An efficient and general enantioselective synthesis of some isoxazole- containing analogues of the neuroexcitant glutamic acid

Article abstract of DOI:10.1016/S0957-4166(98)00275-4

Isoxazole amino acids are an important class of neuroexcitant which are difficult to prepare in enantiopure form. Diastereoselective alkylation of the enantiomerically pure glycine derivative, tert-butoxycarbonyl-2-(tert- butyl)-3-methyl-4-oxo-1-imidazolidinecarboxylate (Boc-BMI) with 4- bromomethyl-2-methoxymethyl-5-methylisoxazolin-5-one 5 or 5-bromomethyl-4- bromo-3-methoxyisoxazole, gives intermediates which under mild hydrolysis conditions produce the amino acids (S)- and (R)-bromohomoibotenic acid and (S)- and (R)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl) propionic acid with e.e. >99%.

Full text of DOI:10.1016/S0957-4166(98)00275-4

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 2757–2760
An efficient and general enantioselective synthesis of some
isoxazole-containing analogues of the neuroexcitant glutamic
acid
Hassan Pajouhesh and Kenneth Curry ∗
CNS Research Division, Precision Biochemicals Inc., 303-2386 East Mall, Vancouver, British Columbia, V6T 1Z3, Canada
Received 20 May 1998; accepted 21 June 1998
Abstract
Isoxazole amino acids are an important class of neuroexcitant which are difficult to prepare in enantiop-
ure form. Diastereoselective alkylation of the enantiomerically pure glycine derivative, tert-butoxycarbonyl-
2-(tert-butyl)-3-methyl-4-oxo-1-imidazolidinecarboxylate (Boc-BMI) with 4-bromomethyl-2-methoxymethyl-5-
methylisoxazolin-5-one 5 or 5-bromomethyl-4-bromo-3-methoxyisoxazole, gives intermediates which under mild
hydrolysis conditions produce the amino acids (S)- and (R)-bromohomoibotenic acid and (S)- and (R)-2-amino-
3-(3-hydroxy-5-methylisoxazol-4-yl) propionic acid with e.e. >99%. © 1998 Elsevier Science Ltd. All rights
reserved.
1. Introduction
(S)-Glutamic acid [(S)-Glu] is well known to be the major excitatory neurotransmitter in the mam-
malian central nervous system. The actions of (S)-Glu are mediated through a diverse set of receptor
sub-populations, each defined pharmacologically by the archetypal chemical which selectively activates
them. 2-Amino-3-(3-hydroxy-5-methylisoxazol-4-yl) propionic acid (AMPA) and 2-amino-4-bromo-3-
hydroxy-5-isoxazolpropionic acid (Br-homo IBO) are functional bioisosteres of (S)-Glu which activate
the AMPA glutamate sub-receptor, potently and selectively. As a part of our ongoing program to develop
new and efficient routes for the synthesis of α-amino acids and related compounds, we have devel-
oped a methodology utilizing Seebach’s chiral gycinate imidazolidines1 for the synthesis of isoxazole-
containing amino acids in e.e.s of greater than 99% and overall yields of greater than 55%.
∗
Corresponding author. E-mail: kencurry@ican.net
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00275-4

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2. Synthesis
The synthesis of (R)- and (S)-AMPA is shown in Scheme 1. Commercially available 3-hydroxy-
3-methylisoxazole 4, was converted to 4-bromoethyl-2-methoxymethyl-5-methylisoxazolin-3-one 5 by
known procedures.2 The (R)- and (S)-imidazolidinones 3 were then treated with LDA at −78°C and the
resulting enolates were added to 5. The alkylated products (2S,5S)-6 and (2R,5R)-6 were purified by flash
chromatography to afford the pure derivatives in 82% and 81.5% yields respectively.
Scheme 1. Reagents and conditions: (i) 1,3,5-trioxane, 62% HBr, 60°C 20 h, CH3OH 2 h, rt; (ii) LDA/THF, −78°C 3 h, NH4Cl;
(iii) TFA, CH2Cl2, N2 rt 15 h, 0.75 M HCl, Dowex 50 WX8-100 ion exchange resin, 48 h reflux
Removal of Boc under anhydrous conditions, followed by mild hydrolysis gave the free (R)- and (S)-
amino acids in 70% and 69% yields respectively with e.e. greater than 99% by chiral HPLC. Specific

H. Pajouhesh, K. Curry / Tetrahedron: Asymmetry 9 (1998) 2757–2760
2759
rotations: (R)-AMPA [α]D20=+23.0 (H2O, c=0.19) [lit.3 [α]D28=+19.2 (H2O, c=0.18)]. Mp 212°C (dec.)
[lit.3 >200°C]. (S)-AMPA [α]D20=−25.5 (H2O, c=0.19) [lit.3 [α]D28=−21.0 (H2O, c=0.19)]. Mp 212°C
(dec.) [lit.3 >200°C].
A similar procedure was employed for the synthesis of (R)- and (S)-Br-homo IBO (Scheme 2).
Thus, treatment of 3-methoxy-5-methylisoxazole 7 with N-bromosuccinimide (NBS)4 produced 5-
bromomethyl-3-methoxyisoxazole 8 which on reaction with neat bromine gave 5-bromomethyl-4-
bromo-3-methoxyisoxazole 9 in good yield.
Scheme 2. Reagents and conditions: (i) NBS, benzoyl peroxide, CCl4, reflux 24 h; (ii) neat Br2 rt 6 h; (iii) LDA, THF −78°C, 2
h then r.t 3 h NH4Cl; (iv) TFA, CH2Cl2, N2, rt 15 h, 0.75 M HCl, Dowex 50 WX8-100 resin, 48 h reflux; (v) 33% HBr/AcOH,
rt overnight, then cation exchange column chromatography

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H. Pajouhesh, K. Curry / Tetrahedron: Asymmetry 9 (1998) 2757–2760
Reaction of the imidazolidinones (R)- and (S)-3 with 9 produced the alkylated adducts (2S,3S-10 and
2R,3R-10) in good yield and with excellent diastereofacial selection.
Analogous deprotection and hydrolysis conditions as employed in the synthesis of (R)- and (S)-1, gave
the free amino acids (R)- and (S)-11. Further treatment with 33% AcOH/HBr at room temperature pro-
vided (R)- and (S)-2 in enantiomerically pure form. Specific rotations: (R)-Br-homo IBO [α]D20=−11.4
(50 mM HCl, c=0.40) [lit.5 [α]D27=−10.8 (50 mM HCl, c=0.40)]. Mp 204°C [lit.5 202°C]. (S)-Br-homo
IBO [α]D20=+11.2 (50 mM HCl, c=0.40) [lit.5 [α]D27=−11.4 (50 mM HCl, c=0.40)]. Mp 204°C [lit.5
202°C].
Structures of all intermediates were confirmed by 1H NMR and the final products were consistent with
the spectral data from 3 and 5, respectively. Chiral HPLC on a Chirex D-penicillamin column showed
single peaks for each isomer.
Previous syntheses of the isoxazole amino acids have led to efficient syntheses of racemic mixtures,2
or inefficient enzymic resolution.3,5 This general synthetic methodology allows for the synthesis of a
wide variety of isoxazole-containing amino acids in multi-gram batches. The yields and stereochemical
purities make this the most convenient currently available procedure for production of these important
biologically active compounds.
References
1. Fitzi, R.; Seebach, D. Tetrahedron 1988, 44, 5277–5292.
2. Begtrup, M.; Sløk, A. F. Synthesis 1993, 861–863.
3. Hansen, J. J.; Lauridsen, J.; Nielsen, E.; Krogsgaard-Larsen, P. J. Med. Chem. 1983, 26, 901–903.
4. Hansen, J. J.; Krogsgaard-Larsen, P. J. Chem. Soc., Perkin Trans. 1 1980, 1826–1833.
5. Hansen, J. J.; Nielsen, B.; Krogsgaard-Larsen, P.; Brehm, L.; Nielsen, E.; Curtis, D. J. Med. Chem. 1989, 32, 2254–2260.