Deconstructive Molecular Editing Technology Involving C-C Bond Scission

项目总结 该项目的总体目标是利用丰富的原料的未开发反应性和 可再生天然产品，能够生产有用的合成中间体和后期产品 生物医学相关分子的功能化。特别是，我们最近制定了新的方法 对于烯烃的选择性C(Sp3)-C(Sp2)键官能化，使用臭氧介导的氧化和 Fe(II)介导的还原碎裂-自由基捕获。最终的结果是取代了烯烃。 C(Sp3)-C(Sp2)键与C(Sp3)-H、C(Sp3)-S、C(Sp3)-O、C=O和C(Sp3)-C(Sp2)键相连。这种基于氧化还原的 脱烯基基化学使我们能够利用容易获得的天然产物(例如，萜类化合物) 作为起始原料简化生物活性天然产物的化学合成靶标和活性 药物成分(原料药)。而许多合成方法依赖于C(Sp2)-C(Sp2)的官能化。 双键，烯烃C(Sp3)-C(Sp2)键官能化的一般方法仍然难以捉摸。我们的 反应是C(Sp3)-C(Sp2)单键的第一个广义官能化；因此，我们设想 它将对全合成、药物后期多样化以及 利用丰富的原料制备高附加值化合物。展望未来，我们建议开发 Fe(II)或Cu(I)催化的烯烃C(Sp3)-C(Sp2)键的官能化反应 C(SP3)-杂原子键。过渡金属催化脱烯基交叉偶联反应的启示 含铜、铁催化分解过氧化氢的生物途径策略 过氧酶。此外，铜具有优异的自由基捕获和还原能力 消除根部交叉联结所需的步骤。我们已经将这些催化策略用于模块化 在萜类和萜类化合物中构建C(SP3)-N键，提供人工萜类生物碱，并 为编辑全碳框架提供新的愿景。我们将把这一策略扩展到C(SP3)-C债券- 例如，与铃木-宫浦偶联、索诺加希拉反应、 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， 这两者都可以转化为关键的反应中间体α-烷氧基过氧化氢。最后， 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。 以获得具有手性四元中心的各种对映体分子。实现这些目标 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新的视野和策略。而我们的节目则是 不针对特定的疾病，总体上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发散修饰的合成中间体。

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.