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Synthetic studies toward aziridinomitosenes and 9-oxo-pyrrolo[1,2-a]indole mitosanes related to the mitomycin and FR heterocycles.

机译：对与丝裂霉素和FR杂环化合物有关的叠氮基丝氨酸和9-氧代-吡咯并[1,2-a]吲哚有丝分裂的合成研究。

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摘要

The aminobenzoquinone mitomycins and the dihydrobenzoxazine FR compounds are potent antitumor antibiotics. Despite structural differences, the compounds are reductively activated to analogous reactive metabolites known as leucoaziridinomitosenes. Leucoaziridinomitosenes contain two electrophilic sites at the C(1) and C(10) positions which are selectively attacked by two guanosines on complementary strands of DNA, thereby resulting in cross-link formation and cell death. Much has been learned about the complex mechanism of action of these compounds, but a better understanding of their mechanisms of action and biological origins is required in order to produce more potent and less cytotoxic synthetic analogs.;The leucoaziridinomitosene derived from the semisynthetic derivative FK317 was targeted for total syntheses. The tetracyclic core of the target was accessed via intramolecular Michael addition of a chiral lithioaziridine into a vinylogous amide. Temporary protection of a stabilizing formyl group, reduction of an enoate, and subsequent transformation of the resulting alcohol provides the free C(10) carbamate. The C(10) carbamate of the intact leucoaziridinomitosene proved to be extremely labile as it was lost under acidic, basic, and neutral conditions which were explored to remove the final aziridine protecting group. Surprisingly, in contrast to the mitomycin leucoaziridinomitosenes, C(10) heterolysis of the FR leucoaziridinomitosenes was more facile than C(1) heterolysis. Nonetheless, a fully functionalized leucoaziridinomitosene derivative of FK317 was obtained.;In order to probe the related biosynthetic pathways of mitomcyin C and FR900482, a mitosane derivative that could be a common precursor of both structural families was targeted for synthesis. Multiple strategies for tetracycle construction focused on addition of a lithioaziridine into an appropriate electrophile. The successful strategy employed a palladium catalyzed coupling of a 3,6-diazabicyclo[3.1.0]hexan-2-one to a functionalized aryl triflate, followed by diastereoselective cyclization to the desired stereoisomer of the tetracycle via carbanion addition into an appended lactam. The top face of the tetracycle is blocked by the large aziridine protecting group, which should facilitate diastereoselective reductive cleavage of a C(9) leaving group from the bottom face of the tetracycle to form the required C(9) stereochemistry. These studies culminated in the successful synthesis of a fully functionalized 9-oxo-pyrrolo[1,2-a]indole mitosane derivative of the mitomycins and FR compounds.
机译：氨基苯醌丝裂霉素和二氢苯并恶嗪FR化合物是有效的抗肿瘤抗生素。尽管结构不同，该化合物仍被还原活化为类似的反应性代谢产物，称为白三氮杂环丁酮。亮丙二氮杂肌酮在C（1）和C（10）位置包含两个亲电位点，它们被DNA互补链上的两个鸟苷选择性攻击，从而导致交联形成和细胞死亡。人们已经对这些化合物的复杂作用机理学到了很多知识，但是为了产生更有效和更少细胞毒性的合成类似物，需要更好地了解它们的作用机理和生物学起源。针对总合成。靶标的四环核心是通过分子内迈克尔将手性硫代氮杂吡啶添加到乙烯基酰胺中而获得的。稳定甲酰基的暂时保护，烯酸酯的还原以及所得醇的后续转化提供了游离的C（10）氨基甲酸酯。事实证明，完整的亮氨二氮杂环丁烯碳烯的C（10）氨基甲酸酯在酸性，碱性和中性条件下会丢失，因此极不稳定，该条件已被研究以去除最终的氮丙啶保护基。出乎意料的是，与丝裂霉素亮氨酸氮芥子丝氨酸丝裂霉素相比，FR亮氨酸氮芥子基亚麻酸丝氨酸的C（10）杂合比C（1）杂溶更容易。尽管如此，仍获得了FK317的功能完全的亮氮丙二烯基亚油基衍生物。为了探查丝裂霉素C和FR900482的相关生物合成途径，将可能是两个结构家族的共同前体的线粒体衍生物作为合成目标。四环构建的多种策略着眼于将硫代氮丙啶添加到适当的亲电子试剂中。成功的策略是将3,6-二氮杂双环[3.1.0]己-2-酮与官能化的三氟甲磺酸芳基酯催化钯偶联，然后通过碳负离子加成至附加的内酰胺中，非对映选择性环化成所需的四环立体异构体。四环的顶面被大的氮丙啶保护基团封闭，这应有助于从四环的底面进行C（9）离开基团的非对映选择性还原裂解，形成所需的C（9）立体化学。这些研究最终成功地合成了丝裂霉素和FR化合物的完全功能化的9-氧代-吡咯并[1,2-a]吲哚米托烷衍生物。

著录项

  • 作者

    Wiedner, Susan D.;

  • 作者单位

    University of Michigan.;

  • 授予单位 University of Michigan.;
  • 学科 Chemistry Organic.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 283 p.
  • 总页数 283
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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