Pipecolidepsin A is a head-to-side-chain cyclodepsipeptide isolated from the marine sponge Homophymia lamellosa. This compound shows relevant cytotoxic activity in three human tumour cell lines and has unique structural features, with an abundance of non-proteinogenic residues, including several intriguing amino acids. Although the moieties present in the structure show high synthetic difficulty, the cornerstone is constituted by the unprecedented and highly hindered g-branched b-hydroxy-a-amino acid D-allo-(2R,3R,4R)-2-amino-3-hydroxy-4,5-dimethylhexanoic acid (AHDMHA) residue, placed at the branching ester position and surrounded by the four demanding residues L-(2S,3S,4R)-3,4-dimethylglutamine, (2R,3R,4S)-4,7-diamino-2,3-dihydroxy-7-oxoheptanoic acid, D-allo-Thr and L-pipecolic acid. Here we describe the first total synthesis of a D-allo-AHDMHA-containing peptide, pipecolidepsin A, thus allowing chemical structure validation of the natural product and providing a robust synthetic strategy to access other members of the relevant head-to-side-chain family in a straightforward manner.

Here we present a new formulation of the recently introduced OxymaPure additive for peptide bond formation, in which the N‐hydroxylamine group is replaced by a potassium salt. The complete suppression of its acidity converts K‐Oxyma into the most suitable coupling choice when peptides are assembled on highly acid‐labile solid‐supports. The coupling efficiency and diminished prospects for epimerization are conserved relative to OxymaPure. In addition, K‐Oxyma displays excellent solubility in a variety of organic solvents and undergoes safer decomposition than classical 1‐hydroxybenzotriazole additives.

The palladium(0) complexes of (E,E,E)‐1,6,11‐tris(arenesulfonyl)‐1,6,11‐triazacyclopentadeca‐3,8,13‐trienes deliver palladium to phosphanes with the generation of high concentrations of catalytically active species such as Pd(PPh3)2. After oxidation of the phosphanes, the palladium is reincorporated into the macrocycle, thus avoiding agglomeration and precipitation. These conclusions were reached by 31P NMR, 19F NMR, and electrospray ionization mass spectrometry studies of telomerization and Tsuji−Trost reactions. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)

The latest twist: The effect of backbone H‐bonding on the stability of proteins was studied by experimental techniques and molecular dynamics simulation. The structure of the coiled‐coil model peptide examined (see picture) is affected by interactions in the solvent‐exposed regions as well as by interhelical hydrophobic interactions.

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Amino acid sequences and linear or head-to-tail cyclopeptides can be represented conveniently in one-line text formulae using the three-letter symbols. However, other - but nonetheless important - topologies of peptides are 'side chain-to-head (or tail)', 'backbone-to-backbone', 'side chain-to-side chain' cyclopeptides, 'side chain-to-side chain' connected peptide strands, and branched peptides (like peptide dendrimers). In general, such structures cannot be described using the three-letter symbols in one-line text: a chemical structure editor is required for symbolic representations according to the IUPAC-IUBMB recommendations. The aim of this contribution is to offer an unambiguous and general nomenclature system that enables researchers to represent all cyclic and branched homo- and hetero-detic peptides in a coherent manner in one-line text - as long as their as constituents can be represented in (three)-letter codes. The application of this new nomenclature would overcome the existing difficulties and provide a way to express complex situations in the shortest way in order to highlight more clearly the salient points in a given scientific communication.

The technique of choice for synthesis of small-scale depsipeptides is on a solid support. However, if expensive monomers have to be incorporated, solid-phase synthesis can quickly turn out to be unattractive because of its low atom economy. Herein, we describe a new type of recoverable and reuseable alpha-hydroxy acid building block for solid-phase synthesis and its application in the synthesis of a number of small cyclic depsipeptides. [structure: see text]

Backbone N-substitution of peptides (N-Me and N-alkyl) has become of special interest as a chemical tool for peptide lead modification, either to improve biological activity or to optimize key pharmacokinetic characteristics. For the synthesis of backbone N-methylated peptides, many protocols have been developed already, yet some effort often has to be made to find appropriate conditions for the acylation of N-Me residues. Fewer examples are reported of peptides with other backbone N-substituents different than N-Me, and their synthesis is frequently reported as difficult. The synthesis of such peptides becomes more difficult as the size of the N-substituent increases. Coupling methods that work for the synthesis of N-methylated peptides were often found to fail when applied to peptides with larger N-substituents. This review addresses the challenges of the synthesis of backbone N-modified peptides, focusing on N-substituents larger than the N-Me group.