Amino acid chlorides: a journey from instability and racemization toward broader utility in organic synthesis including peptides and their mimetics

Prabhu, Girish; Basavaprabhu,; Narendra, N.; Vishwanatha, T. M.; Sureshbabu, Vommina V.

doi:10.1016/j.tet.2015.03.026

Cited by 25 publications

(16 citation statements)

References 244 publications

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“…Thus, the α-C-acylated intermediates 3a–j ( Table 1 ) and 4 ( Table 2 ) were obtained in good yields and excellent chiral integrity (er 3c – f ≥ 99:1). The phthaloyl-protected compounds 3k and 3l were obtained in low yields by the mixed carbonic anhydride method and after screening various alternative coupling reagents (mixed pivalic anhydrides, T3P, DCC, DIC, CDI) we were able to improve the yields of 3k , l to 77% and 60%, respectively, only by using the corresponding N -phthaloyl amino acid chlorides [ 35 – 36 ] as acylating reagents. The increased yield however came at the expense of chiral integrity, with nearly full racemisation.…”

Section: Resultsmentioning

confidence: 99%

Synthesis of functionalised β-keto amides by aminoacylation/domino fragmentation of β-enamino amides

Yanev

Angelov

2018

Beilstein J. Org. Chem.

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Section: Resultsmentioning

confidence: 99%

Synthesis of functionalised β-keto amides by aminoacylation/domino fragmentation of β-enamino amides

Yanev

Angelov

2018

Beilstein J. Org. Chem.

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“…The most favorable strategy to synthesize α-amino aryl-ketone is by Friedel–Crafts acylation [ 3 , 4 ] of arenes, which is known as a reliable method that results in satisfactory product yields [ 5 ] and can utilize convenient optically pure α-amino acid derivatives as skeletons [ 6 ]. The α-amino acid chloride [ 1 , 2 , 7 , 8 ] is widely used as an acyl donor to undergo Friedel–Crafts acylation due to its reactivity. However, this acyl donor is unstable, sensitive to moisture and difficult to handle [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Chiral TFA-Protected α-Amino Aryl-Ketone Derivatives with Friedel–Crafts Acylation of α-Amino Acid N-Hydroxysuccinimide Ester

et al. 2017

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Chiral N-protected α-amino aryl-ketones are one of the useful precursors used in the synthesis of various biologically active compounds and can be constructed via Friedel–Crafts acylation of N-protected α-amino acids. One of the drawbacks of this reaction is the utilization of toxic, corrosive and moisture-sensitive acylating reagents. In peptide construction via amide bond formation, N-hydroxysuccinimide ester (OSu), which has high storage stability, can react rapidly with amino components and produces fewer side reactions, including racemization. This study reports the first synthesis and utilization of N-trifluoroacetyl (TFA)-protected α-amino acid-OSu as a potential acyl donor for Friedel–Crafts acylation into various arenes. The TFA-protected isoleucine derivative and its diastereomer TFA-protected allo-isoleucine derivative were investigated to check the retention of α-proton chirality in the Friedel–Crafts reaction. Further utilization of OSu in other branched-chain and unbranched-chain amino acids results in an adequate yield of TFA-protected α-amino aryl-ketone without loss of optical purity.

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“…[13] HCl is generally regarded as an inhibitor of amidation reactions owing to its undesirable protonation of nucleophiles. [14] However,t he addition of acatalytic amount of HCl seemed to accelerate the formation of 2a rather than inhibiting the attack of NMI and/or 3a under our conditions.T he added HCl should form the Tabelle 1: Comparison between amidation reactions from acid chloride and mixed carbonic anhydride and the positive effect of the additiono f aBrønsted acid.…”

Section: Resultsmentioning

confidence: 54%

N‐Methylated Peptide Synthesis via Generation of an Acyl N‐Methylimidazolium Cation Accelerated by a Brønsted Acid

et al. 2020

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The development of a robust amide‐bond formation remains a critical aspect of N‐methylated peptide synthesis. In this study, we synthesized a variety of dipeptides in high yields, without severe racemization, from equivalent amounts of amino acids. Highly reactive N‐methylimidazolium cation species were generated in situ to accelerate the amidation. The key to success was the addition of a strong Brønsted acid. The developed amidation enabled the synthesis of a bulky peptide with a higher yield in a shorter amount of time compared with the results of conventional amidation. In addition, the amidation can be performed by using either a microflow reactor or a conventional flask. The first total synthesis of naturally occurring bulky N‐methylated peptides, pterulamides I–IV, was achieved. Based on experimental results and theoretical calculations, we speculated that a Brønsted acid would accelerate the rate‐limiting generation of acyl imidazolium cations from mixed carbonic anhydrides.

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Amino acid chlorides: a journey from instability and racemization toward broader utility in organic synthesis including peptides and their mimetics

Cited by 25 publications

References 244 publications

Synthesis of functionalised β-keto amides by aminoacylation/domino fragmentation of β-enamino amides

Synthesis of functionalised β-keto amides by aminoacylation/domino fragmentation of β-enamino amides

Synthesis of Chiral TFA-Protected α-Amino Aryl-Ketone Derivatives with Friedel–Crafts Acylation of α-Amino Acid N-Hydroxysuccinimide Ester

N‐Methylated Peptide Synthesis via Generation of an Acyl N‐Methylimidazolium Cation Accelerated by a Brønsted Acid

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