Synthesis of PDE IVb Inhibitors. 1. Asymmetric Synthesis and Stereochemical Assignment of (+)- and (−)-7-[3-(Cyclopentyloxy)-4-methoxyphenyl]hexahydro-3H-pyrrolizin-3-one

• Published in: Journal of organic chemistry 2011-10, Vol.76 (19), p.7893-7900
• Main Authors: Sukhorukov, Alexey Yu, Boyko, Yaroslav D, Ioffe, Sema L, Khomutova, Yulia A, Nelyubina, Yulia V, Tartakovsky, Vladimir A
• Format: Article
• Language: English
• Subjects: Chemistry Techniques, Synthetic - methods; Cyclic Nucleotide Phosphodiesterases, Type 4 - metabolism; Phosphodiesterase 4 Inhibitors - chemical synthesis; Phosphodiesterase 4 Inhibitors - chemistry; Pyrroles - chemical synthesis; Pyrroles - chemistry; Stereoisomerism; Substrate Specificity
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo201331h

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.