Synthesis and conformational dynamics of tricyclic pyridones containing a fused seven-membered ring.
A new synthetic approach to tricyclic pyridones bearing a fused seven-membered ring is described. These compounds exhibit atropisomerism and exist in enantiomeric forms. Chiral HPLC separation of the enantiomers has allowed the rates of racemization to be measured and hence the free energy barrier for flipping the seven-membered ring to be deduced. Introduction of a further element of planar chirality leads to diastereomeric atropisomerism. The rate of interconversion of the diastereomers has been quantified by 2D EXSY NMR spectroscopy allowing a full description of the conformational dynamics of the system.
Gibson
Karl R
KR
Medicinal Chemistry Department, Merck Sharp & Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Harlow, Essex CM20 2QR, UK.
Hitzel
Laure
L
Mortishire-Smith
Russell J
RJ
Gerhard
Ute
U
Jelley
Richard A
RA
Reeve
Austin J
AJ
Rowley
Michael
M
Nadin
Alan
A
Owens
Andrew P
AP
D000465:Algorithms; D002851:Chromatography, High Pressure Liquid; D020650:Combinatorial Chemistry Techniques; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D011728:Pyridones / Q000138:chemical synthesis*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D011728:Pyridones