Modular Access to Azabicyclo[2.2.2]octanes and Related Azabicycles

Keywords

iodocyclization - piperidines - pyridines - 1,2-bicyclo[1.1.1]pentanes

Significance

To increase the 3D-character of drug-like molecules, medicinal chemists often employ the strategy of replacing aromatic rings with rigid saturated scaffolds. For example, 2-oxabicyclo[2.2.0]octane can be employed as a saturated bioisostere of benzene with improved properties in terms of water solubility (Nat. Commun. 2023, 14, 5608). Typically, this framework is assembled through an approach based on the iodocyclization of cyclic alkenes, though attempts to extend this to the synthesis of the analogous 2-azabicyclo[2.2.0]octanes led only to poor yields. The current report provides a robust synthesis of a series of azabicycles with varying ring sizes, and also highlights their overall synthetic utility, including their use as starting materials for the preparation of 1,2-bicyclo[1.1.1]pentanes.

Comment

Initial studies focused on development of the iodine-mediated conversion of amino alkenes to form cyclic carbamates for the formation of the bicyclic ring. The choice of base, solvent and the stoichiometry of iodine were critical to realize optimal yields, with a telescoped approach developed for the cyclization sequence allowing access to multigram quantities of a 2-azabicyclo[2.2.2]octane system without isolation of the intermediate cyclic carbamate. These conditions were then applied to a broad range of functionalized N-[2.2.1]-, N-[3.2.1]-, N-[3.1.1]- and N-[2.1.1]azabicycles. A scalable approach was also demonstrated for the transformation of N-[2.1.1]azabicycles into 1,2-bicyclo[1.1.1]pentanes that circumvented previous limitations such as the intermediacy of a propellane and/or the use of photochemistry to access gram quantities of these ortho-benzene mimics. Numerous synthetic transformations of the azabicyclic systems are also exemplified as well as validation of their potential to act as isosteres of either pyridine or piperidine rings in drug development.

Publication History

Article published online:
26 November 2025