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Solid‐Phase Total Synthesis of Yaku'amide B Enabled by Traceless Staudinger Ligation
Author(s) -
Itoh Hiroaki,
Miura Kensuke,
Kamiya Koichi,
Yamashita Tomoya,
Inoue Masayuki
Publication year - 2020
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201916517
Subject(s) - chemistry , amide , linker , solid phase synthesis , staudinger reaction , amine gas treating , total synthesis , combinatorial chemistry , steric effects , yield (engineering) , cleavage (geology) , stereochemistry , natural product , peptide , organic chemistry , biochemistry , materials science , geotechnical engineering , fracture (geology) , computer science , engineering , metallurgy , operating system
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 AlMe 3 to deliver 1 in 9.1 % overall yield (24 steps from the resin).