Hydrogen‐Bond‐Enabled Dynamic Kinetic Resolution of Axially Chiral Amides Mediated by a Chiral Counterion

Abstract

Non‐biaryl atropisomers are valuable in medicine, materials, and catalysis, but their enantioselective synthesis remains a challenge. Herein, a counterion‐mediated O‐alkylation method for the generation of atropisomeric amides with an er up to 99:1 is outlined. This dynamic kinetic resolution is enabled by the observation that the rate of racemization of atropisomeric naphthamides is significantly increased by the presence of an intramolecular O−H⋅⋅⋅NCO hydrogen bond. Upon O‐alkylation of the H‐bond donor, the barrier to rotation is significantly increased. Quantum calculations demonstrate that the intramolecular H‐bond reduces the rotational barrier about the aryl–amide bond, stabilizing the planar transition state for racemization by approximately 40 kJ mol −1 , thereby facilitating the observed dynamic kinetic resolution.

Activation of the Si–B interelement bond related to catalysis

“…Of note, the optimised conditions were applied to other substituted naphth-2-yl ethers including ethyl-, benzyl-, isopropyl-, and tert-butyl naphthyl ethers yet in decreased yields; the benzyl ether in axially chiral naphthamide 399 was directly transformed into arylsilane 395y without loss of enantiopurity (Scheme 144, bottom). 163 The substrate scope could be extended to acyclic vinyl ethers such as 400a-b, thus giving access to E-configured vinylsilanes regardless of the substrate's double bond geometry. Moreover, no particularly significant Z/E isomerization was found for (Z)-400a in the absence of 42.…”

Enantioselective Synthesis of Atropisomers with Multiple Stereogenic Axes

“…Later in 2019, Smith and co-workers established an elegant chiral counterion-mediated O-alkylation of atropisomeric amides in high enantioselectivity via DKR, and two interesting examples for the incorporation of two stereogenic axes were described (Scheme 12). [25] Thek ey racemization process at the Ar-CO axis (in red) of 33 was facilitated by the intramolecular O À H•••NCO hydrogen bond, which was demonstrated by quantum calculations.Thus,with the preinstalled ortho-substituted aryl group at the 8-position, the enantioselective O-alkylation of 33 catalyzed by catalyst II enabled the generation of 1,3-diaxial chiral amides 34 with in good yields and high enantioselectivities for both diastereomers.…”

Inversion of the Axial Information during Oxidative Aromatization in the Synthesis of Axially Chiral Biaryls with Organocatalysis as a Key Step

“…In fact, a bulky base such as potassium hexamethyldisilazide gave excellent enantioselectivity (96 % ee ), whereas lower enantioselectivity (89 % ee ) was observed in the case of a smaller base such as KOMe. Thus, the deprotonation proceeds selectively from R‐inside conformer, affording biaryl 7 with R a axial chirality …”