Scaffold diversity through intramolecular cascade reactions of solid-supported cyclic N-acyliminium intermediates.
The solid-phase synthesis of pharmacologically interesting heterocycles is presented. The formation of a series of (5,5)-, (5,6)-, (6,5)-, and (6,6)-fused bicyclic ring systems was systematically studied by implementation of a common strategy involving N-acyliminium intermediates. These are highly reactive and transformed further in intramolecular cascade reactions with strong as well as weak C, N, S, and O-nucleophiles. The methodology was successfully applied to the conversion of peptidomimetics into constrained small molecule core structures, such as the hexahydropyrrolo[2,1- b][1,3]oxazines, generally with full control of diastereoselectivity (>20:1) and in purities above 90%.
Le Quement
Sebastian T
ST
Carlsberg Laboratory, SPOCC Centre, Gamle Carlsberg Vej 10, DK-2500, Valby, Denmark.
Nielsen
Thomas E
TE
Meldal
Morten
M
D002851:Chromatography, High Pressure Liquid; D020650:Combinatorial Chemistry Techniques; D006571:Heterocyclic Compounds / Q000138:chemical synthesis*; D008956:Models, Chemical; D018716:Molecular Mimicry; D010078:Oxazines / Q000138:chemical synthesis; D010455:Peptides / Q000737:chemistry; D011758:Pyrroles / Q000737:chemistry; D013237:Stereoisomerism
D006571:Heterocyclic Compounds; D010078:Oxazines; D010455:Peptides; D011758:Pyrroles