Highly enantioselective catalytic asymmetric synthesis of a (R)-sibutramin precursor.

The first highly enantioselective, catalytic asymmetric synthesis of di-des-methylsibutramine 3 is described. Dienamide 10, prepared by acetic acid anhydride quenching of the condensation product of nitrile 4 with a methallyl magnesium chloride, proved to be an excellent substrate for ruthenium-catalyzed asymmetric hydrogenation with atropisomeric diphosphine ligands. Hydrogenation with a ruthenium/(R)- MeOBiPheP catalyst at S/C = 500, gave the chiral amide (R)-9 in 98.

Highly efficient asymmetric synthesis of sitagliptin.

A highly efficient synthesis of sitagliptin, a potent and selective DPP-4 inhibitor for the treatment of type 2 diabetes mellitus (T2DM), has been developed. The key dehydrositagliptin intermediate 9 is prepared in three steps in one pot and directly isolated in 82% yield and >99.6 wt % purity.

Chemical optimization of artificial metalloenzymes based on the biotin-avidin technology: (S)-selective and solvent-tolerant hydrogenation catalysts via the introduction of chiral amino acid spacers.

Incorporation of biotinylated-[rhodium(diphosphine)]+ complexes, with enantiopure amino acid spacers, in streptavidin affords solvent-tolerant and selective artificial metalloenzymes: up to 91% ee (S) in the hydrogenation of N-protected dehydroamino acids.

Exploring stereogenic phosphorus: synthetic strategies for diphosphines containing bulky, highly symmetric substituents.

Diphosphine ligands bearing highly symmetric, bulky substituents at a stereogenic P atom were prepared, exploiting established protocols, which include the use of chiral synthons such as 3,4-dimethyl-2,5-diphenyl-1,3,2-oxazaphospholidine-2-borane (3a) and phenylmethylchlorophosphine borane (10) and the enantioselective deprotonation of dimethylarylphosphine boranes. However, only (Bu(t)())(Me)PCH(2)CH(2)P(Bu(t)Me (8a) could be prepared from 3a. The diphosphines (S,S)-1,2-bis(mesitylmethylphosphino)ethane, ((S,S)-8b) and (S,S)-1,2-bis(9-anthrylmethylphosphino)ethane ((S,S)-8c), which contain 2,6-disubstituted aryl P-substituents, were prepared by Evans' sparteine-assisted enantioselective deprotonation of P(Ar)(Me)(2)(BH(3)) (Ar = mesityl or 9-anthryl), but the enantioselectivity did not exceed 37% ee.

New Homochiral Ligands Bearing Nonstereogenic Chirotopic Centers. Lithiated N,N'-Dialkylureas as Chiral Bases and Sterically Crowded Phosphines for Asymmetric Catalysis.

The synthesis of new homochiral pseudo-C(2)()-symmetrical ligands of type 1 bearing a nonstereogenic chirotopic center is reported. Two such structural units are combined in the ureas 2 and 10, which proved to be useful for enantioselective deprotonation and alkylation of ketones (up to 88% ee). The monophosphine 3 induced a high enantiomeric excess in the Pd-catalyzed allylation of dimethyl malonate (up to 73% ee).

New Chiral Ligands with Nonstereogenic Chirotopic Centers for Asymmetric Synthesis.

Pseudo-C -symmetrical ligands have been prepared efficiently: The attachment of the chiral alkyl group to the heteroatom (P or N) through a nonstereogenic, chirotopic carbon center facilitates their synthesis as the configuration at this carbon atom no longer needs to be controlled. Two such ligands were combined, for example, in the base 1, which is especially useful for asymmetric deprotonation of prochiral ketones [Eq. (a)].