A Versatile Boc Solid Phase Synthesis of Daptomycin and Analogues Using Site Specific, On-Resin Ozonolysis to Install the Kynurenine Residue
A Versatile Boc Solid Phase Synthesis of Daptomycin and Analogues Using Site Specific, On-Resin Ozonolysis to Install the Kynurenine Residue
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DOI：
10.1002/chem.201903725
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发表时间：
2019-09-30
影响因子：
4.3
通讯作者：
Brimble, Margaret A.
中科院分区：
文献类型：
--
作者：
Xu, Buzhe;Hermant, Yann;Brimble, Margaret A.
采用Boc化学方法，重新固相合成了环脂沉积肽达托霉素。非蛋白质原性氨基酸犬尿氨酸之间具有挑战性的酯键形成是通过苏氨酸残基与受保护的色氨酸的酯化实现的。随后的后期树脂上臭氧分解，受到仿生途径的启发，直接提供犬尿氨酸残基。合成的达托霉素对金黄色葡萄球菌具有较强的抑菌活性（MIC100=1.0 μ g mL(-1)），而采用新方法制备的含有(2R,3R)-3-甲基谷氨酸、(2S,4S)-4-甲基谷氨酸或12位典型谷氨酸的5个达托霉素类似物均无活性，表明(2S,3R)-3-甲基谷氨酸在达托霉素的抑菌活性中起关键作用。
A de novo solid-phase synthesis of the cyclic lipodepsipeptide daptomycin via Boc chemistry was achieved. The challenging ester bond formation between the nonproteinogenic amino acid kynurenine was achieved by esterification of a threonine residue with a protected tryptophan. Subsequent late-stage on-resin ozonolysis, inspired by the biomimetic pathway, afforded the kynurenine residue directly. Synthetic daptomycin possessed potent antimicrobial activity (MIC100=1.0 mu g mL(-1)) against S. aureus, while five other daptomycin analogues containing (2R,3R)-3-methylglutamic acid, (2S,4S)-4-methylglutamic acid or canonical glutamic acid at position twelve prepared using this new methodology were all inactive, clearly establishing that the (2S,3R)-3-methylglutamic acid plays a key role in the antimicrobial activity of daptomycin.