Development of Biocatalysts for Chemodivergent Functionalizations of Heterocycles

杂环化合物化学趋异功能化生物催化剂的开发

基本信息

项目摘要

PROJECT SUMMARY/ABSTRACT Methodological advances that allow for rapid and efficient access to a wide range of functionalized heterocycles are imperative for streamlining drug discovery processes. Given the vast ubiquity of heterocycles in bioactive compounds, the functionalization of existing heterocycles is a common strategy used to tune important pharmacological properties of drugs. Cyclopropanations of heterocycles represent a particularly attractive strategy to achieve synthetic diversification, as the corresponding fused bicyclic frameworks are not only present in bioactive small molecules, but are key chemical synthons en route to more complex scaffolds. The resultant motifs are classified as donor-acceptor cyclopropanes (or push-pull cyclopropanes) and exhibit unique proclivities toward cyclopropane ring opening and subsequent reactivity. Transition metal complexes have been used to access these important synthetic frameworks through metal-carbenoid cyclopropanation reactions, however many of these strategies suffer from low levels of chemo and/or stereoselectivity or depend on a specific class of carbene precursor to achieve high selectivity. Alternatively, enzymes can impart exquisite chemo-, regio-, and stereoselectivities in reactions that are challenging in small molecule catalysis. Directed evolution has provided a powerful platform by which Nature’s enzymes can be repurposed to develop new-to- nature chemical transformations, including engineered P450 enzymes capable of olefin cyclopropanation and C‒H functionalization. The focus of this proposal is to expand the breadth of activity of engineered iron-heme carbenes to include cyclopropanations of heterocycles and to investigate their capacity to elicit cascade reactions on the corresponding cyclopropanes. The specific aims are (1) to evolve hemoprotein variants capable of catalyzing asymmetric cylopropanations of heteroarenes, (2) to expand the scope of this activity to a variety of N-heterocycles, particularly those with no current asymmetric counterpart, and (3) to exploit the hydrogen- bonding network of enzymes to harness the ring-opening reactivity of the corresponding push-pull cyclopropanes. The overall goal is to develop an enzyme-controlled chemodivergent platform for the diversified synthesis of functionalized heterocycles. On a practical level, such a development would represent a powerful tool for medicinal chemists and would provide rapid and efficient access to privileged molecular frameworks in a library fashion. Fundamentally, the proposed research will expand our understanding of enzymatic cascade reactions and explore new catalytic processes that could inspire developments across all pillars of catalysis.
项目总结/文摘

项目成果

期刊论文数量(0)
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Jennifer L. Kennemur其他文献

Asymmetric Ring-Opening Desymmetrization of Substituted Oxetanes
取代氧杂环丁烷的不对称开环去对称化
  • DOI:
  • 发表时间:
    2020
  • 期刊:
  • 影响因子:
    0
  • 作者:
    B. List;Jennifer L. Kennemur
  • 通讯作者:
    Jennifer L. Kennemur
Directed Evolution toward an Iron-Heme Enzyme for Asymmetric C–H Amination
面向不对称 C-H 胺化的铁血红素酶的定向进化
  • DOI:
  • 发表时间:
    2017
  • 期刊:
  • 影响因子:
    0
  • 作者:
    B. List;Jennifer L. Kennemur
  • 通讯作者:
    Jennifer L. Kennemur
Hydrazine-Catalyzed Ring-Closing Carbonyl–Olefin Metathesis for the Synthesis of 2H-Chromenes
肼催化闭环羰基-烯烃复分解反应合成 2H-色烯
  • DOI:
    10.1055/s-0039-1691097
  • 发表时间:
    2019
  • 期刊:
  • 影响因子:
    0
  • 作者:
    B. List;Jennifer L. Kennemur
  • 通讯作者:
    Jennifer L. Kennemur
Organic Photoredox-Catalytic Arene C–H Amination with Primary Amines
伯胺有机光氧化还原催化芳烃 C–H 胺化
  • DOI:
  • 发表时间:
    2018
  • 期刊:
  • 影响因子:
    0
  • 作者:
    B. List;Jennifer L. Kennemur
  • 通讯作者:
    Jennifer L. Kennemur
Tandem Catalytic Dynamic Kinetic Resolutions toward Two-Axis Atropisomers
两轴阻转异构体的串联催化动态动力学分辨率
  • DOI:
  • 发表时间:
    2020
  • 期刊:
  • 影响因子:
    0
  • 作者:
    B. List;Jennifer L. Kennemur
  • 通讯作者:
    Jennifer L. Kennemur

Jennifer L. Kennemur的其他文献

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{{ truncateString('Jennifer L. Kennemur', 18)}}的其他基金

Development of Biocatalysts for Chemodivergent Functionalizations of Heterocycles
杂环化合物化学趋异功能化生物催化剂的开发
  • 批准号:
    10609441
  • 财政年份:
    2022
  • 资助金额:
    $ 6.68万
  • 项目类别:

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