Chemo-enzymatic Total Syntheses of Jorunnamycin A, Saframycin A, and N-Fmoc Saframycin Y3
Chemo-enzymatic Total Syntheses of Jorunnamycin A, Saframycin A, and N-Fmoc Saframycin Y3
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DOI：
10.1021/jacs.8b07161
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发表时间：
2018-08-29
影响因子：
15
通讯作者：
Oguri, Hiroki
中科院分区：
文献类型：
--
作者：
Tanifuji, Ryo;Koketsu, Kento;Oguri, Hiroki
抗肿瘤四氢异喹啉(THIQ)生物碱共享一个共同的五环支架，该支架由非核糖体多肽合成酶生物合成，涉及独特的酶促Pictet Spengler环化反应。在这里，我们报告了精确的化学合成和体外工程生物合成相结合的简明和发散的化学酶法全合成THIQ生物碱。通过化学合成优化了与SfmC相容的设计底物，使负责生物合成安全霉素A的重组酶SfmC适用于这些天然产物及其衍生物的组装。通过简化SfmC催化的多步酶促转化和中间体的化学操作来安装氨基腈和N-甲基，有效地合成了适当官能化的五环骨架。这种方法允许在一天内从两个简单的合成底物开始快速获得精心设计的五环骨架，而不需要分离中间体。进一步的官能团操作使得可以简单快速地合成柔红霉素A、萨夫拉霉素A和N-FMOC萨夫拉霉素Y3，它们可能是人工生产其他抗肿瘤THIQ生物碱及其变异体的通用前体。
The antitumor tetrahydroisoquinoline (THIQ) alkaloids share a common pentacyclic scaffold that is biosynthesized by nonribosomal peptide synthetases involving unique enzymatic Pictet Spengler cyclizations. Herein we report concise and divergent chemoenzymatic total syntheses of THIQ alkaloids by merging precise chemical synthesis with in vitro engineered biosynthesis. A recombinant enzyme SfmC responsible for the biosynthesis of saframycin A was adapted for the assembly of these natural products and their derivatives, by optimizing designer substrates compatible with SfmC through chemical synthesis. The appropriately functionalized pentacyclic skeleton were efficiently synthesized by streamlining the linkage between SfmC-catalyzed multi-step enzymatic conversions and chemical manipulations of the intermediates to install aminonitrile and N-methyl groups. This approach allowed rapid access to the elaborated pentacyclic skeleton in a single day starting from two simple synthetic substrates without isolation of the intermediates. Further functional group manipulations allowed operationally simple and expeditious syntheses of jorunnamycin A, saframycin A, and N-Fmoc saframycin Y3 that could be versatile and common precursors for the artificial production of other antitumor THIQ alkaloids and their variants.