Synthesis of conformationally restricted glutamic acid analogs based on the spiro[3.3]heptane scaffold

A library of isomeric glutamic acid analogs based on the spiro[3.3]heptane skeleton is designed. Two members of the library, (R)- and (S)-2-amino-spiro[3.3]heptane-2,6-dicarboxylic acid hydrochlorides, were synthesized. The stereochemistry of the synthesized amino acids was determined using 1H–1H-NOESY of their diastereomeric derivatives. The aminocarboxylate moiety and the carboxylic group in the synthesized glutamic acid analogs are ‘fixed’ in space relative to each other due to the rigid spirocyclic scaffold and therefore, they can be used to probe topologies of different glutamate receptors.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slide

(aS)-2-Amino-spiro[3.3]heptane-2,6-dicarboxylic acid hydrochlorideC9H14NO4ClEe = 86%[α]D20=-2 (c 0.78, H2O)Source of chirality: (2R)-amino-2-phenylethanolAbsolute configuration: (aS)

(aR)-6-Cyano-6-((1R)-2-hydroxy-1-phenyl-ethylamino)-spiro[3.3]heptane-2-carboxylic acid methyl esterC18H22N2O3De = 86%[α]D20=-68 (c 0.72, MeOH)Source of chirality: (2R)-amino-2-phenylethanolAbsolute configuration: (aR,1R)

(aS)-6-Cyano-6-((1R)-2-hydroxy-1-phenyl-ethylamino)-spiro[3.3]heptane-2-carboxylic acid methyl esterC18H22N2O3De = 86%[α]D20=-42 (c 0.13, MeOH)Source of chirality: (2R)amino-2-phenylethanolAbsolute configuration: (aS,1R)

Methyl (aR,8R)-11-oxo-8-phenyl-10-oxa-7-azadispiro[3.1.5.1]dodecane-2-carboxylateC18H21NO4De = 100%[α]D20=-72 (c 0.6, MeOH)Source of chirality: (2R)amino-2-phenylethanolAbsolute configuration: (aR,8R)

Methyl (aS,8R)-11-oxo-8-phenyl-10-oxa-7-azadispiro[3.1.5.1]dodecane-2-carboxylateC18H21NO4De = 100%[α]D20=-23 (c 0.75, MeOH)Source of chirality: (2R)amino-2-phenylethanolAbsolute configuration: (aS,8R)