Stability studies of oxazolidine-based compounds using 1H NMR spectroscopy.
A series of oxazolidine-based compounds with a variety of substituents in positions 2 and 3 was synthesized and their stability studied. Ring opened intermediates formed on addition of limiting amounts of D(2)O to oxazolidine solutions, as observed by NMR. As the hydrolysis reactions proceeded, a series of novel dimeric beta-amino alcohol compounds formed via an internal reaction between ephedrine and the ring opened intermediates. 2-Phenyl substituted oxazolidine compounds containing electron withdrawing nitro substituents were more rapidly hydrolyzed than the unsubstituted derivative and methoxy substituted compounds, with the nitro substituents appearing to stabilize the ring opened intermediates. Two oxazolidine derivatives, with a methyl and proton at position 2, were found to be more stable to oxazolidine hydrolysis than the 2-phenyl substituted compounds. Oxazolidines incorporating phenyl substituents at position 3 were synthesized and found to be less stable than those incorporating a methyl substituent at position 3. These fundamental structure-activity relationships may be useful when choosing oxazolidine derivatives as synthetic intermediates and as prodrugs for the delivery of compounds containing either beta-amino alcohol or aldehyde components.
Moloney
Gerard P
GP
Department of Medicinal Chemistry, Victorian College of Pharmacy, (Monash University), Parkville, Victoria, Australia.
Iskander
Magdy N
MN
Craik
David J
DJ
D017666:Deuterium Oxide / Q000737:chemistry; D006868:Hydrolysis; D007202:Indicators and Reagents; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D010080:Oxazoles / Q000737:chemistry*; D011355:Prodrugs; D015203:Reproducibility of Results; D013329:Structure-Activity Relationship
D007202:Indicators and Reagents; D010080:Oxazoles; D011355:Prodrugs; C064210:oxazolidine; D017666:Deuterium Oxide