Dynamic kinetic asymmetric transformation of diene monoepoxides: A practical asymmetric synthesis of vinylglycinol, vigabatrin, and ethambutol

The ability to perform a dynamic kinetic asymmetric transformation (DYKAT) using the palladium-catalyzed asymmetric allylic alkylation (AAA) is explor ed in the context of butadiene monoepoxide. The versatility of this commerc ially available, but racemic, four-carbon building block becomes significan tly enhanced via conversion of both enantiomers into a single enantiomeric product. The concept is explored in the context of a synthesis of vinylglyc inol with phthalimide as the nitrogen source. The success of the project re quired a new design of the ligand for palladium wherein additional conforma tional restraints were introduced. Thus, the phthalimide derivative of viny lglycinol was obtained in nearly quantitative; yield and had an ee of 98% w hich, upon crystallization, was enhanced to >99%. This one-step synthesis o f a protected form of vinylglycinol provided short practical syntheses of t he title compounds. Vigabatrin requires only four steps, and ethambutol six . The intermediate to the existing synthesis of ethambutol is available in 87% yield in three steps. (R)-Serine derives from oxidative cleavage of the double bond. The reaction of phthalimide and isoprene monoepoxide demonstr ates the remarkable ability of the chiral ligands to control both regiosele ctivity and enantioselectivity and demonstrates the effectiveness of this p rotocol in creating a quaternary center asymmetrically.