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Solid‐Phase Total Synthesis of Yaku’amide B Enabled by Traceless Staudinger Ligation
Angewandte Chemie International Edition ( IF 12.257 ) Pub Date : 2020-01-13 , DOI: 10.1002/anie.201916517
Hiroaki Itoh; Kensuke Miura; Koichi Kamiya; Tomoya Yamashita; Masayuki Inoue

Here we report a solid‐phase strategy for total synthesis of the peptidic natural product yaku’amide B (1). Compound 1 exhibits potent antiproliferative activity against various cancer cells. Its linear tridecapeptide sequence bears four β,β‐dialkylated α,β‐dehydroamino acid residues [(Z)‐ΔIle‐2/9, (E)‐ΔIle‐4, and ΔVal‐13], 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 highly complex structure, we devised and optimized 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, thereby constructing the three dipeptides with (Z)‐ΔIle or (E)‐ΔIle in a solution and the C‐terminal dipeptide with ΔVal on a Wang‐ChemMatrix resin. Second, application of Eu(OTf)3 led to chemoselective removal of the enamide Boc groups of (Z)‐ΔIle and (E)‐ΔIle without detaching the resin linker. The combination of these two methods allowed us to elongate the NTA‐attached tridecapeptide sequence on the resin. 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). The established route permits efficient access to 1 and should be applicable for the solid‐phase preparation of its analogues and various other natural peptides with non‐proteinogenic amino acid structures.
更新日期:2020-01-14

 

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