A Versatile Boc Solid Phase Synthesis of Daptomycin and Analogues Using Site Specific, On‐Resin Ozonolysis to Install the Kynurenine Residue

Abstract

Ad en ovo solid-phase synthesis of the cyclic lipodepsipeptide daptomycin via Boc chemistry was achieved. The challenging ester bond formation between the nonproteinogenic amino acid kynurenine was achieved by esterification of at hreonine residue with ap rotected tryptophan. Subsequent late-stage on-resin ozonolysis, inspired by the biomimetic pathway,a fforded the kynurenine residue directly.S ynthetic daptomycin possessed potent antimicrobiala c-tivity (MIC 100 = 1.0 mgmL À1 )a gainst S. aureus,w hile five other daptomycin analogues containing (2R,3R)-3-methylglutamic acid, (2S,4S)-4-methylglutamic acid or canonical glutamic acid at position twelve prepared using this new methodology were all inactive, clearly establishing that the (2S,3R)-3methylglutamic acid plays ak ey role in the antimicrobial activity of daptomycin.Supporting information and the ORCID identification number(s) for the author(s) of this articlecan be found under: https://doi.

A Concise Synthetic Strategy Towards the Novel Calcium-dependent Lipopeptide Antibiotic, Malacidin A and Analogues

“…This observation indicates that both the presence and absolute configuration of the β-substituents of the non-canonical amino acids are important for the activity of the antibiotic, most likely through their interaction with Ca 2+ ions to form the active antibiotic-Ca 2+ complex. This observation is not unusual, as previous reports of SAR studies of A54145 D and daptomycin CDLAs showed that removal or reversal of configuration at even one stereocenter may result in a significant reduction or complete loss of bioactivity ( Kralt et al, 2019 ; Xu et al, 2019 ). It is likely that orientation of the β-OH of 3-HyAsp 5 , that forms part of the calcium binding motif, is highly important to provide efficient coordination to Ca 2+ ions.…”

Recent Progress in Solid‐Phase Total Synthesis of Naturally Occurring Small Peptides

“…Kyn residue was then formed in 98 by on-resin ozonolysis of the peptide 97. [75] This strategy enabled the solid-phase synthesis of daptomycin ( 100) with all N-protected amino acids.…”

“…In this approach, Trp was used as the precursor of Kyn to form the linear depsipeptide 96 . Kyn residue was then formed in 98 by on‐resin ozonolysis of the peptide 97 [75] . This strategy enabled the solid‐phase synthesis of daptomycin ( 100 ) with all N ‐protected amino acids.…”

Recent applications of solid-phase strategy in total synthesis of antibiotics

“…Fragment 4 was synthesized from glycine 2 with some modification from literatures 15 and fragment 8 was prepared by oxidative ring-opening of the compound 7. 16 Then, to finish the synthesis of daptomycin, solid-phase synthesis strategy was applied and amino acids residues were assembled via the standard Fmoc-SPPS (Fmoc solid-phase peptide synthesis) strategy. The trityl-resin-linked pentatpeptide 11 was obtained via standard Fmoc-SPPS by coupling with fragment 10 and 8.…”

“…Boc-SPPS could reduce peptide aggregation and suppress aspartimide formation, thus it has several advantages over Fmoc-SPPS, especially when the synthetic target contains base-sensitive moieties. In 2019, Harris, Brimble and coworkers employed a Boc-SPPS approach and realized the total synthesis of daptomycin 16 ( Scheme 5 ).…”