Atropisomerization Barriers of Configurationally Unstable Biaryl Compounds, Useful Substrates for Atroposelective Conversions to Axially Chiral Biaryls

Abstract

Configurationally unstable biaryl lactones of type (M)-1 ⇌ (P)-1 and ring-opened 2-acyl-2‘-hydroxy biaryl compounds of type (M)-4 ⇌ (P)-4 are versatile precursors for the atroposelective preparation of axially chiral biaryls. The activation barriers of their atropisomerization process, which constitutes a fundamental precondition for the dynamic kinetic resolution, were determined by dynamic NMR spectroscopy for rapid processes and by HPLC-monitored racemization of enantiomerically enriched material for smaller interconversion rates. For the lactones, the free activation energies ΔG⧧298 increase with the steric demand of the substituent R ortho to the biaryl axis in the series H < OMe (t1/2 ≈ ms) < Me (t1/2 ≈ s) < Et < i-Pr (t1/2 ≈ min) < t-Bu (t1/2 ≈ d). The formally ring-opened 2-acyl-2‘-hydroxy biaryls, which interconvert via the lactol isomers 5 as the cyclic (and thus configurationally less stable) intermediates, have a significantly slower atropisomerization rate as a result of the high loss in activation entropy ΔS⧧ as a consequence of the required intermediate ring closure 4 → 5.