Synthesis Of Chiral4,5-2-piperidinone Building Blocks

Chiral4,5-disubstituted-piperidinones are six-membered heterocycles with acarbonyl group on the piperidine ring, which are usually considered as useful buildingblocks for the construction of biologically and pharmaceutically active piperidines aswell as more complex nitrogen containing medicinal natural products. Such as theantidepressant drug ()-paroxetine, the cytotoxic and calmodulin antagonistpseudodistomin A and B, and hypotensive activity reserpine etc. Moreover, the poly-functionalized piperidione building block1and2are variable to undergotransformations such as C2-carbonyl reduction, C3-alkylation, C4-arylation,C5-homologation and so on to furnish more advanced architectures.In this thesis, the trans-(4R,5S)-2-piperdinone1and cis-(4S,5S)-2-piperdinone2have been prepared from phthalimide-protected amino acid72a via oxazolidinone-induced enolate alkylation of70developed by professor Evans, to generate the C5chiral centre; Aldol reaction of aldehyde107, prepared from72a via7-step conversion,with methyl acetate to extend a carbon chian get109. Lactamization of aminoester109afforded the desired1and2in an overall yield of22%and21%respectively in14steps,which were separable by silica gel chromatography. However, both1and2were shownto be a mixture of diastereomers with epimerizations on C5, which was probablely dueto the α epimerization of aldehyde107under strong base conditions during thesynthesis.