β²‐amino acids—syntheses, occurrence in natural products, and components of β‐peptides^1,2

Abstract

Although they are less abundant than their alpha-analogues, beta-amino acids occur in nature both in free form and bound to peptides. Oligomers composed exclusively of beta-amino acids (so-called beta-peptides) might be the most thoroughly investigated peptidomimetics. Beside the facts that they are stable to metabolism, exhibit slow microbial degradation, and are inherently stable to proteases and peptidases, they fold into well-ordered secondary structures consisting of helices, turns, and sheets. In this respect, the most intriguing effects have been observed when beta2-amino acids are present in the beta-peptide backbone. This review gives an overview of the occurrence and importance of beta2-amino acids in nature, placing emphasis on the metabolic pathways of beta-aminoisobutyric acid (beta-Aib) and the appearance of beta2-amino acids as secondary metabolites or as components of more complex natural products, such as peptides, depsipeptides, lactones, and alkaloids. In addition, a compilation of the syntheses of both achiral and chiral beta2-amino acids is presented. While there are numerous routes to achiral beta2-amino acids, their EPC synthesis is currently the subject of many investigations. These include the diastereoselective alkylation and Mannich-type reactions of cyclic- or acyclic beta-homoglycine derivatives containing chiral auxiliaries, the Curtius degradation, the employment of transition-metal catalyzed reactions such as enantioselective hydrogenations, reductions, C-H insertions, and Michael-type additions, and the resolution of rac. beta2-amino acids, as well as several miscellaneous methods. In the last part of the review, the importance of beta2-amino acids in the formation of beta-peptide secondary structures is discussed.

Biophysical and Structural Characterization of a Robust Octameric β-Peptide Bundle

“…Additionally, although β-amino acids are not constituents of natural proteins, they are requisite intermediates during metabolism (metabolites of thymine and valine), constituents of natural products (for example, crytophycins), and can be isolated from meteorites in quantities comparable to α-amino acids. 54,56,57 With such an array of functional amino acid products arising from Miller's reaction, it is interesting to ask why α-amino acids were selected in the presence of alternative compounds containing the same functional groups. Possible answers include the following: (1) that the other products did not have the ability to assemble into discrete higher-order structures and/or (2) assemblies of the other products lacked stability to support the complex functions required for the evolution of life.…”

Enantioselective Organocatalytic Aminomethylation of Aldehydes: A Role for Ionic Interactions and Efficient Access to β2-Amino Acids

“…3 Many routes to enantio-enriched β 2 -amino acids have been described; most involve chiral auxiliaries, and few are amenable to large-scale synthesis. 4 Here we report an enantioselective organocatalytic method for aminomethylation of aldehydes, which leads to a new and efficient synthesis of β 2 -amino acids (Scheme 1). Our observations provide evidence that non-Hbonded ionic interactions at the Mannich reaction transition state can influence stereochemical outcome.…”

“…15 To date, utilization β 2 -amino acid building blocks has been limited by the cumbersome routes that are generally required to prepare them. 4 Few β 2 -amino acids are commercially available. In contrast, many β 3 -amino acids (side chain adjacent to nitrogen) are commercially available, and such building blocks are readily prepared from the analogous α-amino acids.…”

β‐Aminopeptidase‐Catalyzed Biotransformations of β2‐Dipeptides: Kinetic Resolution and Enzymatic Coupling

“…-Amino acids are valuable compounds for extending the repertoire of building blocks for peptide design because their incorporation into peptides induces unique secondary-structure elements and leads to increased stability against proteolytic breakdown. [10] Unlike b 3 -amino acids, most of which are by now commercially available, enantiopure b 2 -amino acids with proteinogenic side chains are less easily accessible by chemical synthesis. They cannot be prepared by stereoselective homologation of the naturally occurring a-amino acid analogues, the strategy most commonly applied to the synthesis of enantiopure b 3 -amino acids (Arndt-Eistert reaction).…”