Strain‐Release Driven Spirocyclization of Azabicyclo[1.1.0]butyl Ketones

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Abstract

Due to their intrinsic rigidity, three‐dimensionality and structural novelty, spirocyclic molecules have become increasingly sought‐after moieties in drug discovery. Herein, we report a strain‐release driven synthesis of azetidine‐containing spirocycles by harnessing the inherent ring strain of the azabicyclo[1.1.0]butane (ABB) fragment. Novel ABB‐ketone precursors bearing silyl‐protected alcohols were synthesised in a single step and shown to engage in electrophile‐induced spirocyclization‐desilylation reactions. Primary, secondary and tertiary silyl ethers were effectively transformed into a library of new spiro‐azetidines, with a range of substituents and ring sizes. In addition, the products are generated with synthetically useful ketone and protected‐amine functional groups, which provides the potential for further elaboration and for this chemistry to be utilized in the rapid assembly of medicinally relevant compounds.
Original languageEnglish
Pages (from-to)11824-11829
Number of pages6
JournalAngewandte Chemie - International Edition
Volume60
Issue number21
Early online date22 Mar 2021
DOIs
Publication statusPublished - 17 May 2021

Bibliographical note

Funding Information:
J.T. thanks the Bristol Chemical Synthesis Centre for Doctoral Training and the EPSRC (EP/G036764/1) for funding. We thank H. A. Sparkes for X‐ray analysis.

Publisher Copyright:
© 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH

Structured keywords

  • BCS and TECS CDTs

Keywords

  • Azabicylo[1.1.0]butanes
  • Azetidines
  • heterocycles
  • Spiro compounds
  • Strained molecules

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