Yb(OTf) <sub>3</sub> -Catalyzed [2π + 2σ] Cycloaddition of Bicyclo[1.1.0]butanes with Methylenimines for Modular Synthesis of 1,2,4-Trisubstituted 2-Aza-bicyclo[2.1.1]hexanes
Aromatic rings in drug candidates often exhibit poor developability. Three-dimensional bioisosteres like aza-bicyclo[2.1.1]hexanes (aza-BCHs) improve properties but face limited synthetic access to diverse substitutions. Herein, we report a Yb(OTf)<sub>3</sub>-catalyzed [2π + 2σ] cycloaddition of methylenimines with bicyclobutanes (BCBs), featuring mild conditions, a broad substrate scope, and functional group tolerance. Compatibility with different substitution types of BCBs, amino acid-derived methylenimines, and complex bioactive molecule-derived imines was demonstrated, with gram-scale synthesis and downstream derivatization validating practical utility, expanding the toolbox for 3D heterocyclic scaffolds in drug discovery.
Authors
- Huanping Xie (ORCID: https://orcid.org/0000-0003-3289-2384)
- Yi Heng Cao (ORCID: https://orcid.org/0000-0001-7718-0394)
- Xiaowen Yu (ORCID: https://orcid.org/0000-0002-5757-4983)
- Weiguang Kong
- Ting Li
- Heyun Sheng
- Guodong Jiao
Institutions
- Nanyang Normal University (CN)
- Pharmaceutical Biotechnology (Czechia) (CZ)
Publication Details
- Journal
- Organic Letters
- Published
- 2026-02-12
- DOI
- https://doi.org/10.1021/acs.orglett.6c00360
- Primary Topic
- Cyclopropane Reaction Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 0.00