Novel enantioselective synthesis of (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG-IV)

Article abstract of DOI:10.1016/S0040-4039(00)01629-4

A novel enantioselective synthesis of (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG-IV), a potent group II mGluRs agonist is described. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01629-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9125–9128
Novel enantioselective synthesis of
(2S,2%R,3%R)-2-(2%,3%-dicarboxycyclopropyl)glycine (DCG-IV)
Maura Marinozzi and Roberto Pellicciari*
Dipartimento di Chimica e Tecnologia del Farmaco, Universita` di Perugia, Via del Liceo, 1-06123 Perugia, Italy
Received 2 August 2000; revised 15 September 2000; accepted 20 September 2000
Abstract
A novel enantioselective synthesis of (2S,2%R,3%R)-2-(2%,3%-dicarboxycyclopropyl)glycine (DCG-IV), a
potent group II mGluRs agonist is described. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: metabotropic glutamate receptors; (carboxycyclopropyl)glycines; asymmetric cyclopropanation.
(Carboxycyclopropyl)glycines are conformationally constrained -glutamate analogs having
L
as a common feature a cyclopropyl moiety that introduces chirality and partially reduces
conformational freedom. Several disubstituted and trisubstituted members of this family have
been used widely for the pharmacological and physiological characterization of both ionotropic
(iGluRs) and metabotropic (mGluRs) glutamate receptor pathways.1 Among the disubstituted
members (Fig. 1), (2S,1%R,2%S)-2-(2%-carboxycyclopropyl)glycine (L-CGA C, 1)2 is a highly
potent and selective agonist of the N-methyl- -aspartic acid (NMDA) receptor site of the
D
ionotropic NMDA receptor complex, while (2S,1%S,2%S)-2-(2%-carboxycyclopropyl)glycine (L-
CCG I, 2)3 is a potent albeit not very selective agonist of the mGluR2 subtype of group II
mGluRs. The introduction of an additional substituent in the 3% position leads to compounds
Figure 1.
* Corresponding author. Tel: +39-0755855120; fax: +39-0755855124; e-mail: rp@unipg.it
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01629-4

9126
widely differing in their biological properties according to the nature of the substituent and its
overall chirality. Thus, (2S,1%S,2%S,3%R)-2-(2%-carboxy-3%-phenylcyclopropyl)glycine (PCCG-4, 3)4
characterized by a lipophilic moiety at C-3% is a mGluR2 antagonist, while (2S,2%R,3%R)-2-(2%,3%-
dicarboxycyclopropyl)glycine (DCG-IV, 4)5 is a relatively potent and selective agonist of group
II mGluR2 and mGluR3 subtypes. Recently, the high potency of DCG-IV (4) as an anticonvul-
sant agent has confirmed the important role of group II mGluRs in the control of seizure
activity via modulation of neuronal
-glutamate release.6
L
In connection with our continuing studies in the excitatory amino acids field, we needed large
amounts of DCG-IV (4) and became engaged in the development of a new route for its
preparation. When we started our work, indeed, the only reported synthesis of 4 was suffering
from the burden of many steps and a poor overall yield.7 Although during the course of this
work two new improved synthesis8,9 of DCG-IV (4) have appeared, we deem of interest to
describe the alternative route that we have followed, which involves as a key step the highly
stereocontrolled conjugate 1,4-addition of the anion of a trans-chloroallyl phosphonamide
reagent to an a,b-unsaturated carbonyl derivative (Scheme 1). Whereas in most auxiliary-con-
trolled formal [2+1] cycloadditions, the auxiliary group is attached to the olefin residue, in this
methodology recently developed by Hanessian10 the chiral information is carried out by the
chiral chloroallylphosphonamide, acting as a vinylcarbene equivalent.
Scheme 1. (a) BuLi, THF, −78°C, 54%; (b) i. O3, CH2Cl2–MeOH, solvent red 19, −78°C; ii. NaBH4, 80%; (c)
TBDMSiCl, imidazole, CH2Cl2–DMF, rt, quantitative; (d) i. O3, CH2Cl2, −78°C; ii. 32% H2O2; (e) CH2N2, Et2O, rt,
79%; (f) nBu4NF, THF, rt, 81%; (g) i. morpholine, AlMe3, CH2Cl2, reflux, quantitative; (h) (COCl)2, DMSO, Et3N,
CH2Cl2, −60°C, 86%; (i) i. R-a-phenylglycinol, MeOH, rt; ii. TMSCN, 0°C, then rt, iii. mpc, 60%; (l) i. Pb(OAc)4,
CH2Cl2–MeOH (1:1), rt; ii. 6N HCl, reflux; iii. Dowex 50WX2-200, 1N NH4OH, 60%

9127
Thus, treatment at −78°C of trans–trans tert-butyl sorbate (5) with the anion of (R,R)-trans-
chloroallyl phosphonamide10 (6) generated at −78°C (BuLi, THF) followed by flash chromatog-
raphy (EtOAc–methanol 95:5), afforded the corresponding cis,trans,trans-cyclopropane
derivative 7 as single diastereoisomer in 54% yield. The key derivative 7 was then transformed
into the corresponding alcohol 8 by selective ozonolysis11 of the propenyl side chain, carried out
at −78°C in dichloromethane–methanol (1:1) in the presence of the solvent red 19, followed by
reductive quenching with sodium borohydride (80%). Removal of the chiral auxiliary and
generation of a second carboxy moiety was then achieved by submitting 8 to protection of the
hydroxy group (tert-butyldimethylsilyl chloride, imidazole, CH2Cl2–DMF) followed by ozonoly-
sis (CH2Cl2, −78°C) of the silyl derivative 9 thus obtained. Esterification of 10 (CH2N2, Et2O,
0°C) followed by removal of the TBDMSi moiety with tetrabutylammonium fluoride in THF
afforded the corresponding lactone 12 in 79% yield. Ring opening of the lactone 12 with the
Weinreb reagent12 (AlMe3, morpholine, CH2Cl2, rt) provided almost quantitatively the corre-
sponding hydroxymethyl morpholine amide 13 which was readily oxidized to the aldehyde 14 by
the Swern protocol13 in 86% yield. A diastereoselective Strecker synthesis14 involving the
condensation of 14 with optically active R-(−)-a-phenylglycinol (MeOH, rt, 3 h) followed by
nucleophilic addition of a cyanide ion to the Schiff base (TMSCN, 0°C then rt, 12 h) afforded
the (2S,2%R,3%R)-aminonitrile 15 along with minor amounts of the (2R,2%R,3%R)-diastereoisomer
1
(95:5 by H NMR). Separation of the two a-aminonitriles by flash chromatography (light
petroleum–EtOAc, 8:2) afforded the desired isomer 15 which was then submitted to oxidative
cleavage with lead tetraacetate15 (CH2Cl2–MeOH, 0°C, 10 min) acidic (6N HCl) hydrolysis and
ion exchange resin chromatography (Dowex 50WX2-200, 1N NH4OH) to afford (2S,2%R,3%R)-2-
(2%,3%-dicarboxycyclopropyl)glycine DCG-IV (4),16 in 8.5% overall yield with analytical data
identical with those of an authentic sample.
In summary, the new synthetic route that we have developed for DCG IV (4) can usefully be
employed for the preparation of large amounts of the compound, thus satisfying the current
large demand for this important pharmacological tool.
Acknowledgements
The financial support of this work by the Alexis Corporation, is gratefully acknowledged.
References
1. Schoepp, D. D.; Jane, D. E.; Monn, J. A. Neuropharmacology 1999, 38, 1432–1476.
2. Pellicciari, R.; Curini, M.; Natalini, B.; Ceccherelli, P. IX International Symposium on Medicinal Chemistry;
Berlin, 1986; p. 118.
3. Ishida, M.; Akagi, H.; Shimamoto, K.; Ohfune, Y.; Shinozaki, H. Brain Res. 1990, 537, 311–314.
4. (a) Pellicciari, R.; Marinozzi, M.; Natalini, B.; Costantino, G.; Luneia, R.; Giorgi, G.; Moroni, F.; Thomsen, C.
J. Med. Chem. 1996, 39, 2259–2269; (b) Thomsen, C.; Bruno, V.; Nicoletti, F.; Marinozzi, M.; Pellicciari, R. Mol.
Pharmacol. 1996, 50, 6–9.
5. (a) Ishida, M.; Saitoh, T.; Shimamoto, K.; Ohfune, Y.; Shinozaki, H. Br. J. Pharmacol. 1993, 109, 1169–1177; (b)
Brabet, I.; Parmentier, M.-L.; De Colle, C.; Bockaert, J.; Acher, F.; Pin, J.-P. Neuropharmacology 1998, 37,
1043–1051.
6. Attwell, P. J. E.; Singh Kent, N.; Jane, D. E.; Croucher, M. J.; Bradford, H. F. Brain Res. 1998, 805, 138–143.

9128
7. Ohfune, Y.; Shimamoto, K.; Ishida, M.; Shinozaki, H. Bioorg. Med. Chem. Lett. 1993, 3, 15–18.
8. Ma, D.; Cao, Y.; Yang, Y.; Cheng, D. Org. Lett. 1999, 1, 285–287.
9. Wichmann, J.; Adam, G. Eur. J. Org. Chem. 1999, 11, 3131–3133.
10. Hanessian, S.; Andreotti, D.; Gomtsyam, A. J. Am. Chem. Soc. 1995, 117, 1039–1040.
11. Veysoglu, T.; Mitscher, L. A.; Swayze, J. K. Synthesis 1980, 807–810.
12. Lipton, M.; Basha, A.; Weinreb, S. M. Org. Synth. 1988, 59, 49–53.
13. Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem. 1978, 43, 2480–2482.
14. Chakraborty, T. K.; Azhar Hussain, K.; Venkat Reddy, G. Tetrahedron 1995, 51, 9179–9190.
15. Gawley, R. E.; Rein, K.; Chemburkar, S. J. Org. Chem. 1989, 54, 3002–3004.
16. Analytical data for compounds 12, 14 and 15:
1
12: H NMR (CDCl3) l 1.45 (9H, s, tBu), 1.85 (1H, t, J=3.0 Hz, CHCO2tBu), 2.45 (1H, m, CHCH2O), 2.60
(1H, m, CHCO), 4.21 (1H, d, J=10.2 Hz, CHaO), 4.30 (1H, dd, J=4.2 and 10.2 Hz, CHbO);
1
14: mp 80–2°C; H NMR (CDCl3) l 1.45 (9H, s, tBu), 2.40–2.50 (1H, m, CHCHO), 2.80 (1H, dd, J=6.4 and
10.7 Hz, CHCON), 3.10 (1H, t, J=6.4 Hz, CHCO2tBu), 3.45–3.80 (8H, m, morpholine ring), 9.20 (1H, d, J=7.1
Hz, CHO);
1
15: mp 49–50°C; [h]2D0 −144.5 (c 1.5, CHCl3); H NMR (CDCl3) l 1.45 (9H, s, tBu), 2.05 (1H, td, J= 6.6, 9.3
and 18.5 Hz, CHCHCN), 2.25–2.45 (2H, m, CHCON and CHCO2tBu), 2.65 (2H, brs, OH and NH), 3.20–3.80
(11H, m, morpholine ring, CH2OH and 2-CH), 3.90–4.05 (1H, m, CHPh), 7.10–7.30 (5H, m, aromatics); 13C
NMR l 25.30, 27.35, 28.02, 29.63, 42.57, 46.10, 62.98, 66.38, 66.51, 67.25, 81.86, 119.00, 127.34, 128.23, 128.82,
138.09, 165.57, 170.18.
.