Triazoles peptides

Functionalized 1,2,3-triazoles 86 and 87 were prepared by [2 + 3] cycloadditions of resin-bound a-azido esters 85 with substituted alkynes <02TL4059>. Regiospecific copper(I)-catalyzed 1,3-dipolar cycloadditions of resin-bound alkynes 88 with azides afforded solid-supported 1,2,3-triazoles 89, which were ligated further to give 1,4-substituted-1,2,3-triazole peptide compounds <02JOC3057>. 

In peptide syntheses, where partial racemization of the chiral a-carbon centers is a serious problem, the application of 1-hydroxy-1 H-benzotriazole ( HBT") and DCC has been very successful in increasing yields and decreasing racemization (W. Kdnig, 1970 G.C. Windridge, 1971 H.R. Bosshard, 1973), l-(Acyloxy)-lif-benzotriazoles or l-acyl-17f-benzo-triazole 3-oxides are formed as reactive intermediates. If carboxylic or phosphoric esters are to be formed from the acids and alcohols using DCC, 4-(pyrrolidin-l -yl)pyridine ( PPY A. Hassner, 1978 K.M. Patel, 1979) and HBT are efficient catalysts even with tert-alkyl, choles-teryl, aryl, and other unreactive alcohols as well as with highly bulky or labile acids. 

Canthine skeleton 52 Cardiotonic agent, heart failiu-e 3 Caspase-3 inhibitors, non-peptide 269 Catch and release , 2,4,5-trisubstituted pyrimidines 98 Chloro dehydroxylation 17 Click chemistry, 1,4-disubstituted triazoles 45... 

The alkoxycarbonyl protecting groups can also be introduced into amines by, triazolides (Table 4—7). With A-tert-butoxycarbonyl-1,2,4-triazole the tert-butoxy-carbonyl protecting group (Boc) is transferred readily onto amino functions of primary amines, trimethylbenzyl ammonium salts of amino acids, or peptides.[ 1965 Alternatively, the Boc group can be transferred with terf-butylphenylcarbonate in the presence of 1,2,4-triazole. In this latter approach the triazolide is presumably formed as an intermediate. ... 

Besides CDI, other azolides such as A N -oxalyldiimidazole, AyST-carbonyldi-1,2,4-triazole, MN -oxalyldi-1,2,4-triazole, and phosphorous and phosphoric imidazolides have been used in the synthesis of peptide bonds, as displayed in Table 5-4. 

The amino acid attached to a polymer is treated with an vV-protected, carboxyl-activated amino acid to give the supported peptide. In the following reaction the triazolide was formed in situ from the p-nitrophenyl ester and 1,2,4-triazole 1341... 

Triisopropylbenzenesulfonyl)-3-nitro-1,2,4-triazole in the presence of 4-rtiorpholine pyridine-1-oxide was used with advantage as a coupling reagent for a solid-phase (p-alkoxybenzyl ester type resin) synthesis of peptides such as Leu-AIa-Gly-Val-OH or Leu-enkephalinamide (Tyr-Gly-Gly-Phe-Leu-NHs). The overall yield in the latter case was 70%, the purity of the peptide was 85-90%, and racemization was virtually zero.[38]... 

More recently, Somfai and coworkers have reported on the efficient coupling of a set of carboxylic acids suitable as potential scaffolds for peptide synthesis to a polymer-bound hydrazide linker [24]. Indole-like scaffolds were selected for this small library synthesis as these structures are found in numerous natural products showing interesting activities. The best results were obtained using 2-(7-aza-l H-benzo-triazol-l-yl)-l,l,3,3-tetramethyluronium hexafluoride (HATU) and N,N-diisopropyl-ethylamine (DIEA) in N,N-dimethylformamide as a solvent. Heating the reaction mixtures at 180 °C for 10 min furnished the desired products in high yields (Scheme 7.4). In this application, no Fmoc protection of the indole nitrogen is required. 

Due to its wide application in peptide synthesis, 1-hydroxybenzotriazole 1001 is the most commonly used benzo-triazole derivative with hundreds of references in Chemical Abstracts each year. Utility of compound 1001 comes from its readiness to form esters with carboxylic acids in the presence of dehydrating agents (DAs). Obtained esters 1002 react eagerly with amines to produce amides 1003 in high yields (Scheme 165). More details about this application are given in Section 5.01.12. 

Halotriazoles can act as halogenating agents and A-acyltriazoles can act as acyl transfer reagents. Triazole can be used for the synthesis of peptide bonds and is superior to imidazole in that less racemization is observed. It can also be used to transfer the t-butyloxycarbonyl (t-Boc) protecting group to the nitrogen of amino acids. For details see Polya <84CHEC-I(5)733, p. 786). 

An extensive review of the chemistry of aliphatic and aromatic azides is given by Boyer and Canter [167] and Gray [168]. Organic azides are subject to various reactions such as the Bergmann degradation and the synthesis of peptides, the well known Curtius rearrangement, the Darapsky synthesis of a-aminoacids [169], for synthesis of triazoles [170], tetrazoles ( Schmidt reaction ) [169] and [171] etc. These reactions lie beyond the scope of the present book. 

The 1,2,4-triazole moiety, like the 1,2,4-oxadiazole and 1,3,4-oxadiazole discussed in Section 11.2.5, has been used extensively as an ester or amide bioisostere but has rarely been inserted into peptide segments 109-112 1,2,4-Triazoles are complementary to the 1,2,4- and 1,3,4-oxadiazoles due to their ability to donate a hydrogen bond as well as accept a hydrogen bond. 

The synthesis of the peptide-based triazole 63 is shown in Scheme 19J102l Coupling of Boc-Ser(Bzl)-OH (61) with ethyl ox am i drazon ate11131141 proceeded under mixed anhydride conditions177 using ethyl chloroformate as the activating reagent. The product acylamidrazone 62 thus formed was simply heated in xylenes under Dean-Stark conditions to form the desired triazole 63. 

Unlike 1,2,4- and 1,3,4-oxadiazoles, the 1,2,4-triazole heterocycle has the possibility of existing in different tautomeric forms (Scheme 20). X-ray crystal analysis of the peptide-based triazole 63 showed only one tautomerJ102 Additionally, the 13C NMR spectrum for this compound indicated only one tautomeric form since the signals due to C3 and C5 appeared as sharp peaks. This is not the case for some other peptidergic triazoles (Table 5) where peaks corresponding to C3 and C5 were broad and of low intensity or not visible. Differences in tautomeric preferences have been explained by the ability of some triazole-containing peptides to form intermolecular hydrogen bonds and thus stabilize one tautomer over the other. 

Table 5 Synthesis of Peptide-Based 1,2,4-Triazoles by the Prepara-...

The driving force of the terminal step is the formation of the very stable urea derivative 50, which is formed stoichiometrically. Further reagents employed in peptide bond forming reactions are diimide EDC 52 and triazole HOBT 53 which react similarly to DCC 45 but... 

Koenig W, Geiger R, New methods for the synthesis of peptides Activation of the carboxyl group with dicyclohexylcarbodiimide by using 1 -hydroxybenzo-triazoles as additives, Chem. Ber., 103 788-798, 1970. 

Another approach to labeling OC with 18F was reported by Hostetler et al. [61]. OC was labeled via an in situ peptide coupling of 4-[18F]fluorobenzoic acid ([18F]FBA) with the N-terminus of OC to provide 4-[18F]fluorobenzoyl-OC ([18F]FB-OC).The process of synthesizing [18F]FB-OC involved a new efficient, one-pot synthesis of [18F]FBA using a microwave cavity and the combination of reagents,1,3-dicyclohexylcarbodiimide and l-hydroxy-7-azabenzo-triazole. Unfortunately, [18F]FB-OC also showed high liver uptake and low uptake in so-... 

Click chemistry also found applications in peptides and peptidomimetics. Alkyne-azide cycloaddition between two peptide strands provided an efficient convergent synthesis of triazole ring-based P-tum mimics <07CC3069>. The synthesis of a-substituted prolines has been accomplished by microwave-assisted Huisgen 1,3-dipolar cycloaddition between azides and orthogonally protected a-propynyl proline in the presence of Cu(I) sulfate <07SL2882>. The synthesis of new trifluoromethyl peptidomimetics with a triazole moiety has been reported <07TL8360>. 

There are some literature reports on the reactions of 1,2,4-triazoles. 2-Amino-4-aryl-5-( I //-l, 2,4-triazol-1 -yl)thiazolc derivatives were synthesized from the reaction of a-bromo substituted acetophenone and thiourea <07SC199>. 5-Amino-l-methyl-l//-[l,2,4]triazole-3-carboxylic acid were employed as precursors in peptide synthesis <07SC1917>. 3-... 

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