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: 10464580
• 负责人: Jennifer L. Kennemur
• 金额: $ 6.68万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-10 至 2025-04-09
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10464580
• 关键词: Acetals; Alkenes; Catalysis; Chemicals; Complex; Cytochrome P450; Development; Directed Molecular Evolution; Engineering; Enzymes; Event; Evolution; Exhibits; Goals; Heavy Metals; Heme; Heme Iron; Hemeproteins; Hydrogen Bonding; In Situ; Indoles; Laboratories; Libraries; Metals; Methodology; Methods; Modeling; Molecular; Nature; Outcome; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Process; Production; Property; Proteins; Pyrroles; Reaction; Research; Research Proposals; Role; Route; System; Testing; Therapeutic; Transition Elements; Variant; Walking; Work; carbene; catalyst; chemical reaction; cost; cyclopropane; drug discovery; improved; metal complex; mutant; novel therapeutics; programs; pyridine; research and development; scaffold; small molecule; tool

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.

项目摘要/摘要 方法进步，允许快速高效地访问各种功能化的 杂环化合物对于简化药物发现过程是必不可少的。鉴于杂环化合物无处不在 在生物活性化合物中，现有杂环的官能化是一种常用的调整策略 药物的重要药理作用。杂环的环丙烷化反应代表了一种特殊的 实现合成多样化的有吸引力的战略，因为相应的融合双环框架不是 只存在于生物活性小分子中，但它们是通往更复杂支架的关键化学合成子。 生成的基序被归类为给体-受体环丙烷(或推拉式环丙烷)并展示 独特的环丙烷开环倾向和随后的反应性。过渡金属络合物 已被用于通过金属-卡宾环丙烷化反应获得这些重要的合成骨架 然而，这些策略中的许多策略都存在低水平的化学和/或立体选择性或依赖于 对特定类别的卡宾前体实现高选择性。或者，酶可以赋予精致的 在小分子催化中具有挑战性的反应中的化学、区域和立体选择性。定向 进化已经提供了一个强大的平台，通过这个平台，大自然的酶可以被重新利用来开发新的 天然化学转化，包括能够催化烯烃环丙烷化的工程P450酶和 C-H功能化。这项提议的重点是扩大工程铁血红素的活性范围。 卡宾包括杂环的环丙烷化反应并考察其引发级联反应的能力 在相应的环丙烷上。具体的目标是(1)进化出能够 催化杂芳烃的不对称环丙烷，(2)将该活性的范围扩大到各种 N-杂环，特别是那些目前没有不对称对映体的杂环，以及(3)开发氢- 结合酶网络以利用相应推拉的开环反应性 环丙烷。总体目标是开发一种酶控制的化学发散平台，用于多样化的 官能化杂环的合成。在实践层面上，这样的发展将代表着一种强大的 药物化学家的工具，并将提供快速和有效的访问特权分子框架在 图书馆时尚。从根本上说，拟议的研究将扩大我们对酶级联反应的理解 并探索新的催化工艺，以促进所有催化领域的发展。