Studies in Organocatalysis – STUDORCA

Task 1: For this part of the project, we are studying the generation of zwitterionic ketoenolates, yet unknown reactive intermediates, from various 1,3-dicarbonyl presursors and chiral Lewis bases, in the presence of electrophilic formal cycloaddition reaction partners for the preparation of enantio-enriched spiro compounds.
Task 2: This part of the project is focusing on the identification of a new class of organocatalysts for iminium activation on the basis of the hydrazide functional group. Our design involves a spirobicyclic architecture with an “all carbon” spiro carbon atom. The methods developed in Task 1 should allow the preparation of the designed molecules. Alternatively, enantioselective Mannich-type reactions are also considered.

Task 1: To date, and after many efforts, we have successively generated one desired zwitterionic ketoenolate by the condensation of a NHC with an alpha-oxo-ketene. In this specific case, the zwitterionic ketoenolate was found too stable or hindered to react satisfactorily with the tested reaction partners (imines, 1-oxa- or 1-aza-dienes, 1,3-dipoles). Other Lewis bases are under investigation to prepare more reactive zwitterionic ketoenolates.
During this work, some unexpected NHC-catalyzed hydrogen / deuterium atom exchange reactions were observed between some of the tested pseudo-acid substrates and deuterated chloroform. This interesting serendipitous observation could be generalized and rationalized, and these results were published (JOC 2015, 80, 1092).

Task 2: Because the route studied in Task 1 in not yet productive to prepare the desired spiro compounds, and according to the proposed workflow, we are studying alternative methods. More specifically, current work focuses on inter- and intramolecular Mannich-type reactions.

A this stage, future prospects remain the initially defined objectives.

2 publications, 2 invited lectures (national et international), 2 posters

The basic research described in this proposal concerns studies in fundamental organic chemistry in the field of organocatalysis. Despite the considerable progresses of the science of organic synthesis and the advent of organocatalysis, general methods to generate chiral “all carbon” quaternary centers with high levels of stereoselectivity are rare, and this synthetic issue remains a challenge. Chiral “all carbon” quaternary centers can be found in spiro bicyclic compounds, a class of molecules with spectacular chemical and conformational properties. We propose to develop a general and flexible stereoselective organocatalytic approach to spiro compounds containing a chiral “all carbon” spiro carbon atom using the reactivity of zwitterionic ketoenolate equivalents mediated by Lewis base catalysts (NHCs and isothioureas). We also propose to develop a new class of organocatalysts for iminium activation with enhanced catalytic activity and stereoselectivity when compared to state of the art organocatalysts. These new organocatalysts have been rationally designed around a conformationally constraint spiro bicyclic core containing a chiral “all carbon” spiro carbon atom, and they may be prepared by the method we propose to develop using the reactivity of zwitterionic ketoenolate equivalents. We anticipate that our designed organocatalysts for iminium activation will allow for unprecedentedly efficient and stereoselective reactions, more specifically for the preparation of molecules with chiral “all carbon” quaternary centers.