A Facile Synthesis of 1,5‐Disubstituted Tetrazole Peptidomimetics by Desulfurization/Electrocyclization of Thiopeptides

Abstract

The cis-amide bond isostere, 1,5-disubstituted tetrazole,has been introduced in the peptideb ackbone by as imple route startingf rom the thiopeptide. The desired 1,5-disubstituted tetrazole peptidomimetics were synthesized by the desulfurization of thiopeptides by using HgCl 2 in the presence of NaN 3 /TEA in DMF in good yields. Various other thiophilic reagents including hypervalent iodine reagents failed to deliver the tetrazole product with the exception of CBr 4 /PPh 3 ,w hich resulted in moderate yields. The advantage of the presentp rotocol over previousm ethods has been demonstrated by the selective insertion of tetrazole into peptide-thiopeptide hybrids. Also, the protocol is compatible with commonly employed urethane protecting groups (Fmoc, Boc, and Cbz) in peptidec hemistry.T hiopeptide Boc-Pro-y[CSNH]-Val-OMe (2i)a nd two tetrazole pepti-domimeticsC bz-Ala-y[CN 4 ]-Phe-OMe( 3d)a nd Boc-Proy[CN 4 ]-Val-OMe( 3i)w ere obtained as single crystalsa nd their molecular structures have been confirmed by X-ray crystallography.

Mechanochemical Synthesis of Amides with Uronium-Based Coupling Reagents: A Method for Hexa-amidation of Biotin[6]uril

“…3 Although direct condensation of carboxylic acids and amines with water as a single by-product can be considered a "green" landmark in the field, it remains impractical because of the process's harsh reaction conditions (T > 100 °C) and limited substrate scope. [4][5][6] A robust method of amide synthesis commonly requires prior activation of a carboxylic function to replace OH with a better leaving group. [7][8][9] Notably, this is also the case in biosynthetic pathways, including the translation process and non-ribosomal enzymatic transformations.…”

Synthesis of 1, 5‐ Disubstituted Tetrazole via Ugi Azide Reaction: An Asymmetric Induction Approach

“…In particular, 1,5‐disubstituted tetrazoles have been found to mimic cis‐amide bonds of peptides and their site specific incorporation enhances the biochemical properties of bradykinin, deamino‐oxytocin, HIV‐protease inhibitors and phenothiazine analogues. [19] We recently demonstrated the mild, chemoselective and non‐racemizable synthesis of tetrazole peptidomimetics through thiopeptides and NaN 3 using desulfurization chemistry (Figure a) …”