Strain-Release-Driven Homologation of Boronic Esters: Application to the Modular Synthesis of Azetidines

Alexander Fawcett, Amna Murtaza, Charlotte H. U. Gregson, Varinder K. Aggarwal*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

23 Citations (Scopus)
108 Downloads (Pure)

Abstract

Azetidines are important motifs in medicinal chemistry, but there are a limited number of methods for their synthesis. Herein, we present a new method for their modular construction by exploiting the high ring strain associated with azabicyclo[1.1.0]butane. Generation of azabicyclo[1.1.0]butyl lithium followed by its trapping with a boronic ester gives an intermediate boronate complex which, upon N-protonation with acetic acid, undergoes 1,2-migration with cleavage of the central C-N bond to relieve ring strain. The methodology is applicable to primary, secondary, tertiary, aryl, and alkenyl boronic esters and occurs with complete stereospecificity. The homologated azetidinyl boronic esters can be further functionalized through reaction of the N-H azetidine, and through transformation of the boronic ester. The methodology was applied to a short, stereoselective synthesis of the azetidine-containing pharmaceutical, cobimetinib.

Original languageEnglish
Pages (from-to)4573–4578
Number of pages6
JournalJournal of the American Chemical Society
Volume141
Issue number11
Early online date5 Mar 2019
DOIs
Publication statusPublished - 20 Mar 2019

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