Peptides synthesis, 1,2,4-triazole

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. 

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. 

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-... 

Ethyl l-hydroxy-l//-l,2,3-triazole-4-carboxylate (20) has been investigated as an additive to carbodiinoides particularly for solid-phase peptide synthesis. No racemization was observed when Fmoc-protected anoino acids were coupled to the resin-bound peptides, except for histidine residues which under these reaction conditions racenoized extensively unless the activation time was kept to one minute and three equivalents of ethyl 1-hydroxy-1//-1,2,3-triazole-4-carboxylate (20) were added. Under the latter conditions no racemization was detected.The efficiency of this newly developed method has been well documented by the successful synthesis of deglycosylated human erythropoietin.t ... 

Peptide synthesis /-Amyl chloroformate. Bis-(2,4-dinitrophenyl)carbonate. Bis-o-phenylene pyrophosphite. i-Butyl chloroformate. sec-Butyl chloroformate. /-Butyl chloroformate. /-Butyl 2,4,5-trichlorophenyl carbonate. CopoIy(ethylene-N-hydroxymaleimide). N,N-Diethyl-I-propynylamine. Di-(p-nitrophenyl)sulfate. Ethoxyacetylene. N-Ethoxycarbonyl-2-ethoxy-l,2-dihydroquinoline. N-Ethylbenzisoxazolium fluoroborate. Ethyl chloroformate. N-Ethyl-5-phenylisoxazolium-3 -sulfonate. N-Hydroxysuccinimide trifluoroacetate. Methyl-morpholine. 4-Methylthiophenol. p-Nitrophenol. Oxalylchloride. Pentachlorophenol. Pentamethylbenzyl chloride. /-Pentyl chloroformate. Phenacyl bromide. Polyhexamethylene carbodiimide. Tetraethyl pyrophosphite. 1,2,4-Triazole. 

Peptide synthesis. The addition of this triazole (1-2 equivalents) in the DCC-method of peptide synthesis decreases racemization, prohibits the formation of N-acylurea, and improves the yields of high-purity peptides.2 Several substituted 1-hydroxybenzotriazoles are also effective. 

PEPTIDE SYNTHESIS r-Amyl chloro-formate. f-Butyl azidoformate. Diethyl methyleneraalonate. N-Ethoxycarbonyl-2-ethoxy-l,3-dihydroquinoline. Hexamethylphosphoric triamide. 1-Hydroxybenzo triazole. Triphenylphosphine—2,2 -Dipyridyl disulfide. Triphenyl phosphite. 

Bifunctional catalysis. Some time ago Swain and Brown1 observed that 2-hydroxypyridine catalyzed the mutarotation of tetramethylglucose by a concerted base-acid catalysis and that it is more effective than pyridine plus phenol. A few years later Beyerman and van den Brink2 showed that 2-hydroxypyridine and other bifunctional compounds catalyze the reaction of amines with cyano-methyl esters (reactive esters) as well as low-energy esters in peptide synthesis. Pyrazole and 1,2,4-triazole (1,1188), were equally effective. 

Polystyrene-sulfonyl hydrazide resins 153 reacted with various amines to give regiospecifically 1,4-disubstituted-l,2,3-triazoles 154 via traceless cleavage reactions <04TL6129>. A library of peptidotriazoles were prepared by solid-phase peptide synthesis combined with a regiospecific copper(I)-catalyzed 1,3-dipolar cycloaddition between resin-bound alkynes and protected amino azides <04JCO312>. 

The first example of a peptide synthesis in an ionic hquid vras described by Plaque-vent et al.. [BMIMjfPFe] vras used as a solvent for natural and synthetic amino acids, which were coupled with two ionic coupling agents based on triazoles [201] (Fig. 5.2-7). If no coupling agent or DCC was used, no reaction vras observed. Yields as high as 87% were observed and the type of extraction procedure used made a significant difference to the isolated yields. 

The application of additives was investigated in order to suppress or diminish side reactions (A-acyl urea formation and racemization). Al-Hydroxysuccinimide (HOSu), 1-hydroxybenzotriazole (HoBt), and ethyl l-hydroxy-lH-l,2,3-triazole-4-carboxylate are potential additives in the DCC-based coupling synthesis. Solid-phase peptide synthesis (SPPS) is a variant of the linear (stepwise) coupling of amino acids in the C N direction using two major protection groups Boc/Bzl (iert-butoxycarbonyl/benzyl) and Fmoc/tBu (/9-fluorenylmethoxycarbonyl/ieri-butyl). The synthetic scheme for peptides on a polymer (Atherton and Sheppard, 1989 Fields, 1997) is illustrated in Figure 8.1. 

Nevertheless, its coupling efficiency depends on the reaction medium and in solvents like DMF, which increase the rate of aminolysis, its usefulness is limited. 1,2,4-Triazole is now seldom used in peptide synthesis, whereas other catal)dic additives like 1-hydroxybenzotriazole are widely used as activated esters as well as in conjunction with coupling reagents like 1,3-dicyclohexylcarbodiimide. 

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. 

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]... 

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. 

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

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. 

---