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: 10376330
• 负责人: OHYUN KWON
• 金额: $ 29.79万
• 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/10376330
• 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; Institutes; Lactams; Maleic Anhydride; Mediating; Methods; Methylation; Modification; Molecular; Natural Products; Operative Surgical Procedures; Organic Synthesis; Oxidation-Reduction; Ozone; Pain; Pathway interactions; Periodicity; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phenols; Physical condensation; Process; Production; Psoriasis; Pulmonary Emphysema; Reaction; Research; Route; Salts; Side; Sleep; Sodium Chloride; Source; Steroids; Synthesis Chemistry; Technology; Terpenes; Therapeutic; Transition Elements; Vision; antimicrobial; base; carbonyl compound; chemical synthesis; controlled release; functional group; halogenation; macromolecule; novel strategies; oxidation; 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.

项目摘要 该项目的首要目标是利用丰富原料材料的未开发反应性， 可再生的天然产物，使有用的合成中间体和后期阶段的生产 生物医学相关分子的功能化。特别是，我们最近制定了新的办法， 对于烯烃的选择性C（sp3）-C（sp2）键官能化，使用O3介导的氧化和 Fe（II）介导的还原性断裂-自由基捕获。最终结果是取代了烯烃 C（sp3）-C（sp2）键与C（sp3）-H、C（sp3）-S、C（sp3）-O、C=O和C（sp3）-C（sp2）键。这种基于氧化还原的 脱烯基自由基化学允许我们使用容易获得的天然产物（例如，萜类化合物） 作为起始材料，以简化生物活性天然产物靶标和活性 药物成分（API）。虽然许多合成方法依赖于C（sp2）-C（sp2）的官能化， 尽管存在双键，但用于官能化烯烃C（sp3）-C（sp2）键的通用方法仍然难以捉摸。我们 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、药物的后期多样化和药物的生产产生广泛的影响。 从丰富的起始原料中制备增值化合物。展望未来，我们建议开发 Fe（II）-或Cu（I）-催化的烯烃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交叉偶联的灵感 策略起源于生物途径的H2 O2分解催化的铜和铁的含 过氧化物酶此外，Cu具有优异的自由基捕获和还原能力， 消除自由基交叉偶联所需的步骤。我们使用这些催化策略， 在萜烯和萜类化合物内构建C（sp3）-N键，提供人工萜类生物碱，以及 为编辑全碳框架提供了新的视角。我们将这个策略扩展到C（sp3）-C键- 与例如Suzuki-Miyaura偶联，Sonogashira反应， 三氟甲基化和氰化。我们将扩大烷基自由基的来源，包括羰基和酚， 两者都可转化为关键的反应中间体α-烷氧基过氧化氢。最后， 利用已确立的对映选择性烯丙基化的能力，我们将寻求建立一种不同的路线 以获得具有手性季中心的多种对映体纯分子。实现这些 拟议的目标将对精细化学品的可持续合成产生重大影响。这些研究还将 为烯烃和其他天然产物的编辑提供了新的视野和策略。虽然我们的计划确实如此 不针对特定的疾病，它可以通过产生有价值的 用于和促进生物医学相关分子的不同修饰的合成中间体。