1-Hydroxy benzotriazole peptide coupling

In the first step amine 11 is coupled with carboxylic acid 15 to form an amide The method employed here for coupling an a-chiral carboxylic acid with an amine was developed in the context of peptide synthesis. Its success is based on DCC-mediated formation (see Chapter 5) of the reactive 1-hydroxy benzotriazole ester 55, which reacts with an amine to give the corresponding amide. In most cases reaction takes place without raccmi/ation, and often in the absence of side reactions that cause other procedures to The alcohol is converted into a silyl ether in the second step. 

N-oxide salts (HBTU and TBTU, respectively) [39], or from l-hydroxy-7-azabenzotriazole (HOAt) such as N-[(dimethylamino)-lH-l,2,3-triazolo[4,5-fe] pyridino-l-y]methylene]-N-methy]methanaminium tetrafluoroborate N-oxide (HATU) [40], are well established reagents. They are especially devoted to peptide coupling reactions due to their efficiency and the low degree of undesirable race-mization produced in the final peptide compared to the use of classical carbodi-imide-coupling methods. Therefore, as the polystyrene-supported HOBt is an often used polymeric reagent (Section 7.6.3) [41], its transformation in a supported HOBt and tetramethylurea-derived aminium salt analog to HBTU and TBTU resulted directly. Thus, the reaction of polystyrene-2% divinylbenzene copolymer resin P-HOBt (20) with tetramethylchloroformamidinium tetrafluoroborate (21) (4 equivalents) in the presence of triethylamine gave polymeric N-[(lH-benzotriazol-l-yl)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate N-oxide (P-TBTU, 22) (Scheme 7.6) [42],... 

Beilstein Handbook Reference) Benzazimidol hydrate IH-Benzotriazole, 1-hydroxy- IH-Benzotriazole, 1-hydroxy-, hydrate BRN 0004515 CCRIS 2605 EINECS 219-989-7 HOBt 1-Hydroxybenzotriazole l-Hydroxybenzotriazole hydrate 1-Hydroxy-IH-benzotriazole hydrate N-Hydroxy-benzotriazole hydrate. Widely used additive to decrease racemization during dicyclohexylcarbodiimide-catalyzed peptide coupling. Crystals mp = 157-158°, Janssen Chimica Lancaster Syrrthesis Co. Sigma-Aldrich Fine Chem. 

R2 = Me) with phosgene and subsequently treating this mixture first with hydroxy-benzotriazole 1315 and then with KPE. Peptide coupling is often carried out in DMF in the presence of BOP, whereby the reaction goes to completion within 2 h [991-994],... 

Other auxiliary nucleophiles can be used in combination with DCC. The most important ones include 7-aza-l,2,3-benzotriazol-l-ol (7, HOAt)f l and 3-hydroxy-l,2,3-benzotriazin-4(3//)-one (8, HODhbt) which will be described in the section concerning the fragment condensation (Section 4.3.2.2). The use of isolated 3-hydroxy-l,2,3-benzotriazin-4(3//)-ones (8, HODhbt)f l will be discussed under active esters, (Section 4.3.3.1.5). The use of HOAt in peptide chemistry has been discussed by Carpino.f It decreases the time course of coupling reactions, reduces the loss of chiral integrity, and provides a visual indication, yellow to colorless, of the reaction endpoint in solution. HOAt was shown to be a superior coupling additive in both solutiont and solid-phase synthesesf when compared with HOBt. HOAt can be used as a direct substitute for HOBt. Furthermore, HOAt like HOBt is compatible with a variety of activation methods. The performance of HOAt derivatives was compared... 

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