Entwicklung einer induzierten Staudinger-Zyklisierung und ihre Anwendung in der Synthese von zyklischen Peptiden und Proteinen (English shop)

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The aim of this work was to develop, on the basis of the traceless Staudinger ligation, a spectrum of methods for the induced cyclization of peptides and proteins. This was based on the work of van Maarseveen et al.¹⁶³, who induced the cyclization of dipeptides by means of a borane-protected phosphinothioester through basic deprotection. The main focus here was above all on finding a suitable system with mild cleavage conditions and applying it to peptide cyclizations.
In addition, the bioorthogonality of the Staudinger ligation was to be exploited.
On the basis that borane complexes are not stable towards acids, a strategy was developed to deprotect the phosphine in one step together with the amino acid side chains. It could be shown that S-acetyl(diphenylphosphino-(borane))methylthiol can be deprotected with TFA. In this process, unreactive borates are formed as the boron compound, which do not influence the further course of the reaction. After deprotection and addition of base, an acetyl transfer mediated by the Staudinger ligation onto azidoglycine and benzyl azide to give N-acetylglycine and N-acetylbenzylamine could be achieved with good conversions.
These results were subsequently transferred to the cyclization of peptides. The advantage over basic deprotection lies in the fact that peptides obtained synthetically via Fmoc-based methods, after conversion to the thioester, are deprotected by the acid simultaneously at the amino acid side chains and at the phosphine. In this way, the chemoselectivity of the Staudinger ligation is exploited. The method was applied to various peptides, and the cyclic products are obtained in good yields. A broad range of functional groups in the amino acid side chains is tolerated.
Only in the case of lysine- and arginine-containing peptides do side reactions occur due to deprotonation of the side chains.
A solution is offered by adjusting the pH in aqueous buffers in order to minimize the deprotonations. The yields obtained when carrying out the cyclization in aqueous media are comparable to those in organic solvent.
The application to the cyclization of lysine- and arginine-containing peptides was also successful.