化学
脯氨酸
生产(经济)
食品科学
比例(比率)
生物化学
氨基酸
物理
量子力学
经济
宏观经济学
作者
Kai‐Jiong Xiao,Christopher K. Prier,Anna Fryszkowska,Yangzhong Qin,Alexandra C. Sun,Yingju Xu,Jonathan Vroom,Jeffrey T. Kuethe,Xue Zheng,Yonggang Chen,Lushi Tan,Teng Peng,Erica L. Schwalm,Summer A. Baker Dockrey,Keith Mattern,Mengbin Chen,E. B. Sirota,Mary Stanik,Jack Liang,Gregory A. Cope
标识
DOI:10.1021/acs.oprd.5c00136
摘要
Direct, stereoselective hydroxylation of unactivated C–H bonds has the potential to dramatically streamline organic synthesis, and enzymes are particularly well-suited for facilitating these transformations, enabling clean and efficient processes that are scalable for industrial applications. Here, we report the development of a chemoenzymatic process for producing trans-3-hydroxy-l-proline (1), a key intermediate in synthesizing the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor enlicitide decanoate (MK-0616). This process proceeds by direct biocatalytic aerobic C(sp3)–H hydroxylation of l-proline, mediated by an engineered Fe(II)- and α-ketoglutarate (α-KG)-dependent oxygenase. Through integrated enzyme discovery, protein engineering, and process development, we achieved a robust large-scale biocatalytic oxidation using minimal enzyme loading at high substrate concentrations. In combination with a high-yielding in situ protection and an efficient isolation procedure, this methodology has been used to produce high-purity N-Cbz-trans-3-hydroxy-l-proline 5 at >400 kg scale.
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