Enantioselective Organocatalyzed Michael Addition of Isobutyraldehyde to Maleimides in Aqueous Media.

Thiourea was introduced into (R,R)-1,2-diphenylethylenediamine as an organocatalyst to promote the reaction between isobutyraldehydes and maleimides. Enantioselective Michael addition reaction was carried out as an eco-friendly method using water as the solvent. As a result of the reaction between isobutyraldehyde and maleimide, ≥97% yield and 99% enantioselectivity were obtained at a low catalyst loading of 0.01 mol%. The solvent effect can be explained by theoretical calculations that indicate the participation of a transition state, in which the CF3 substituent of the catalyst is a hydrogen bond activated by the surrounding water molecules. This discovery enabled the use of low catalyst loading in the organic reactions of chiral substances for pharmaceutical applications. Furthermore, a solvent effect for Michael reaction of the organocatalysts was proposed, and the organic reaction mechanisms were determined through quantum calculations.

Enantioselective Thiolysis and Aminolysis of Cyclic Anhydrides Using a Chiral Diamine-Derived Thiourea Catalyst.

Catalytic desymmetrization of cyclic anhydrides has been widely investigated in the field of organocatalysis. Using this approach, many stereocenters can be established in a single, symmetry-breaking transformation. Herein, a thiourea organocatalyst was prepared in a single step from a chiral diamine, (R,R)-1,2-diphenylethylenediamine, and used for the desymmetrization of various cyclic anhydrides through double hydrogen-bonding activation. The asymmetric ring-opening reaction of the cyclic anhydride proceeded via the enantioselective addition reaction catalyzed by diamine thiourea. Thiolysis afforded the desired products in the yields of 86-98% and enantioselectivities of 60-94%, while aminolysis afforded the yields of 90-94% and enantioselectivities of 90-95%.

Enantioselective organocatalytic Michael reactions using chiral (R,R)-1,2-diphenylethylenediamine-derived thioureas.

Although the Michael addition is a very well-known and widely applied reaction, cost-effective, metal-free, and readily prepared organic catalysts remain rare. A chiral, bifunctional, (R,R)-1,2-diphenylethylenediamine-derived thiourea organic catalyst was developed and applied to asymmetric Michael additions of nitroalkenes under neutral conditions. Generally, fluorine-substituted thiourea catalysts exhibited high chemical yields and enantioselectivities under neutral conditions. The mild reactions were tolerant of many functional groups and afforded good-to-excellent yields, as well as high diastereo- and enantioselectivities for the Michael adducts. The utility of the transformation was demonstrated by the synthesis of a bioactive compound, (R)-Phenibut.

Synthesis and biological evaluation of cyclic sulfamide derivatives as 11ß-hydroxysteroid dehydrogenase 1 inhibitors.

A new series of cyclic sulfamide derivatives were synthesized and evaluated for their ability to inhibit 11ß-HSD1. Among this series, 18e showed good in vitro activity toward human 11ß-HSD1, selectivity against 11ß-HSD2, microsomal stability, and pharmacokinetic and safety profiles (hERG, CYP, and acute toxicity). Additionally, 18e exhibited good in vivo efficacy in rat and monkey models.

Highly enantioselective additions of diethylzinc to aldehydes using 2-triflamido-methyl-2'-hydroxy-1,1'- binaphthyl.

[reaction: see text] A new N-triflated amino alcohol-titanium catalyst was designed for the asymmetric ethylation of aldehydes. This binaphthyl-based sulfonamido alcohol ligand shows uniformly high yield and enantioselectivity in the diethylzinc additions of aromatic, aliphatic, and unsaturated aldehydes.

Enantioselective additions of diethylzinc and diphenylzinc to aldehydes using 2-dialkyl-aminomethyl-2'-hydroxy- 1,1'-binaphthyls.

[reaction: see text] A set of 2-dialkylaminomethyl-2'-hydroxy-1,1'-binaphthyls was prepared and used in the catalytic asymmetric additions of diethylzinc and diphenylzinc to various types of aldehydes. These binaphthyl-based axially chiral amino alcohols show high enantioselectivity in the addition of organozincs to aromatic and aliphatic aldehydes.