The vicinal difluoro motif in organic chemistry : the synthesis and behaviour of compounds derived from 2,3-diflurosuccinic acids
Abstract
The following work describes the synthesis of compounds carrying a vicinal difluoro
motif and the evaluation of this structural element to influence the conformation of
organic molecules. The synthesis of erythro and threo 1,2-difluoro-1,2-diphenylethane
was achieved by bromofluorination and subsequent halogen exchange from stilbene.
Oxidative degradation of the phenyl rings allowed to access erythro and threo 2,3-
difluorosuccinic acids and a variety of derivatives thereof. The conformations of these
compounds were investigated by means of X-ray analysis and NMR spectroscopy.
Conformational analysis of derivatives of 2,3-difluorosuccinic acid was carried out
using JHFandJHHNMR coupling constants. A clear preference for the conformations in
which the two vicinal C-F bonds are gauche emerged from these calculations, which
was confirmed by temperature and solvent dependent NMR analyses.
The vicinal difluoro motif was incorporated into small peptide structures. In the solid
state, a strong preference to align the vicinal C-F bonds gauche to each other was
observed and when adjacent to an amide moiety, the C-F bond was found to prefer an
anti periplanar orientation with respect to the carbonyl bond. These effects appeared to
override steric and electrostatic interactions. The conformation of these fluorinecontaining
peptides showed a clear dependence on the stereochemicaol rientation of the
C-F bonds, and this appears to be an effective tool for influencing the secondary and
consequently tertiary structure in a predictable manner. In order to access single
enantiomerso f peptides having the vicinal difluoro, motif, a stereoselectiver oute to R,R
and SS 2,3-difluorosuccinic was developed. This involved nucleophilic fluorination of
the cyclic sulfates generated from (R, R)- and (SS)- diethyl tartrates and subsequent
deoxofluorination of the intermediate fluorohydrins.
Type
Thesis, PhD Doctor of Philosophy
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