Hydroxylation of β-dicarbonyls with zirconium catalysts

A process for preparing a compound of Formula I that is achiral, racemic or enantiomerically enriched at the hydroxylation center indicated by *

• wherein
• R1 is H;
• or alkoxy, alkyl, cycloalkyl, cycloalkoxy, a phenyl ring, a phenoxy ring, each optionally substituted;
• R2 is H;
• or alkyl, cycloalkyl, a phenyl ring, each optionally substituted;
• R3 is H;
• or alkoxy, alkyl, cycloalkyl, cycloalkoxy, a phenyl ring;
• a phenoxy ring, each optionally substituted;
• or
• R2 and R3 can be taken together to form an optionally substituted linking chain of 3 to 6 carbon members, optionally including no more than two carbon members as C(═O), and optionally fused to an optionally substituted phenyl ring;
• or
• R1 and R3 can be taken together to form an optionally substituted linking chain of 2 to 5 carbon members, optionally including no more than one carbon member as C(═O), and optionally fused to an optionally substituted phenyl ring;
• comprising:
• contacting a compound of Formula II
• wherein
• R1, R2 and R3 are as defined above, with a zirconium complex and an oxidant;
• and
• wherein the zirconium complex comprises zirconium and a chiral ligand of Formula III
• or the zirconium complex comprises zirconium and a chiral ligand of Formula ent-III
• wherein
• J is an optionally substituted linking chain of 2 to 4 members consisting of at least one carbon atom member and optionally one member selected from nitrogen and oxygen, of which no more than two carbon atom members are substituted as C(═O);
• the linking chain optionally fused through adjacent linking chain members to 1 or 2 rings or ring systems selected from the group consisting of a C3-C8 cycloalkyl ring, a C3-C8 nonaromatic heterocyclic ring, a phenyl ring and a 1,2-naphthalenyl ring system, each ring or ring system unsubstituted or substituted with at least one moiety other than hydrogen selected from the group consisting of alkyl, haloalkyl, alkoxy, haloalkoxy, halogen and nitro;
• such that the attached nitrogen atoms are held in a stereospecific orientation with respect to J and each other as depicted;
• each R6 is independently selected from the group consisting of halogen;
• NO2;
• cyano;
• C2-C5 alkoxycarbonyl;
• N(C1-C4 alkyl)2;
• CON(C1-C4alkyl)2;
• C1-C4 alkoxy;
• C2-C5 alkylcarbonyloxy;
• C2-C5 alkoxycarbonyloxy;
• optionally substituted phenylcarbonyloxy;
• (C1-C4 alkyl)silyl;
• tri(C1-C4 alkyl)siloxy;
• C1-C4 alkyl optionally substituted with 1-3 phenyl rings;
• C3-C6 cycloalkyl optionally substituted with C1-C2 alkyl;
• adamantyl;
• and a phenyl ring unsubstituted or substituted with at least one moiety other than hydrogen selected from the group consisting of alkyl, haloalkyl, alkoxy, haloalkoxy, halogen and nitro;
• and
• when two R6 are attached to adjacent phenyl ring carbon atoms, said two R6 may be taken together with the phenyl ring to form a naphthalene ring system optionally substituted on either ring of said naphthalene ring system;
• and
• each n is independently an integer from 0 to 4.