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).

Convergent Total Synthesis of Yaku'amide A

“…[4] HPLC has been established as the most reliable technique for distinguishing yakuamide A from its isomers. [5] Accordingly, we were pleased to find that our synthetic sample of 1 was identical by HPLC to a synthetic sample from the Inoue laboratory that was previously demonstrated to be identical to naturally occurring 1.…”

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

“…In this manner, bogorol A was successfully obtained by acid-mediated cleavage from the resin. Similarly, the combination of Staudinger ligation and solid-phase synthesis provides an efficient way to yield yaku'amide B (31) [41,42] and nobilamides B (32) [43,44] and the cyclic depsipeptide nobilamide D. [43] The aromatic δ-amino acids, like p-aminobenzoic acid, and its analogues are unique building blocks contained in the natural linear peptides, such as cystobactamids, [45][46][47][48] albicidin [49,50] and coralmycin A (38). [51] Due to the low reactivity of aromatic amines in the coupling with carboxylic acids, incorporation of the aromatic δ-amino acids into the peptide chain remains challenging.…”

Sustainable Triazine-Based Dehydro-Condensation Agents for Amide Synthesis

“…In this frame, dehydro-condensation reactions are a well-known and consolidated protocol for the synthesis of amides, although toxic dehydro-condensation agents are often used to promote the reaction [17,19]. For example, carbodiimides such as dicyclohexylcarbodiimide (DCC) or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide chlorohydrate Hydroxybenzotriazole (HOBt) [24][25][26], 1-hydroxy-7-azabenzotriazole (HOAt) [27][28][29], and uronium or guanidinium salt derivatives such as, e.g., hexafluorophosphate azabenzotriazole tetramethyl uronium (HATU), hexafluorophosphate benzotriazole tetramethyl uronium (HBTU), hexafluorophosphate chlorobenzotriazole tetramethyl uronium (HCTU), and 1-cyano-2-ethoxy-2-oxoethylidenaminooxy)-dimethylamino-morpholino-carbenium hexafluorophosphate (COMU) (Figure 1) have also been efficiently used to promote carbodiimide-mediated peptide coupling reactions [18,30], although with scarce environmental and economic sustainability [9,10,31]. In fact, DCC and EDC lead to the formation of toxic by-products [17], while uronium derivatives may contain highly harmful hydrazide impurities [19].…”