2-Piperidone type of chiral building block for 3-piperidinol alkaloid synthesis

An enantiomeric pair of a new 2-piperidone type of chiral building block (1) has been prepared by bakers' yeast reduction of β-keto ester (2) or lipase-mediated transesterification of hydroxy ester (±)-(1), derived from NaBH₄ reduction of 2, in enantiopure form. The absolute stereochemistry of (-)-1 was verified by its conversion to known piperidine (-)-3, an intermediate for the synthesis of (-)-spectaline. The 2-piperidone (-)-1 was converted to all four diastereomers of 2,6-disubstituted 3-piperidinol chiral building blocks on the basis of homologation of (-)-1 at the lactam carbonyl using the Eschenmoser method via corresponding thiolactams (-)-9, (-)-20, (- )-25, (-)-27, and (-)-34, followed by stereocontrolled reduction of the resulting vinylogous urethanes (+)-10, (+)15, (+)-23, (+)-28, and (+)-32, respectively, and epimerization of the hydroxyls at the 3-position [(-)-16 via (+)-17 to (-)-18 and (+)-29 via (+)-30 to (+)-31]. The versatility of these chiral building blocks has been demonstrated by the chiral synthesis of the 3-piperidinol alkaloids (+)-prosafrinine, (-)-iso-6-cassine, (-)- prosophylline, and (-)-prosopinine from (-)-37, (-)-14, (+)-36, and (-)-26, respectively.