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: 10001071
• 负责人: Liming Zhang
• 金额: $ 27.97万
• 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 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10001071
• 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.

摘要 我们的小组以前开发了一种通过金催化的多功能α-氧代金卡宾的简便方法。 容易获得的炔的分子间氧化。这一战略的两个突出特点是：a）避免 危险和潜在爆炸性的α-重氮羰基化合物和B）卡宾的异常亲电性质 中心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， 可以说是金属卡宾的最有价值的转化，即，协同插入未活化的C（sp3）-H 键和它们的对映选择性版本，还没有实现我们的氧化金催化，直到最近的 我们进行了初步研究。此外，失活的C（sp3）-H键大多未屈服于卡宾 插入。在本提案中，我们旨在解决这些关键缺点，并证明 这种方法相对于主流Rh-重氮化学的改进远远超出了安全性的提高。 在金催化下， 缺电子炔的分子间氧化。这些受体/受体型卡宾是例外的 亲电性，加上足够的空间屏蔽，能够分子内插入到 C（sp3）-H键，从而提供了高效和流线型的获得大量的这些环状化合物的途径。 酮，包括各种双环和多环酮。通过调节EWG、金催化剂和催化剂的浓度， 在反应条件下，金卡宾部分的反应性可以基本上被调节以适应不 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，不能插入失活的C-H键 同行通过使用新设计的手性NHC配体，这些高度手性的C-H插入可用于制备手性化合物。 反应性金卡宾将能够合成具有高e.e.的手性环戊酮，相对于 中度e.e.（≤80%），以及失活C-H键的不对称官能化。 该策略还将在综合规划中提供显著的益处，因为它能够实现一种全新的 进入C-H插入，并在官能团相容性方面提出了独特的解决方案， 保护基团策略，因为C-C三键在各种耐受性方面与羰基明显不同。 反应条件此外，炔合成的丰富化学性质使人们能够随时获得炔底物 具有良好控制的立体化学，其重氮羰基对应物可能需要特别的 努力因此，我们的方法将打开未知的，但有效地获得有价值的功能性产品， 否则通过重氮化学实际上是难以获得的或合成效率极低。 这种氧化C-H插入的合成效用将在以下的简洁的全合成中证明： 苦毒素，其中插入失活的C-H键将作为流线化步骤。

项目成果

Reactivities of α-Oxo BMIDA Gold Carbenes Generated by Gold-Catalyzed Oxidation of BMIDA-Terminated Alkynes.

金催化氧化 BMIDA 封端的炔烃生成的 α-Oxo BMIDA 金卡宾的反应性。

• DOI: 10.1002/anie.202218175
• 发表时间: 2023
• 期刊: Angewandte Chemie (International ed. in English)
• 作者: Zheng,Yang;Jiang,Jingxing;Li,Yue;Wei,Yongliang;Zhang,Junqi;Hu,Jundie;Ke,Zhuofeng;Xu,Xinfang;Zhang,Liming
• 通讯作者: Zhang,Liming