Described herein are catalytic hydrogenation and the use of ruthenium complexes having a bidentate diphosphine ligand or two monodentate phosphine ligands, two carboxylate ligands, and optionally a diamine ligand in hydrogenation processes for the reduction of imines into the corresponding amines.

A ligand having the structure or its enantiomer; (I) wherein: each one of R.sub.a, R.sub.b, R.sub.c and R.sub.d is selected from alkyl, cycloalkyl, and aryl; the bridge group is selected from CH.sub.2NH; *CH(CH.sub.3)NH(C*,R); and the organocatalyst is an organic molecule catalyst covalently bound to the bridge group. Also, a catalyst having the structure or its enantiomer: (II) wherein: each one of R.sub.a, R.sub.b, R.sub.c and R.sub.d is selected from alkyl, cycloalkyl, and aryl; the bridge group is selected from CH.sub.2NH; *CH(CH.sub.3)NH(C*,R); and *CH(CH.sub.3)NH(C*,S); the organocatalyst is an organic molecule catalyst covalently bound to the bridge group; and M is selected from the group consisting of Rh, Pd, Cu, Ru, Ir, Ag, Au, Zn, Ni, Co, and Fe. ##STR00001##

Described herein are catalytic hydrogenation and the use of ruthenium complexes having a bidentate diphosphine ligand or two monodentate phosphine ligands, two carboxylate ligands, and optionally a diamine ligand in hydrogenation processes for the reduction of imines into the corresponding amines.

The invention provides a method comprising hydrogenating a ketone in the presence of (i) a base, (ii) hydrogen gas and (iii) a catalyst comprising a charged or neutral complex of formula (I):

##STR00001## wherein: Mn is a manganese atom or a manganese ion in oxidation state (I) to (VII); R.sup.1 and R.sup.2 are each independently optionally substituted C.sub.4-8monocyclic aryl or C.sub.3-7monocyclic heteroaryl moieties; -Fc- denotes a ferrocene (bis(η.sup.5-cyclopentadienyl)iron) moiety covalently bonded via adjacent carbon atoms of one of the two cyclopentadienyl moieties, and which may be optionally further substituted, in either cyclopentadienyl ring; —Z— is an alkylene linker of the formula —(CH.sub.2).sub.1-6— in which one or more of the hydrogen atoms of the alkylene may be independently substituted; —N.sup.x is an optionally substituted nitrogen-containing heteroaryl moiety, with the proviso that at least one of R.sup.1, R.sup.2 and —N.sup.x is substituted one or more times with an electron donating group; and L.sup.1-L.sup.3 constitute one, two or three ligands, wherein, when the complex of formula (I) is charged, the catalyst comprises one or more additional counterions to balance the charge of the complex.

The present disclosure discusses (i) a compound having a chemical formula according to Formula (I), or its enantiomer; and (ii) a compound that is reactive with a hydride to produce a compound having a chemical formula according to Formula (I), or its enantiomer. Formula (I) is: Formula (I) where R.sub.1 and R.sub.2 are H, optionally substituted C.sub.1-C.sub.3 alkyl, or linked together to form an optionally substituted C.sub.3 or C.sub.4 alkyl group; R.sub.3 and R.sub.3′ are H; R.sub.4 and R.sub.4′ are the same, and are optionally substituted C.sub.1-C.sub.6 alkyl; and R.sub.5 and R.sub.5′ are the same, and are optionally substituted aryl or heteroaryl. In some examples, R4 and R5 are linked, and R.sub.4′ and R.sub.5′ are linked, where both linking groups are the same. The present disclosure also discusses methods of asymmetric reduction of an imine, and methods of forming the catalysts and pre-catalysts. ##STR00001##

The present disclosure provides a method for efficiently producing and providing compounds having a spirooxindole skeleton, for example compounds having a spirooxindole skeleton and having antitumor activity that inhibit the interaction between Mdm2 protein and p53 protein, or intermediates thereof, using an asymmetric catalyst. Compounds having optically active tricyclic dispiroindole skeletons are obtained through catalytic asymmetric 1,3-dipolar cycloaddition reaction using ketimine as a reaction substrate and using a chiral ligand and a Lewis acid.

The present disclosure provides a method for efficiently producing and providing compounds having a spirooxindole skeleton, for example compounds having a spirooxindole skeleton and having antitumor activity that inhibit the interaction between Mdm2 protein and p53 protein, or intermediates thereof, using an asymmetric catalyst. Compounds having optically active tricyclic dispiroindole skeletons are obtained through catalytic asymmetric 1,3-dipolar cycloaddition reaction using ketimine as a reaction substrate and using a chiral ligand and a Lewis acid.

The present disclosure discusses (i) a compound having a chemical formula according to Formula (I), or its enantiomer; and (ii) a compound that is reactive with a hydride to produce a compound having a chemical formula according to Formula (I), or its enantiomer. Formula (I) is: Formula (I) where R.sub.1 and R.sub.2 are H, optionally substituted C.sub.1-C.sub.3 alkyl, or linked together to form an optionally substituted C.sub.3 or C.sub.4 alkyl group; R.sub.3 and R.sub.3are H; R.sub.4 and R.sub.4 are the same, and are optionally substituted C.sub.1-C.sub.6 alkyl; and R.sub.5 and R.sub.5 are the same, and are optionally substituted aryl or heteroaryl. In some examples, R4 and R5 are linked, and R.sub.4 and R.sub.5 are linked, where both linking groups are the same. The present disclosure also discusses methods of asymmetric reduction of an imine, and methods of forming the catalysts and pre-catalysts.

##STR00001##

Synthesis of organic compounds that has chirality is an important technique in the fields of pharmaceuticals, agrichemicals, health foods and the like. However, raw materials of a catalyst used for the synthesis of such compounds are expensive, and the synthesis needs many steps, so that it is difficult to reduce the cost. Linking a catalyst center to a polymer chain or a resin through an organic group enables to use the catalyst repeatedly and produce a chiral compound at low cost.

The present disclosure provides a method for efficiently producing and providing compounds having a spirooxindole skeleton, for example compounds having a spirooxindole skeleton and having antitumor activity that inhibit the interaction between Mdm2 protein and p53 protein, or intermediates thereof, using an asymmetric catalyst. Compounds having optically active tricyclic dispiroindole skeletons are obtained through catalytic asymmetric 1,3-dipolar cycloaddition reaction using ketimine as a reaction substrate and using a chiral ligand and a Lewis acid.