Enantioselective synthesis of antiinfluenza compound A-315675.
Drug discovery efforts at Abbott Laboratories have led to the identification of influenza neuraminidase inhibitor A-315675 (1) as a candidate for development as an antiinfluenza drug. A convergent, stereoselective synthesis of this highly functionalized pyrrolidine is reported that utilizes pyrrolinone 2 as the key intermediate. The C5, C6 stereochemistry was established through a diastereoselective condensation of chiral imine compound 3 with silyloxypyrrole 4 to give pyrrolinone 2. The stereochemical outcome of this reaction depended critically on the choice of the imine functional group (FG), with tritylsulfenyl and (R)-toluenesulfinyl providing the desired products in good yields as crystalline intermediates. Conversion of pyrrolinone 2 into 1 was accomplished in seven subsequent steps, including Michael addition of cis-1-propenylcuprate at C4 and introduction of a cyano group as a carboxylic acid equivalent at C2.
DeGoey
David A
DA
Infectious Disease Research Division, Abbott Laboratories, 200 Abbott Park Road, Abbott Park, Illinois 60064, USA. david.degoey@abbott.com
Chen
Hui-Ju
HJ
Flosi
William J
WJ
Grampovnik
David J
DJ
Yeung
Clinton M
CM
Klein
Larry L
LL
Kempf
Dale J
DJ
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D007251:Influenza, Human; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D009439:Neuraminidase / Q000037:antagonists & inhibitors*; D009975:Orthomyxoviridae / Q000187:drug effects*; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000494:pharmacology; D013237:Stereoisomerism
C456059:A 315675; D000998:Antiviral Agents; D011759:Pyrrolidines; D009439:Neuraminidase