Catalytic Asymmetric Reductive Condensation of N–H Imines: Synthesis of C2‐Symmetric Secondary Amines

A highly diastereoselective and enantioselective Brønsted acid catalyzed reductive condensation of N?H imines was developed. This reaction is catalyzed by a chiral disulfonimide (DSI), uses Hantzsch esters as a hydrogen source, and delivers useful C₂‐symmetric secondary amines.     

Highly Enantioselective Hetero-Diels-Alder Reaction of 1,3-Bis(silyloxy)-1,3-dienes with Aldehydes Catalyzed by Chiral Disulfonimide

Bulking up with F: The title reaction proceeds using 1?mol?% of the new perfluoroisopropyl chiral disulfonimide catalyst 1 to deliver several 2,6-disubstituted and 2,5,6-trisubstituted dihydropyrones in good yields and with excellent enantiomeric ratios. The utility of this methodology is illustrated with the first enantioselective synthesis of a potent aromatase inhibitor.     

Organocatalytic Enantioselective Mukaiyama–Mannich Reaction of Isatin-Derived Ketimines for the Synthesis of Oxindolyl-β3, 3-Amino Acid Esters

Mukaiyama–Mannich reactions of ester enolate equivalents with aldimines have been elegantly used for the asymmetric synthesis of β-amino acids; nevertheless, the corresponding asymmetric reaction employing ketimines are unexplored. Herein, the first organocatalytic enantioselective Mukaiyama–Mannich reaction employing isatin-derived ketimines with unsubstituted silyl ketene acetals is disclosed towards the scalable synthesis of 2-oxoindolinyl-β^{3, 3}-amino acid esters at room temperature with excellent enantioselectivities (ee >99.5 %). Ultra-low catalyst loadings (as low as 250 ppm) could be used for the quantitative product formation with high enantiopurity. The synthetic utility of this protocol has been showcased in the short formal synthesis of pharmaceutically demanded (+)-AG-041R, a potent gastrin/CCK-B receptor antagonist.     

Deracemizing α‐Branched Carboxylic Acids by Catalytic Asymmetric Protonation of Bis‐Silyl Ketene Acetals with Water or Methanol

We report a highly enantioselective catalytic protonation of bis‐silyl ketene acetals. Our method delivers α‐branched carboxylic acids, including nonsteroidal anti‐inflammatory arylpropionic acids such as Ibuprofen, in high enantiomeric purity and high yields. The process can be incorporated in an overall deracemization of α‐branched carboxylic acids, involving a double deprotonation and silylation followed by the catalytic asymmetric protonation.     

Disulfonimide‐Catalyzed Asymmetric Reduction of N‐Alkyl Imines

A chiral disulfonimide (DSI)‐catalyzed asymmetric reduction of N‐alkyl imines with Hantzsch esters as a hydrogen source in the presence of Boc₂O has been developed. The reaction delivers Boc‐protected N‐alkyl amines with excellent yields and enantioselectivity. The method tolerates a large variety of alkyl amines, thus illustrating potential for a general reductive cross‐coupling of ketones with diverse amines, and it was applied in the synthesis of the pharmaceuticals (S)‐Rivastigmine, NPS R‐568 Hydrochloride, and (R)‐Fendiline.