Dynamic Kinetic Resolution of Axially Chiral Naphthamides via Atroposelective Allylic Alkylation Reaction

Abstract

Axially chiral amides are usually found in many biologically active compounds and are useful ligands in asymmetric catalysis. Herein, by using the dynamic kinetic resolution approach, an asymmetric allylic alkylation reaction of racemic amide naphthols is disclosed, which leads to generation of the axially chiral naphthamides in good to excellent yields (up to 97%) and enantioselectivities (up to 96:4 e.r.). Density functional theory was used to gain a theoretical understanding of the enantioselectivities in this reaction.

Recent Advances in Catalytic Asymmetric Construction of Atropisomers

“…Diversely, Cheng et al applied asymmetric O-allylic alkylation of amide naphthols 412 using hydroquinine catalyst to derive axially chiral naphthamides 413 that were free of perisubstitution (Scheme 136). 268 A variety of benzyl substituents on MBH carbonates, amide N-substituents as well as C4substitutions on naphthalene ring were well accommodated. With CPA catalysis and tactical fine-tuning of substrates, atroposelective arylation of monocyclic 1,4-benzoquinones 48 with 2-naphthols followed by DDQ oxidation yielded two classes of stable aryl-p-quinone atropisomers (417, 418) that served as atropisomerically pure platform molecules (Scheme 138).…”

“…Diversely, Cheng et al applied asymmetric O -allylic alkylation of amide naphthols 412 using hydroquinine catalyst to derive axially chiral naphthamides 413 that were free of peri -substitution (Scheme ). A variety of benzyl substituents on MBH carbonates, amide N -substituents as well as C4-substitutions on naphthalene ring were well accommodated. Introducing an 8-methoxy substituent on amide naphthol ( 412 - 2 ) increased the rotational barrier of C (carbonyl) –C (aryl) bond by 19.1 kcal/mol (compared to the 8-H analogue) thus enabled kinetic resolution.…”

Organocatalytic Atroposelective Dynamic Kinetic Resolution Involving Ring Manipulations

“…In the same year, Li and colleagues documented a similar strategy for the synthesis of atropisomeric amides by using Morita‐Baylis‐Hillman (MBH) adducts 46 to couple with amide naphthols 44 (Scheme 19). [48] In the presence of 10 mol% of hydroquinine catalyst Cat. 15* , the desired asymmetric allylic alkylation (AAA) reaction proceeded smoothly at −40 °C, giving rise to axially chiral naphthamides 47 in good to excellent yields (up to 97%) and enantioselectivities (up to 92% ee).…”

Stereodynamic Strategies to Induce and Enrich Chirality of Atropisomers at a Late Stage

“…In 2019, Cheng and colleagues described a similar strategy for the atroposelective dynamic kinetic resolution of amides using hydroquinine-catalyzed asymmetric allylic alkylation reaction with Morita−Baylis−Hillman (MBH) adducts to generate enantioenriched naphthamides (Figure 95). 310 starting with the reaction between 95.1 and 95.2, using hydroquinine 95.3 as the optimal catalyst. The solvent, additive, and reaction temperature were further optimized to produce 95.4 in 88% yield and 84% ee.…”