Example

ESR 2: Diana Gimenez-Ibanez: October 15th - November 15th 2016

Title: Perfluoroaromatic reagents as a tool for peptide-sugar conjugation

Host University: Westfälische Wilhelms- Universität Münster, Germany

Accommodation:Edith-Stein-Kolleg Student Accommodation, Munster, Germany

Science: We have explored the potential use of pentafluoropyridine and based reagents as potential scaffolds for peptide-sugar conjugation. Model protected nucleophilic aminoacids such as Boc-Tyr-OMe and Boc-Cys-OMe have been synthetized and different parameters for the perfluoroaromatic tagging optimized (i.e. solvent, reaction time, aminoacid/perfluoroaromatic ratio). Analysis of the reaction outcomes showed this step to take place almost quantitatively in the tyrosine based aminoacid, leading to the desired and O-perfluorotagged derivative (Scheme 1). In comparison, cysteine based aminoacid was observed to undergo oxidation of the free thiol groups into cystine dimers.

Scheme 1: Aminoacid-pentafluoropyridine coupling reactions.

In a second step, we hypothesized that sugar incorporation would be enable either by direct pentafluoropyridine substitution or by displacement of other F atoms located at the aromatic ring. To prove this idea, we undertook the reaction of the previous intermediate PFP tagged Tyrosine with sugars, having either a S-based reacting group in a not sterically restricted position, a less nucleophilic and more hindered hydroxy group in β, and the corresponding fluoro-sugar (Scheme 2).

Scheme 2: Sugar-aminoacid coupling and displacement reactions.

Mass analysis of the crude reactions confirmed the formation of both expected products when reaction was placed in the presence of the more reactive thiosugar_1. In comparison, one single reaction product could be observed in the presence of the less reactive sugar_2 and, due to the major hindrance and the inductive effect imposed by the fluorine atom over the vicinal position, no product was formed when employing the fluorosugar_3.

In order to assess the suitability of the sugar coupling procedure in longer sequences, we carried out the corresponding reactions employing model nucleophilic peptides, having Cys and Tyr resides (Scheme 3). We could observe in the reaction mixtures the formation of the corresponding sugar coupled products. Reactions were scaled up in order to achieve enough amount to perform HPLC purification of the novel compounds and complete their physical/chemical characterization in Durham University.

Scheme 3:Example of a sugar-peptide coupling reaction using a model Tyrosine containing hexapeptide.

New Skills acquired

  • Improved knowledge of sugar systems, reactivity and general sugar chemistry.
  • Organic synthesis methodology applied to this specific area.
  • Time management and work planning.
  • Team working