Thermodynamic epimeric equilibration and crystallisation-induced dynamic resolution of lobelanine, norlobelanine and related analogues.

The step-economical synthesis of lobelanine involving a ring closing double aza-Michael (RCDAM) reaction is revisited and successfully extended to the synthesis of various configurationally more stable analogues. Owing to the presence of a configurationally labile ß-aminoketone subunit, lobelanine is prone to self-catalyze mutarotation in solution. Through the synthesis of original lobelanine analogues, we studied the influence of (i) the size of the central heterocycle, (ii) the bulkiness of the nitrogen protecting group, and (iii) the phenacyl arm substituent on the thermodynamic equilibrium and its displacement by crystallisation-induced dynamic resolution (CIDR). We demonstrated that fine structural tuning combined with optimized CIDR conditions favours the first efficient diastereoselective synthesis of lobelanine's analogues.

Switchable stereocontrolled divergent synthesis induced by aza-Michael addition of deactivated primary amines under acid catalysis.

Switchable tandem intramolecular aza-Michael/Michael and double aza-Michael reactions allow the oriented synthesis of highly functionalised cyclic skeletons. Conjugate addition of deactivated anilines triggers chemo- and stereo-divergent ring-closure reaction pathways with a striking selectivity depending on reaction conditions.