| Abstract
| - In the synthesis of peptidomimetics containing α-hydroxy-β-amino acid, the coupling of this Nβ-protected β-amino acid with amine components was generally performed without the protection ofits α-hydroxyl group. However, the formation of dipeptides in low yield was often observed whensterically hindered amine components were used. Boc-Apns-OH [Apns: (2S,3S)-3-amino-2-hydroxy-4-phenylbutanoic acid, allophenylnorstatine] (6), which is one of such β-amino acid derivatives, isintensively employed as a core structure in the development of HIV-1 protease inhibitors. Therehave been no precise studies, to date, that have examined amide bond formation with α-hydroxy-β-amino acid derivatives as an acyl component. To determine the cause of this low-yield reaction,we studied the amide bond formation focusing on the activation step of Nβ-protected α-hydroxy-β-amino acid by using a model coupling reaction between 6 and H-Dmt-OR [Dmt: (R)-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid] (7). A significant amount of homobislactone 9 was formed throughthe activation of the carboxyl group of 6 to the benzotriazole-type active esters such as OBt andOAt. In addition, this homobislactone formation was markedly increased in the presence of acatalytic amount of a base, which exhibited good correlation with the low yield of the amide bondformation, suggesting that homobislactone formation is one major reason for the low yield of theamide bond formation. Moreover, homobislactones were also formed in other derivatives of theNβ-protected α-hydroxy-β-amino acid, suggesting a common feature of this type of amino acids.The use of a strong activation method like EDC−HOAt without base addition enhanced amidebond formation, although a small amount of homobislactone may be formed during the couplingreaction.
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