Expanded substrate scope and catalyst optimization for the catalytic kinetic resolution of N-heterocycles

Abstract

The scope, reactivity, and selectivity of the chiral hydroxamic acid-catalyzed kinetic resolution of chiral amines are improved by a new catalyst structure and a more environmentally friendly reaction protocol. In addition to increasing selectivity across all substrates, these conditions make possible the resolution of N-heterocycles containing lactams or other basic functional groups that can inhibit the catalyst.

Stereoelectronic Basis for the Kinetic Resolution of N‐Heterocycles with Chiral Acylating Reagents

“…The catalytic kinetic resolution of 3‐benzylmorpholine 1 with a chiral hydroxamic acid proceeds with good selectivity (s=29) 5b. This is sufficient for isolating recovered starting material in enantiopure form,1b but is not suitable for preparing the amides with sufficient enantioselectivity or for dynamic kinetic resolutions.…”

“…For initial studies, we selected ( S )‐ O‐ Me‐mandelic acid, which is readily prepared8 or commercially available. The stoichiometric reagent prepared with (4a R ,9a S )‐hydroxamic acid5b gave a modest increase in selectivity (Table 1, entry 1). Surprisingly, the reagent prepared from ( R )‐ O ‐Me‐mandelic acid and the (4a R ,9a S )‐hydroxamic acid was completely unselective (entry 2), prompting a further investigation into the nature of the leaving group.…”

A NADH-accepting imine reductase variant: Immobilization and cofactor regeneration by oxidative deamination

“…Therefore, a variety of chemical methods for the asymmetric synthesis of enantiopure amines were developed, albeit their eco-efficient preparation remains challenging (Ghislieri and Turner, 2014). Options for secondary amine synthesis include organocatalytic or transition-metal catalyzed hydrogenation of imines (Gamenara and Domínguez de Maria, 2014;Hsieh et al, 2012;Li and Xiao, 2008). Even though much progress was made in the last decades, numerous (de)protection steps and the application of expensive and toxic metals (Nugent and El-Shazly, 2010) are necessary.…”

A Late-Stage Strategy for the Functionalization of Triazolium-Based NHC Catalysts

“…We were inspired by work of Bode and coworkers, who reported the selective bromination of the amide precursor. We envision that a halo-indanol adduct, accessible via a selective bromination, 12 would serve as a suitable substrate in a Suzuki-Miyaura cross-coupling reactions. 13 A potential issue with this approach is the basic conditions required for this transformation, which can deprotonate the triazolium to form the reactive carbene.…”