Spirocyclic Azetidines as Lactam Bioisosteres in Isoindolinones Through Facile C1 Stitching Enabled by Dual Energy- and Electron-Transfer Photocatalysis
- 1Energy and Environmental Nanotech Platform, National University of Singapore (Suzhou) Research Institute, No.377 Linquan Street, Suzhou, Jiangsu, China
- 2Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore, 117543
Abstract
Bioisosteric replacement of nitrogen-containing cyclic structures with smaller, more conformationally rigid ring systems such as azetidines and spirocyclic azetidines has emerged as an effective strategy to improve the physicochemical and pharmacokinetic profiles of nitrogen-bearing drug candidates. Despite extensive studies, the use of spirocyclic azetidines as bioisosteres has been limited to simple ring systems and has not been extended to medicinally relevant complex pharmacophores. Herein, we introduce benzo-fused spirocyclic azetidines as three-dimensional bioisosteres of lactam moieties in isoindolinones, significant structural motifs present in >40,000 bioactive compounds. Our synthetic strategy is to “stitch” in one step a broad range of oxadiazoline carbene precursors and substituted 1-azabicyclo[1.1.0]butanes (ABBs), thus accessing structurally diverse spirocyclic azetidines. This reaction is mechanistically novel, merging strain-release activation of ABB with a dual energy-transfer/single-electron-transfer photocatalytic cascade, enabling formal C1-insertion under mild conditions. The physicochemical and metabolic profiling suggests that these spirocyclic azetidine bioisosteres retain key physicochemical properties while improving metabolic stability. Moreover, docking studies indicate conserved recognition with the potential for interaction rewiring at selected targets. Given the ubiquitous presence of lactam and amide-containing motifs in bioactive molecules and drug candidates, this work opens new avenues for drug discovery and clinical development.
Related
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- Condition-Controlled Divergent Reactivity of Nitroaldol Isatin Adducts with Phenols: Friedel–Crafts Alkylation, Skeletal Rearrangement, and Spirocyclic Oxime Formation
- Modular synthesis of functionalized azetidines through visible-light copper-catalyzed carboamination of 1,3-dienes with azabicyclo[1.1.0]butanes
BibTeX
@misc{shen2026spirocyclic,
title = {{Spirocyclic Azetidines as Lactam Bioisosteres in Isoindolinones Through Facile C1 Stitching Enabled by Dual Energy- and Electron-Transfer Photocatalysis}},
author = {Zi-An Shen and Mengyang Zhang and Sirui Wu and Yixin Lu},
howpublished = {ChemRxiv},
year = {2026},
month = oct,
doi = {10.26434/chemrxiv.15010214/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010214/v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Spirocyclic Azetidines as Lactam Bioisosteres in Isoindolinones Through Facile C1 Stitching Enabled by Dual Energy- and Electron-Transfer Photocatalysis
AU - Zi-An Shen
AU - Mengyang Zhang
AU - Sirui Wu
AU - Yixin Lu
PY - 2026
DA - 2026/10/11
PB - ChemRxiv
DO - 10.26434/chemrxiv.15010214/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010214/v1
AB - Bioisosteric replacement of nitrogen-containing cyclic structures with smaller, more conformationally rigid ring systems such as azetidines and spirocyclic azetidines has emerged as an effective strategy to improve the physicochemical and pharmacokinetic profiles of nitrogen-bearing drug candidates. Despite extensive studies, the use of spirocyclic azetidines as bioisosteres has been limited to simple ring systems and has not been extended to medicinally relevant complex pharmacophores. Herein, we introduce benzo-fused spirocyclic azetidines as three-dimensional bioisosteres of lactam moieties in isoindolinones, significant structural motifs present in >40,000 bioactive compounds. Our synthetic strategy is to “stitch” in one step a broad range of oxadiazoline carbene precursors and substituted 1-azabicyclo[1.1.0]butanes (ABBs), thus accessing structurally diverse spirocyclic azetidines. This reaction is mechanistically novel, merging strain-release activation of ABB with a dual energy-transfer/single-electron-transfer photocatalytic cascade, enabling formal C1-insertion under mild conditions. The physicochemical and metabolic profiling suggests that these spirocyclic azetidine bioisosteres retain key physicochemical properties while improving metabolic stability. Moreover, docking studies indicate conserved recognition with the potential for interaction rewiring at selected targets. Given the ubiquitous presence of lactam and amide-containing motifs in bioactive molecules and drug candidates, this work opens new avenues for drug discovery and clinical development.
ER -