Direct Asymmetric Reductive Amination for the Synthesis of (S)-Rivastigmine

Abstract

In this article we demonstrate how asymmetric total synthesis of (S)-rivastigmine has been achieved using direct asymmetric reductive amination as the key transformation in four steps. The route started with readily available and cheap m-hydroxyacetophenone, through esterification, asymmetric reductive amination, N-diphenylmethyl deprotection and reductive amination, to provide the final (S)-rivastigmine in 82% overall yield and 96% enantioselectivity. In the asymmetric reductive amination, catalysed by the iridium–phosphoramidite ligand complex and helped by some additives, the readily prepared 3-acetylphenyl ethyl(methyl)carbamate directly reductively coupled with diphenylmethanamine to yield the chiral amine product in 96% ee and 93% yield.

Reductive Amination in the Synthesis of Pharmaceuticals

“…Chang and Huang et al performed direct asymmetric reductive amination using a benzhydrylamine and iridium phosporamidite catalytic system to form the chiral center (Scheme 16). 37 Methylation was achieved with the use of formaline and NaBH(OAc) 3 . The reductive amination of 2.4.j was carried out on an 80 mg scale (57% RME), and the methylation step was done on a 60 mg scale (8% RME, 8.3 equiv of NaBH(OAc) 3 ).…”

Secondary amines as coupling partners in direct catalytic asymmetric reductive amination

“…Reductive amination (RA) is nature's choice to synthesize essential biomonomers including amino acids inside organisms,7 and the most practical method for the artificial synthesis of pharmaceutical related and bulk fundamental amines 8. As for DARA, since its maiden voyage in the preparation of herbicide metolachlor,9 progress has been made through biocatalysis,10 organocatalysis11 and transition-metal catalysis 12. This research journey is highlighted by its successful application in the production of two pharmaceutical drugs, sitagliptin10 a and suvorexant 12 e .…”

Squaraine Dyes: Interaction with Bovine Serum Albumin to Investigate Supramolecular Adducts with Aggregation‐Induced Emission (AIE) Properties

“…[9,10] AIE is a unique photophysical phenomenon associated with chromophore aggregation.F luorogens with aggregation-induced emission characteristics have recently emerged as an ew class of fluorescent bioprobes for biosensing [11,12] and cell imaging. [13,14] Instead of fluorescenceq uenching, the emission of luminogens with AIE characteristics is turned on when they are aggregated. Suzuki and Yokoyama noticedacolour change of as quaraine dye upon complexation with BSA [15] while the group of Ramaiah showed ah uge enhancementi nf luorescence quantum yields for as quaraine binding to BSA.…”