Practical synthesis of 3-Oxa/Aza-bicyclo[3.1.1]heptanes from 3-Oxa/Aza[3.1.1]propellanes

Abstract

While bicyclo[1.1.1]pentanes (BCPs) and bicyclo[3.1.1]heptanes (BCHeps) serve as established 3D bioisosteres for para- and meta-substituted benzenes, accessible via ring-opening of their corresponding propellanes, the integration of heteroatoms into these propellane scaffolds has remained elusive. Herein, we report the practical synthesis of 3-oxa/aza[3.1.1]propellanes, two heteroatom-containing analogues of propellane, from 1,5-diiodo-3-hetero-BCHeps. On this basis, radical-based transformations of 3-oxa/aza[3.1.1]propellane are established, enabling efficient and divergent access to a broad range of bridgehead-disubstituted 3-oxa/aza-BCHep derivatives as saturated isosteres of meta-substituted benzenes. Furthermore, representative 3-oxa-BCHep derivatives are converted into functionalized synthetic building blocks; this scaffold is also introduced into the antiepileptic drug URB597 and anticancer drug sonidegib. These results demonstrate that the 3-oxa/aza[3.1.1] frameworks provide a general and feasible synthetic platform for the construction of heteroatom-containing cage-like bioisosteres and the optimization of drug properties. While bicyclo[1.1.1]pentanes (BCPs) and bicyclo[3.1.1]heptanes (BCHeps) serve as established 3D bioisosteres for para- and meta-substituted benzenes, accessible via ring-opening of their corresponding propellanes, the integration of heteroatoms into these propellane scaffolds has remained elusive. Herein, the authors report the practical synthesis of 3-oxa/aza[3.1.1]propellanes, two heteroatom-containing analogues of propellane, from 1,5-diiodo-3-hetero-BCHeps.