Synthesis of Antiepileptic Drug ()-Lacosamide and Chronic Pain Reliever ()-Lacosamide from Chiral Glycine Enolate Equivalent.

A short enantioselective and azide-free synthesis of antiepileptic drug ()-lacosamide and pain reliever ()-lacosamide on a large scale has been articulated from an uncommon chiral synthon "glycine enolate equivalent of 4-benzyl--glycinyl oxazolidinone". Evans' asymmetric alkylation using -(-Boc-glycinyl) oxazolidinone was standardized to ensure the stereoselective formation of (Z)-enolate for a diastereofacial selection in the -alkylation process of chiral glycine enolate equivalent with different alkyl halides such as methyl iodide, methoxymethyl chloride, benzyl bromide, -NOCHCHBr, allyl bromide, and -OCHCHCHBr in the presence of lithium diisopropyl amide at -78 °C in THF. This optimized asymmetric -alkylation method with methoxymethyl chloride on lithium-mediated (Z)-enolate of (4/4)-4-benzyl--glycinyl oxazolidinones was extended following other subsequent reactions to produce the final lacosamides with no racemization in ∼36 to 45% overall yields from commercially available 4-benzyl-2-oxazolidinone and -Boc-glycine.