Click Azide−Nitrile Cycloaddition as a New Ligation Tool for the Synthesis of Tetrazole-Tethered C-Glycosyl α-Amino Acids

Abstract

Glycoproteins play a key role in a multitude of biological events in living organisms. Hence, neoglycopeptides obtained from unnatural C-glycosyl alpha-amino acids can be used as synthetic probes in studies aiming at clarifying the role of the carbohydrate domain in glycoprotein biological activity. A new class of C-glycosyl alpha-amino acids featuring a nitrogenated heterocycle ring holding the carbohydrate and glycinyl moiety was designed in our laboratory. Having previously prepared isoxazole-, 1,2,3-triazole-, and pyridine-tethered compounds, the family has now been enlarged by a group of newcomers represented by tetrazole derivatives. Two sets of compounds have been prepared, one being constituted of C-galactosyl and C-ribosyl O-tetrazolyl serines while the other contains S-tetrazolyl cysteine derivatives. In both cases, the synthetic scheme involved a two-step route, the first one being the thermal cycloaddition of a sugar azide with p-toluensulfonyl cyanide (TsCN) to give a 1-substituted 5-sulfonyl tetrazole and the second the replacement of the tosyl group with a serine or cysteine residue. For the high efficiency and operational simplicity, the azide-TsCN cycloaddition appears to be a true click process. Finally, one of the amino acids prepared was incorporated into a tripeptide.

Synthesis and biological properties of amino acids and peptides containing a tetrazolyl moiety

“…An original approach to the synthesis of non-natural tetrazole-containing C-glycosyl-a-amino acids and peptides was proposed by Aldhoun et al 116 The key step of this procedure is the click reaction between azidomethyltetraacetyl-b-D-galactopyranoside 115 and TsCN, in which the CN group is activated by an electron-withdrawing toluenesulfonyl moiety. The reaction of the resulting 1-substituted 5-sulfonyltetrazole 116 with N-Fmoc-protected cysteine 117 affords S-[1-(b-D-galactopyranosylmethyl)tetrazol-5-yl]-N-Fmoc-cysteine (118) (Scheme 43).…”

Cycloaddition Reactions with Azides: An Overview

“…Thus, this class of heterocycles presently plays a crucial role in the fi eld of coordination chemistry, 75 material science application and medicinal chemistry. 76,77 The pharmacokinetic potential of tetrazoles, frequently used as metabolically stable surrogates of carboxylic acids, makes the synthesis of this nitrogen -rich heterocycle particularly fascinating.…”

“…75 Against all odds, only nitriles activated by strong electron -withdrawing groups can be effectively used as dipolarophiles. 77 The fi rst examples of a direct 1,5 -substituents tetrazole synthesis via an intermolecular [2 + 3] -cycloaddition reaction of organic azides (based on the results for a similar synthesis of triazoles) were developed by Sharpless et al in 2002 using sulfonyl or acyl cyanides (Scheme 9.8 ). 76,78 In both cases, the Click reaction involved simple heating of the organic azides (hindered, aliphatic or aryl azides) and the nitriles into a homogenous liquid at higher reaction temperature (80 -100 ° C), in which no further purifi cation was necessary.…”

“…79,80 Thus, Dondoni et al 77 synthesized a new class of tetrazole -tethered C -glycosyl α -amino acids using serine and cysteine as nucleophiles based on Demko ' s and Sharpless ' aforementioned Click azide -sulfonyl cyanide cycloaddition/sulfonyl substitution route (Scheme 9.8 ).…”

First X-ray structural characterisation of host–guest interactions in tetra-tetrazole macrocycles

“…[10][11][12] The development of "click" chemistry methodology, as described by Sharpless and co-workers, 13,14 has resulted in a recent increase in tetrazole structures, which suggests that molecular recognition studies of tetrazoles will become increasing important. [15][16][17][18][19][20][21] Our interest in tetrazoles concerns their use as precursors for the formation of new functionalised polytetrazole macrocycles, which can find application, for example, as sensors or in molecular recognition. We have previously reported the addition of pendant short-chain alkyl halides and vinyl arms to various bistetrazoles, as well as the synthesis and structural characterisation of tetra-tetrazole macrocycles from 1,2-, 1,3-and 1,4-dicyanobenzene derivatives, using short four-carbon, medium six-carbon and long eight-carbon alkyl linkers.…”