C^α‐Tetrasubstituted amino acid based peptides in asymmetric catalysis

Abstract

C(alpha)-tetrasubstituted alpha-amino acids constitute a powerful tool for controlling the conformation of short peptide sequences. Chiral peptides may be used in stereoselective reactions both for asymmetric induction and in kinetic resolution. By reviewing recent data from our own laboratories and by presenting new results on the stereoselective oxidation of chalcone to the corresponding oxide, this contribution shows that the control of peptide conformation is a critical issue in order to achieve successful stereoselective catalysis.

Catalysis by Peptide‐Based Enzyme Models

“…Importantly, a strong correlation was observed between the rigidity of the b-hairpin structure and the enantioselectivity of the catalyst [9]. This hypothesis was confirmed by studies by Toniolo et al of related catalysts in which the b-turn inducing a-amino isobutyric acid (Aib) residue was replaced by other C a -tetrasubstituted amino acids [10]. Conformational analysis by 1 H-nuclear magnetic resonance (NMR) and Fourier transform infrared spectroscopy confirmed that the conformational constraint plays a key role in the enantioselectivity of the catalyst.…”

“…Strategies that will be discussed are the use of small oligopeptides with a persistent secondary structure, the spontaneous self-assembly of simple peptidic fragments into large aggregates, and the incorporation of peptide fragments in multivalent structures such as dendrimers and nanoparticles. 10.2.1.1 Catalytically Active Peptide Foldamers Inspired by enzyme models, Miller et al started by embedding nucleophiles in conformationally restricted peptidic structures in order to discover catalysts for asymmetric acyl-transfer reactions [8]. Histidine residues served as nucleophiles in a series of b-turn-type peptides for the kinetic resolution of trans-(AE)-N-(2-hydroxycyclohexyl)acetamide.…”

“…While the core of each protein is mainly hydrophobic, the outer surface ranges in polarity from hydrophilic to amphiphilic to lipophilic. 10.3.1.1 Early Heme-Peptide Models: Porphyrin as Template Studies on natural proteins have shown that the protein environment modulates the specific function in a hierarchical manner [87]: the primary coordination sphere (i.e., the presence of one or both axial ligands, and their type and donor properties) controls the intrinsic reactivity of the metal center. Factors such as the local dielectric constant, hydrophobicity, hydrogen bonding, and steric interactions between the primary sphere and its immediate surroundings (i.e., the second coordination sphere) contribute to the next level of control.…”

“…The determination of the structure of reduced and oxidized complexes could address this issue. 10.3.1.2.2 Water-Soluble Models: Four-Helix Bundles A second class of heme protein maquettes involves a four-helix bundle [95,97,108] (Figure 10.19), in analogy to the topology of many natural heme binding proteins such as cytochrome b 562 and the central core of cytochrome bc 1 . These model systems can bind between one and four heme moieties, depending on the design.…”

Design and Synthesis of Chiral .ALPHA.,.ALPHA.-Disubstituted Amino Acids and Conformational Study of Their Oligopeptides

“…49) On the other hand, Toniolo and co-workers reported asymmetric epoxidation 50) and oxidation reactions 51,52) using the helical secondary structures of a,a-disubstituted amino acid peptides. 53) The author has started to study the utilization of chiral cyclic a,a-disubstituted amino acids for drug design, and for the development of asymmetric reactions.…”