Catalytic Enantioselective Synthesis of Inherently Chiral Macrocycles by Dynamic Kinetic Resolution

Kinetically
fast racemization of chiral substrates through an achiral
intermediate and enantioselective functionalization of one of the
enantiomeric substrates forms the basis of the dynamic kinetic resolution
(DKR) of centrally chiral molecules. We report herein DKR of inherently
chiral macrocycles through enantioselective alkylation of one of the
two rapidly interconverting conformers. Reaction of heteracalixaromatics
with bromomethylarenes in the presence of a catalytic amount of Cinchonine-derived chiral phase transfer catalyst (PTC)
affords inherently chiral O-alkylated products in
90%–99% yields with up to 95% enaniomeric excess. Density functional
theory calculations indicate that a host–guest-like interaction
between the macrocyclic substrate and catalyst effectively differentiates
the reactivity of two enantiomers devoid of chiral elements.