Fluorine is the most electronegative atom and its nucleus has a spin of ½, which allows its use in magnetic resonance techniques (NMR, MRS, MRI).
Fluorinated organic compounds are not present in most biological systems, making fluorine a useful diagnostic tool in medicine. Fluorinated α-amino acids make excellent probes for incorporation into proteins and peptides. It is important that the amino acid probe contains more than three chemically equivalent fluorine atoms, as this significantly enhances its sensitivity. The Mitsunobu reaction can be leveraged to introduce moieties containing up to nine equivalent fluorine atoms.
As part of my thesis, I prepared appropriately protected L-homoserine, which was subjected to the Mitsunobu reaction in the presence of perfluoro-tert-butanol (PFTB), which contains nine equivalent fluorine atoms. The Mitsunobu reaction is a method for the dehydrative coupling of primary or secondary alcohols with pronucleophiles. Fluorinated alcohols with sufficiently low pKa values, such as PFTB, can be used as pronucleophiles.
By optimizing the reaction conditions, I obtained the perfluorinated derivative of protected L-homoserine in 67 % yield. The main goal of the thesis was the preparation of an N-Fmoc-protected building block which could be used further in solid-phase peptide synthesis (SPPS). For this reason, I exchanged the protective groups of the fluorinated derivative of protected L-homoserine, affording N-Fmoc-O-(perfluoro-tert-butyl)-L-homoserinate in 77 % yield.
The deprotection procedure I used in my thesis showed improved reaction efficiency compared to previously reported methods in the literature. The overall yield of the synthesis – from introduction of protecting groups to L-homoserine, to exchange of protective groups – was 26 %. This showed an improvement over a previous literature reported synthesis of only 4 % yield.
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