Enantioselective Synthesis of 5,5-Disubstituted Hydantoins by Brønsted Base/H-Bond Catalyst Assisted Michael Reactions of a Design Template.

A new method for the enantioselective synthesis of 5,5-disubstituted (quaternary) hydantoins was developed on the basis of an organocatalytic Michael reaction approach involving the use of 2-benzylthio-3,5-dihydroimidazol-4-ones as key hydantoin surrogates. The method is general with respect to the substitution pattern at the hydantoin N1 (alkyl, aryl, acyl), N3 (aryl), and C5 (linear/branched alkyl, aryl) positions and affords essentially single diastereomeric products with enantioselectivities higher than 95 % ee in most cases. Among the bifunctional Brønsted base/H-bond catalysts examined, a known squaramide-tertiary amine catalyst and a newly prepared squaramide-tertiary amine catalyst provide the highest selectivity so far with either nitroolefins or vinyl ketones as the acceptor components. Kinetic measurements support a first-order rate dependence on both reaction partners, the donor template and the Michael acceptor, whereas competitive 1 H NMR spectroscopy experiments reveal the high ability of the template for catalyst binding.

Base-Catalyzed Asymmetric α-Functionalization of 2-(Cyanomethyl)azaarene N-Oxides Leading to Quaternary Stereocenters.

A simple, new strategy for the direct asymmetric α-functionalization of 2-alkyl azaarenes is described. Specifically, a Brønsted base catalyzed conjugate addition of substituted 2-cyanomethylpyridine (and pyrazine) N-oxides to acrylate equivalents to afford hitherto elusive 2-tert-alkyl azaaryl adducts with high enantioselectivity (up to 94% ee) is realized. Extension of the method to the α-amination reaction by using azodicarboxylate esters as electrophiles is also demonstrated. Key for success is the N-oxide functionality of substrates that acts as a removable activating and stereodirecting group. A bifunctional Brønsted base catalyst bearing a squaramide with an attached bulky silyl group is also disclosed.

Catalytic Enantioselective Synthesis of N,C(α),C(α)-Trisubstituted α-Amino Acid Derivatives Using 1H-Imidazol-4(5H)-ones as Key Templates.

1H-Imidazol-4(5H)-ones are introduced as novel nucleophilic α-amino acid equivalents in asymmetric synthesis. These compounds not only allow highly efficient construction of tetrasubstituted stereogenic centers, but unlike hitherto known templates, provide direct access to N-substituted (alkyl, allyl, aryl) α-amino acid derivatives.