Asymmetric Reductive Amination of α-Keto Acids Using Ir-Based Hydrogen Transfer Catalysts: An Access to Unprotected Unnatural α-Amino Acids.

A direct asymmetric reductive amination of α-keto acids catalyzed by Cp*Ir complexes bearing a chiral -(2-picolyl)sulfonamidato ligand is described. The combined use of optically active 2-phenyglycinol as an aminating agent is effective for the chemo- and stereoselective transfer hydrogenation using formic acid. The subsequent elimination of the hydroxyethyl moiety by orthoperiodic acid can afford various unprotected α-amino acids in satisfactory isolated yields (20 examples) with excellent optical purities (up to >99% ee).

Asymmetric Hydrogenation of α-Alkyl-Substituted β-Keto Esters and Amides through Dynamic Kinetic Resolution.

Asymmetric hydrogenation of α-alkyl-substituted β-keto esters and amides with the DIPSkewphos/3-AMIQ-Ru(II) catalyst system through dynamic kinetic resolution was examined. A series of β-keto esters and amides with a simple or functionalized α-alkyl group were applicable to this reaction, affording the α-substituted β-hydroxy esters and amides in ≥99% ee (/ ≥ 99:1) in many cases. The 5 g scale reaction was readily achieved.

Asymmetric Transfer Hydrogenative Amination of Benzylic Ketones Catalyzed by Cp*Ir(III) Complexes Bearing a Chiral -(2-Picolyl)sulfonamidato Ligand.

A convenient asymmetric reductive amination of benzylic ketones (α-arylated ketones) catalyzed by newly designed Cp*Ir complexes bearing a chiral -(2-picolyl)sulfonamidato ligand was developed. Using readily available β-amino alcohols as chiral aminating agents, a range of benzo-fused and acyclic ketones were successfully reduced with formic acid in methanol at 40 °C to afford amines with favorable chemo- and diastereoselectivities. The amino alcohol-derived chiral auxiliary was easily removed by mild periodic oxidants, leading to optically active primary β-arylamines without erosion of the optical purity (up to 97% ).

Asymmetric hydrogenation of alkynyl ketones with the η(6)-arene/TsDPEN-ruthenium(II) catalyst.

Enantioselective hydrogenation of alkynyl ketones catalyzed by Ru(OTf)(TsDPEN)(η(6)-p-cymene) (TsDPEN = N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine) affords the propargylic alcohols in up to 97% ee. The alkynyl moieties are left intact in most cases. The reaction can be conducted with a substrate-to-catalyst molar ratio as high as 5000 under 10 atm of H2.

Chiral eta(6)-arene/N-tosylethylenediamine-ruthenium(II) complexes: solution behavior and catalytic activity for asymmetric hydrogenation.

Aromatic ketones are enantioseletively hydrogenated in alcohols containing [RuX{(S,S)-Tsdpen}(eta(6)-p-cymene)] (Tsdpen=TsNCH(C(6)H(5))CH(C(6)H(5))NH(2); X=TfO, Cl) as precatalysts. The corresponding Ru hydride (X=H) acts as a reducing species. The solution structures and complete spectral assignment of these complexes have been determined using 2D NMR ((1)H-(1)H DQF-COSY, (1)H-(13)C HMQC, (1)H-(15)N HSQC, and (1)H-(19)F HOESY).

Asymmetric hydrogenation of alpha-hydroxy ketones catalyzed by MsDPEN-Cp*Ir(III) complex.

Asymmetric hydrogenation of a series of alpha-hydroxy aromatic ketones in methanol catalyzed by Cp*Ir(OTf)(MsDPEN) (MsDPEN = N-(methanesulfonyl)-1,2-diphenylethylenediamine) affords the 1-aryl-1,2-ethanediols in up to 99% ee. The reaction can be conducted with a substrate-to-catalyst molar ratio as high as 6000 under 10 atm of H2. 1-hydroxy-2-propanone is also hydrogenated with high enantioselectivity.

Asymmetric hydrogenation of alpha-chloro aromatic ketones catalyzed by eta6-arene/TsDPEN-ruthenium(II) complexes.

Asymmetric hydrogenation of various alpha-chloro aromatic ketones with Ru(OTf)(TsDPEN)(eta6-arene) (TsDPEN = N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine) produces the chiral chlorohydrins in up to 98% ee. This reaction can be conducted even on a 206-g scale. The hydrogenation of an alpha-chloro ketone with a phenol moiety has been utilized for the synthesis of (R)-norphenylephrine without protection-deprotection operations.

The hydrogenation/transfer hydrogenation network: asymmetric hydrogenation of ketones with chiral eta6-arene/N-Tosylethylenediamine-ruthenium(II) catalysts.

Chiral eta6-arene/N-tosylethylenediamine-Ru(II) complexes, known as excellent catalysts for asymmetric transfer hydrogenation of aromatic ketones in basic 2-propanol, can be used for asymmetric hydrogenation using H2 gas. Active catalysts are generated from RuCl[(S,S)-TsNCH(C6H5)CH(C6H5)NH2](eta6-p-cymene) in methanol, but not 2-propanol, or by combination of Ru[(S,S)-TsNCH(C6H5)CH(C6H5)NH](eta6-p-cymene) and CF3SO3H or other non-nucleophilic acids. This method allows, for the first time, asymmetric hydrogenation of simple ketones under acidic conditions.