Catalytic Dynamic Kinetic Resolutions in Tandem to Construct Two-Axis Terphenyl Atropisomers

The defined structure
of molecules bearing multiple stereogenic
axes is of increasing relevance to materials science, pharmaceuticals,
and catalysis. However, catalytic enantioselective approaches to control
multiple stereogenic axes remain synthetically challenging. We report
the catalytic synthesis of two-axis terphenyl atropisomers, with complementary
strategies to both chlorinated and brominated variants, formed with
high diastereo- and enantioselectivity. The chemistry proceeds through
a sequence of two distinct dynamic kinetic resolutions: first, an
atroposelective ring opening of Bringmann-type lactones produces a
product with one established axis of chirality, and second, a stereoselective
arene halogenation delivers the product with the second axis of chirality
established. In order to achieve these results, a class of Brønsted
basic guanidinylated peptides, which catalyze an efficient atroposelective
chlorination, is reported for the first time. In addition, a complementary
bromination is reported, which also establishes the second stereogenic
axis. These bromo-terphenyls are accessible following the discovery
that chiral anion phase transfer catalysis by C2-symmetric phosphoric acids allows catalyst control in the
second stereochemistry-determining event. Accordingly, we established
the fully catalyst-controlled stereodivergent synthesis of all possible
chlorinated stereoisomers while also demonstrating diastereodivergence
in the brominated variants, with significant levels of enantioselectivity
in all cases.