The vicinal difluoro motif: the synthesis and conformation of erythro- and threo-diastereoisomers of 1,2-difluorodiphenylethanes, 2,3-difluorosuccinic acids and their derivatives

David O'Hagan, Henry S. Rzepa, Martin Schuler, Alexandra M. Z. Slawin

Research output: Contribution to journalArticlepeer-review

43 Citations (Scopus)

Abstract

Background: It is well established that vicinal fluorines (RCHF-CHFR) prefer to adopt a gauche rather than an anti conformation when placed along aliphatic chains. This has been particularly recognised for 1,2-difluoroethane and extends to 2,3-difluorobutane and longer alkyl chains. It follows in these latter cases that if erythro and threo vicinal difluorinated stereoisomers are compared, they will adopt different overall conformations if the fluorines prefer to be gauche in each case. This concept is explored in this paper with erythro- and threo- diastereoisomers of 2,3-difluorosuccinates. Results: A synthetic route to 2,3-difluorosuccinates has been developed through erythro- and threo- 1,2-difluoro-1,2-diphenylethane which involved the oxidation of the aryl rings to generate the corresponding 2,3- difluorosuccinic acids. Ester and amide derivatives of the erythro- and threo- 2,3-difluorosuccinic acids were then prepared. The solid and solution state conformation of these compounds was assessed by X-ray crystallography and NMR. Ab initio calculations were also carried out to model the conformation of erythro- and threo- 1,2-difluoro-1,2-diphenylethane as these differed from the 2,3-difluorosuccinates. Conclusion: In general the overall chain conformations of the 2,3-difluorosuccinates diastereoisomers were found to be influenced by the fluorine gauche effect. The study highlights the prospects of utilising the vicinal difluorine motif (RCHF-CHFR) as a tool for influencing the conformation of performance organic molecules and particularly tuning conformation by selecting specific diastereoisomers (erythro or threo).

Original languageEnglish
Article number19
Number of pages13
JournalBeilstein Journal of Organic Chemistry
Volume2
DOIs
Publication statusPublished - 2 Oct 2006

Keywords

  • PEPTIDASE-IV INHIBITORS
  • BIS(2-METHOXYETHYL)AMINOSULFUR TRIFLUORIDE
  • COUPLING-CONSTANTS
  • FLUORINATION
  • STABILITY
  • PYRROLIDINE
  • HYDROGEN
  • SOLVENT
  • REAGENT

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