Development of a Convergent Enantioselective Synthetic Route to (-)-Myrocin G.,The Journal of Organic Chemistry

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Development of a Convergent Enantioselective Synthetic Route to (-)-Myrocin G.
The Journal of Organic Chemistry ( IF 3.3 ) Pub Date : 2020-07-02 , DOI: 10.1021/acs.joc.0c00891
Martin Tomanik ₁ , Christos Economou ₁ , Madeline C Frischling ₁ , Mengzhao Xue ₁ , Victoria A Marks ₁ , Brandon Q Mercado ₁ , Seth B Herzon _{1,

2}

Affiliation

Myrocins are a family of antiproliferative antibiotic fungal metabolites possessing a masked electrophilic cyclopropane. Preliminary chemical reactivity studies imputed the bioactivity of these natural products to a DNA cross-linking mechanism, but this hypothesis was not confirmed by studies with native DNA. We recently reported a total synthesis of (−)-myrocin G (4), the putative active form of the metabolite myrocin C (1), that featured a carefully orchestrated tandem fragment coupling–annulation cascade. Herein, we describe the evolution of our synthetic strategy toward 4 and report the series of discoveries that prompted the design of this cascade coupling. Efforts to convert the diosphenol (−)-myrocin G (4) to the corresponding 5-hydroxy-γ-lactone isomer myrocin C (1) are also detailed. We present a preliminary evaluation of the antiproliferative activities of (−)-myrocin G (4) and related structures, as well as DNA cross-linking studies. These studies indicate that myrocins do not cross-link DNA, suggesting an alternative mode of action potentially involving a protein target.

中文翻译：

（-）-Myrocin G的收敛对映选择性合成路线的发展。

Myrocins是具有掩蔽的亲电环丙烷的抗增殖抗生素真菌代谢产物家族。初步的化学反应性研究将这些天然产物的生物活性归因于DNA交联机制，但对天然DNA的研究并未证实这一假设。我们最近报道了代谢产物myrocin C（1）的推定活性形式（-）-myrocin G（4）的总合成，其特征是精心设计的串联片段偶联-环流级联反应。在此，我们描述了合成策略向4的演变，并报告了促使该级联耦合设计的一系列发现。努力转化二酚（-）-myrocin G（4）到相应的5-羟基-γ-内酯异构体myrocin C（1）也有详述。我们目前对（-）-myrocin G（4）和相关结构的抗增殖活性进行初步评估，以及DNA交联研究。这些研究表明，myrocins不会使DNA交联，表明可能涉及蛋白质靶标的另一种作用方式。

更新日期：2020-07-17

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