Total Synthesis of Cyclic Lipodepsipeptide Ophiotine
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TOTAL SYNTHESIS OF CYCLIC LIPODEPSIPEPTIDE OPHIOTINE
Jing Wang,1,2 Chao Liu,3 Hong-Gang Hu,3 Yan Zou,3 Qin-Jie Zhao,3 and Guang-Ming Ye1,2*
The first total synthesis of the natural nematicidal cyclic lipodepsipeptide ophiotine via a convergent strategy that involved both solid-phase peptide synthesis and liquid phase chemistry is reported. The pre-made dipeptide building block was synthesized in the liquid phase, which was then assembled into the peptide backbone through standard Fmoc chemistry on solid support. After cleavage from the resin, the linear peptide was cyclized by the liquid phase macrocyclization and the side chain deprotection successively, which led to the crude ophiotine. Finally, the crude product was purified by preparative reverse-phase highperformance liquid chromatography, and its structure was confirmed by NMR and HR-ESI-MS. Keywords: ophiotine, cyclic lipodepsipeptide, solid-phase peptide synthesis. Cyclic peptides have attracted a great deal of attention during recent years because of their intriguing chemical structures and potent biological activities. Owing to their better structural stability in vivo compared with their linear counterparts, they are considered as promising drug candidates [1]. Among normal cyclic peptides, natural cyclic lipopeptides, which are found in natural organisms such as fungus bacteria, marine organisms containing ester bonds are regarded as potential leading compounds for novel antimicrobial agents [2–5]. It was reported that many cyclic lipopeptides such as polymyxin [6], daptomycin [7], paenibacterin [8], pseudofactin [9], surfactin [10], iturin [11], and fengycin [12] showed great antimicrobial activity. Ophiotine is a newly discovered natural nematicidal cyclic lipodepsipeptide isolated from Phaeosphariaceous fungus that parasitize eggs of the plant parasitic cyst nematode Heterodera filipjevi. Ophiotine displays obvious nematicidal activity at 100 μg/mL [13], which makes it a leading compound for novel nematicidal therapy. However, the content of ophiotine in Phaeosphariaceous fungus was quite small; only 20.9 mg ophiotine can be obtained from 1 L of the seed culture by biological extraction [13]. This extremely low extraction yield and time-consuming procedure can hardly meet the requirements of further biological activity and structure–activity relationship studies. Therefore, the chemical total synthesis of ophiotine is urgently needed. In previous studies, the total synthesis of lipopeptide was achieved through total liquid phase chemistry [14, 15]; however, the synthetic procedures were complicated and time-consuming due to the repeated and tedious purification process, which led to unsatisfactory chemical yields. Herein we planned to obtain the cyclic lipodepsipeptide via a more efficient solid-phase synthesis/liquid-phase macrocyclization strategy. Our work began with the retrosynthetic analysis. The macrocyclization point was identified between the non-chiral β-Ala and Thr residue according to the reported article [16]. Considering the racemizat
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