Enantio‐ and diastereoselective syntheses of cyclic C^α‐tetrasubstituted α‐amino acids and their use to induce stable conformations in short peptides

Abstract

Cα‐Tetrasubstituted α‐amino acids are widely used to design and prepare peptides and peptide mimics with constrained conformations. Subcategories of these compounds are cyclic Cα‐tetrasubstituted α‐amino acids, in which both α‐substituents are covalently connected. This survey presents recent advances in the synthesis and application of cyclic Cα‐tetrasubstituted α‐amino acids in a systematic order beginning with cyclopropane amino acids, continuing with four, five, six membered rings, and ring structures larger than six‐membered. We discuss synthetic routes to the cyclic Cα‐tetrasubstituted α‐amino acids and their use as conformation determining elements in peptides. © 2007 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 90: 8–27, 2008. This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com

Design, conformational studies and analysis of structure–function relationships of PTH (1–11) analogues: the essential role of Val in position 2

“…1a). The introduction of the conformationally constrained C a -tetrasubstituted amino acids (Toniolo et al 2001;Maity and König 2008) in the sequence stabilizes the ordered structure of analogues from V to X (Fig. 1b); however, their spectrum is less intense than that of analogue I.…”

“…While alanine is easily accommodated in both folded and extended structures, theoretical and experimental studies performed on Aib (Kaul and Balaram 1999;Toniolo et al 2001;Torras et al 2008;Maity and König 2008) have highlighted its strong tendency to induce folded structures in the 3 10 -/a-helical region (u, w & ±60°, ±30°). On the contrary, semi-extended or fully-extended conformations are extremely rare for this residue.…”

Helical screw‐sense preferences of peptides based on chiral, Cα‐tetrasubstituted α‐amino acids

“…An impressive variety of additional chiral, cyclic C α ‐tetrasubstituted α‐amino acids were synthesized but, in general, scarce information on their conformational properties was reported, mainly for compounds not specifically designed to assess their preferred screw sense (for comprehensive review articles and selected, recent examples see Refs. and 165–168, respectively).…”

Synthesis of new functionalized aziridine-2- and azetidine-3-carboxylic acid derivatives of potential interest for biological and foldameric applications

“…Furthermore, 3-aminoazetidine-3-carboxylic acid derivatives 8 also represent interesting conformationally constrained functionalized C α -tetrasubstituted α-amino acids, which have not been studied in the foldameric field. Related C α -tetrasubstituted α-amino acids such as Aib (9) and 1-aminocyclobutane-1-carboxylic acid (10, Ac 4 c) are known to form short peptides with a conformational preference for β-turns and 3 10 -helices (Toniolo et al 2006;Maity and König 2008;Soloshonok and Sorochinsky 2010).…”