The Ugi‐azide reaction of an enantiopure amino acid derived isocyanides, amino acid esters, aldehydes and TMS‐N3 in MeOH:THF solvent system at 50 °C yielded peptidomimetics comprising tetrazole as amide bond isostere. Both N‐terminal (α‐isocyanoesters) and C‐terminal isocyanides (Nβ‐Cbz‐protected amino alkyl isocyanides) have been employed to yield diversified tetrazole peptidomimetics, having the possibility of further derivatization through either N‐ or C‐terminal chain elongation. Ugi‐azide reaction is a isocyanide based multi‐component reaction (IMCR), as a result, change in amino acid derived isocyanides had given structurally diverse products of biological interest. Good yields of products were obtained after column purification and were stable for shelf storage. The products are novel and were well characterized by Mass, 1H NMR and 13C NMR spectral studies. The present method offers several advantages such as one‐pot simple procedure, high yields and easy purification of products.
The synthesis of α-amino thioacids and peptide thioacids and their applications in chemoselective amide bond formation, ligation of peptides/proteins/glycopeptides and synthesis of peptidomimetics are reviewed. A variety of successful methods including both C-terminal and N-terminal activations for the coupling of α-amino thioacids and peptide thioacids have ascertained the thioacid-based protocol as a benign alternative to some of the traditional methods of amide/peptide bond formation which employs carboxyl activation. In addition to the couplings involving unprotected peptide fragments and solid phase synthesis, their use in the synthesis of different classes of peptidomimetics such as thioxopeptides, imide conjugates and acylsulfonamide-peptide conjugates only illustrates the versatility of this functionality in generating diverse classes of molecules, some of which are relevant to drug discovery and chemical biology. A note on more reactive seleno counterparts of thioacids, which can be useful in selective cases, is provided.
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