Bicycloheptanes as meta-Substituted Arene Bioisosteres

Key words

bioisosteres - bicycloheptanes - [3.1.1]propellane - meta-substitution

Significance

Over the past decade, bicyclo­pentanes (BCPs) have emerged as arene bioisosters in medicinal chemistry. However, BCPs are limited to serve as bioisosteric replacements for unsubstituted and para-substituted arenes. To address this, Anderson and co-workers have developed a synthesis of a variety of bicycloheptanes (BCHeps) and have demonstrated their value as bioisosteric replacements for meta-substituted arenes.

Comment

Anderson and co-workers have demonstrated ring-opening difunctionalization of [3.1.1]propellane via several reaction conditions including photoredox- and metallaphotoredox-­catalyzed cross-couplings. Reaction products such as intermediate A could be further functionalized through Kumada coupling (shown) or lithium–­halogen exchange/electrophile capture. The synthesis of BCHep analogues of sonidegib (BCHep-sonidegib) and URB597 (not shown) were exemplified. In line with the outlined hypothesis, the BCHep analogues of these active pharmaceutical ingredients (APIs) were shown to provide similar vector projections and physicochemical properties with improvements in in vitro clearance and membrane permeability in comparison to the parent meta-substituted arene APIs.

Publication History

Article published online:
14 April 2023