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 beta-keto ester (2) or li pase-mediated transesterification of hydroxy ester (+/-)-(1), derived from NdBH4 reduction of 2, in enantiopure form. The absolute stereochemistry of (-)-1 was verified by its conversion to known piperidine (-)-3, an intermed iate for the synthesis of (-)-spectaline. The 2-piperidone (-)-1 was conver ted to all four diastereomers of 2,6-disubstituted 3-piperidinol chiral bui lding blocks on the basis of homologation of (-)-1 at the lactam carbonyl u sing the Eschenmoser method via corresponding thiolactams (-)-9, (-)-20, (- )-25, (-)-27, and (-)-34, followed by stereocontrolled reduction of the res ulting vinylogous urethanes (+)-10, (+)-15, (+)-23, (+)-28, and (+)-32, res pectively, and epimerization of the hydroxyls at the 3-position [(-)-16 via (+)-17 to.(-)-18 and (+)-29 via (+)-30 to (+)-31]. The versatility of thes e chiral building blocks has been demonstrated by the chiral synthesis of t he 3-piperidinol alkaloids (+)-prosafrinine, (-)-iso-6-cassine, (-)-prosoph ylline, and (-)-prosopinine from (-)-37, (-)-14, (+)-36, and (-)-26, respec tively.