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
Year: 2026
Type: preprint
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.
Source: ChemRxiv
Institution: Zhejiang Normal University
Language: English
Subfield: Organic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: green
Award: 基于高阶环加成策略的手性七元杂环稠环骨架的催化不对称构建
OpenAlex ID: W7214931735