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摘要 : 以抗生素万古霉素为代表的非核糖体肽属于非核糖体肽合成酶(NRPSs)合成的一大类次级天然产物。

 以抗生素万古霉素为代表的非核糖体肽属于非核糖体肽合成酶(NRPSs)合成的一大类次级天然产物。Christina White及同事报告了一种受NRPS启发的合成策略:使用两种小分子铁催化剂促进对氨基酸和肽的靶向C-H氧化修饰,同时保留α中心手性 —— 这种合成的难度众所周知 ——以生成多种多样的氨基酸和肽。


Oxidative diversification of amino acids and peptides by small-molecule iron catalysis


Secondary metabolites synthesized by non-ribosomal peptide synthetases display diverse and complex topologies and possess a range of biological activities1, 2. Much of this diversity derives from a synthetic strategy that entails pre-3 and post-assembly2 oxidation of both the chiral amino acid building blocks and the assembled peptide scaffolds. The vancomycin biosynthetic pathway is an excellent example of the range of oxidative transformations that can be performed by the iron-containing enzymes involved in its biosynthesis4. However, because of the challenges associated with using such oxidative enzymes to carry out chemical transformations in vitro, chemical syntheses guided by these principles have not been fully realized in the laboratory5. Here we report that two small-molecule iron catalysts are capable of facilitating the targeted C–H oxidative modification of amino acids and peptides with preservation of α-centre chirality. Oxidation of proline to 5-hydroxyproline furnishes a versatile intermediate that can be transformed to rigid arylated derivatives or flexible linear carboxylic acids, alcohols, olefins and amines in both monomer and peptide settings. The value of this C–H oxidation strategy is demonstrated in its capacity for generating diversity: four ‘chiral pool’ amino acids are transformed to twenty-one chiral unnatural amino acids representing seven distinct functional group arrays; late-stage C–H functionalizations of a single proline-containing tripeptide furnish eight tripeptides, each having different unnatural amino acids. Additionally, a macrocyclic peptide containing a proline turn element is transformed via late-stage C–H oxidation to one containing a linear unnatural amino acid.

来源: Nature 浏览次数:1


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