Synthesis of analogues of GABA. VI. Stereoisomers of cis-3-Aminocyclohexanecarboxylic acid

Abstract

The syntheses are described of (1R,3S)- and (1S,3R)-3-aminocyclohexanecarboxylic acids via unsaturated intermediates suitable for tritium labelling. The absolute stereochemistry was determined by an alternative synthesis of the (1R,3S) isomer from (R)-3-oxocyclohexanecarboxylic acid. The (1S,3R) isomer showed a similar potency to GABA as an inhibitor of the uptake of radioactive GABA by rat brain slices whereas the (1R,3S) isomer was at least 20 times less potent.

Synthesis of γ‐Aminobutyric Acid Analogs

“…1-Trialkylsilyl acetylenic ketones (389) were derived from the appropriate a-amino acid by reaction of the Weinreb amide (388) with the lithium acetylide (Scheme 14.107). Reduction of the ketones with the chiral oxazaborolidine (390) afforded the corresponding alcohol (391) in good yields and high diastereoselectivity. Oxidative hydroboration yields the N-Boc-statine (365a) [286,288].…”

“…Hydrolysis of the ester and resolution via crystallization with L-or D-ornithine yielded enantiomerically pure (S,S,)-and (R,R)-(580). Catalytic reduction and removal of the phthaloyl protecting group produced (S,R)-and (R,S)-(581), respectively, in high optical purity [391].…”

“…Birch reduction of (R)-(583), prepared from (R)-(582), yields a mixture from which enantiomerically pure (R)-(584) is obtained, after recrystallization (Scheme 14.158) [391].…”

GABA Uptake Inhibitors. Design, Molecular Pharmacology and Therapeutic Aspects

“…The lack of specificity of 2 as a substrate for neuronal GABA transport [36,37], and the observation that 1 appears to be transported with equal efficiency by neuronal and glial uptake mechanisms, in both cases without using GABA transport carriers [38], have markedly reduced the value of these amino acids as marker substrates. Like 2, cis-3-aminocyclohexanecarboxylic acid (3-ACHC), the active enantiomer being (1S,3R)-3-ACHC (4) [39], was considered to be a selective substrate for neuronal GABA transport mechanism(s) [40,41], but 4 actually interacts with glial as well as neuronal GABA transport [37,42]. provided a chiral GABA analogue showing a different enantiopharmacological profile.…”

Nitrilase‐ and Nitrile Hydratase‐Catalyzed Enantioselective Preparation of Non‐Proteinogenic Amino Acids

“…The preparation of both enantiomers of cis -3 -aminocyclohexanecarboxylic acids was achieved via classical fractional crystallization of the diastereomeric L -ornithine and brucine salts [23] . Both isomers of 3 -oxo -cyclopentane carboxylic acid were obtained by resolution of their brucine adducts, following several transformation steps to either enantiomer of cis -and trans -3 -aminocyclopentanecarboxylic acid [24] .…”