Stashkevych O,
Kokhalskyi V,
Mynak Y,
Levterov V,
Shablykin O,
Pishel I,
Mykhailiuk PK *.
Enamine Ltd, Kyiv, Ukraine
Bicyclic Isosteres of Pyridine/Piperidine: From Synthesis to Applications.
Angew. Chem. Int. Ed. 2025;
DOI:
10.1002/anie.202517814
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.
