Steric impact of aza-amino acid on solid-phase aza-peptide bond synthesis

Troska, Alla; Arujõe, Meeli; Mastitski, Anton; Järv, Jaak; Ploom, Anu

doi:10.1016/j.tetlet.2021.152973

Cited by 4 publications

(3 citation statements)

References 20 publications

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“…To begin with, we performed a reaction using iodobenzene ( 1a , 3 equiv) and l -phenylalanine tert -butyl ester ( 2a , 1 equiv) in the presence of Pd(OAc) 2 (5 mol %), Xanthphos (10 mol %), CsOH·H 2 O (10 equiv), and CHCl 3 (3 equiv) in anhydrous toluene under an inert atmosphere at 80 °C for an extended time of 48 h. The reaction gave trace amount of the product ( 3a ), attributable to low nucleophilicity of the α-amino group. The other factor is the presence of side chains that creates steric hindrance, demanding the use of a non-conventional heating source for activation of substrates . To provide sufficient activation energy, we used MW irradiation.…”

Section: Resultsmentioning

confidence: 99%

Palladium-Catalyzed Aminocarbonylation of (Hetero)aryl Iodides with α-Amino Acid Esters as Nucleophiles

Rathod

Jain

2022

J. Org. Chem.

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We report palladium-catalyzed aminocarbonylation of (hetero)aryl iodides with α-amino acid esters as nucleophiles. The synthesized N-capped α-amino acids are biologically important building blocks. The mild conditions provide products with high enantioselectivity at 80 °C in 35 min. The reactions are performed under air in a sealed vessel using chloroform as an in situ CO source. For the first time, regioselective carbonylation of histidine is also presented.

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Section: Resultsmentioning

confidence: 99%

Palladium-Catalyzed Aminocarbonylation of (Hetero)aryl Iodides with α-Amino Acid Esters as Nucleophiles

Rathod

Jain

2022

J. Org. Chem.

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“…Using the graph shape index values Ξ, it was revealed that the effect of the bulkiness of group R (X) on the reaction rate of aza-peptide synthesis is 2.5 times higher than that of substituent R 1 (VIII) [75]. As steric hindrances govern nucleophilic substitution reactions at carbonyl carbon atoms in general, this effect is also observed in conventional peptide synthesis.…”

Section: Aza-peptide Bond Synthesismentioning

confidence: 97%

“…Additionally, we have demonstrated that the rate of aza-peptide bond formation in compound XII sig nificantly depends on the bulkiness of the aza-amino acid side chain R and of the amino acid side group R 1 [74,75]. The influence of these substituents was quantified with the graph shape index values Ξ, which were specifically derived for characterization of the amino acid side chain bulkiness [76].…”

Section: Aza-peptide Bond Synthesismentioning

confidence: 99%

Aza-peptides: expectations and reality

Arujõe¹,

Järv²,

Mastitski³

et al. 2022

PEAS

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The replacement of the α-carbon atom in an α-amino acid structure by a nitrogen atom yields alkylcarbazic acids, also known as α-aza amino acids. Although the topology of α-amino acids and α-aza amino acids is similar, their chemical and stereochemical properties are significantly different. For this reason, the application of the common solid-phase peptide synthesis (SPPS) protocol cannot be used for aza-peptide bond synthesis without changes. On the other hand, the aza-peptide bond is more stable than the common peptide bond, therefore these compounds are very attractive targets for drug design. In this review, we summarize data on aza-peptide bond chemistry, with implications for the improvement of aza-peptide chemical synthesis.

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