A unified synthesis of all stereoisomers of 2-(aminomethyl)cyclobutane-1-carboxylic acid

All four stereoisomers of 2-(aminomethyl)cyclobutane-1-carboxylic acid have been prepared starting from a single chirally derivatized unsaturated γ-lactam. A photochemical [2+2] cycloaddition reaction of this compound with ethylene was employed to create the four-membered ring exclusively with a cis ring configuration. The two diastereoisomers were separated conveniently by chromatography then the chiral appendage replaced by the more convenient Boc protecting group. Base-mediated lactam hydrolysis provided each of the cis target structures as single enantiomers. An efficient, tandem epimerization/hydrolysis protocol was applied to a carboxamide derivative of each cis compound, to furnish the corresponding trans compounds as single isomers, for the first time.