Radiofluorination via Staudinger Ligation

Objectives: The chemical labeling of biomolecules continues to be an important tool for the study of the cellular fate.[1] In particular the introduction of ¹⁸F into higher molecular weight compounds like peptides, proteins, oligonucleotides or antibodies represents a special challenge. Usually they can not be labelled with ¹⁸F at high specific activity directly due to the rough reaction conditions. To circumvent this problem prostetic groups were used for ¹⁸F labeling of peptides and proteins. Therefore ¹⁸F labeled small organic molecules were synthesised capable of being linked to peptides, proteins or antibodies under mild conditions. Only a handful of reactions are known for the selective introduction of these labeling agents.
Methods: Although several bioconjugation techniques are available for preparation of bioconjugates substituted with a limited number of functional groups, truly chemoselective ligation reactions are rather limited. Most ligation reactions rely on the reaction of an electrophile with a nucleophile. As biological systems are rich in diverse electrophilic and nucleophilic sites, only a few functional groups are available that exhibit orthogonal reactivity to the functional groups present. Bioorthogonal reactions like the [3+2] Huisgen cycloaddition[3] were applicated for the selective radiolabeling[4] of biomolecules. The Staudinger Ligation introduced by Saxon and Bertozzi[5] exploits the smooth reaction between an azide and a phosphane to form an amide bridge between the labeling agent and the respective biomolecule.
Results: Substituted phosphanes were used as synthons for the Staudinger Ligation. The preparation of these compounds succeeds via Pd-catalyzed P-C cross coupling of iodophenyl benzoates with HPPh₂. No extensive protection group chemistry is needed for this coupling reaction.[2] The radiofluorination proceeds under standard conditions and the subsequent ligation reaction occurs under mild conditions (20 min, 50 watt microwave) that affords the respective Staudinger products in high yields.
Conclusions: Our first promising results show the potential of this labeling method for the radiofluorination of various organic model compounds and biomolecules. The experimental details will be presented.

References: [1] J. A. Prescher, C. R. Bertozzi, Nature Chem. Biol. 2005, 1, 13-21. [2] C. Mamat, A. Flemming, M. Kckerling, J. Steinbach, F. R. Wuest, Eur. J. Org. Chem. 2009, submitted. [3] C. Mamat, T. Ramenda, F. R. Wuest, Mini-Rev. Org. Chem. 2009, 6, 21-34. [4] T. Ramenda, R. Bergmann, F. Wuest, Lett. Drug Design Disc. 2007, 4, 279-285. [5] K. L. Kiick, E. Saxon, D. A. Tirrell, C. R. Bertozzi, Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 19-24.