New approaches to optically active 2-tert-alkyl azaaryl compounds and 5,5-disubstituted hydantoins

Abstract

The aim of this thesis has been the development of new pronucleophiles for organocatalytic reactions,leading to 2-tert-alkyl azaaryl adducts and 5,5-disubstituted hydatoins, products that are of interest inbiological and medicinal chemistry. To this end, we have developed for the first time 2-(cyanomethyl)azaarene N-oxides and 1H-imidazol-4(5H)-ones and 1H-imidazol-5(4H)-ones (Figure 1) aseasily enolizable pronucleophiles .Figure 1On one hand, 2-(cyanomethyl)azaarene N-oxides were tested in the addition to ¿-oxyenones (whose utilitywas first recognized by this group, JACS 2014, 136, 17869¿17881) using a new family ofmultifunctional squaramide-Brønsted base catalysts bearing a bulky silyl group. Reactions performedwith these catalysts gave the addition products (with quaternary stereocenters) with high yields andexcellent enantiolectivities (up to 93 % yield; up to 94% ee) (JACS 2016, 138, 3282¿3285).Scheme 2On the other hand, 1H-imidazol-4(5H)-ones and 1H-imidazol-5(4H)-ones were synthesized and evaluatedas new pronucleophiles in conjugated reactions. After acidic or basic hydrolysis, these compounds allowhighly efficient construction of 5,5-disubstituted hydantoins. Their addition to nitroolefins and vinylketones carried out with squaramide type bifunctional catalysts proceed in general with excellentstereoselectivities (up to >98:2 dr; up to >99% ee) (doi:10.1002/chem.201800506) (Scheme 3).Scheme 3In conclusion, three new pronucleophiles and two new bifunctional catalysts have been described forthe organocatalytic asymmetric formation of quaternary stereocentres. 2-Cyanomethylazaarene Noxideshave demonstrated their utility as efficient reagents for the asymmetric synthesis of ¿-quaternary o-substituted alkylazaarenes via soft enolization conditions. 1H-Imidazol-4(5H)-ones I and1H-Imidazol-5(4H)-ones II have proved to be excellent substrates for the organocatalytic Michaelreaction of enantiomerically enriched 5,5-disubstituted hydantoins.