Catalytic asymmetric synthesis of alfa,alfa-disubstituted alfa-thio- and alfa-amino acid derivatives

Abstract

The aim of this thesis has been the development of new pronucleophiles for organocatalytic reactions,leading to ¿,¿-dialkyl ¿-thio- and ¿,¿-dialkyl ¿-amino carboxylic acid derivatives, products that are ofinterest in biological and medicinal chemistry. To this end, we have developed 5H-thiazolones and 1Himidazol-4(5H)-ones for the first time (Figure 1).Figure 1.On one hand, 5H-thiazol-4-ones (sulfur equivalents of the widely employed 5H-oxazol-4-ones) weretested in the addition to nitroolefins and to azadicarboxylates using a new family of ureidopeptidicorganocatalysts. Reactions performed with these catalysts gave the addition products with high yields andwith excellent selectivities (up to >95:5 dr and 99% ee) (ACIE 2013, 52, 11846¿11851).Scheme 1.On the other hand, 1H-imidazol-4(5H)-ones were synthesized and evaluated as novel pronucleophiles inconjugated reactions. These compounds not only allow highly efficient construction of tetrasubstitutedstereogenic centers, as in the examples mentioned above, but unlike hitherto known templates providedirect access to N-substituted ¿-amino acid derivatives. Their addition to nitroolefins and to ¿-oxyenones(whose utility was first recognized by this group, JACS 2014, 136, 17869¿17881) carried out withbifunctional squaramide catalysts proceed with very good stereoselectivities (ACIE 2015, 54,6883¿6886), while the ureidopeptidic organocatalysts did not show such selectivity.Scheme 2.In conclusion, two new pronucleophiles were developed, as well as new bifunctional Brønsted baseorganocatalysts. Exploration of the properties of both heterocycles led to four successful reactions,providing access to a wide range of ¿,¿-disubstituted ¿-mercaptocarboxylic and ¿,¿-disubstituted ¿-amino acid derivatives, which presumably could be employed as building blocks for more complexstructures.