One of the most important reactions in organic chemistry--amide bond formation--is often overlooked as a contemporary challenge because of the widespread occurrence of amides in modern pharmaceuticals and biologically active compounds. But existing methods are reaching their inherent limits, and concerns about their waste and expense are becoming sharper. Novel chemical approaches to amide formation are therefore being developed. Here we review and summarize a new generation of amide-forming reactions that may contribute to solving these problems. We also consider their potential application to current synthetic challenges, including the development of catalytic amide formation, the synthesis of therapeutic peptides and the preparation of modified peptides and proteins.

Rethinking amide bond synthesis

Foldamers are sequence-specific oligomers akin to peptides, proteins and oligonucleotides that fold into well-defined three-dimensional structures They offer the chemical biologist a broad pallet of building blocks for the construction of molecules that test and extend our understanding of protein folding and function Foldamers also provide templates for presenting complex arrays of functional groups in virtually unlimited geometrical patterns, thereby presenting attractive opportunities for the design of molecules that bind in a sequence- and structure-specific manner to oligosaccharides, nucleic acids, membranes and proteins We summarize recent advances and highlight the future applications and challenges of this rapidly expanding field

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Foldamers as versatile frameworks for the design and evolution of function

The present review offers an overview of nonclassical (e.g., with no pre- or in situ activation of a carboxylic acid partner) approaches for the construction of amide bonds. The review aims to comprehensively discuss relevant work, which was mainly done in the field in the last 20 years. Organization of the data follows a subdivision according to substrate classes: catalytic direct formation of amides from carboxylic and amines (section 2); the use of carboxylic acid surrogates (section 3); and the use of amine surrogates (section 4). The ligation strategies (NCL, Staudinger, KAHA, KATs, etc.) that could involve both carboxylic acid and amine surrogates are treated separately in section 5.

Nonclassical Routes for Amide Bond Formation

The investigation of biological processes by chemical methods, commonly referred to as chemical biology, often requires chemical access to biologically relevant macromolecules such as peptides and proteins. Building upon solid-phase peptide synthesis, investigations have focused on the development of chemoselective ligation and modification strategies to link synthetic peptides or other functional units to larger synthetic and biologically relevant macromolecules. This Review summarizes recent developments in the field of chemoselective ligation and modification strategies and illustrates their application, with examples ranging from the total synthesis of proteins to the semisynthesis of naturally modified proteins.

Chemoselective Ligation and Modification Strategies for Peptides and Proteins

Direct and waste-free amidations and cycloadditions by organocatalytic activation of carboxylic acids at room temperature.

A versatile method for the synthesis of enantiomerically pure isoxazolidine monomers for the synthesis of β3-oligopeptides via α-keto acidhydroxylamine (KAHA) ligation is presented. This one-pot synthetic method utilizes in situ generated nitrones bearing gulose-derived chiral auxiliaries for the asymmetric 1,3-dipolar cycloaddition with methyl 2-methoxyacrylate. The resulting enantiomerically pure isoxazolidine monomers bearing diverse side chains (proteinogenic and non-proteinogenic) can be synthesized in either configuration (like- and unlike-configured). The scalable and enantioselective synthesis of the isoxazolidine monomers enables the use of the synthesis of β3-oligopeptides via iterative α-keto acidhydroxylamine (KAHA) ligation.

Synthesis of Enantiomerically Pure Isoxazolidine Monomers for the Preparation of β3‐Oligopeptides by Iterative α‐Keto AcidHydroxylamine (KAHA) Ligations

The chemoselective synthesis of amides by decarboxylative couplings of alpha-ketoacids and isoxazolidines makes possible an iterative approach to poly-beta3-peptides. Peptide assembly occurs under aqueous conditions and requires no coupling reagents. The requisite isoxazolidine monomers are prepared in enantiopure form by a convenient two-step protocol starting from the appropriate aldehydes.

Iterative, Aqueous Synthesis of β3‐Oligopeptides Without Coupling Reagents.

Synthesis of an enantiopure isoxazolidine monomer for β3-aspartic acid in chemoselective β-oligopeptide synthesis

Iterative, Aqueous Synthesis of β3-Oligopeptides without Coupling Reagents

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Synthesis of Enantiomerically Pure Isoxazolidine Monomers for the Preparation of β3‐Oligopeptides by Iterative α‐Keto AcidHydroxylamine (KAHA) Ligations

Iterative, Aqueous Synthesis of β3‐Oligopeptides Without Coupling Reagents.

Synthesis of an enantiopure isoxazolidine monomer for β3-aspartic acid in chemoselective β-oligopeptide synthesis

Iterative, Aqueous Synthesis of β3-Oligopeptides without Coupling Reagents