Metal-free, direct conversion of α-amino acids into α-keto γ-amino esters for the synthesis of α,γ-peptides

Hernández, Dácil; Boto, Alicia; Guzmán, D.; Álvarez, Eleuterio

doi:10.1039/c7ob02033c

Cited by 8 publications

(5 citation statements)

References 52 publications

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“…These substrates underwent radical decarboxylation–oxidation by treatment with (diacetoxyiodo)benzene (DIB) and iodine under irradiation with visible light, generating a 2-acetoxypyrrolidine (not shown) . This intermediate was treated in situ with a Lewis acid to generate an iminium ion ( 8a or 9a ), which was trapped by C-nucleophiles. , In the case of small nucleophile allyltrimethylsilane (allylTMS), both substrates were transformed into 2,4-cis products 10 and 11 . The prevalence of the cis product over the less hindered trans isomer is due to a stereoelectronic effect described by Woerpel for 4-substituted five-membered cyclic iminium ions. , Thus, when the substituent at C-4 is an oxygenated function, the iminium intermediate 8a or 9a adopts an envelop conformation, where axial H-groups hinder the introduction of nucleophiles from the face opposite to the OP group.…”

Section: Results and Discussionmentioning

confidence: 99%

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“Doubly Customizable” Unit for the Generation of Structural Diversity: From Pure Enantiomeric Amines to Peptide Derivatives

2021

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Readily available, low-cost 4R-hydroxy-l-proline (Hyp) is introduced as a “doubly customizable” unit for the generation of libraries of structurally diverse compounds. Hyp can be cleaved at two points, followed by the introduction of new functionalities. In the first cycle, the removal and replacement of the carboxylic group are carried out, followed (second cycle) by the scission of the 4,5-position and manipulation of the resulting chains. In this way, three new chains are generated and can be transformed independently to afford a diversity of products with tailored substituents, such as β-amino aldehydes, diamines, β-amino acid derivatives, including N-alkylated ones, or modified peptides. Many of these products are high-profit compounds but, in spite of their commercial value, are still scarce. Moreover, the process takes place with stereochemical control, and either pure R or S isomers can be obtained with small variations of the synthetic route.

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Section: Results and Discussionmentioning

confidence: 99%

“…6 This intermediate was treated in situ with a Lewis acid to generate an iminium ion (8a or 9a), which was trapped by C-nucleophiles. 6,7 In the case of small nucleophile allyltrimethylsilane (allylTMS), both substrates were transformed into 2,4-cis products 10 and 11.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“Doubly Customizable” Unit for the Generation of Structural Diversity: From Pure Enantiomeric Amines to Peptide Derivatives

2021

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“…In both cases, an oxidative radical decarboxylation took place, followed in the first case (conversion 11→ 12/13) by the addition of silyl enol ethers to give derivatives 12 or 13 in good global yields. In that way, an ordinary α,α-unit was converted into α,γ-peptide hybrids, which have elicited interest for their antimicrobial, antitumour, antihypertensive, and anti-Alzheimer properties, as well as their superior resistance to protease degradation ( Ordóñez and Cativiela, 2007 ; Hernández et al, 2017 ).…”

Section: Oxidative O -Radical Scission-addition Of...mentioning

confidence: 99%

“Cut and Paste” Processes in the Search of Bioactive Products: One-Pot, Metal-free O-Radical Scission-Oxidation-Addition of C, N or P-Nucleophiles

et al. 2022

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Hypervalent iodine reagents have been applied in many metal-free, efficient synthesis of natural products and other bioactive compounds. In particular, treatment of alcohols, acetals and acids with hypervalent iodine reagents and iodine results in O-radicals that can undergo a β-scission reaction. Under these oxidative conditions, derivatives of amino acids, peptides or carbohydrates are converted into cationic intermediates, which can subsequently undergo inter- or intramolecular addition of nucleophiles. Most reported papers describe the addition of oxygen nucleophiles, but this review is focused on the addition of carbon, nitrogen and phosphorous nucleophiles. The resulting products (nucleoside and alkaloid analogs, unnatural amino acids, site-selectively modified peptides) are valuable intermediates or analogs of bioactive compounds.

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“…In a second approach for the generation of peptide libraries by site-selective modification, the core of the starting amino acid (customizable unit) undergoes a scission process and is converted into a very different one (e.g., by cleavage of the lateral chain and attachment of a new one). Recently, our group has introduced new customizable units that allow the site-selective modification of peptides and the creation of both cationic or hydrophobic residues [ 111 , 115 , 116 , 117 , 118 , 119 ]. Peptide ligation is also possible, as shown in the Scheme 8 .…”

Section: Discovery Of New Ampsmentioning

confidence: 99%

The Road from Host-Defense Peptides to a New Generation of Antimicrobial Drugs

2018

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Host-defense peptides, also called antimicrobial peptides (AMPs), whose protective action has been used by animals for millions of years, fulfill many requirements of the pharmaceutical industry, such as: (1) broad spectrum of activity; (2) unlike classic antibiotics, they induce very little resistance; (3) they act synergically with conventional antibiotics; (4) they neutralize endotoxins and are active in animal models. However, it is considered that many natural peptides are not suitable for drug development due to stability and biodisponibility problems, or high production costs. This review describes the efforts to overcome these problems and develop new antimicrobial drugs from these peptides or inspired by them. The discovery process of natural AMPs is discussed, as well as the development of synthetic analogs with improved pharmacological properties. The production of these compounds at acceptable costs, using different chemical and biotechnological methods, is also commented. Once these challenges are overcome, a new generation of versatile, potent and long-lasting antimicrobial drugs is expected.

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Metal-free, direct conversion of α-amino acids into α-keto γ-amino esters for the synthesis of α,γ-peptides

Cited by 8 publications

References 52 publications

“Doubly Customizable” Unit for the Generation of Structural Diversity: From Pure Enantiomeric Amines to Peptide Derivatives

“Doubly Customizable” Unit for the Generation of Structural Diversity: From Pure Enantiomeric Amines to Peptide Derivatives

“Cut and Paste” Processes in the Search of Bioactive Products: One-Pot, Metal-free O-Radical Scission-Oxidation-Addition of C, N or P-Nucleophiles

The Road from Host-Defense Peptides to a New Generation of Antimicrobial Drugs

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