Stereoselective multicomponent assembly of enantiopure oxazolopiperidines and –azepines

A multicomponent reaction (MCR) based on a cyclohydrocarbonylation (CHC) driven by hydroformylation was set up towards the efficient diastereoselective preparation of oxazolo-piperidines (4a-e) and –azepines (7a-d). The bicyclic oxazolidines were obtained from chiral N-alkenyl amino alcohols via transient cyclic iminium intermediates that underwent an intramolecular cyclization from the appendant oxygen. Based on a series of different experimental conditions, the diastereocontrol observed during the formation of the oxazolidines is best explained by the stereoelectronic effect induced by an 1,3-allylstrain in a common cyclic iminium intermediate (A). This new sequence is suitable for diversity oriented syntheses, allowing the preparation of enantiopure (S)- and (R)-coniceine in five steps from commercially available material