Preparation of pyrrolidine-based PDE4 inhibitors via enantioselective conjugate addition of alpha-substituted malonates to aromatic nitroalkenes.
[reaction: see text] The enantioselective conjugate addition of alpha-substituted malonates to aromatic nitroalkenes generates a stereocenter at the carbon bearing the aromatic group and an adjacent prochiral center from the alpha-substituted malonate. Nitro reduction followed by diastereoselective cyclization provides pyrrolidinones with two contiguous stereocenters, one of which is quaternary. This sequence was used for the preparation of the PDE4 inhibitor IC86518. Additional examples of the enantioselective Michael addition illustrate the scope of the reaction.
Nichols
Paul J
PJ
Department of Process Chemistry Research, Array BioPharma, 3200 Walnut Street, Boulder, Colorado 80301, USA. pnichols@arraybiopharma.com
Demattei
John A
JA
Barnett
Bradley R
BR
Lefur
Nicole A
NA
Chuang
Tsung-Hsun
TH
Piscopio
Anthony D
AD
Koch
Kevin
K
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000475:Alkenes / Q000737:chemistry*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D008314:Malonates / Q000737:chemistry*; D015394:Molecular Structure; D009574:Nitro Compounds / Q000737:chemistry*; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism
D000475:Alkenes; C515622:IC86518; D008314:Malonates; D009574:Nitro Compounds; D011759:Pyrrolidines; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4