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.

Lactocin S is a lantibiotic peptide with potent antibacterial activity against a range of gram-positive bacteria. Because of challenges in obtaining sufficient quantities of this compound from natural sources, the stereochemistry of the lanthionine residues in lactocin S had not been confirmed. This report describes the chemical synthesis of lactocin S on chlorotrityl polystyrene resin in 10% overall yield using intramolecular cyclization to form the lanthionine rings and employing fragment coupling for the two N-terminal residues. This represents the first report of solid-supported synthesis of a naturally occurring lantibiotic. Comparison to lactocin S isolated from Lactobacillus sakei L45 using a combination of HPLC, MS/MS sequencing, bacterial testing, and chiral GC-MS analysis confirmed the initially proposed structure and the stereochemistry of the DL-lanthionine residues.

Scheme 1. The a-ketoacid-5-oxaproline ligation. R = aminoacid sidechain, DMSO = dimethylsulfoxide.[*] Dr. Scheme 2. Synthesis of enantiopure (S)-N-Boc-5-oxaproline 5. DMAP = 4-dimethylaminopyridine, Boc = tert-butoxycarbonyl. . Angewandte Communications Angewandte Chemie 5115

A novel protecting group for enantiopure α-ketoacids delivers C-terminal peptide α-ketoacids directly upon resin cleavage and allows the inclusion of all canonical amino acids, including cysteine and methionine. By using this approach, SUMO2 and SUMO3 proteins were prepared by KAHA ligation with 5-oxaproline. The synthetic proteins containing homoserine residues were recognized by and conjugated to RanGAP1 by SUMOylation enzymes.

Lan‐tastic! A lanthionine analogue of lacticin 3147 A2 (Lan‐A2, 2) containing multiple thioether bridges (see picture) has been successfully synthesized by a combination of solid‐ and solution‐phase peptide synthesis. Chemically synthesized Lan‐A2 (2) exhibits synergistic biological activity similar to natural lacticin A2 (1) in the presence of natural lacticin A1 against Gram‐positive bacteria.

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The primary products of the chemical ligation of α-ketoacids and 5-oxaproline peptides are esters, rather than the previously reported amides. The depsipeptide product rapidly rearranges to the amide in basic buffers. The formation of esters sheds light on possible mechanisms for the type II KAHA ligations and opens an avenue for the chemical synthesis of depsiproteins.

Chemical synthesis of lantibiotic analogues wherein monosulfide bridges are replaced with other groups can shed light on structure-activity relationships and generate variants that are resistant to aerobic oxidation and have better metabolic stability. This work describes the first complete synthesis of a carbocyclic lantibiotic analogue 2, using sequential on-resin ring-closing olefin metathesis and solution-phase peptide synthesis. The methodology described should find wide application for the preparation of rigidified peptidomimetics containing multiple carbocyclic rings. [structure: see text].