Solid Phase‐Supported Synthesis of Muraymycin Analogues

Abstract

Naturally occurring muraymycin nucleoside antibiotics represent a promising class of novel antimicrobials as they inhibit MraY, an enzyme involved in bacterial cell wall biosynthesis. The synthesis of muraymycins and their analogues is challenging as it involves multi‐step routes, thus hampering detailed structure‐activity relationship (SAR) studies. In this work, we report a novel solid phase‐based synthetic strategy for accessing muraymycin analogues via a modular approach, thereby enabling a more efficient access to structural variations, particularly of the muraymycin peptide moiety. The efficiency of this new method was exemplified in an alanine scan of the peptide unit. The inhibitory in vitro activities of the resultant analogues towards MraY provided novel SAR insights. Overall, this new synthetic method for the preparation of muraymycin analogues might support the development of these antibacterial agents towards potential drug candidates.

Muraymycin Nucleoside Antibiotics: Structure-Activity Relationship for Variations in the Nucleoside Unit

“…We had previously described different solution-phase syntheses of muraymycin analogues, either based on a tripartite [38] or a bipartite [41] strategy. However, we have recently reported a novel synthetic approach towards muraymycin analogues, based on solid-phase peptide synthesis (SPPS) to construct a building block for the complete peptide unit [42]. We have decided to apply this new strategy for the synthesis of target structures 13-15 (Scheme 2).…”

“…The synthesis of the peptide-aldehyde unit 17, based on a solid phase-supported approach, has been performed as recently reported [42]. Thus, the stage was set for the preparation of target structures 13-15 (Scheme 4).…”

“…Subsequent global acidic deprotection using 80% aqueous TFA and HPLC purification afforded target compounds 13-15 as their bis-TFA salts in 13%-25% yields over two steps from 18-20 (Scheme 4). The synthesis of the peptide-aldehyde unit 17, based on a solid phase-supported approach, has been performed as recently reported [42]. Thus, the stage was set for the preparation of target structures 13-15 (Scheme 4).…”

“…(SPPS) to construct a building block for the complete peptide unit [42]. We have decided to apply this new strategy for the synthesis of target structures 13-15 (Scheme 2).…”

“…Thus, these muraymycin analogues should be accessible by reductive amination of the peptide-derived aldehyde 17 with different nucleosyl amino acids 18-20, to be followed by global acidic deprotection. The protected peptide building block 17 was readily accessible using our novel SPPS method as described [42], leaving the main synthetic challenge to be the stereoselective preparation of nucleosyl amino acids 18-20. For the synthesis of 5,6-dihydrouracil derivative 16, we have used a solution-phase route (vide infra) as this compound had already been prepared prior to the recent development of the SPPS-based method.…”