Study of the effect of the nature of the side chain in esters of  -amino acids on the diastereoselectivity of condensation with 5(4H)-oxazolone in the synthesis of dipeptides with N-terminal N-acetylphenylalanine

Краснов, В. П.; Zhdanova, E. A.; Solieva, N. Z.; Садретдинова, Л. Ш.; Bukrina, I. M.; Demin, A. M.; Левит, Г. Л.; Ежикова, М. А.; Кодесс, М. И.

doi:10.1023/b:rucb.0000042296.13831.bd

Cited by 10 publications

(4 citation statements)

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“…Thus, the structure of the ester group exerts a weak effect on the diastereoselectivity of the reaction, unlike, e.g., the structure of the side chain of amino acids. 12 It is most likely that stereodifferentiation is deter mined by the interaction of the groups closest to the reac tion centers. Methyl and ethyl (S) valinate hydrochlorides and benzyl (S) valinate p toluenesulfonate were synthesized as described previously.…”

Section: Resultsmentioning

confidence: 99%

Study of the inf luence of the alkyl ester group in (S)-valinates on diastereoselectivity of their condensation with N-acetylphenylalanine by the mixed anhydride method

et al. 2006

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The dynamic kinetic resolution in the synthesis of alkyl N acetylphenylalanyl (S) valinates was studied by the mixed anhydride method. The structure of the ester group of the amino component appeared to exert no substantial effect on the diastereoselectivity of the reaction.The dynamic kinetic resolution (DKR) method has attracted increasing attention of researchers in the recent time. The in situ epimerization of a chiral substrate occurs during this method, which makes it possible to perform syntheses with high diastereoselectivity. 1-6 5(4H ) Oxazo lones are very convenient substrates in DKR processes, because they are rapidly racemized and react readily with nucleophiles. They are widely used for syntheses of modi fied α amino acids and their derivatives. 7-10The synthesis of peptides by the mixed anhydride method is accompanied (under certain conditions) by substantial racemization, which proceeds mainly through the formation of 5(4H ) oxazolones. 11 The reaction of the latter with esters of amino acids affords a diastereomeric mixture of peptides. Diastereoselectivity in this process takes place when, along with the fast racemization of intermediate 5(4H ) oxazolone, one of its stereoisomers reacts with the amino component more rapidly than an other. 7 Therefore, the formation of dipeptide is the DKR process. The determination of factors favoring an increase in differences in the rates of interaction of oxazolone stereoisomers with the amino component provides a pos sibility of diastereoselective synthesis of dipeptides.In the previous work 12 we studied the influence of the nature of the side chain of the amino component on the diastereoselectivity of syntheses of dipeptides of N acetyl (S) phenylalanine (1). It is found that the introduction of 20% excess triethylamine provides the fast racemization of intermediate 5(4H ) oxazolone. The (R) isomer of 5(4H ) oxazolone 2″ reacts more rapidly with ethyl esters of (S) amino acids (Ala, Phe, Val, Glu), which results in the predominant formation of (R,S) diastereomers, whose content in the mixture is 61-90%. The main product of this DKR is dipeptide with the (R) phenylalanine residue.The purpose of the present work is to study the influ ence of the R substituent in the ester group of the amino component on the diastereoselectivity of condensation of alkyl (S) valinates with N acetyl (S) phenylalanine (1) (Scheme 1). (3, 7), Et (4, 8), Bu t (5, 9), Bn (6, 10) Scheme 1 R = Me

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Section: Resultsmentioning

confidence: 99%

Study of the inf luence of the alkyl ester group in (S)-valinates on diastereoselectivity of their condensation with N-acetylphenylalanine by the mixed anhydride method

et al. 2006

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“…The chirality of those sites should be preserved to maintain the properties of the substrates unaltered, conferring peculiar features to the synthetized molecules, especially in the case of bioactive compounds. Nevertheless, the condensation of N -protected chiral amino acids is known to be accompanied by substantial racemization at the α proton [ 1 ], resulting in the loss of stereocenter configuration in the target amides. Several causes contribute to the racemization of chiral substrates, but the phenomenon usually takes place on the N -protected amino acid/coupling agent reactive intermediate generated during the activation of the amino acid ( vide infra ) [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

“…Considering NAPA’s molecular structure ( 2b ), we envisioned its synthesis relying on a direct amidation reaction between N -acetyl- l -phenylalanine and 1,3,4,6-tetra- O -acetyl-glucosamine ( 1 ), which could be easily prepared following a reported procedure [ 22 ]. The condensation step, although based on a simple reaction, represents the most delicate point in the process because of the ubiquitous and recurring tendency of N -acetyl protected amino acids to give azlactones, i.e., to racemize, when activated by a coupling agent under a basic environment [ 1 ]. The intermediate L-2a could be converted to NAPA via direct O -deacetylation reaction.…”

Section: Introductionmentioning

confidence: 99%

N-Acetyl-l-phenylalanine Racemization during TBTU Amidation: An In-Depth Study for the Synthesis of Anti-Inflammatory 2-(N-Acetyl)-l-phenylalanylamido-2-deoxy-d-glucose (NAPA)

et al. 2023

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A thorough study on the amidation conditions of N-acetyl-l-phenylalanine using TBTU and various bases is reported for the synthesis of 2-(N-acetyl)-l-phenylalanylamido-2-deoxy-d-glucose (NAPA), a promising drug for the treatment of joints diseases. TBTU-mediated diastereoselective amidation reaction with 1,3,4,6-tetra-O-acetyl-β-d-glucosamine always gave racemization of N-acetyl-l-phenylalanine. The stereochemical retention under amidation conditions was studied in detail in the presence of difference bases and via other control experiments, evidencing the possibility to reduce racemization using pyridine as base.

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“…2-Phenyl-5(4H)-oxazolones are important intermediates in the synthesis of several molecules including amino acids, peptides, antimicrobial or antitumor compounds and heterocyclic precursors, as well as in biosensor coupling and photosensitive composition devices for proteins [6,7,8,9,10,11]. …”

Section: Introductionmentioning

confidence: 99%

Dodecatungstophosphoric Acid (H3PW12O40), Samarium and Ruthenium (ІІІ) Chloride Catalyzed Synthesis of Unsaturated 2-Phenyl-5(4H)-oxazolone Derivatives under Solvent-free Conditions

2008

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Study of the effect of the nature of the side chain in esters of -amino acids on the diastereoselectivity of condensation with 5(4H)-oxazolone in the synthesis of dipeptides with N-terminal N-acetylphenylalanine

Cited by 10 publications

References 4 publications

Study of the inf luence of the alkyl ester group in (S)-valinates on diastereoselectivity of their condensation with N-acetylphenylalanine by the mixed anhydride method

Study of the inf luence of the alkyl ester group in (S)-valinates on diastereoselectivity of their condensation with N-acetylphenylalanine by the mixed anhydride method

N-Acetyl-l-phenylalanine Racemization during TBTU Amidation: An In-Depth Study for the Synthesis of Anti-Inflammatory 2-(N-Acetyl)-l-phenylalanylamido-2-deoxy-d-glucose (NAPA)

Dodecatungstophosphoric Acid (H3PW12O40), Samarium and Ruthenium (ІІІ) Chloride Catalyzed Synthesis of Unsaturated 2-Phenyl-5(4H)-oxazolone Derivatives under Solvent-free Conditions

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