Total synthesis of pseudacyclins A–E by an on-resin head-to-side chain concomitant cyclization-cleavage reaction

Abstract

Taking advantage of the nucleophile-sensitive ester link of oxime resin, a novel synthetic strategy was applied to the first synthesis of a type of cyclic peptides known as pseudacyclins A-E. The endocyclic ornithine side-chain part was incorporated by an on-resin acid-catalyzed concomitant cyclization-cleavage reaction after a selective deprotection of orthogonally protected ornithine. The synthetic methodology gives high macrocyclization yields and low oligomerization sideproducts. The combination used of solid-phase/solution-phase strategy was efficient to prepare pseudacyclins and could prove useful to prepare other natural cycle-tail peptides.

Recent Advances in Macrocyclic Drugs and Microwave-Assisted and/or Solid-Supported Synthesis of Macrocycles

“…An alternative methodology was also developed using entirely on-resin synthesis and biorthogonal protection in N -Boc-L-Thr(O t Bu)-OH [ 50 ]. In 2018, Bérubé et al reported the on-resin synthesis of pseudacyclins A–E via a similar head-to-side chain concomitant cyclization–cleavage strategy [ 51 ].…”

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

“…Voyer and co‐workers have reported the solid‐phase synthesis of pseudacyclins A−E by using an oxime resin, which is removable by nucleophilic replacement (Scheme 24). [93] Based on this character of the oxime resin, Boc SPPS was appropriately chosen to synthesize these peptides. It began with anchoring ʟ‐Ile or ʟ‐Val ( 158 ) onto the oxime resin ( 159 ), followed by elongation of the peptide with Boc chemistry.…”