Catalytic Asymmetric Route to Enantioenriched Cyclic Allenes and a Nickel-catalyzed Dynamic Kinetic Resolution of Cyclic Allenes

高度官能化的杂环是医药领域中的重要基元。尽管已经有了 合成有机方法学的许多值得注意的进展，高效合成对映体富集物 杂环化合物在该领域仍然是一个持续的挑战。该提案的主要目标是访问 利用杂环烯丙烯中间体的富对映体化合物。已避免了环烯烃 从历史上看，这是由于它们的高反应性。然而，这项拟议的研究试图利用环烯来 高效建造复杂的脚手架。此外，环状联烯的固有手性为我们提供了 以获得富含对映体的加合物。以受控方式操纵杂环烯将提供 合成富含对映体的复杂杂环的新策略。 这一提议包括两种策略，即利用杂环烯来生成富含对映体 产品。在目标1中，草环烯前体的不对称催化合成将被优化为 最终能够方便地获得富含对映体的草环烯。对转移能力的调查 从烯丙烯前体到富含对映体的环加合物的立体化学信息将是 描述。AIM 2的研究将允许通过过渡金属-来获得富含对映体的杂环- 催化动力学拆分杂环烯类化合物。优化转型与探索 描述了衬底范围的大小。这些研究最终将证明张力循环的效用。 不对称合成中的烯。

Highly functionalized heterocycles are important motifs in pharmaceuticals. Although there have been many noteworthy advances in synthetic organic methodologies, the efficient synthesis of enantioenriched heterocycles remains an ongoing challenge in the field. The primary goal of this proposal is to access enantioenriched compounds utilizing heterocyclic allene intermediates. Cyclic allenes have been avoided historically due to their high reactivity. However, the proposed research seeks to harness cyclic allenes for the efficient construction of complex scaffolds. Moreover, the inherent chirality of cyclic allenes opens opportunities to access enantioenriched adducts. The manipulation of heterocyclic allenes in a controlled manner would offer new tactics for the synthesis of enantioenriched, complex heterocycles. This proposal includes two strategies that utilize heterocyclic allenes to generate enantioenriched products. In Aim 1, an asymmetric, catalytic synthesis of oxacyclic allene precursors will be optimized to ultimately enable facile access to enantioenriched oxacyclic allenes. An investigation into the ability to transfer stereochemical information from the allene precursor all the way to enantioenriched cycloadducts will be described. The studies in Aim 2 will allow access to enantioenriched heterocycles via a transition metal- catalyzed dynamic kinetic resolution of heterocyclic allenes. Optimization of the transformation and exploration of the substrate scope is described. These studies would ultimately demonstrate the utility of strained cyclic allenes in asymmetric synthesis.