
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IR (neat): 3400–3200, 1692 cmϪ1; 1H NMR (CDCl3): δ 0.86 (m, 1H,
CH-cyclopropyl), 1.21 (m, 1H, CH-cyclopropyl), 1.47–1.70 (m,
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CH-cyclopropyl), 1.24 (m, 1H, CH-cyclopropyl), 1.44 (s, 9H, t-Bu),
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CEL (OD); mobile phase, 10% propan-2-ol in n-hexane; flow rate,
1 mL minϪ1; UV detection at 225 nm.
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J. Chem. Soc., Perkin Trans. 1, 2001, 1851–1852