Asymmetric syntheses of 3,4-syn- and 3,4-anti-3-substituted-4-aminopiperidin-2-ones: application to the asymmetric synthesis of (+)-(3S,4R)-cisapride

The conjugate addition of lithium (R)-N-benzyl-N-(α-methylbenzyl)amide to δ-(N-allylamino)-α,β-unsaturated esters, followed by N-deallylation and cyclisation of the resultant β,δ-diamino esters, gives the corresponding 4-aminopiperidin-2-ones as single diastereoisomers (>99:1 dr). Subsequent deprotonation with LiHMDS and functionalisation of the resultant lithium enolate gives 3,4-anti-3-substituted-4-aminopiperidin-2-ones in >99:1 dr. Alternatively, in situ oxidation of the intermediate lithium (Z)-β-amino enolates formed upon conjugate addition gives α-hydroxy-β,δ-diamino esters, which after N-deallylation and cyclisation gives the corresponding 3,4-syn-3-hydroxy-4-aminopiperidin-2-ones in >99:1 dr. The utility of this methodology was successfully demonstrated in a concise asymmetric synthesis of the gastroprokinetic agent (+)-(3S,4R)-cisapride {(+)-(3S,4R)-N(1)-[3′-(4″-fluorophenoxy)propyl]-3-methoxy-4-(2‴-methoxy-4‴-amino-5‴-chlorobenzamido)piperidine} in nine steps from commercially available starting materials with an overall yield of 19%.

Graphical abstractThe diastereoselective anti-aminohydroxylation of a δ-amino-α,β-unsaturated ester, followed by cyclisation to give the corresponding 3,4-syn-3-hydroxy-4-aminopiperidin-2-one were used as the key steps in the synthesis of the gastroprokinetic agent (+)-(3S,4R)-cisapride in nine steps from commercially available starting materials with an overall yield of 19%.Figure optionsDownload full-size imageDownload as PowerPoint slide