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

• Published in: Journal of organic chemistry Vol. 70; no. 20; pp. 7963 - 7971
• Main Authors: Izquierdo, Sandra, Rúa, Federico, Sbai, Abdelouahid, Parella, Teodor, Álvarez-Larena, Ángel, Branchadell, Vicenç, Ortuño, Rosa M
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 30.09.2005; Amer Chemical Soc
• Subjects: Alicyclic compounds; Alicyclic compounds, terpenoids, prostaglandins, steroids; Amino Acids - chemistry; Carboxylic Acids - chemistry; Chemistry; Chemistry, Organic; Cyclobutanes - chemistry; Exact sciences and technology; Hydrogen Bonding; Magnetic Resonance Spectroscopy; Models, Molecular; Organic chemistry; Peptides; Peptides - chemical synthesis; Peptides - chemistry; Physical Sciences; Preparations and properties; Science & Technology; Stereoisomerism; CHAIN; ENERGY; ALANINE; AMINO-ACIDS; GAMMA-PEPTIDES; STABILITY; ESTERS; X-RAY; Molecular rigidity; Peptides; NMR spectrometry; Organic carbamate; Stereoselectivity; Amine; Carboxylic acid; Aminoacid; Cyclobutane derivatives; Dipeptides; Density functional method; Peptide synthesis; Conformational equilibrium; Intramolecular hydrogen bond; Structural analysis
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo0510843

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.