Development of New Enantioselective Methodology for Natural Products Synthesis
One class of polycyclic compounds that show high biological activity for many type of living organisms are the different types of quinolizidine alkaloids. The quinolizidine skeleton is found in a large number of natural occurring compounds (Figure 1).
These alkaloids, together with non-natural derivatives thereof, have attracted strong interest among both chemists and biologists because of their challenge as synthetic targets and diverse biological activity. Although several methods for the construction of quinolizine derivatives are known, the development of new stereoselective, efficient and short routes to this class of compounds would open up new opportunities for natural product synthesis and medicinal chemistry.
An ongoing project involves the development of a short enantioselective one pot, two step synthesis to the indolo[2,3-a] quinolizidine and the benzo[a]quinolizidine skeleton. The sequence involves a organocatalytic conjugate addition and subsequent acid catalyzed acyliminiumion cyclization (Scheme 1).
The proposed mechanism for this annulation strategy is induced by the formation of an iminiumion that will activate the a,b-unsaturated aldehyde 1 towards enol attack of the electron deficient amide 2. This step is the enantioselectivity-determining step; the bulky groups on the catalyst will direct nucleophilic attack from the bottom face. Subsequent cyclization gives the hemiacetal as a single diastereoisomer. Treatment of the reaction mixture with acid leads to the elimination of water and the formation of an intermediate acyliminium ion. Nucleophilic attack by the indole or phenyl moiety in an electrophilic aromatic substitution gives the products.