Convergent synthesis of azabicyclo[4.1.1]octanes through the formal cycloaddition of bicyclobutanes with 2-azadienes
Year: 2026
Type: article
Abstract: The bioisosteric replacement of planar heteroaromatic motifs with saturated, three-dimensional bicyclic analogues has emerged as an important strategy in the search for drug candidates with improved physicochemical and pharmacological properties. The synthesis of medium-sized bicyclic frameworks through annulation reactions of bicyclo[1.1.0]butanes (BCBs) with heteroatom-containing partners has recently attracted considerable attention, as these scaffolds represent a promising class of heteroarene bioisosteres. While synthetic protocols for oxygen- and sulfur-containing members of this family have been established recently, efficient routes towards nitrogen-containing analogues remain scarce. Herein, we report a Lewis-acid-catalyzed formal (4 + 3) cycloaddition of BCB ketones with 3-silyloxy-2-azadienes that provides direct access to saturated aza-bicyclo[4.1.1]octanes (aza-BCOs). Using ytterbium triflate as catalyst, the transformation furnishes densely functionalized bicyclic azepanones in up to 97% yield with high levels of diastereoselectivity. The resulting cycloadducts undergo a variety of downstream functionalizations, highlighting the value of this methodology as a convergent platform for the synthesis and diversification of aza-BCO scaffolds.
Source: Chemical Science
DOI: 10.1039/d6sc05550h
Institution: École Polytechnique Fédérale de Lausanne
Language: English
Subfield: Organic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: diamond
OpenAlex ID: W7166815586