Atom-Economical and Scalable Asymmetric Synthesis of Daridorexant Key Starting Material ( S )-2-Methylproline via the Memory of Chirality

α-Methylproline is a key starting material (KSM) for important drugs, such as Daridorexant, Veliparib, Trofinetide, Enlicitide chloride, and Usnoflast. A practical and scalable asymmetric synthesis of ( S )-2-methylproline and its derivatives has been disclosed here using a diketopiperazine intermediate-based strategy that leverages the memory of chirality. Commencing from an inexpensive starting material, l -proline, it proceeds through dimerization and alkylation, followed by hydrolysis under mild conditions, avoiding column chromatography to furnish enantiomerically pure ( S )-2-methylproline.HCl, which was also converted to ( S )-Boc-2-methylproline and ( S )-2-methylproline methyl ester.HCl. In contrast to prior multistep approaches, which rely on expensive chiral auxiliaries and hazardous reagents, this concise three-step route offers operational simplicity, scalability, and superior stereochemical control, making it an attractive method for the synthesis of proline-derived building blocks for peptidomimetics and pharmaceutical applications.