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

Gerardo A Acosta,Beatriz G De La Torre,Miriam Royo,Fernando Albericio,Laura Murray

doi:10.3389/fchem.2020.00298

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.

Highlights

Peptides are an important class of Active Pharmaceutical Ingredients (APIs) (Henninot et al, 2018; Lau and Dunn, 2018; Al Shaer et al, 2020; de la Torre and Albericio, 2020)
As the aromatic ring of the Tyr side chain should confer more rigidity to the pending unit than the side chains of Cys or Lys/Orn/Dab/Dap studied in previous works (Acosta et al, 2017; Abdel Monaim et al, 2018), we first investigated the relevance of cyclodepsipeptide size with respect to facilitating the cyclization
Model peptides with 6, 7, 8, and 9 amino acids were prepared, which correspond to cycles of 23, 26, 29, and 32-member rings, respectively (Figure 4). The sequence of these peptides was based on our previous works, related to the preparation of cyclo thiodepsipeptides and homodetic peptides as well (Acosta et al, 2017; Abdel Monaim et al, 2018)

Summary

INTRODUCTION

Peptides are an important class of Active Pharmaceutical Ingredients (APIs) (Henninot et al, 2018; Lau and Dunn, 2018; Al Shaer et al, 2020; de la Torre and Albericio, 2020). The production of peptides ready for use in humans is relatively affordable thanks to the development of two complementary technologies, namely solid-phase peptide synthesis (SPPS) and reversed-phase high-performance liquid chromatography (RP-HPLC) The former was first described by Bruce Merrifield (Merrifield, 1963), and later refined by several groups, while the latter, founded on the pioneering work of Jim Waters (McDonald, 2006), allows the purification of complex synthetic crude peptides. As an activated N-acylurea (N-acyl-N’-methylurea), this resin is susceptible to being a leaving group when under the attack of a nucleophile such as a thiol and to rendering, in this case, the peptide thioester (Figure 2) This resin is considered a “safety catch,” in the terms described by Patek and Lebl, namely stable throughout peptide elongation and activated to be labile to a given reagent (Patek and Lebl, 1999). We report on a further application of the Fmoc-MeDbz/MeNbz-resin strategy for the synthesis of Tyr-cyclodepsipeptides

RESULTS AND DISCUSSION

CONCLUSIONS

DATA AVAILABILITY STATEMENT