Synthesis of Monofluoroalkene-Based Dipeptide Bioisosteres via Regioselective Ring Opening of 1,1-Difluorocyclopropanes

This work is dedicated to Professor Emeritus Koichi Narasaka (The University of Tokyo) with gratitude on the occasion of his 80^th birthday (sanju).

Abstract

Monofluoroalkene-based dipeptide bioisosteres were synthesized via (I) difluorocyclopropane ring opening and (II) S_N2′-type defluorination. (2,2-Difluorocyclopropyl)methyl acetates were treated with acetonitrile in the presence of trifluoromethanesulfonic acid (triflic acid, TfOH). Elimination of acetic acid resulted in regioselective cleavage of the C–C bond distal to the CF₂ moiety (ring opening), and then a Ritter-type N-terminal introduction afforded N-(2,2-difluorohomoallyl)acetamides. The obtained difluoroacetamides underwent allylic substitution of bromine for fluorine in an AlBr₃/CuBr system to generate 3-fluoroallylic bromides, whose substitution with n-Bu₄NCN facilitated C-terminal introduction. Conversion of the cyano group into a carbamoyl group afforded the desired monofluoroalkene-based dipeptide bioisosteres.

Key words

alkenes - amides - bioisosteres - C–C bond cleavage - cyclopropanes - fluorine - Ritter reaction

Publication History

Received: 27 August 2024

Accepted after revision: 02 January 2025

Accepted Manuscript online:
02 January 2025

Article published online:
03 February 2025

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