Design of Stronger Brønsted Acid Catalyts for Highly Enantioselective Mukaiyama-Mannich Reactions

Since chiral binaphthol-derived phosphoric acids were demonstrated by Akiyama’s group and Terada’s group in 2004 as efficient catalysts for asymmetric Mannich reactions, the field of enantioselective Brønsted acid catalysis has attracted great attention from the synthetic chemical community. Significant efforts has been made in that field is the design of new Brønsted acid catalyst scaffolds to overcome certain limitations: such as low reactivity of catalysts and the limitation of the scope of substrates. Although several Brønsted acid catalysts have recently been developed for the asymmetric Mukaiyama-Mannich reactions, the enantioselectivities of the reactions is not always satisfactory. Thus, the design of more reactive and selective chiral Brønsted acid catalyst is highly desirable. Recently, we have developed a BINOL-derived chiral phosphoric acid bearing 2,4,6-trimethyl-3,5-dinitrophenyl substituents for highly enantioselective Mukaiyama-Mannich reaction and the adducts was obtained in good yields with high diastereo- and enantioselectivities. Furthermore, a powerful chiral BINOL-derived disulfonimide catalyst bearing 4-methyl-3,5-dinitrophenyl substituent has been developed to overcomes the long-standing limitation of the chiral phosphoric acid catalyzed-asymmetric Mukaiyama-Mannich reaction, that is the requirement of the 2-hydroxyphenyl moiety. To our delight, this chiral disulfonimide catalyst allow more challenging imines containing no 2-hydroxyphenyl moiety to give β-amino acid esters in good yields with high diastereo- and enantioselectivities.

References

Zhou; H. Yamamoto. Angew. Chem. Int. Ed. 2016, 55, 8970.

Zhou; H. Yamamoto. Org. Lett.. 2016, 18, 4974.