Synthesis of PDE IVb Inhibitors. 3. Synthesis of (+)-, (-)-, and (±)-7-[3-(cyclopentyloxy)-4-methoxyphenyl]hexahydro-3H-pyrrolizin-3-one via reductive domino transformations of 3-β-carbomethoxyethyl-substituted six-membered cyclic nitronates.
Simple three-step asymmetric and racemic syntheses of GlaxoSmithKline's highly potent PDE IVb inhibitor 1 were developed. The suggested approach is based on reductive domino transformations of 3-β-carbomethoxyethyl-substituted six-membered cyclic nitronates, which are easily accessed by a stereoselective [4 + 2] cycloaddition of an appropriate nitroalkene to vinyl ethers. In vitro studies of PDE IVb inhibition by enantiomeric pyrrolizidinones (+)-1 and (-)-1 were performed.
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991, Leninsky prosp. 47, Moscow, Russia. sukhorukov@ioc.ac.ru
Alexey Yu
AY
Sukhorukov
Yaroslav D
YD
Boyko
Yulia V
YV
Nelyubina
Stephane
S
Gerard
Sema L
SL
Ioffe
Vladimir A
VA
Tartakovsky
Laurette
L
Laurette Malleret
Azzaq
A
Belaaouaj
D003500:Cyclization; D015394:Molecular Structure; D058988:Phosphodiesterase 4 Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry*; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry*; D011760:Pyrrolidinones / Q000737:chemistry* / Q000494:pharmacology
C569344:(-)-7-(3-(cyclopentyloxy)-4-methoxyphenyl)hexahydro-3H-pyrrolizin-3-one; D058988:Phosphodiesterase 4 Inhibitors; D011758:Pyrroles; D011760:Pyrrolidinones