Expedient Access to Enantioenriched 1-Azaspiro Cyclobutanones Enabled by Modified Heyns Rearrangement |
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Authors: | Shibaram Panda Prof. Dr. Prasanta Ghorai |
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Affiliation: | Department of Chemistry, Indian Institute of Science Education and Research (IISER) Bhopal, Bhopal By-pass Road, Bhauri, 462066 Bhopal, India |
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Abstract: | Leveraging the unexplored regions of chemical space, the integration of spirocyclic cyclobutane in a molecular scaffold opens up a new vista in modern drug discovery. Despite recent advancements in achieving the synthesis of such motifs, strategies for their asymmetric construction have not been well-recognized and remain a formidable challenge. Herein, for the first time, we have demonstrated a chiral Brønsted acid-catalyzed enantioselective synthesis of 1-azaspiro cyclobutanone enabled by an unusual reactivity of enamine that explore the potentiality of Heyns rearrangement upon electrophilic modification. This design strategy offers viable access to a wide range of cyclobutanone containing spiroindoline and spiropyrrolidine derivatives in good yields with excellent stereoselectivities (up to >99 % ee, >20 : 1 dr). Furthermore, the practicality of this methodology has been shown by a scale-up synthesis of spirocyclic products and their facile post-synthetic modifications. |
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Keywords: | Aza-Spirocycle Chiral Phosphoric Acid Cyclobutanone Heyns Rearrangement Organocatalysis |
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