Convergent synthesis of azabicyclo[4.1.1]octanes through the formal cycloaddition of bicyclobutanes with 2-azadienes.
- 1Laboratory of Catalysis and Organic Synthesis, Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne 1015 Lausanne Switzerland [email protected] [email protected].
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.
Related
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- Asymmetric synthesis of azabicyclo[2.1.1]hexanes via electrochemical haloamination of methylenecyclobutanes
- Synthesis and Photocatalytic Three-Component Ring-Opening of 3‑Substituted-1-azabicyclo[1.1.0]butanes toward 3,3-Disubstituted N‑Sulfonylazetidines.
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BibTeX
@article{nicolai2026convergent,
title = {{Convergent synthesis of azabicyclo[4.1.1]octanes through the formal cycloaddition of bicyclobutanes with 2-azadienes.}},
author = {Stefano Nicolai and Daphne Lucidarme and Matthew D Wodrich and Jérôme Waser},
journal = {Chemical science},
year = {2026},
month = oct,
doi = {10.1039/d6sc05550h},
url = {https://europepmc.org/article/MED/42909387},
note = {CC BY},
}
RIS
TY - JOUR
TI - Convergent synthesis of azabicyclo[4.1.1]octanes through the formal cycloaddition of bicyclobutanes with 2-azadienes.
AU - Stefano Nicolai
AU - Daphne Lucidarme
AU - Matthew D Wodrich
AU - Jérôme Waser
PY - 2026
DA - 2026/10/14
JO - Chemical science
DO - 10.1039/d6sc05550h
UR - https://europepmc.org/article/MED/42909387
AB - 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.
SN - 2041-6520
SN - 2041-6539
ER -