Practical and Facile Access to Bicyclo[3.1.1]heptanes: Potent Bioisosteres of meta-Substituted Benzenes

Abstract

There is increasing interest in replacement of the planar aromatic rings of drug candidates with three-dimensional caged scaffolds in order to improve the physical properties, but bioisosteres of meta-substituted benzenes have remained elusive. We focused on the bicyclo[3.1.1]­heptane (BCH) scaffold as a novel bioisostere of meta-substituted benzenes, anticipating that [3.1.1]­propellane (2) would be a versatile precursor of diversely functionalized BCHs. Here, we describe a practical preparative method for [3.1.1]­propellane from newly developed 1,5-diiodobicyclo[3.1.1]­heptane (1), as well as difunctionalization reactions of 2 leading to functionalized BCHs. We also report postfunctionalization reactions of these products.

Photochemical Intermolecular [3σ + 2σ]-Cycloaddition for the Construction of Aminobicyclo[3.1.1]heptanes

“…This reaction design would provide unique functionalized bicyclo[3.1.1]­heptanes, which expands chemical space because of the several diversifiable positions on the bicyclo[3.1.1]­heptane ring. Additionally, this bicyclic motif can potentially act as a precise meta-substituted arene bioisostere . This photocatalytic approach would overcome the challenge for the construction of multifunctionalized bicyclo[3.1.1]­heptanes in a sustainable and straightforward manner.…”

Synthese im Blickpunkt: Bioisosteres of meta‐substituted benzenes

“…A few months later, an alternative route strategy to access (5) was published by Uchiyama, Hi rano and co-workers (Figure 2c). 13) The key feature of their strategy is to access 1,5-diiodobicyclo[3.1.1]propellane (9) (I 2 -BCH), a bench stable solid that can be readily converted into (5) through a fast halogenmetal exchange step. Their devised synthesis starts from the commercially available dicarboxylic acid (10) that, after esterification, is functionalised at the α-position with diiodomethane to form (11).…”

Selective [2σ + 2σ] Cycloaddition Enabled by Boronyl Radical Catalysis: Synthesis of Highly Substituted Bicyclo[3.1.1]heptanes

“…Saturated rings with well-defined 3D shape have frequently emerged in drug discovery under the concept “escape from flatland” . Among them, bicyclo[3.1.1]­heptane (BCH) has recently been employed as an effective 3D bioisostere of benzene . In fact, BCH-containing natural products, such as α-pinene and massarinolin A, have long been investigated either directly or as key synthetic intermediates for biomedical purposes .…”

“…The typical synthesis necessitated an intramolecular reaction of a suitably functionalized substrate, such as the biosynthetic cyclization of limonene-type molecules, photochemical cross [2π + 2π] cycloaddition of 1,6-dienes, or ring contraction of bicyclo[3.2.1]­octanes . Very recently, elegant three component approaches using preformed [3.1.1] propellane as a reactant has been employed for efficient synthesis of bridge-substituted BCHs . Despite the advancement, more flexible routes for diversely substituted BCHs have remained highly desirable.…”