01864nas a2200217   4500008004100000022001400041245014000055210006900195260000800264300001400272490000700286520107500293653002401368653001701392653002301409653002001432100002301452700001901475700002401494856012801518       2025                        eng d  a1083-616000aAtom-economical and scalable asymmetric synthesis of daridorexant key starting material (S)-2-methylproline via the memory of chirality0 aAtomeconomical and scalable asymmetric synthesis of daridorexant  cDEC  a3223-32280 v293 a<p>
	alpha-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.</p>
10aalpha-methylproline10aatom economy10amemoryof chirality10aStereoselective1 aBhatt, Gaurang, J.1 aKumar, Shubham1 aMhaske, Santosh, B.  uhttps://library.ncl.res.in/content/atom-economical-and-scalable-asymmetric-synthesis-daridorexant-key-starting-material-s-2