Insertion Into Unactivated/Deactivated C(sp3)-H Bonds Enabled by Oxidatively Generated, Highly Reactive a-Oxo Gold Carbenes: A Safe Non-Diazo yet More Potent Approach

通过氧化生成的高反应性 a-Oxo 金卡宾插入未活化/失活的 C(sp3)-H 键：一种安全的非重氮且更有效的方法

• 批准号: 9751339
• 负责人: Liming Zhang
• 金额: $ 28.04万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA BARBARA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9751339
• 关键词: Address; Alkynes; Biological; Catalysis; Chemistry; Complex; Coupled; Cyclohexanones; Disease Management; Electrons; Generations; Goals; Gold; Hydrogen Bonding; In Situ; Ligands; Mainstreaming; Medical; Metals; Methods; Molecular Probes; Nature; Pathway interactions; Pharmaceutical Chemistry; Pharmaceutical Preparations; Preparation; Reaction; Research; Research Personnel; Route; Safety; Scheme; Structure; Synthesis Chemistry; Time; Transition Elements; base; carbene; carbonyl compound; catalyst; cyclic ketone; cyclopentanone; design; diazo compound; drug candidate; functional group; improved; novel; oxidation; programs; stereochemistry; success

Abstract Our group previously developed a facile access to versatile α-oxo gold carbenes via gold-catalyzed intermolecular oxidation of readily available alkynes. Two salient features of this strategy are a) the avoidance of hazardous and potentially explosive α-diazo carbonyl compounds and b) the exceptionally electrophilic nature of the carbene center. Despite various synthetic methods developed by us and other researchers based on this approach, the arguably most valuable transformation of metal carbenes, i.e., concerted insertion into unactivated C(sp3)-H bonds and their enantioselective versions, have not been realized by our oxidative gold catalysis until a recent preliminary study by us. Moreover, deactivated C(sp3)-H bonds have mostly not been succumbed to carbene insertions. In this proposal, we aim to address these critical shortcomings and demonstrate that the advantages of this approach over the mainstream Rh-diazo chemistry are much beyond the improvement of safety. Electron-withdrawing group-substituted α-oxo gold carbenes will be generated via gold-catalyzed intermolecular oxidation of electron-deficient alkynes. These acceptor/acceptor-type carbenes are of exceptional electrophilicity and, coupled with sufficient steric shielding, are capable of intramolecular insertions into C(sp3)-H bonds, thereby affording highly efficient and streamlining access to a large array of these cyclic ketones including various bicyclic and polycyclic ones. By adjusting the EWG, the gold catalyst, and the reaction conditions, the reactivities of the gold carbene moiety can be substantially tuned to accommodate not only unactivated C-H bonds but also deactivated ones. In contrast, the mainstream Rh-diazo approach is mostly incapable of insertion into deactivated C-H bonds due to the generally lesser reactivity of the Rh carbene counterparts. By the use of newly designed chiral NHC ligands, enantioselective C-H insertions by these highly reactive gold carbenes would enable the synthesis of chiral cyclopentanones with high e.e., in contrast to the moderate e.e. (≤80%) in the Rh-diazo approach, and asymmetric functionalization of deactivated C-H bonds. This strategy would also offer significant benefit in synthetic planning, as it enables a completely novel entry into C-H insertion and presents unique solutions in terms of functional group compatibility and protecting group strategies, as C-C triple bonds are distinctively different from carbonyl in tolerance of various reaction conditions. Moreover, the rich chemistry of alkyne synthesis enables ready access to alkyne substrates with well-controlled stereochemistries, the diazo carbonyl counterparts of which may require extraordinary efforts. As such, our approach would open uncharted yet efficient access to valuable functional products, which would otherwise be practically inaccessible or synthetically prohibitively inefficient via the diazo chemistry. The synthetic utility of this oxidative C-H insertion will be demonstrated in a succinct total synthesis of picrotoxinin, where insertion into a deactivated C-H bond would serve as a streamlining step.

抽象的 我们的团队之前开发了一种通过金催化轻松获得多功能 α-氧代金卡宾的方法 该策略的两个显着特征是 a) 避免了容易获得的炔烃的分子间氧化。 危险且具有潜在爆炸性的 α-重氮羰基化合物和 b) 卡宾的异常亲电性质 尽管我们和其他研究人员基于这种方法开发了各种合成方法，但 可以说是金属卡宾最有价值的转化，即协同插入未活化的 C(sp3)-H 键及其对映选择性版本，直到最近我们的氧化金催化才得以实现 此外，我们的初步研究表明，失活的C(sp3)-H键大多不会屈服于卡宾。 在本提案中，我们旨在解决这些关键缺点并证明其优点。 这种方法相对于主流的Rh-重氮化学来说远远超出了安全性的提高。 金催化生成吸电子基团取代的α-氧代金卡宾 这些受体/受体型卡宾具有特殊的缺电子炔烃的分子间氧化作用。 亲电性，加上足够的空间屏蔽，能够进行分子内插入 C(sp3)-H 键，从而提供对大量这些循环的高效且简化的访问 通过调整 EWG、金催化剂和 酮，包括各种双环和多环酮。 反应条件下，金卡宾部分的反应性可以进行大幅调整以适应不 不仅有未活化的C-H键，还有失活的C-H键，相比之下，主流的Rh-重氮方法大多是。 由于Rh卡宾的反应性通常较低，无法插入失活的C-H键 通过使用新设计的手性 NHC 配体，这些高度对映选择性的 C-H 插入 与活性金卡宾相比，活性金卡宾能够合成具有高 e.e. 的手性环戊酮 Rh-重氮方法中的中等 e.e. (≤80%)，以及失活 C-H 键的不对称功能化。 该策略还将在综合规划中提供显着的好处，因为它能够实现一种全新的 进入C-H插入领域，并在官能团兼容性和 保护基策略，因为 C-C 三键与羰基在耐受各种 此外，炔合成的丰富化学性质使得能够容易地获得炔底物。 具有良好控制的立体化学，其重氮羰基单元可能需要非凡的 因此，我们的方法努力将为有价值的功能产品开辟未知但有效的途径，这 否则，通过重氮化学实际上无法获得或合成效率低得令人望而却步。 这种氧化性 C-H 插入的合成效用将在以下物质的简洁全合成中得到证明： 印防己毒素，其中插入失活的 C-H 键将作为简化步骤。