Synthesis of Eupalinilide E, a Promoter of Human Hematopoietic Stem and Progenitor Cell Expansion
Synthesis of Eupalinilide E, a Promoter of Human Hematopoietic Stem and Progenitor Cell Expansion
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DOI：
10.1021/jacs.6b03055
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发表时间：
2016-05-11
影响因子：
15
通讯作者：
Siegel, Dionicio
中科院分区：
文献类型：
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作者：
Johnson, Trevor C.;Chin, Matthew R.;Siegel, Dionicio
改善造血干细胞和祖细胞（HSPC）的体外和体内生产有可能解决用于治疗各种血液疾病和病症的这些细胞的供应短缺问题。 Eupalinilide E 促进人类 HSPC 的扩增并抑制随后的分化，从而导致临床有用细胞数量的增加。这种天然产物是发现驱动扩张同时抑制分化的新方法的重要工具。然而，在检查通过新机制发生的这些效应的过程中，天然产物被消耗，这限制了进一步的研究。为了提供更新和改进的 eupalinilide E 获取途径，已开发了一种实验室合成方法并在本文中进行了报道。该合成路线采用在单个容器中以有用规模进行的反应，单批次可达到 >400 mg。实现该方法的关键转化包括非对映选择性硼基烯炔环化和后期双烯丙基C-H氧化，以及适应的Luche还原和铝介导的环氧化反应，以最大限度地提高合成效率。对合成的 eupalinilide E 的重新测试证实了该化合物具有扩增 HSPC 和抑制分化的能力。
Improving the ex vivo and in vivo production of hematopoietic stem and progenitor cells (HSPCs) has the potential to address the short supply of these cells that are used in the treatment of various blood diseases and disorders. Eupalinilide E promotes the expansion of human HSPCs and inhibits subsequent differentiation, leading to increased numbers of clinically useful cells. This natural product represents an important tool to uncover new methods to drive expansion while inhibiting differentiation However, in the process of examining these effects, which occur through a novel mechanism, the natural product was consumed, which limited additional, investigation. To provide renewed and improved access to eupalinilide E, a laboratory synthesis has been developed and is reported herein. The synthetic route access >400 mg in a single batch, employing reactions conducted on useful scales in a single vessel. Key transformations enabling the approach include a diastereoselective borylative enyne cyclization and a late-stage double allylic C-H oxidation as well as adapted Luche reduction and aluminum-mediated epoxidation reactions to maximize the synthetic efficiency. Retesting of the synthetic eupalinilide E confirmed the compound's ability to expand HSPCs and inhibit differentiation.