由于环状化合物在药物化学中的广泛使用,合成四元碳环的制备方法的发展越来越重要。在这里,我们报告了一种生产含有环丁烷基序的螺环环氧化物和氮丙啶的新方法的开发。在两步一锅法中,将双环[1.1.0]丁基亚砜锂化并添加到酮中,醛或亚胺,并且所得中间体通过C-Cσ-键烷氧基或氨基加成与三氟甲磺酸芳基酯交叉偶联,并伴随着环氧化物或氮丙啶的形成。经过精心优化,设想了一种非常有效的反应,该反应可以耐受多种芳香族和脂肪族底物。最后,通过几个高产率的开环反应,我们证明了产品作为模块化构建模块的优异适用性,可将三维结构引入目标分子中。
应变螺环环氧化物和氮丙啶是通过原位生成的1-锂双环[1.1.0]丁烷之间的三组分偶联合成的,各种各样的酮,醛和N-甲苯磺酰基亚胺,和芳基三氟甲磺酸酯。关键步骤涉及双环[1.1.0]丁基甲醇酯中间体的高度非对映选择性钯催化的C−Cσ键烷氧基芳基化(或氨基芳基化)。
The development of preparative methods for the synthesis of four-membered carbocycles is gaining increasing importance due to the widespread utility of cyclic compounds in medicinal chemistry. Herein, we report the development of a new methodology for the production of spirocyclic epoxides and
aziridines containing a cyclobutane motif. In a two-step one-pot process, a bicyclo[1.1.0]butyl sulfoxide is lithiated and added to a ketone, aldehyde or imine, and the resulting intermediate is cross-coupled with an aryl triflate through C-C σ-bond alkoxy- or aminopalladation with concomitant epoxide or aziridine formation. After careful optimization, a remarkably efficient reaction was conceived that tolerated a broad variety of both aromatic and aliphatic substrates. Lastly, through several high yielding ring-opening reactions, we demonstrated the excellent applicability of the products as modular building blocks for the introduction of three-dimensional structures into target molecules.
Strained spirocyclic epoxides and
aziridines were synthesized via three‐component coupling between in situ generated 1‐lithio bicyclo [1.1.0]butane, a broad variety of ketones, aldehydes and N‐tosyl imines, and aryl triflates. The key step involves a highly diastereoselective palladium‐catalyzed C−C σ‐bond alkoxyarylation (or aminoarylation) of bicyclo [1.1.0]butyl carbinolate intermediates.