ABSTRACT
The N-difluoromethyl triazolo-ß-aza-ε-amino acid present in the core of peptides led to constrained conformations due to CH-F and NH-F interactions. Pseudotetrapeptides were obtained in excellent yields directly by click chemistry between azidodifluoroacetamides and alkynes, both linked to an amino acid. This work demonstrates that the N-difluoromethyltriazole scaffold can induce extended structures to ß-strand mimics.
Subject(s)
Hydrocarbons, Fluorinated/chemistry , Peptidomimetics/chemistry , Triazoles/chemistry , Click Chemistry , Molecular StructureABSTRACT
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.