Solid-Phase Synthesis of Head to Side-Chain Tyr-Cyclodepsipeptides Through a Cyclative Cleavage From Fmoc-MeDbz/MeNbz-resins

Abstract

Cyclic depsipeptides constitute a fascinating class of natural products. Most of them are characterized by an ester formed between the β-hydroxy function of Ser/Thr-and related amino acids-and the carboxylic group of the C-terminal amino acid. Less frequent are those where the thiol of Cys is involved rendering a thioester (cyclo thiodepsipeptides) and even less common are the cyclo depsipeptides with a phenyl ester coming from the side-chain of Tyr. Herein, the preparation of the later through a cyclative cleavage using the Fmoc-MeDbz/MeNbz-resin is described. This resin has previously reported for the synthesis of cyclo thiodepsipeptides and homodetic peptides. The use of that resin for the preparation of all these peptides is also summarized.

Metal-Free Selective Modification of Secondary Amides: Application in Late-Stage Diversification of Peptides

“…Based on our previous work on synthesis of C-terminal modified peptides , and acylation strategies for amide activation that are limited to C-terminal modification, − we hypothesized that the amide bond next to Ser/Thr or Cys could be weakened by the N-functionalization with the respective side chains of these residues through carbonyl or thiocarbonyl insertion (Figure a). The resulting oxazolidinone or thiazolidinone cyclic moiety will weaken the amide bond by introducing a twist that distorts the pi-pi overlap of the C–N bond. , Interception of these intermediates with primary/secondary amines and alcohols would furnish the desired transamidated and esterified products (Figure a).…”

Safety-Catch Linkers for Solid-Phase Peptide Synthesis

“…It has been utilized in the synthesis of cysteine-rich proteins, such as the cyclotides Kalata B1 and MCoTI-II, through a single cyclization/folding step within the ligation/folding buffer [40]. Furthermore, the MeDbz linker has been used for the on-resin cyclization of side-chain (SH of Cys, NH 2 of Dab, OH of Tyr)-to-tail cyclic peptides [80][81][82] and for the preparation of C-terminal modified peptides [83,84]. This concept of using unsymmetrical diamino benzoic resin has been further described by other groups who utilize different protecting groups for the second amine function [75,85,86].…”

A versatileo-aminoanilide linker for native chemical ligation

“…35 Besides CPS, the Nbz/MeNbz and Bt linkers have found other important applications, enabling the access to posttranslational modications at the C-terminal peptide side of high structural and biomedical relevance, including C-terminal peptide esters and N-alkylamides and [36][37][38] head-to-tail and side chain-to-tail cyclic peptides. [39][40][41] From a synthetic point of view, it would be very attractive to use a single 1,2-diaminobenzene-type moiety for the preparation of peptides featuring C-terminal Nbz and Bt-type functionalities that combines the advantages of Dbz-COOH and MeDbz-COOH. Here, we show that C-terminal peptides amidated with 1,2-diaminobenzene (Dbz) can be efficiently converted in peptide-Nbz or peptide-Bt derivatives from the same initial peptide-Dbz-PAL-resin (PAL ¼ 4-(4-(aminomethyl)-3,5dimethoxyphenoxy)butanoic/pentanoic acid) precursor.…”

“…Besides CPS, the Nbz/MeNbz and Bt linkers have found other important applications, enabling the access to posttranslational modifications at the C-terminal peptide side of high structural and biomedical relevance, including C-terminal peptide esters and N -alkylamides and 36–38 head-to-tail and side chain-to-tail cyclic peptides. 39–41…”