Enantioselective Prototropy as a Powerful Synthetic Tool
Final Report Abstract
The aim of the research project “Enantioselective Prototropy as a Powerful Synthetic Tool” was to access chiral molecules by a 1,3-prototropic shift. The chirality of molecules is crucial in medicinal applications since it can be the deciding factor between desired or undesired effects of a biologically active molecule. To support the development of synthetic methodologies towards new biologically relevant chemical entities, the 1,3-prototropic shift was explored as a synthetic tool. It was the aim of the first work package to significantly expand the scope of the reaction by using a superbasic catalyst, more specifically a bifunctional iminophosphorane (BIMP). Within this research project, the 1,3-prototropic shift reaction was studied in the context of unprecedented and atom economic dynamic kinetic asymmetric transformations (DYKAT) of 1,4-dihydronaphthalene-derived diesters and diamides. The reaction resulted in 1,2-dihydronaphthalenes with high enantioselectivities (up to 98%ee) and yields (up to 96%). Under optimised reaction conditions, mixtures of up to three stereoisomers of the starting material were investigated, including the cis-isomer and both trans-enantiomers. Mechanistic studies suggested that the cis-isomer serves as an achiral intermediate, which can easily epimerise to both enantiomers of the trans-isomer under the reaction conditions. However, only one of the enantiomers of the latter is rapidly converted by the chiral BIMP catalyst in the 1,3-prototropic shift reaction. Since one of the two enantiomers is preferably processed by the catalyst, high enantioselectivities were achieved even when using a mixture of stereoisomers as the starting material. Diester and diamide substituted 1,4-dihydronaphthalenes are ideal substrates for this transformation and give access to highly enantioenriched products with synthetically useful functionalities.
