title: Analysis of amide bond formation with an alpha-hydroxy-beta-amino acid derivative, 3-amino-2-hydroxy-4-phenylbutanoic acid, as an acyl component: byproduction of homobislactone.
abstract: In the synthesis of peptidomimetics containing alpha-hydroxy-beta-amino acid, the coupling of this N(beta)-protected beta-amino acid with amine components was generally performed without the protection of its alpha-hydroxyl group. However, the formation of dipeptides in low yield was often observed when sterically 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 beta-amino acid derivatives, is intensively employed as a core structure in the development of HIV-1 protease inhibitors. There have been no precise studies, to date, that have examined amide bond formation with alpha-hydroxy-beta-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 N(beta)-protected alpha-hydroxy-beta-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 through the activation of the carboxyl group of 6 to the benzotriazole-type active esters such as OBt and OAt. In addition, this homobislactone formation was markedly increased in the presence of a catalytic amount of a base, which exhibited good correlation with the low yield of the amide bond formation, suggesting that homobislactone formation is one major reason for the low yield of the amide bond formation. Moreover, homobislactones were also formed in other derivatives of the N(beta)-protected alpha-hydroxy-beta-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 amide bond formation, although a small amount of homobislactone may be formed during the coupling reaction.
authors.affiliation: Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science, Kyoto Pharmaceutical University, Yamashina-Ku, Kyoto 607-8412, Japan. kiso@mb.kyoto-phu.ac.jp
authors.forename: Y
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Y
authors.initials: Y
authors.lastname: Kinoshita
authors.forename: K
authors.initials: K
authors.lastname: Hidaka
authors.forename: A
authors.initials: A
authors.lastname: Kiso
authors.forename: H
authors.initials: H
authors.lastname: Uchibori
authors.forename: T
authors.initials: T
authors.lastname: Kimura
authors.forename: Y
authors.initials: Y
authors.lastname: Kiso
mesh_terms: D000614:Aminocaproates / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D007783:Lactones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010654:Phenylbutyrates / Q000737:chemistry* / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D000614:Aminocaproates; D007783:Lactones; D010654:Phenylbutyrates; D011480:Protease Inhibitors; C434294:homobislactone; C034495:3-amino-2-hydroxy-5-methylhexanoic acid; C034940:3-amino-2-hydroxy-4-phenylbutanoic acid