Decarboxylative functionalization strategy for rapid assembly of bifunctional adamantane meta-arene bioisosteres.

The use of rigid saturated bioisosteres as replacements for aromatic rings has emerged as a powerful strategy for improving the physiochemical and pharmacokinetic profiles of medicinal lead compounds. While significant progress has been made in developing surrogates for para-substituted arenes, practical access to meta-arene bioisosteres remains a significant challenge. We describe a strategy to convert the inexpensive, commercially available feedstock 1,3-adamantanedicarboxylic acid into diverse disubstituted adamantanes whose geometric properties are a good match for native meta-disubstituted benzenes. The ready availability of robust methods for decarboxylative coupling enables the modular introduction of C-N, C-O, and C-C substituents without the need for de novo synthesis of the adamantyl core.