Deconstructive Molecular Editing Technology Involving C-C Bond Scission

涉及 C-C 键断裂的解构性分子编辑技术

• 批准号: 10600382
• 负责人: OHYUN KWON
• 金额: $ 4万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10600382
• 关键词: Alkaloids; Alkenes; Alzheimer' s Disease; Antifungal Agents; Area; Asthma; Breathing; Carbon; Chemicals; Chemistry; Chronic Bronchitis; Coupling; Disease; Funding; Goals; Grant; Hydrogen Peroxide; Hypersensitivity; Mediating; Methods; Modification; Molecular; Natural Products; Oxidation-Reduction; Ozone; Pain; Pathway interactions; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phenols; Process; Production; Psoriasis; Pulmonary Emphysema; Reaction; Route; Sleep; Source; Technology; Terpenes; Therapeutic; Transition Elements; Vision; antimicrobial; base; carbonyl compound; chemical synthesis; novel strategies; oxidation; pi bond; programs; single bond; stem

Supplement for Dehnert, Brady – Project Summary Description of Funded Grant (Project Summary for R01 GM141327) The overarching goal of this project is to harness the untapped reactivity of abundant feedstock materials and renewable natural products to enable the production of useful synthetic intermediates and the late-stage functionalization of biomedically relevant molecules. In particular, we have recently formulated new approaches for selective C(sp3)–C(sp2) bond functionalization of alkenes, using a combination of O3-mediated oxidation and Fe(II)-mediated reductive fragmentation–radical capture. The net result has been replacement of the alkene C(sp3)–C(sp2) bond with C(sp3)–H, C(sp3)–S, C(sp3)–O, C=O, and C(sp3)–C(sp2) bonds. This redox-based dealkenylative radical chemistry has allowed us to employ readily available natural products (e.g., terpenoids) as starting materials to streamline the chemical synthesis of biologically active natural product targets and active pharmaceutical ingredients (APIs). While many synthetic methods rely on the functionalization of C(sp2)–C(sp2) double bonds, generalized methods for functionalizing alkene C(sp3)–C(sp2) linkages remain elusive. Our reaction is the first generalized functionalization of the C(sp3)–C(sp2) single bond; therefore, we envisioned that it would have broad impact on total synthesis, the late-stage diversification of pharmaceuticals, and the preparation of value-added compounds from abundant starting materials. Going forward, we propose to develop Fe(II)- or Cu(I)-catalyzed functionalization of alkene C(sp3)–C(sp2) bonds for the construction of C(sp3)–C and C(sp3)–heteroatom bonds. Our inspiration for these transition metal–catalyzed dealkenylative cross-coupling strategies originated from the bio-pathway for H2O2 decomposition catalyzed by Cu- and Fe-containing peroxygenases. Furthermore, Cu possesses exceptional capacity for both the radical capture and reductive elimination steps necessary for radical cross-couplings. We have used these catalytic strategies for modular construction of C(sp3)–N bonds within terpenes and terpenoids, affording artificial terpenoid alkaloids, and to provide a new vision for the editing of all-carbon frameworks. We will expand this strategy to C(sp3)–C bond- forming processes related to, for example, Suzuki–Miyaura coupling, the Sonogashira reaction, trifluoromethylation, and cyanation. We will expand the source of alkyl radicals to include carbonyls and phenols, both of which can be converted into α-alkoxy hydroperoxides—the pivotal reaction intermediates. Finally, leveraging the power of well-established enantioselective allylation, we will seek to establish a divergent route to access a wide variety of enantiopure molecules featuring chiral quaternary centers. Realization of these proposed aims would substantially impact the sustainable synthesis of fine chemicals. These studies will also provide new visions and strategies for the editing of alkenes and other natural products. While our program does not target a specific disease, collectively it could impact a variety of therapeutic areas by producing valuable synthetic intermediates for and facilitating divergent modification of biomedically relevant molecules.

Dehnert的补充，布雷迪 - 项目摘要 资金赠款的描述（R01 GM141327的项目摘要） 该项目的总体目标是利用丰富的原料材料的未开发反应性和 可再生天然产品可以生产有用的合成中间体和晚期 生物医学相关分子的功能化。特别是，我们最近制定了新方法 对于选择性C（SP3）–C（SP2）烷烃的键功能化，使用O3介导的氧化和 Fe（II）介导的减少片段化 - 激进捕获。最终结果是替代烯烃 C（sp3）–c（sp2）与C（sp3）–h，c（sp3）–s，c（sp3）–o，c = o和c（sp3）–c（sp2）键。这个基于氧化还原的 DealKenylative自由基化学使我们能够采用随时可用的天然产品（例如，萜类化合物） 作为简化生物活性天然产物目标化学合成和活性的化学合成的起始材料 药物成分（API）。虽然许多合成方法依赖于C（SP2）–C（SP2）的功能化 双键，用于算术烯烃C（SP3）–C（SP2）链接的广义方法仍然难以捉摸。我们的 反应是C（SP3）–C（SP2）单键的第一个广义功能化；因此，我们设想 它将对总合成，药物的晚期多样化以及 从丰富的起始材料中制备增值化合物。展望未来，我们建议开发 Fe（II） - 或Cu（i） - 烯烃C（SP3）–C（SP2）键的催化功能化，用于构建C（SP3）–C和 C（SP3） - 近光键。我们对这些过渡金属与催化的DealKenylative交叉耦合的灵感 策略起源于H2O2分解的生物体育道，由Cu-和Fe催化 过氧酶。此外，CU具有从根治性捕获和减少的能力 自由基跨耦合所需的消除步骤。我们已经将这些催化策略用于模块化 C（SP3） - 萜烯和萜类化合物内的N键，可提供人工萜类生物碱，以及 为全碳框架编辑提供新的愿景。我们将将此策略扩展到C（SP3）–C键 - 形成与铃木– Miyaura耦合相关的过程，Sonogashira反应， 三氟甲基化和氰化。我们将扩大烷基自由基的来源，包括羰基和苯酚， 两者都可以转化为α-烷氧基氢过氧化物 - 关键反应中间体。最后， 利用良好的对映选择性盟友的力量，我们将寻求建立一条不同的途径 访问具有手性Quaternary中心的各种映射分子。实现这些 拟议的目标将大大影响精细化学物质的可持续合成。这些研究也将 为烯烃和其他天然产品的编辑提供新的愿景和策略。虽然我们的计划确实 不针对特定疾病，总体可以通过产生价值影响各种治疗领域 合成中间体，用于生物医学相关分子的不同变化。