Bifunctional-thiourea-catalyzed diastereo- and enantioselective aza-Henry reaction.

Bifunctional thiourea 1a catalyzes aza-Henry reaction of nitroalkanes with N-Boc-imines to give syn-beta-nitroamines with good to high diastereo- and enantioselectivity. Apart from the catalyst, the reaction requires no additional reagents such as a Lewis acid or a Lewis base. The N-protecting groups of the imines have a determining effect on the chirality of the products, that is, the reaction of N-Boc-imines gives R adducts as major products, whereas the same reaction of N-phosphonoylimines furnishes the corresponding S adducts. Various types of nitroalkanes bearing aryl, alcohol, ether, and ester groups can be used as nucleophiles, providing access to a wide range of useful chiral building blocks in good yield and high enantiomeric excess. Synthetic versatility of the addition products is demonstrated by the transformation to chiral piperidine derivatives such as CP-99,994.

Enantio- and diastereoselective Michael reaction of 1,3-dicarbonyl compounds to nitroolefins catalyzed by a bifunctional thiourea.

We synthesized a new class of bifunctional catalysts bearing a thiourea moiety and an amino group on a chiral scaffold. Among them, thiourea 1e bearing 3,5-bis(trifluoromethyl)benzene and dimethylamino groups was revealed to be highly efficient for the asymmetric Michael reaction of 1,3-dicarbonyl compounds to nitroolefins. Furthermore, we have developed a new synthetic route for (R)-(-)-baclofen and a chiral quaternary carbon center with high enantioselectivity by Michael reaction. In these reactions, we assumed that a thiourea moiety and an amino group of the catalyst activates a nitroolefin and a 1,3-dicarbonyl compound, respectively, to afford the Michael adduct with high enantio- and diastereoselectivity.

Enantioselective aza-Henry reaction catalyzed by a bifunctional organocatalyst.

[reaction: see text] The aza-Henry reaction of imines with nitroalkanes was promoted by chiral thiourea with an N,N-dimethylamino group to give beta-nitroamines with good enantioselectivity. Various N-protected imines were examined as substrates. N-Phosphinoylimine gave the best result in terms of chemical yield and enantioselectivity (up to 91% yield, up to 76% ee).