Development of Pd-Catalyzed Asymmetric Allylic Alkylation with Low Catalyst Loading for Large-Scale Production of Ethyl (R)-1-Allyl-2-oxocyclohexane-1-carboxylate

Abstract

Asymmetric allylic alkylation (AAA) presents an exceptionally powerful and efficient tool for the rapid synthesis of a diverse range of chiral compounds with high yields and excellent levels of enantioselectivity. To support the production of ethyl (R)-1-allyl-2-oxocyclohexane-1-carboxylate 1 on a large scale, a highly practical and economical AAA process is highly desirable. Herein, we report a greatly improved reaction protocol by thorough optimization of the original conditions developed by Trost et al. Multiple reaction parameters including reaction temperature, concentration, stoichiometric amount of TMG (1,1,3,3-tetramethylguanidine), and water are thoroughly investigated. It was determined that the reaction rate was significantly improved in the presence of 2.0 equiv of TMG and an optimal amount of water (Pd:H2O = 1:160) at 10–15 °C. Our efforts led to the design and development of a highly efficient chemical process using [η3-C3H5PdCl]2 as low as 0.025 mol % under solvent-free conditions, enabling facile and robust scaleup in an economical and sustainable fashion on a large scale.

Simple Coumarin-Based Fluorescent Probe for Recognition of Pd(II) and Its Live Cell Imaging

“…Palladium(II), one of the biological toxicity metal ions, can cause eye irritations, skin cancer, and several cellular processes and biological activity disorders. 1 However, they have wide industrial applications, such as pharmaceuticals, 2 fuel cells, 3 manufacturing electrical products, 4 and so on. In this case, people are easily exposed to palladium(II) ions and susceptible to poisoning.…”

Development of a Kilogram-Scale Chemical Process for a Chiral Spirocyclic Isoxazolone

“…As previously reported, we developed a highly efficient and sustainable chemical process of Pd-catalyzed AAA with very low catalyst loading by thorough optimization of the original conditions developed by Trost and co-workers (Scheme ). The key improvements include the increase of the amount of TMG to two equivalents, addition of optimal amount of water (Pd/H 2 O = 1:160) and identification of the ideal reaction temperature (10–15 °C) to achieve a high reaction rate. Eventually, our efforts enabled us to smoothly scale up to produce 7 in an economical and sustainable fashion on large scale.…”