(+)- and (−)-2-Aminocyclobutane-1-carboxylic Acids and Their Incorporation into Highly Rigid β-Peptides: Stereoselective Synthesis and a Structural Study

Several derivatives of (+)- and (−)-2-aminocyclobutane-1-carboxylic acid, 1, have been prepared
through enantiodivergent synthetic sequences. The stereoselective synthesis of free amino acid
(+)-1 has been achieved, and this product has been fully characterized for the first time.
Stereocontrolled alternative synthetic methodologies have been developed for the preparation of
bis(cyclobutane) β-dipeptides in high yields. Among them, enantio and diastereomers have been
synthesized. β,β- and β,δ-Dimers resulting from the coupling of a cyclobutane residue and a linear
amino acid have also been prepared. The ability of the cyclobutane ring as a structure-promoting
unit both in the monomers and in the dimers has been manifested. The NMR structural study and
DFT theoretical calculations evidence the formation of strong intramolecular hydrogen bonds giving
rise to cis-fused [4.2.0]octane structural units that confer high rigidity on these molecules both in
solution and in the gas phase. The contribution of a cis−trans conformational equilibrium derived
from the rotation around the carbamate N−C(O) bond has also been observed, the trans form being
the major conformer. In the solid state, this equilibrium does not exist, and moreover, intermolecular
hydrogen bonds are present.