Practical Syntheses of Both Enantiomers of the Conformationally Restricted GABA Analogue cis-(2-Aminocyclobutyl)acetic Acid

Two efficient routes have been established for the preparation of both enantiomers of cis‐(2‐aminocyclobutyl)acetic acid, a conformationally restricted analogue of GABA. Both procedures converged on the racemic N‐tert‐butoxycarbonyl derivative of the target compound, which was resolved through chiral derivatization with an oxazolidinone auxiliary, which also allowed determination of the absolute configuration of the new compounds. The first route involved the homologation of cis‐2‐aminocyclobutanecarboxylic acid, whereas the second route employed an intramolecular photocyclization protocol, which provided an expedient, cis‐selective access to the lactam form of the target structure. Two complementary construction approaches ― homologation of a β‐amino acid and atom‐efficient photocyclization of an azepin‐2‐one ― followed by chiral resolution provide access to both enantiomers of this cyclobutane‐restricted GABA analogue.