Rigid nonproteinogenic cyclic amino acids as ligands for glutamate receptors: trans‐Tris(homoglutamic) acids

Abstract

The second-generation asymmetric synthesis of the trans-tris(homoglutamic) acids reported herein proceeds via Strecker reaction of chiral ketimines, obtained from condensation of racemic 2-ethoxycarbonylmethylcyclopentanone and commercially available (S)- and (R)-1-phenylethylamine, respectively. In the key stereodifferentiating step, the cyanide addition leads to mixtures of diastereomeric alpha-amino nitrile-esters, the composition of which is independent of the reaction temperature and the type of the solvent, respectively. Hydrolysis of the alpha-amino nitrile-esters with concentrated H(2)SO(4) yielded diastereomeric mixtures of secondary alpha-amino amido-esters, which after separation were hydrogenolyzed and hydrolyzed each to the enantiomeric trans-1-amino-2-carboxymethylcyclopentanecarboxylic acids. Their configuration was completely established by NMR methods, CD spectra, and X-ray analysis of the trans-1S,2R-configured secondary alpha-amino amido-ester. In receptor binding assays and functional tests, trans-1S,2R-1-amino-2-carboxymethylcyclopentanecarboxylic acid hydrochloride was found to behave as a selective mGluR(2)-antagonist without relevant binding properties at iGluRs.

Bicyclic glutamic acid derivatives

“…The combined organic extracts were washed with water, brine, dried, concentrated, and finally dried in high vacuum. 17 Further crystallisation with EA/CH 6:4 ¼ >8:2 gave a 1:1 mixture of 5c and 5d (for separation see under 5d). The residue of this mother liquor was subjected to column chromatography (CC) on SiO 2 .…”

“…The residue of this mother liquor was subjected to column chromatography (CC) on SiO 2 . 17 Further crystallisation with EA/CH 6:4 ¼ >8:2 gave a 1:1 mixture of ent-5c and ent-5d (see under ent5d). The residue of this mother liquor was subjected to CC on SiO 2 .…”

“…A solution of mixtures 3a-d and ent-3a-d, respectively, 17 (9.0 g, 30 mmol) in CH (30 mL) was added dropwise to concentrated H 2 SO 4 (60 mL) at À108C. Stirring was maintained at À108C for 3 h and at r.t. for a period of 96 h. The mixture was poured onto ice (300 g), and the solids were filtered off.…”

“…[13][14][15][16] More recently, we have shown that this route is also capable for the synthesis of cyclic trans-tris(homoglutamic) acids. 17 In the course of this investigation we realised that the secondary a-amino a-carbamoyl-g-esters, as their precursors, are also key intermediates for the synthesis of bicyclic glutamate derivatives. 18 Herein we wish to report on the access to and on the elucidation of the relative and absolute configuration of those 3-azabicyclo [4.3.0]nona-2,4-diones and 2-azabicyclo[3.3.0]octan-3-ones.…”

“…þ5 (c 0.465, MeOH) (6% imide 6b, cyclisation in solution), respectively, as a colourless oil, NMR data. 17 …”