Enantiodivergent One‐Pot Synthesis of Axially Chiral Biaryls Using Organocatalyst‐Mediated Enantioselective Domino Reaction and Central‐to‐Axial Chirality Conversion

Abstract

Enantiodivergent one‐pot synthesis of biaryls was developed using a catalytic amount of a single chiral source. A domino organocatalyst‐mediated enantioselective Michael reaction and aldol condensation provided centrally chiral dihydronaphthalenes with excellent enantioselectivity, from which an enantiodivergent chirality conversion from central‐to‐axial chirality was achieved. Both enantiomers of biaryls were obtained with excellent enantioselectivity. All transformations can be conducted in a single reaction vessel. A plausible reaction mechanism for the enantiodivergence is proposed.

Enantioselective Synthesis of Atropisomers by Oxidative Aromatization with Central-to-Axial Conversion of Chirality

“…In 2021, Hayashi’s group reported an enantiodivergent synthesis of axially chiral biaryls ( Scheme 26 ) [ 144 ]. This one-pot synthesis incorporates a multiple-step strategy, starting with an aminocatalyzed one-pot enantioselective Michael reaction and aldol condensation domino reaction between 2-(nitromethyl)benzaldehydes 108 and substituted cinnamaldehydes 107 to give the chiral intermediate 109 in up to 99% ee .…”

Recent advances in the catalytic asymmetric construction of atropisomers by central-to-axial chirality transfer

“…Inspired by this report, the first one-pot enantiodivergent synthesis of axially chiral biaryls via an organocatalyzed domino reaction and central-to-axial chirality transfer was developed very recently by the same group in 2021. 50…”

Atroposelective Construction of Axially Chiral 2-Aryl-Pyrroloquinolones

“…The latter was predictable since the bromine atom is no longer in close proximity with the tricyclic core due to bond angles in 5-membered aromatic systems (119°in 4m vs 114°in 4s). We then examined the configurational stability of quinolone 5a by determining experimentally 20 and theoretically 21 the enantiomerization Gibbs free energy barrier (ΔG ‡) and the racemization half-time (Scheme 3, bottom). We found that the racemization half-time of 5a was higher than 14 days at 110 °C, which ranks this compound in Class 3 atropisomer and corresponds to configurationally robust molecules.…”