Solid‐Phase Total Synthesis of Yaku'amide B Enabled by Traceless Staudinger Ligation

Abstract

We report a solid‐phase strategy for total synthesis of the peptidic natural product yaku'amide B (1), which exhibits antiproliferative activity against various cancer cells. Its linear tridecapeptide sequence bears four β,β‐dialkylated α,β‐dehydroamino acid residues and is capped with an N‐terminal acyl group (NTA) and a C‐terminal amine (CTA). To realize the Fmoc‐based solid‐phase synthesis of this complex structure, we developed new methods for enamide formation, enamide deprotection, and C‐terminal modification. First, traceless Staudinger ligation enabled enamide formation between sterically encumbered alkenyl azides and newly designed phosphinophenol esters. Second, application of Eu(OTf)3 led to chemoselective removal of the enamide Boc groups without detaching the resin linker. Finally, resin‐cleavage and C‐terminus modification were simultaneously achieved with an ester–amide exchange reaction using CTA and AlMe3 to deliver 1 in 9.1 % overall yield (24 steps from the resin).

Divergent Solid‐Phase Synthesis and Biological Evaluation of Yaku'amide B and Its Seven E/Z Isomers

“…Compared with solution‐phase synthesis, solid‐phase peptide synthesis (SPPS) is generally more efficient for the practical supply of a target and more flexible for preparation of analogues in a divergent fashion [18, 19] . In 2020, we disclosed an Fmoc‐based SPPS of 1 , [20] thereby increasing the overall yield and decreasing the purification steps from the solution‐phase synthesis reported in 2015. In this synthesis, a modified traceless Staudinger ligation was developed and applied to the stereoselective construction of the sterically cumbersome ( E )/( Z )‐ΔIle residues in solution (Figure 1 b).…”

“…Because of the high swelling property of the crosslinked poly(ethylene glycol)‐based polymer in various media, [35, 36] 16 was considered suitable for both condensation of the carboxylic acids in an organic solvent and traceless Staudinger ligation in an aqueous solvent. Hence, the synthesis of 1 – 8 started with esterification of 18 using resin 16 by the action of N , N′ ‐dicyclohexylcarbodiimide (DCC) and N , N ‐dimethyl‐4‐aminopyridine (DMAP) in N ‐methyl‐2‐pyrrolidone (NMP) [20] . Solid‐phase traceless Staudinger ligation between the resin‐attached alkenyl azide and phosphinophenol ester 22 was performed at 50 °C in 1,2‐dimethoxyethane/H 2 O to forge the hindered enamide of 29 between Val‐12 and ΔVal‐13 (73 % yield over 2 steps).…”

“…Lastly, the NTA and CTA moieties were installed according to the previous total synthesis of 1 [20] . The Fmoc group of the resin‐linked eight tridecapeptides 32 was exchanged with the NTA structure by treatment with piperidine and then with carboxylic acid 23 , (1‐cyano‐2‐ethoxy‐2‐oxoethylidenaminooxy)dimethylamino‐morpholino‐carbenium hexafluorophosphate (COMU), [40] and 2,4,6‐collidine.…”

“…Hence, the synthesis of 1-8 started with esterification of 18 using resin 16 by the action of N,N'-dicyclohexylcarbodiimide (DCC) and N,N-dimethyl-4-aminopyridine (DMAP) in N-methyl-2-pyrrolidone (NMP). [20] Solid-phase tracelessS taudingerl igationb etween the resin-attached alkenyl azide and phosphinophenol ester 22 was performed at 50 8C in 1,2-dimethoxyethane/H 2 Ot of orge the hindered enamide of 29 between Val-12 and DVal-13 (73 %y ield over 2steps). Then, piperidine-mediated Fmoc removal and condensation of N a -Fmoc-amino acid in the presence of O-(7-aza-1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU)/1-hydroxy-7-azabenzotriazole (HOAt) [37] and iPr 2 NEt were repeated twice from dipeptide 29 at 40 8Cu nder microwave irradiation [38] using 24 and 27.T he obtained tetrapeptide functioned as the branching point for the divergentsynthesis.…”

Proapoptotic Peptide Brush Polymer Nanoparticles via Photoinitiated Polymerization‐Induced Self‐Assembly

“…Traditional approaches for protecting active peptides from enzymatic digestion capitalize on chemical modification of the peptide . These approaches include cyclization, lipidation, conjugation of PEG, introduction of unnatural amino acids, peptide backbone modification (e.g., N‐methylation), and capping of N‐ or C‐terminus, among others . Consequently, modified peptides are rendered inaccessible to, or unrecognizable by the active site of protease.…”