19 環状ヘミアミナール構造を有する大環状デプシペプチドの合成研究 : 海洋藍藻由来のソママイドAの全合成(口頭発表の部)

抄録

Somamide A (1) is a unique cyclic depsipeptide having the 3-amino-6-hydroxy-2-piperidone (Ahp) unit, 2-amino-2-butenoic acid (Abu), and sulfoxide. It was isolated from assemblages of the marine cyanobacteria Lyngbya majuscula and Schizothrix sp. in Fijian Islands by Gerwick and coworkers. As an extension of our interests on the synthesis of biologically and structurally intriguing aquatic natural products, we succeeded in the total synthesis of somamide A (1). For the synthesis of the Abu-containing depsipeptide fragment of somamide A, we chose the stereospecific dehydrative elimination of the corresponding N-acyl thereonine ester. After several trials utilizing thionyl chloride, Burgess reagent, and DAST, we finally found out that Martin's sulfurane (dephenyl bis(1,1,1,3,3,3-hexafluoro-2-phenyl-2-propyl)sulfurane) was quite effective for the stereospecific dehydration to give the Abu residue. The synthesis of the building blocks, the depsipeptide 4, dipeptide 5, and 5-hydroxynorvaline derivative 6 was efficiently accomplished. After assembling these three fragments, the linear precursor 22 was simultaneously deprotected at the C- and N-terminals and subjected to macrolactamization using pentafluorophenyl diphenylphosphinate (FDPP, Ph_2P(O)OC_6F_5) to give the macrocyclic depsipeptide 23 in 64% yield. Removal of the TBS group from 23 followed by treatment with 1-hydroxy-1,2-benziodoxol-3(1H)-one 1-oxide (IBX) then TBAF afforded somamide A (1) as the major product (50%) together with the minor product 24 (39%). The latter was slowly and spontaneously transformed to 1 in air at room temperature. Oxidation of 24 with aqueous hydrogen peroxide also afforded 1 in 57% yield. Thus we could complete the total synthesis of somamide A (1) and indicate that 24 will be a true natural product whereas 1 will be an artifact. Our strategy for the construction of the Ahp moiety will be useful for the synthesis of the Ahp-containing natural products. Furthermore, we have found that martin's sulfurane is a powerful reagent for the dehydrative elimination of the N-acyl-β-hydroxy-α-amino acid esters to the α,β-dehydroamino esters.