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

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.