An efficient and stereoselective synthesis of (2S,1′S,2′S)-2-(carboxycyclopropyl) glycine (LCCG-I): Conformationally constrained L-glutamate analogues

Article abstract of DOI:10.1016/S0957-4166(00)00434-1

Conformationally restricted metabotropic glutamate receptor agonist (2S,1′S,2′S)-2-(Carboxycyclopropyl) glycine (LCCG-I) 1 have been efficiently synthesized in a stereoselective manner. A convenient five step synthesis of 1 from readily available (-)-dime

Full text of DOI:10.1016/S0957-4166(00)00434-1

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 4537–4541
An efficient and stereoselective synthesis of
(2S,1%S,2%S)-2-(carboxycyclopropyl) glycine (LCCG-I):
conformationally constrained -glutamate analogues
L
Hassan Pajouhesh,* John Chen and Seyed Hossein Pajouhesh
CNS Research Division Precision Biochemicals Inc., 303-2386 East Mall, Vancouver, BC, V6T 1Z3, Canada
Received 26 September 2000; accepted 24 October 2000
Abstract
Conformationally restricted metabotropic glutamate receptor agonist (2S,1%S,2%S)-2-(Carboxycyclo-
propyl) glycine (LCCG-I) 1 have been efficiently synthesized in a stereoselective manner. A convenient five
step synthesis of 1 from readily available (−)-dimenthyl (1S,2S)-cyclopropane-1,2-dicarboxylate 5 in 49%
overall yield is described. © 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction
Rigid or conformationally restricted analogues of -glutamate of known stereochemistry have
L
been synthesized for the elucidation of the pharmacology of the large family of glutamate
receptors.1,2 (2S,1%S,2%S)-2-(Carboxycyclopropyl) glycine 1 (LCCG-I),3,4 which is the extended
glutamate conformation, has received much attention from neuroscientists recently, because it is
a selective agonist for metabotropic glutamate receptors mGLu2 and mGLu3 and it is capable
of activating multiple other mGLu subtypes at low micromolar concentrations.5 The mGLuRs
are coupled to G-proteins that mediate a variety of transduction mechanisms. As a part of our
ongoing program to develop new and efficient routes for the synthesis of a-amino acids and
related compounds, we have developed a methodology utilizing readily available (−)-dimenthyl
(1S,2S)-cyclopropane-1,2-dicarboxylate for the synthesis of LCCG-I 1.
2. Synthesis
The synthesis of LCCG-I 1 is shown in Scheme 1. In designing a practical asymmetric
synthesis we chose (−)-dimenthyl (1S,2S)-cyclopropane-1,2-dicarboxylate 5 {[h]2D5=+17.8
* Corresponding author. E-mail: pajuhesh@precisionbio.com
0957-4166/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00434-1

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Scheme 1. Reagent and conditions: (i) p-Toluenesulfonic acid monohydrate, toluene, 140°C, 24 h, Dean–Stark; (ii)
LiTMP (1.6 M n-butyllithium, 2,2,6,6-tetramethylpiperidine), −78°C, THF, N2, 1 h, then bromochloromethane, 2 h;
(iii) NaOH, i-PrOH, 50°C, overnight, then 85°C, 2 h, yield 96%; (iv) 1.0 M BH3·THF, −78°C, N2, THF, 4 h, then
rt, overnight, yield 81%; (v) DMSO, CH2Cl2, oxalylchloride, −78°C, N2, 20 min, Et3N, 0°C, yield 96%; (vi)
(R)-a-phenylglycinol, MeOH, 1 h, rt, TMSCN, 0°C, then rt, overnight, flash chromatography, yield 88%; (vii) lead
tetraacetate, CH2Cl2:MeOH (1:1, v/v), 0°C, 10 min, work-up, 6N HCl, 6 h, reflux, then anion-exchange chromatog-
raphy (elution with 0.5 M HOAc), yield 75%
(CHCl3, c=1.0}, which can be easily prepared via stereoselective cyclopropanation of (−)-dimen-
thyl succinate 4 by known procedures.6 Choosing this key intermediate as a starting material
and with two fixed stereogenic centers now gives us the opportunity to synthesize LCCG-I 1,

H. Pajouhesh et al. / Tetrahedron: Asymmetry 11 (2000) 4537–4541
4539
simply by a few functional group transformations. The diester 5 was partially hydrolyzed with
NaOH to the mono-acid 6 in 96% yield. The reduction of this compound to alcohol 7 was
accomplished with BH3·THF at −78°C and then at room temperature overnight. Swern
oxidation7 of 7 gave aldehyde 8 almost in a quantitative yield. Asymmetric Strecker reaction of
aldehyde 8 using the inexpensive chiral auxiliary (R)-a-phenylglycinol (MeOH, room tempera-
ture, 2 h)8 followed by treatment of the resulting Schiff base with TMSCN for 12 h to give a
90:10 (1H NMR) mixture of the two expected diastereomeric a-aminonitrile derivatives 9 and 10
in 95% yield which were easily separated by standard silica gel column chromatography. The
a-aminonitrile 9 was finally submitted to oxidative cleavage with lead tetraacetate followed by
hydrolysis8 with 6N HCl and ion exchange chromatography using Dowex 1X8-50 (0.5 M
HOAc) to afford (2S,1%S,2%S)LCCG-I 1 {[h]2D0=+103.5 (c=0.31, H2O)} in 49% overall yield
from 5.
1
Structures of all intermediates were confirmed by H NMR and the enantiomeric excess of 1
was established by comparison of its physical properties with those reported in the literature4
and by chiral HPLC (Chirex D-penicillamin column).
The methodology described here has the generality for the synthesis of other diastereomeric
forms such as (2R,1%S,2%S) CCG by simply changing the (R)-a-phenylglycinol to (S)-a-phenyl-
glycinol. This general synthetic methodology allows for the synthesis of (LCCG-I) on at least
4–6 g scale. The yields and stereochemical purities make this the most convenient and efficient
method for the production of this biologically important and active compound.
3. Experimental
3.1. General
Melting points were obtained with a Fisher–Johns apparatus and are uncorrected. Optical
1
rotations were measured using an Optical Activity AA-1000 polarimeter. H and 13C spectra
were recorded on a Bruker AC-200 spectrometer with SiMe4 as internal standard and using
CDCl3 as solvent. Elemental analysis were performed by the Canadian Microanalytical Service
Ltd. HPLC was carried out with a Varian 9012 pump and Varian 9050 UV–vis detector.
Column chromatography was performed using silica gel 60 of 230–400 mesh.
3.2. Synthesis of 2-carbomenthyloxy (1S,2S)-cyclopropane-1-carboxylic acid 6
To a suspension of diester 5 (70.2 g, 172.8 mmol) in 450 ml isopropyl alcohol was added a
solution of NaOH (7.56 g) in 36 ml of water. The reaction mixture stirred at 50°C overnight and
then for an additional 2 h at 85°C. The mixture was then concentrated and 360 ml of water was
added. The aqueous layer was extracted with ether three times and it was then acidified with 2N
HCl and extracted with ether. The organic layer was dried (MgSO4) and evaporated to give 44.2
g (96%) of pure 6 as oil. lH (CDCl3): 0.7 (d, 3H, J=7.0), 0.9 (d, 6H, J=6.8), 0.95–2.0 (complex
11H), 2.2 (m, 2H), 3.7 (t, 1H), 4.68 (dt, 1H, J=5.4, 10.5), 10.1 (br, 1H).

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3.3. Synthesis of 2-carbomenthyloxy (1S,2S)-cyclopropane-1-hydroxymethyl 7
The mono-acid 6 (38.4 g, 143.4 mmol) was dissolved in THF (120 ml) and cooled to −78°C
under nitrogen. BH3·THF (1.0 M, 157.8 ml) was added dropwise and the resulting solution was
stirred at the same temperature for 4 h and gradually warmed to room temperature overnight.
Water (180 ml) was added and stirred for 30 min and then followed by addition of K2CO3 (51
g). The solution was extracted with ether several times and the combined ether extracts were
dried and evaporated. The residue was purified by flash chromatography (hexane:ether, 7:3) to
give 29.3 g (81%) of alcohol 7. lH (CDCl3): 0.7 (d, 3H, J=7.0), 0.82 (d, 6H, J=6.8), 0.98–2.0
(complex, 14 H), 3.5 (m, J=6.0, 8.0, 2 H), 4.6 (dt, 1H, J=5.4, 10.5).
3.4. Synthesis of 2-carbomenthyloxy (1S,2S)-cyclopropane-1-carboxaldehyde 8
A solution of dry DMSO (27 ml, 380 mmol) in CH2Cl2 (420 ml) was added dropwise to a
solution of oxalyl chloride (16.68 ml, 191 mmol) in CH2Cl2 (420 ml) at −78°C under N2. The
resulting solution was stirred at the same temperature for 20 min. Then alcohol 7 (25.5 g, 100
mmol) was added and stirred for an additional 20 min at −78°C. Et3N (80 ml) was added and
gradually warmed to 0°C. To the residue a sat. aqueous solution of NH4Cl was added. The
aqueous layer was extracted with CH2Cl2 and the combined organic layer was dried and
evaporated. The residue was purified by flash column chromatography (hexane:ether, 7:3) to
give 24.2 g (96%) of aldehyde 8. lH (CDCl3): 0.78 (d, 3H, J=7.0), 0.82 (d, 6H, J=6.8), 0.98–2.0
(m, 11H), 2.2 (m, 1H), 2.38 (dt, 1H, J=6.0, 12), 4.7 (dt, 1H, J=5.4, 10.5), 9.22 (s, 1H).
3.5. Synthesis of (2S,1%S,2%S)-N-[(R)-h-phenylglycinol]-[2%-carbomenthyloxycyclopropyl]-
glycinonitrile 9
To a solution of aldehyde 8 (24.16 g, 95.8 mmol) in 720 ml of methanol was added (R)-phenyl
glycinol (13.4 g, 97.72 mmol) and the resulting solution stirred at rt for 1 h. The solution was
then cooled to 0°C and TMSCN (25.6 ml, 191.6 mmol) was added dropwise, and the mixture
was stirred at rt overnight. To the solution was added 3N HCl (600 ml) and the mixture was
extracted with CHCl3. The combined organic layer was dried and evaporated. The residue was
purified by column chromatography (ether:hexane 1:1) to give 33.4 g (88%) of diastereomerically
pure 9. [h]2D0 −49.4 (c=0.80, CH2Cl2). lH (CDCl3): 0.78 (d, 3H, J=7.0), 0.95 (d, 6H, J=6.8),
0.98–2.0 (m, 6H), 3.3–3.50 (m, 2H), 3.7–3.8 (m, 2H), 4.2 (dd, 1H, J=9.0, 4.0) 4.6 (m, 1H) 7.4
(m, 5H).
3.6. Synthesis of (2S,1%S,2%S)-2-(carboxycyclopropyl) glycine 1
Lead tetraacetate (16.64 g, 37.57 mmol) was added to a cold solution of nitrile 9 (13.65, 34.19
mmol) in CH2Cl2:CH3OH (1:1) (290 ml). The resulting reaction mixture was stirred at 0°C for
10 min. Water (220 ml) was added and the resulting mixture was filtered with the aid of Celite.
The aqueous layer was extracted with CH2Cl2 and it was then dried and evaporated. The residue
was dissolved in 6N HCl (500 ml) and refluxed for 6 h. The reaction mixture was washed with
CH2Cl2 two times and evaporated to dryness. The residue was submitted to anion-exchange
resin chromatography to give 4.0 g (74%) of pure LCCG-I 1. [h]2D0=+103.5 (c=0.31, H2O); lH
(D2O): 1.3 (ddd, 1H, J=5.0, 6.1, 8.6), 1.4 (ddd, 1H, J=5.0, 5.1, 9.0), 1.8 (dddd, 1H, J=4.0, 6.1,

H. Pajouhesh et al. / Tetrahedron: Asymmetry 11 (2000) 4537–4541
4541
9.0,10.0), 1.85 (ddd, 1H, J=4.0, 5.0, 8.6). Anal. calcd for C6H9O4N: C, 45.28; H, 5.70; N, 8.80.
Found: C, 45.31; H, 5.73; N, 8.71.
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