Synthesis of Chiral Scaffolds Based on Polyfunctional Cyclobutane β‐Amino Acids

Abstract

Chiral scaffolds have been synthesized through selective transformations from conveniently protected cyclobutane β-amino acids. The obtained derivatives present additional functional groups, such as hydroxyl, carboxyl, or carbon-carbon triple bond, linked to the amino acid core through a flexible C 1 or C 2 alkyl fragment. The resultant molecules are highly versatile to be used as chiral precursors for the production of polyfunc-tional chemical platforms. These can be suitable for the synthesis of complex molecules, through condensation reactions, such as peptide coupling, dehydration between a carboxylic acid and an alcohol, or click chemistry. To illustrate some of these possibilities, two hybrid tripeptides have been prepared as examples of their synthetic potential.

Expanding the Chemical Space of 1,2-Difunctionalized Cyclobutanes

“…A vast majority of the reported methods not only do not aim at the synthesis of pure enantiomer but even provide diastereomeric mixtures. A number of recent publications provide exceptions to one or both of the above points; − important (and already classical) examples include stereoisomeric 2-aminocyclobutanecarboxylic acids prepared and used by the groups of Ortuño, ,− Aitken, − Bolm, and others as the building blocks for the synthesis of peptidomimetics and organocatalysts.…”

Direct Access to Unnatural Cyclobutane α-Amino Acids through Visible Light Catalyzed [2+2]-Cycloaddition

“…In this regard, cyclobutane amino acids (CBAAs) have evolved as an interesting class of derivatives for the development of new classes of strained, conformational restricted peptide mimetics for medical applications as well as diverse uses as synthetic building blocks or catalysts. − As a result, many efforts have been set to the synthesis of cyclobutane α-, − β-, − and γ-amino acids − (Scheme a). However, although some derivatives exhibit potent biological activities, − cyclobutane α-amino acids have recently received much less attention, which might be due to a lack of efficient, straightforward approaches for their preparation. − …”