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Solid-phase Synthesis of [4.4] Spirocyclic Oximes
Published on: February 6, 2019
Traceless Nitro Group Directing Strategy: Modular Syntheses of the Scaffolds of Polycyclic Alkaloids
Qing Li1, Yuting Zhao2, Xinyu Zhu1
1Department of Medicinal Chemistry, China Pharmaceutical University, 211198 Nanjing, China.
None:
The synthetic value of nitroalkanes has been widely recognized but still remains an unexplored space. Integrating nitroalkane-directed C-C bond formations with nitro group manipulations could achieve diverse and efficient syntheses of complex molecules. Herein, we report a nitro-Mannich/lactamization/nitrous acid elimination cascade process to enable the modular construction of the scaffolds of piperidone- and isoquinolone-centered polycyclic alkaloids. The cascade transformation renders the nitro group into a traceless directing group via NO2 elimination, circumventing the limitations imposed by "aromatization-driven" or "β-EWG-driven" modes and providing a "β-aryl activation" type through hyperconjugation, along with expedient access to a broad scope of piperidone/isoquinolone molecules, including oxyberberine, nauclefine, and aromathecin alkaloids. Leveraging the diversity of cyclic imines and nitrobutyrates, the nitro-Mannich/lactamization/nitrous acid elimination cascade reaction offers a transition-metal-free and modular platform for rapidly assembling natural-product-like polycyclic scaffolds, which hold significant promise for accelerating bioactive molecule discovery and advancing pharmacological research.
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