1-hydroxybenzotriazole reagent

With the dicyclohexylcarbodiimide (DCQ reagent racemization is more pronounced in polar solvents such as DMF than in CHjCl2, for example. An efficient method for reduction of racemization in coupling with DCC is to use additives such as N-hydroxysuccinimide or l-hydroxybenzotriazole. A possible explanation for this effect of nucleophilic additives is that they compete with the amino component for the acyl group to form active esters, which in turn reaa without racemization. There are some other condensation agents (e.g. 2-ethyl-7-hydroxybenz[d]isoxazolium and l-ethoxycarbonyl-2-ethoxy-l,2-dihydroquinoline) that have been found not to lead to significant racemization. They have, however, not been widely tested in peptide synthesis. 

Fig. 6 Commonly used additives and coupling reagents. DCC dicyclohexylcarbodiimide, HOSu A-hydroxysuccinimide, HOBt 1 -hydroxybenzotriazole, HOAt 1 -hydroxy-7-azabenzotriazole...

Hydroxybenzotriazole is also useful in conjunction with DCCI.138 For example, Boc-protected leucine and the methyl ester of phenylalanine can be coupled in 88% yield with these reagents. 

At the present time, the coupling is usually done via an activated ester (see Section 3.4). The coupling reagent and one of several A-hydroxy heterocycles are first allowed to react to form the activated ester, followed by coupling with the depro-tected amino group. The most frequently used compounds are A-hydroxysuccinimide, 1-hydroxybenzotriazole (HOBt), and l-hydroxy-7-azabenzotriazole (HOAt).47... 

Another family of coupling reagents frequently used with the Fmoc method is related to A-hydroxybenzotriazole and A-hydroxy 7-azabenzotriazole but also incorporates phosphonium or amidinium groups. The latter can exist in either the O-(uronium) or A-(guanidinium) forms.48 Both can effect coupling. The former are more reactive but isomerize to the latter. Which form is present depends on the protocol of preparation, including the amine used and the time before addition of the carboxylic acid 49 The... 

B Castro, J-R Dormoy, G Evin, C Selve. Peptide coupling reagents. Part VII. Mechanism of the formation of active esters of hydroxybenzotriazole in the reaction of carboxylate ions on the BOP reagent for peptide coupling. A comparison with Itoh s reagent. J Chem Res (S) 82, 1977. 

HYDROXYBENZOTRIAZOLE AS ADDITIVE IN COUPLINGS OF N-ALKOXYCARBONYLAMINO ACIDS EFFECTED BY PHOSPHONIUM AND URONIUM SALT-BASED REAGENTS... 

FIGURE 2.22 Couplings using phosphonium and uronium salt-based reagents with 1-hydroxybenzotriazole as additive.60 The additional HOBt promotes formation of the benzotriazolyl ester, which is the precursor of the peptide. 

GC Windridge, EC Jorgensen. 1-Hydroxybenzotriazole as aracemization-suppressing reagent for the incorporation of /m-ben/.yl-i,-histidine into peptides. J Am Chem Soc 93, 6318, 1971. 

O-ACYL AND A/-ACYL N -OXIDE FORMS OF 1 -HYDROXYBENZOTRIAZOLE ADDUCTS AND THE URONIUM AND GUANIDINIUM FORMS OF COUPLING REAGENTS... 

Coupling the substituents to the polyacid core is a key step. The reaction must have a high yield to limit purification problems and show high selectivity between the amines and alcohols present to limit side reactions. The amidifica-tion reaction chosen is a coupling reaction used in peptide chemistry. The reaction is carried out at room temperature in the presence of a coupling reagent such as NjAT -dicyclohexylcarbodiimide, l-(3-dimethylaminopropyl)-3-ethylcar-bodiimide or l-ethoxycarbonyl-2-ethoxyl-l,2-dihydroquinoline, possibly in the presence of an activator such as hydroxybenzotriazole or N-hydroxysuccimide (Fig. 8). 

Scheme 36. Reagents and conditions (a) ethyl 3-3(3-dimethyl aminopropyl) carbodii-mide (EDC), hydroxybenzotriazole (HOST).

For the preparation of large compound libraries, the cost of reagents and resins is a further issue that must be considered. Some supports, e.g. resin-bound phenols or N-hydroxybenzotriazole, which enable the preparation of resin-bound, reactive esters (Section 3.3.3), can be reused many times without the need to dismantle the reactor, and are therefore much more cost-efficient than supports that can only be used once [136,137], Reactions such as the acylation of amines with resin-bound acylating agents have the additional advantage that only one equivalent of amine is needed, which again leads to a substantial reduction of costs. 

The reagent is prepared by reaction of 1-hydroxybenzotriazole with diethyl chlo-rophosphate and N(C2H5)3. 

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