Enantioselective Strain-Release Formal (3 + 3) Cycloaddition of 1-Azabicyclo[1.1.0]butanes to Chiral 1,4-Diazabicyclo[3.1.1]heptanes via Relay Dy/Ir Catalysis
Abstract
*Email: [email protected]; [email protected] ABSTRACT: Pyrazines and piperazines are privileged 1,4-diaza motifs, yet neither combines conformational rigidity with a stereochemically defined three-dimensional shape. Here we report the first catalytic enantioselective formal (3 + 3) cycloaddition of 1-azabicyclo[1.1.0]butanes (ABBs), providing direct access to enantioenriched 1,4diazabicyclo[3.1.1]heptanes—rigid, C(sp3)-rich scaffolds that serve as chiral three-dimensional complements to these classical motifs. Relay Dy/Ir catalysis merges Dy(OTf)3-promoted ABB strain release with iridium-catalyzed asymmetric allylic amination of allylamine-derived N,C,C synthons, extending ABB chemistry beyond conventional strain-release functionalization and previously reported racemic cycloadditions. The method furnishes 50 examples in up to 93% yield and 99% ee, with broad functional-group tolerance and compatibility with drug- and natural-product-derived substrates. Control experiments, 1H NMR studies, and DFT calculations support a staged mechanism involving carbonyl-assisted N,O-bidentate activation of the ABB by Dy(OTf)3. Preparative-scale synthesis, orthogonal product diversification, and access to pyrazineand piperazine-related drug analogues demonstrate the synthetic versatility and scaffold-hopping potential of this platform.
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BibTeX
@misc{jin2026enantioselective,
title = {{Enantioselective Strain-Release Formal (3 + 3) Cycloaddition of 1-Azabicyclo[1.1.0]butanes to Chiral 1,4-Diazabicyclo[3.1.1]heptanes via Relay Dy/Ir Catalysis}},
author = {Jun-Cheng Jin and Jian Zhang and Qi-Guo Zheng and Hanliang Zheng and Wei-Ping Deng},
howpublished = {ChemRxiv},
year = {2026},
month = sep,
doi = {10.26434/chemrxiv.15009675/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009675/v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Enantioselective Strain-Release Formal (3 + 3) Cycloaddition of 1-Azabicyclo[1.1.0]butanes to Chiral 1,4-Diazabicyclo[3.1.1]heptanes via Relay Dy/Ir Catalysis
AU - Jun-Cheng Jin
AU - Jian Zhang
AU - Qi-Guo Zheng
AU - Hanliang Zheng
AU - Wei-Ping Deng
PY - 2026
DA - 2026/09/29
PB - ChemRxiv
DO - 10.26434/chemrxiv.15009675/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009675/v1
AB - *Email: [email protected]; [email protected] ABSTRACT: Pyrazines and piperazines are privileged 1,4-diaza motifs, yet neither combines conformational rigidity with a stereochemically defined three-dimensional shape. Here we report the first catalytic enantioselective formal (3 + 3) cycloaddition of 1-azabicyclo[1.1.0]butanes (ABBs), providing direct access to enantioenriched 1,4diazabicyclo[3.1.1]heptanes—rigid, C(sp3)-rich scaffolds that serve as chiral three-dimensional complements to these classical motifs. Relay Dy/Ir catalysis merges Dy(OTf)3-promoted ABB strain release with iridium-catalyzed asymmetric allylic amination of allylamine-derived N,C,C synthons, extending ABB chemistry beyond conventional strain-release functionalization and previously reported racemic cycloadditions. The method furnishes 50 examples in up to 93% yield and 99% ee, with broad functional-group tolerance and compatibility with drug- and natural-product-derived substrates. Control experiments, 1H NMR studies, and DFT calculations support a staged mechanism involving carbonyl-assisted N,O-bidentate activation of the ABB by Dy(OTf)3. Preparative-scale synthesis, orthogonal product diversification, and access to pyrazineand piperazine-related drug analogues demonstrate the synthetic versatility and scaffold-hopping potential of this platform.
ER -