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: 10727693
• 负责人: OHYUN KWON
• 金额: $ 7.99万
• 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/10727693
• 关键词: Air; Alcohols; Alkaloids; Alkenes; Alkylation; Alzheimer' s Disease; Amination; Antifungal Agents; Area; Ascorbic Acid; Asthma; Breathing; Carbon; Chemicals; Chemistry; Chronic Bronchitis; Complex; Coupling; Disease; Goals; Hydrogen; Hydrogen Bonding; Hydrogen Peroxide; Hydroxylation; Hypersensitivity; Imines; Lactams; Maleic Anhydride; Mediating; Methods; Methylation; Modification; Molecular; Natural Products; Operative Surgical Procedures; Organic Synthesis; Oxidation-Reduction; Ozone; Pain; Pathway interactions; Periodicity; Pharmacologic Substance; Phenols; Physical condensation; Preparation; Process; Production; Psoriasis; Pulmonary Emphysema; Reaction; Research; Route; Salts; Side; Sleep; Sodium Chloride; Source; Steroids; Synthesis Chemistry; Technology; Terpenes; Therapeutic; Transition Elements; Vision; antimicrobial; carbonyl compound; chemical synthesis; controlled release; functional group; halogenation; macromolecule; novel strategies; oxidation; pharmacologic; pi bond; programs; single bond; small molecule; stem; tertiary amine

PROJECT SUMMARY 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.

项目概要 该项目的总体目标是利用丰富的原料和未开发的反应性 可再生天然产物，能够生产有用的合成中间体和后期 特别是，我们最近制定了新的方法。 用于烯烃的选择性 C(sp3)–C(sp2) 键功能化，结合使用 O3 介导的氧化和 Fe(II) 介导的还原断裂-自由基捕获最终结果是烯烃的取代。 C(sp3)–C(sp2) 键与 C(sp3)–H、C(sp3)–S、C(sp3)–O、C=O 和 C(sp3)–C(sp2) 键。 -基于 脱烯基自由基化学使我们能够使用现成的天然产物（例如萜类化合物） 作为起始材料来简化生物活性天然产物靶标和活性物质的化学合成 虽然许多合成方法依赖于 C(sp2)–C(sp2) 的功能化。 双键，功能化烯烃 C(sp3)–C(sp2) 连接的通用方法仍然难以捉摸。 反应是 C(sp3)–C(sp2) 单键的第一个广义官能化；因此，我们设想 它将对全合成、药物后期多样化以及 展望未来，我们建议开发从丰富的起始原料制备增值化合物。 Fe(II)-或 Cu(I)-催化烯烃 C(sp3)–C(sp2) 键的官能化，用于构建 C(sp3)–C 和 C(sp3)–杂原子键。我们对这些过渡金属催化的脱烯基交叉偶联的灵感。 策略起源于含铜和铁催化的 H2O2 分解生物途径 此外，Cu 还具有出色的自由基捕获和还原能力。 我们已将这些催化策略用于模块化。 在萜烯和萜类化合物中构建 C(sp3)–N 键，提供人工萜类生物碱，并 为全碳框架的编辑提供了新的愿景，我们将把这一策略扩展到C(sp3)–C键-。 与铃木-宫浦耦合、Sonogashira 反应等相关的形成过程， 我们将扩大烷基的来源以包括羰基和酚类， 两者都可以转化为关键的反应中间体α-烷氧基氢过氧化物。 利用成熟的对映选择性烯丙基化的力量，我们将寻求建立一条不同的路线 获得各种具有手性四元中心的对映体纯分子。 拟议的目标将对精细化学品的可持续合成产生重大影响。 我们的项目为烯烃和其他天然产物的编辑提供了新的愿景和策略。 不针对特定疾病，但它可以通过产生有价值的成果来影响各种治疗领域 用于并促进生物医学相关分子的不同修饰的合成中间体。