Shifting Native Chemical Ligation into Reverse through N!S Acyl Transfer Scheme 11. Fmoc-based approaches to glycopeptide thioester synthesis: a) using the sulfonamide safety-catch linker;[5b] b) phenolic ester;[16a] c) N-alkyl cysteine, R = b-d-Gal, R1 = CH2CH2CO2H;[51] d–f) Cys terminated peptides.[27,48] 5. Summary and Outlook N!S acyl transfer is clearly emerging as a useful route to peptide thioesters, which are important intermediates in protein synthesis. It is especially interesting that native peptides have the ability to rearrange into thioesters, since this suggests that proteins have always had, at least in theory, an inherent ability to make themselves through N!S acyl transfer and NCL. The required information for the production of the key components for NCL, which can be challenging to produce with modern syn- thetic methods, is already installed in an Xaa–Cys motif. The biological relevance or consequence of this process is yet to be examined in detail. One could take the view that cysteine is an amino acid whose rogue properties re- quire that it is “tied up” in disulfide bonds or coordinated to metals if it cannot be deleted entirely. It would be ex- pected that hyperthermophiles would evolve to remove all but the most essential Cys residues. Indeed, hyperther- Isr. J. Chem. 2011, 51, 885 – 899 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.ijc.wiley-vch.de 897