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 exceptionallypowerfuland efficient tool for the rapid synthesis of a diverse range of chiralcompounds 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 AAAprocess is highly desirable. Herein, we report a greatly improvedreaction protocol by thorough optimization of the original conditionsdeveloped by Trost et al. Multiple reaction parameters including reactiontemperature, concentration, stoichiometric amount of TMG (1,1,3,3-tetramethylguanidine),and water are thoroughly investigated. It was determined that thereaction rate was significantly improved in the presence of 2.0 equivof TMG and an optimal amount of water (Pd:H2O = 1:160)at 10-15 & DEG;C. Our efforts led to the design and developmentof a highly efficient chemical process using [& eta;(3)-C3H5PdCl](2) as low as 0.025 mol % undersolvent-free conditions, enabling facile and robust scaleup in aneconomical and sustainable fashion on a large scale.