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

摘要 我们的团队之前开发了一种通过金催化的方法来方便地获得多功能的α-氧代金卡宾 容易获得的炔烃的分子间氧化。这一战略的两个显著特征是：a)避免 危险的和潜在的爆炸性的α-重氮羰基化合物和b)卡宾的特殊亲电性 中间。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 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形式，直到最近才被我们的氧化金催化实现 由我们进行初步研究。此外，失活的C(SP3)-H键大多没有屈服于卡宾 插页。在这项提案中，我们的目标是解决这些关键的缺点，并证明 这种方法超过了主流的Rh-重氮化学，远远超出了安全性的提高。 吸电子基团取代的α-氧代金卡宾将通过金催化生成 缺电子炔烃的分子间氧化。这些受体/受体类型的卡宾是例外的 亲电性，并结合足够的空间屏蔽，能够在分子内插入到 C(SP3)-H键，从而提供高效和流畅的途径来获得大量的这些环 酮，包括各种双环和多环的酮。通过调整EWG、黄金催化剂和 反应条件下，金卡宾部分的反应性可以实质上调节以适应 不仅有未活化的C-H键，也有失活的C-H键。相比之下，主流的Rh-重氮方法大多是 由于通常Rh卡宾的反应性较低而不能插入失活的C-H键 对口单位。通过使用新设计的手性NHC配体，这些高度选择性的C-H插入 活性金卡宾将能够合成具有高e.e.手性环戊酮，而不是 适度的e.e。Rh-重氮方法中的≤(80%)，以及失活C-H键的不对称官能化。 这一战略还将在综合规划方面提供显著的好处，因为它能够实现一种全新的 进入C-H插入，并在官能团兼容性和 保护基团策略，因为C-C三键在耐受性方面与羰基明显不同 反应条件。此外，炔烃合成的丰富化学成分使人们能够很容易地获得炔烃底物。 具有良好控制的立体化学，其重氮羰基的对应物可能需要非凡的 努力。因此，我们的方法将打开对有价值的功能产品的未知但有效的访问，这 否则将几乎无法通过重氮化学获得或合成效率极低的化合物。 这种氧化C-H插入的合成用途将在简明的全合成中得到证明。 印防己毒素，其中插入失活的C-H键将作为流线型步骤。

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.