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Synthesis and reactivity of various isomers of 7-aza-1-hydroxybenzotriazole (HOAt): Implications for a mechanistic understanding of their use as peptide coupling additives
Abstract
Previously it was suggested that the reason for the superior performance, in terms of both reactivity and avoidance of loss of configuration in peptide coupling observed for 7-HOAt over HOBt or 4-HOAt was due to the involvement of a cyclic transition state at the stage of the key intermediate, the active ester [J. Am. Chem. Soc., 1993, 115 , 4397]. Synthesis of the two remaining isomers, the 5- and the 6-compounds, and examination of the reactivity of all four isomers has added further evidence in support of this theory. For example, upon conversion to the corresponding active esters, it was found that in reactions with amines, the 7-derivative stands out as being the most reactive. Similarly when used as additive for segment coupling in the presence of a carbodiimide only the 7-isomer provides for low-racemization coupling whereas the 4-, 5- and 6-HOAt derivatives show results which are similar to those of HOBt. Finally in the case of a reaction for which neighboring group effects are not pertinent, such as S N2 displacement on the methyl group of the four isomeric O-methyl ethers, the order of reactivity appears to parallel the pKa data with the 4-isomer being more reactive than the 7-isomer. ^
Subject Area
Organic chemistry
Recommended Citation
Imazumi, Hideko, "Synthesis and reactivity of various isomers of 7-aza-1-hydroxybenzotriazole (HOAt): Implications for a mechanistic understanding of their use as peptide coupling additives" (1999). Doctoral Dissertations Available from Proquest. AAI9950165.
https://scholarworks.umass.edu/dissertations/AAI9950165