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
• 负责人: Jennifer L. Kennemur
• 金额: $ 6.91万
• 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/10609441
• 关键词: Acetals; Alkenes; Catalysis; Chemicals; Classification; 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; Medicine; Metals; Methodology; Methods; Modeling; Molecular; Nature; Outcome; Periodicity; Pharmaceutical Preparations; Pharmacologic Substance; 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; drug-like compound; improved; metal complex; mutant; novel therapeutics; pharmacologic; 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.

项目总结/摘要 方法上的进步，使人们能够迅速有效地获得各种功能化的 杂环对于简化药物发现过程是必要的。鉴于杂环化合物的广泛存在 在生物活性化合物中，现有杂环的功能化是用于调节 药物的重要药理学性质。杂环的环丙烷化代表了一种特别的 有吸引力的策略，以实现合成多样化，因为相应的稠合双环框架不是 仅存在于生物活性小分子中，但却是形成更复杂支架的关键化学物质。 所得基序被分类为供体-受体环丙烷（或推拉环丙烷），并表现出 环丙烷开环和随后的反应性的独特倾向。过渡金属配合物 已经被用于通过金属-类卡宾环丙烷化来获得这些重要的合成框架 然而，这些策略中的许多策略具有低水平的化学和/或立体选择性或依赖于 对特定种类的卡宾前体进行反应以实现高选择性。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选择性、区域选择性和立体选择性。引导 进化提供了一个强大的平台，通过这个平台，自然界的酶可以被重新利用，以开发新的 天然化学转化，包括能够烯烃环丙烷化的工程化P450酶， C-3 H官能化。该提案的重点是扩大工程铁血红素的活性广度 卡宾，包括杂环的环丙烷化，并研究其引发级联反应的能力 在相应的环丙烷上。具体目标是（1）进化出能够 催化杂芳烃的不对称环丙烷化，（2）将该活性的范围扩展到各种 N-杂环，特别是那些目前没有不对称对应物的杂环，以及（3）开发氢- 酶的键合网络，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化学趋化剂平台， 官能化杂环的合成。在实际层面上，这种发展将代表一种强大的 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， 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 反应和探索新的催化过程，可以激发所有催化支柱的发展。