title: Synthesis of PDE IVb inhibitors. 1. Asymmetric synthesis and stereochemical assignment of (+)- and (-)-7-[3-(cyclopentyloxy)-4-methoxyphenyl]hexahydro-3H-pyrrolizin-3-one.
abstract: Asymmetric synthesis of GlaxoSmithKline's highly potent phosphodiesterase inhibitor 1 has been accomplished in nine steps and 16% overall yield. The original strategy suggested involves as a key step the silylation of enantiopure six-membered cyclic nitronates 4 obtained by a highly stereoselective [4 + 2]-cycloaddition of an appropriate nitroalkene 5 to trans-1-phenyl-2-(vinyloxy)cyclohexane. Functionalization of the resulting 5,6-dihydro-4H-1,2-oxazine and subsequent stereoselective reduction of 1,2-oxazine ring in intermediate 2 furnished the pyrrolizidinone framework with the recovery of chiral auxiliary alcohol.
authors.affiliation: N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991, Leninsky prosp. 47, Moscow, Russian Federation. sukhorukov@server.ioc.ac.ru
authors.forename: Alexey Yu
authors.initials: AY
authors.lastname: Sukhorukov
authors.forename: Yaroslav D
authors.initials: YD
authors.lastname: Boyko
authors.forename: Sema L
authors.initials: SL
authors.lastname: Ioffe
authors.forename: Yulia A
authors.initials: YA
authors.lastname: Khomutova
authors.forename: Yulia V
authors.initials: YV
authors.lastname: Nelyubina
authors.forename: Vladimir A
authors.initials: VA
authors.lastname: Tartakovsky
mesh_terms: D060326:Chemistry Techniques, Synthetic / Q000379:methods*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism*; D058988:Phosphodiesterase 4 Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry*; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry*; D013237:Stereoisomerism; D013379:Substrate Specificity
chemical_list: C569344:(-)-7-(3-(cyclopentyloxy)-4-methoxyphenyl)hexahydro-3H-pyrrolizin-3-one; D058988:Phosphodiesterase 4 Inhibitors; D011758:Pyrroles; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4