Diastereoselective synthesis of 4-substituted 5-( p-tolylsulfinyl)-5,6-dehydropiperidin-2-ones. A new approach to methyl l-(2 S,4 S)-4-methyl-6-oxopipecolate

Abstract

The sulfoxide-mediated diastereoselective Michael reaction of homochiral α-sulfinylketimines 1a– d and β-substituted ene esters 2a– d (Hua's reaction) was explored. Straightforward cyclization of the open-chain adducts take place under the reaction conditions to provide the 4-substituted 5-( p-tolylsulfinyl)-5,6-dehydropiperidin-2-ones 3 and 7– 12, whose stereochemistry is formed in the prior step. Furthermore, the role of the metal ion of the aza-enolate reagents and the steric demands of the O-alkyl ester group have been examined. It seems that the anti-diastereoselectivity depends on metal chelation by the oxygen of the ester as well as the oxygen of the sulfinyl group and the nitrogen in the aza-enolate (( Z)-configuration). In addition, the synthesis of methyl l-(2 S,4 S)-4-methyl-6-oxopipecolate has been achieved from the suitably functionalized 2-sulfinylketimine 1a (five steps; overall yield: 53–65%).