An Operationally Simple and Mild Oxidative Homocoupling of Aryl Boronic Esters To Access Conformationally Constrained Macrocycles

Constrained macrocyclic
scaffolds are recognized as challenging
synthetic motifs with few general macrocyclization methods capable
of accessing these types of systems. Although palladium catalyzed
oxidative homocoupling of aryl boronic acids and esters to biphenyls
has been recognized as a common byproduct in Suzuki–Miyaura
cross-couplings for decades, this reactivity has not been leveraged
for the synthesis of challenging molecules. Here we report an oxidative
boronic ester homocoupling reaction as a mild method for the synthesis
of strained and conformationally restricted macrocycles. Higher yields
and better efficiencies are observed for intramolecular diboronic
ester homocouplings when directly compared to the analogous intramolecular
Suzuki–Miyaura cross-couplings or reductive Yamamoto homocouplings.
Substrates included strained polyphenylene macrocycles, strained cycloalkynes,
and a key macrocyclic intermediate toward the synthesis of acerogenin
A. Notably, this oxidative homocoupling reaction is performed at room
temperature, open to atmosphere, and without the need to rigorously
exclude water, thus representing an operationally simple alternative
to traditional cross-coupling macrocyclizations. The mechanism of
the reaction was investigated indicating that 1–5 nm palladium
nanoparticles may serve as the active catalyst.