Hydrogen‐Bonding Assisted Catalytic Kinetic Resolution of Acyclic β‐Hydroxy Amides

Abstract

Enantioenriched acyclic a-substituted b-hydroxy amides are valuable compounds in chemical, material and medicinal sciences, but their enantioselective synthesis remains challenging. A catalytic kinetic resolution (KR) of such amides with selectivity factor(s) up to > 200 is developed via enantioselective acylation of primary alcohol with N-heterocyclic carbene. An enhanced selectivity for the catalytic KR process is realized using cyclic tertiary amine as base additive. Diastereomeric transition state models for the process are proposed to rationalize the origin of enantioselectivity. Scheme 1. Previously reported kinetic resolution of alcohol using oxidative NHC-catalysis and this study.

Carbene-catalyzed kinetic resolution of bispirooxindoles: selective lactam amidation and access to challenging chiral scaffolds

“…Molecular sieves (MSs) have been shown to perform an essential role in many NHC-catalyzed asymmetric reactions. 33 Gratifyingly, with 10 mg of a 4 Å MS as an additive, the amidation of lactam was achieved and provided the product (3 S ,4′ R ,5′ R )- 3aa with 96% ee and the recovered (3 R ,4′ S ,5′ S )- 1a with 90% ee, with an S -factor of 245 (Table 1, entry 13). In addition, investigation of the amount of DBU used indicated that increasing it could preserve a comparatively favorable enantioselective performance, whereas reducing it provided a rather inferior result (see ESI Table S1,† and Table 1, entries 9 and 10).…”

Kinetic Resolutions Enabled by N-Heterocyclic Carbene Catalysis: An Update

“…Enantioenriched acyclic α-substituted β-hydroxy amides are valuable pharmacophores and versatile precursors to enantioenriched 1,3-diols, 1,3-amino-alcohols, β-hydroxy acids and β-amino acids, but their enantioselective synthesis remains challenging. Recently, Guin et al [18] realized the kinetic resolution of acyclic α-substituted β-hydroxy amides utilizing enantioselective acylation of primary alcohol via oxidative NHC catalysis (Scheme 12). The selectivity factor (s) was up to ＞200.…”

N-Heterocyclic carbene catalyzed desymmetrization of diols: access to enantioenriched oxindoles having a C3-quaternary stereocenter

“…Our group is interested in developing new asymmetric organic transformations with NHC-catalysis. 8 Following our recent study 9 and the literature, 10 we envisaged that the intramolecular hydrogen bonding between diols of achiral 3,3′-bis(hydroxymethyl)oxindoles may lead to a less flexible spiro-cyclic structure, which would ease the selective esterification of one of the alcohols of the substrate by the in situ formed chiral acyl azolium intermediate (Scheme 1b).…”