Peptide ligation at hydrophobic sites is possible with a ligation–desulfurization strategy in which penicillamine serves as a precursor of valine. The β,β‐dimethylcysteine peptides reacted surprisingly fast in native chemical ligation reactions. Even the sterically crowded and unpolar Leu–Val bond can be formed in high yield.

Vitamin C for peptide ligation: Phosphine and thiol additives maintain reducing environments and increase the reactivities of peptide thioesters in native chemical ligation. Thiol additives such as thiophenol also act as radical scavengers that inhibit phosphine‐induced desulfurization of cysteine. This role can be assumed by the odourless, nontoxic, highly water‐soluble and inexpensive ascorbate, which can replace the usually added thiols.

The native chemical ligation enables the chemoselective coupling of two unprotected protein segments. In the initial format of this reaction, the side chain of N-terminal cysteine residues serves to capture a peptide thioester. The N-terminus of the cysteinyl peptide is involved in a subsequent intramolecular aminolysis reaction, upon which the "native" peptide bond is established. Considerable efforts have been invested to remove the restriction to cysteine-containing ligation sites. In this review, we focus on the combination of two chemoselective reactions, native chemical ligation, and desulfurization, which has extended the repertoire of accessible ligation junctions. Based on this two-step approach, native alanine-containing peptides are accessible through postligation desulfurization of cysteine-ligation products. Recently, significant progress has been achieved in the development of new thiolated building blocks that serve as precursors to other amino acids. Ligations at phenylalanine can be accomplished by means of a beta-mercaptophenylalanine building block and subsequent desulfurization. The building blocks beta-mercaptovaline (penicillamine) and gamma-mercaptovaline provide access to hydrophobic ligation sites (Xaa-Val). Lysine has been equipped with a delta- and gamma-mercapto groups, which enables ligations at both the alpha- and the epsilon-amino group. This review also describes the recent improvements of desulfurization chemistry, which have widened the scope of the ligation-desulfurization approach and offer a promising alternative for the synthesis of Cys-free peptides and glycopeptides.

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Review: 60 refs.