Janus all-cis 2,3,4,5,6-pentafluorocyclohexyl building blocks applied to medicinal chemistry and bioactives discovery chemistry

Joshua Clark, Rifahath M. Neyyappadath, Cihang Yu, Alexandra M. Z. Slawin, David B. Cordes, David O'Hagan

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Abstract

Monoalkylated derivatives of the unusually polar all- cis 2,3,4,5,6- pentafluorocyclohexyl (Janus face) motif are prepared starting from an aryl hydrogenation of 2,3,4,5,6- pentafluorophenylacetate methyl ester 15 . The method used Zeng's Rh(CAAC) carbene catalyst 4 in the hydrogenation following the protocol developed by Glorius. The resultant Janus pentafluorocyclohexylacetate methyl ester 16 was converted to the corresponding alcohol 18 , aldehyde 13 , bromide 29 and azide 14 through functional group manipulations, and some of these building blocks were used in Ugi-multicomponent and Cu-catalysed click reactions. NBoc protected pentafluoroarylphenylalanine methyl ester 35 was also subject to an aryl hydrogenation, and then deprotection to generate the Janus face ß-pentafluorocyclohexyl-alanine amino acid 15 , which was incorporated into representative members of an emerging class of candidate antiviral compounds. Log P measurements demonstrate that the all- cis 2,3,4,5,6-pentafluorocyclohexyl ring system is more polar than a phenyl ring. In overview the paper introduces new building blocks containing this Janus ring and demonstrates their progression to molecules typically used in bioactives discovery programmes.
Original languageEnglish
Article number202102819
Pages (from-to)16000-16005
Number of pages7
JournalChemistry - A European Journal
Volume27
Issue number64
Early online date6 Oct 2021
DOIs
Publication statusPublished - 17 Nov 2021

Keywords

  • Organofluorine chemistry
  • Janus motif
  • Aryl hydrogenation
  • Organic chemistry
  • Fluorocyclohexanes

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