Solid-phase synthesis of unnatural amino acids using unactivated alkyl halides

O’Donnell, Martin J.; Lugar, Charles W.; Pottorf, Richard S.; Zhou, Changyou; Scott, William L.; Cwi, Cynthia

doi:10.1016/s0040-4039(97)01762-0

Cited by 33 publications

(9 citation statements)

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“… 14 − 16 These procedures are often adapted 15 , 16 from published chemistry. 1 , 15 , 18 We were developing a new D3 laboratory, The Combinatorial Synthesis of N-Acylated Unnatural Amino Acid Amides, based on the published reaction sequence shown in Scheme 3 . 1 It would be compatible with a wide variety of R 2 groups obtained from carboxylic acids R 2 CO 2 H. For this adaptation to be successful, it would soon become apparent that understanding and addressing our earlier, parenthetical observation of R 2 -dependent hydrolytic instability would be critically important.…”

Section: Resultsmentioning

confidence: 99%

Unexpected Hydrolytic Instability of N-Acylated Amino Acid Amides and Peptides

et al. 2014

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Remote amide bonds in simple N-acyl amino acid amide or peptide derivatives 1 can be surprisingly unstable hydrolytically, affording, in solution, variable amounts of 3 under mild acidic conditions, such as trifluoroacetic acid/water mixtures at room temperature. This observation has important implications for the synthesis of this class of compounds, which includes N-terminal-acylated peptides. We describe the factors contributing to this instability and how to predict and control it. The instability is a function of the remote acyl group, R2CO, four bonds away from the site of hydrolysis. Electron-rich acyl R2 groups accelerate this reaction. In the case of acyl groups derived from substituted aromatic carboxylic acids, the acceleration is predictable from the substituent’s Hammett σ value. N-Acyl dipeptides are also hydrolyzed under typical cleavage conditions. This suggests that unwanted peptide truncation may occur during synthesis or prolonged standing in solution when dipeptides or longer peptides are acylated on the N-terminus with electron-rich aromatic groups. When amide hydrolysis is an undesired secondary reaction, as can be the case in the trifluoroacetic acid-catalyzed cleavage of amino acid amide or peptide derivatives 1 from solid-phase resins, conditions are provided to minimize that hydrolysis.

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Section: Resultsmentioning

confidence: 99%

Unexpected Hydrolytic Instability of N-Acylated Amino Acid Amides and Peptides

et al. 2014

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“…The conditions of the UPS were further optimized to allow the alkylation reactions also with a variety of less reactive alkyl halides[67].Scheme 32. Subsequent hydrolysis afforded the amine 196, which was for detection purposes, converted to a UV active compound 197.…”

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Recent Advances in the Synthesis of Unnatural α-Amino Acids

Perdih¹,

Dolenc

2007

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The synthesis of unnatural -amino acids is an area of research that has gained a lot of attention in recent years. The availability of synthetic methods for novel unnatural amino acid derivatives and related compounds will be a critical point in the de novo design of molecules that mimic the conformation of the natural, active peptides. These molecules (peptidomimetics) are designed to display high receptor affinity and selectivity, in addition to enhanced bioavailability and metabolic stability.This review focuses on selected recent synthetic methodologies leading to unnatural -amino acids including chiral catalysts that enable enantioselective synthesis and microwave-assisted synthesis. Solid phase synthesis and construction of organometallic amino acids reveal the scope of influence that this field has in organic chemistry. Additionally, the article is aimed to provide a brief insight into the biosynthetic approaches to the synthesis of -amino acid derivatives, and to give the reader an appreciation of the field.

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“…To access intermediate A , a resin bearing the benzophenone imine of glycine was alkylated. − This step introduced considerable structural diversity from a rich pool of alkyl or benzyl halides, and stereoisomeric mixtures were formed. Acidic hydrolysis of the imine provided the key resin-bound, racemic, unnatural amino acid intermediate A . , …”

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confidence: 99%

Multi-Institution Research and Education Collaboration Identifies New Antimicrobial Compounds

et al. 2020

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New antibiotics are urgently needed to address increasing rates of multidrug resistant infections. Seventy-six diversely functionalized compounds, comprising five structural scaffolds, were synthesized and tested for their ability to inhibit microbial growth. Twenty-six compounds showed activity in the primary phenotypic screen at the Community for Open Antimicrobial Drug Discovery (CO-ADD). Follow-up testing of active molecules confirmed that two unnatural dipeptides inhibit the growth of Cryptococcus neoformans with a minimum inhibitory concentration (MIC) ≤ 8 μg/mL. Syntheses were carried out by undergraduate students at five schools implementing Distributed Drug Discovery (D3) programs. This report showcases that a collaborative research and educational process is a powerful approach to discover new molecules inhibiting microbial growth. Educational gains for students engaged in this project are highlighted in parallel to the research advances. Aspects of D3 that contribute to its success, including an emphasis on reproducibility of procedures, are discussed to underscore the power of this approach to solve important research problems and to inform other coupled chemical biology research and teaching endeavors.

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Solid-phase synthesis of unnatural amino acids using unactivated alkyl halides

Cited by 33 publications

References 4 publications

Unexpected Hydrolytic Instability of N-Acylated Amino Acid Amides and Peptides

Unexpected Hydrolytic Instability of N-Acylated Amino Acid Amides and Peptides

Recent Advances in the Synthesis of Unnatural α-Amino Acids

Multi-Institution Research and Education Collaboration Identifies New Antimicrobial Compounds

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