臺灣國際科展

Asymmetric Total Synthesis of GlaxoSmithKline’s Potent Phosphodiesterase PDE IVb Inhibitor

科展類別
臺灣國際科展作品
屆次
2011年
科別
化學
得獎情形
一等獎
學校名稱
Moscow Chemical Lyceum
作者
Yaroslav Boyko

摘要或動機

Phosphodiestarase of subtype PDE IVb inhibitors are considered as perspective drugs for the treatment of the central nervous system disorders (depression, Alzheimer’s disease, Parkinson’s disease). Pyrrolizidinone Glaxo-1, proposed by GlaxoSmithKline, is a highly potent PDE IVb inhibitor (IC50 = 63 nM), then conventional phosphodiesterase inhibitors Ro-20-1724, Rolipram and Cilomilast. However the activity of the Glaxo-1 was studied on a racemic sample, since the asymmetric approach to its synthesis has not been developed. Therefore the purpose of this research was the development of an efficient synthetic scheme enabling enantioselective excess to both (-)- and (+)-Glaxo-1, which can be than subjected to biological studies. \r
The key stage in proposed asymmetric synthesis (-)- and (+)-Glaxo-1 is stereoselective [4+2]-cycloaddition of the nitroolefin to an optically activity vinyl ethers, derived from (-)- or (+)-trans-2-phenylcyclohexanols. The resulting chiral cyclic nitronates are transformed into a functionalized cyclic oxime ethers using tandem sylilation-nucleophilic substitution procedure. Reduction and decarboxylation of these products lead to optically pure Glaxo-1 and the regeneration of chiral 2-phenylcyclohexanols (91%). \r
Thus both enantiomers (+) and (-)-Glaxo-1 were obtained selectively in average yield 12% from isovaniline and nitroethane. The study of biological profiles of each enantiomer of Glaxo-1 will be conducted in near future.


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