Alcohols as Replacements of the Central Amide in β-Turns, Synthesis of Pro-Aib Hydroxyethylene Isostere and Analysis in Model β-Turn Peptides

Lama, Teresa; Valle, Susan E. Del; Genest, Nicolas; Lubell, William D.

doi:10.1007/s10989-007-9093-0

Cited by 11 publications

(9 citation statements)

References 21 publications

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“…Of importance is that the stereochemistry of the carbon atom bearing the hydroxyl group was of critical importance for binding, highlighting the value of accessing diverse stereodefined isomers. Lubell has reported on the merits of replacing the amide bond with a hydroxyl group as Pro-Aib hydroxyethylene isosteres of β turns …”

Section: Introductionmentioning

confidence: 99%

“…Lubell has reported on the merits of replacing the amide bond with a hydroxyl group as Pro-Aib hydroxyethylene isosteres of β turns. 55 ■ RESULTS AND DISCUSSION Retrosynthesis. As our main objective, we devised a strategy that would provide access to four enantiomerically distinct pseudodiproline Pro-Cyp dimers linked to a transconfigured cyclopentane carboxylic acid via an R-or Shydroxymethylene tether starting with L-proline as a common progenitor.…”

Section: ■ Introductionmentioning

confidence: 99%

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Design of Pseudodiproline Dimers as Mimetics of Pro-Pro Units: Stereocontrolled Synthesis, Configurational Relevance, and Structural Properties

2021

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Stereocontrolled methods are described for the synthesis of hitherto unreported pseudodiproline dimers in which a cyclopentane carboxylic acid is linked to a pyrrolidine residue by a stereochemically defined hydroxymethylene tether. These prolinecyclopentane (Pro-Cyp) dimers have interesting structural characteristics as seen in their X-ray crystal structures as well as their nuclear magnetic resonance (NMR) spectra in CDCl 3 . They can be considered to be novel Pro-Pro mimetics, which can be used to replace natural diproline sequences with potential applications in medicinal chemistry. They also represent a new concept in the peptidomimetic design of chimeric proline-based amino acids as carbocyclic hydroxyethylene isosteres of inhibitor molecules, in which the stereodefined bridging hydroxyl group can simulate a tetrahedral intermediate in an enzyme complex.

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Section: Introductionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

Design of Pseudodiproline Dimers as Mimetics of Pro-Pro Units: Stereocontrolled Synthesis, Configurational Relevance, and Structural Properties

2021

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“…Stereochemical and hydrogen-bonding influences on conformation were studied by replacement of the Pro-Aib amide bond by a hydroxyethylene isostere in a model β-turn peptide (Scheme ). Hydroxyethylene diastereomers Boc-Phe-Pro-ψ[−CH-(OH)–CH 2 ]-Aib-NH(α-Me)Bn [( S , S )- and ( S , R )- 97 ] were synthesized respectively by reductions of homoallylic ketone 14 with NaBH 4 in EtOH and with Li(O t -Bu) 3 H, followed by oxazolidinone formation to provide ( S , S )- and ( S , R )- 95 . Acids ( S , S )- and ( S , R )- 96 were respectively prepared by olefin ozonolysis and sodium chlorite oxidation .…”

Section: Applicationsmentioning

confidence: 99%

Applications of γ,δ-Unsaturated Ketones Synthesized by Copper-Catalyzed Cascade Addition of Vinyl Grignard Reagents to Esters

2018

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CONSPECTUS: γ,δ-Unsaturated ketones, so-called homoallylic ketones, have served as versatile building blocks for the synthesis of a variety of heterocycles, carbocycles, natural products, and reactive intermediates. Procured by a variety of processes, including conjugate addition of vinyl organometallic reagents to unsaturated ketones, allylation of silyl enol ethers, and rearrangements, homoallylic ketones are often synthesized by step-intensive methods. The cascade addition of 2 equiv of vinyl Grignard reagent to a carboxylate was reported by the Lubell laboratory in 2003 to give effective access to homoallylic ketones from a variety of aromatic, aliphatic, and α-amino methyl esters. Employing readily accessible vinyl magnesium halides in the presence of a catalytic amount of copper salt, this cascade reaction provides high yields of homoallylic ketones with minimal side product by a process featuring the assembly and collapse of a tetrahedral intermediate with expulsion of alkoxide ion, followed by conjugate addition to the resulting enone. Application of the cascade reaction to the synthesis of various homoallylic ketones has provided versatile building blocks for the synthesis of targets for different applications. For example, by employing (hetero)aryl di-and tricarboxylates as precursors, copper-catalyzed cascade additions have provided donor−acceptor and star-shaped monomers for optical-electronic materials. Amino ester starting materials have given homoallylic ketones for the synthesis of various peptidomimetics, including heteroarylalanines, hydroxyethylene isoesters, and diazepinone turn mimics. Moreover, anthranilate has served as building block to prepare various pyrrole, quinoline, benzodiazepine, and benzotriazepine heterocyles. In addition, cascade additions on hydroxyprolinates have given access to bipyrrole precursors of the prodigiosin family of natural products. In the interest to highlight the utility of the copper-catalyzed cascade addition of vinyl Grignard reagents to carboxylates, this Account provides details on the broad scope of substrates that deliver homoallylic ketone products as well as an overview of the wide range of applications in which this method may impact including materials and peptide science, heterocycle and natural product synthesis, and medicinal chemistry.

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“…[21] In recent years, many nonhydrolyzable mimetics have been developed, including ( E )-alkene (ψ[( E )-C(R)=CH]) 6 ,[22] ketomethylene (ψ[COCH 2 ]) 7 ,[23] hydroxyethylene (ψ[CH(OH)CH 2 ]) 8 ,[24] dihydroxyethylene (ψ[CH(OH)CHOH]) 9 ,[25] hydroxyethylamine (ψ[CH(OH)CH 2 NH]) 10 ,[26] and methyleneamine (ψ[CH 2 NH]) 11 [2,3,27] moieties (Fig. 2).…”

Section: Peptide-like Molecules (Plms)mentioning

confidence: 99%

Peptide-Like Molecules (PLMs): A Journey from Peptide Bond Isosteres to Gramicidin S Mimetics and Mitochondrial Targeting Agents

Wipf¹,

Xiao²,

Stephenson³

2009

Chimia

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Peptides are natural ligands and substrates for receptors and enzymes and exhibit broad physiological effects. However, their use as therapeutic agents often suffers from poor bioavailability and insufficient membrane permeability. The success of peptide mimicry hinges on the ability of bioisosteres, in particular peptide bond replacements, to adopt suitable secondary structures relevant to peptide strands and position functional groups in equivalent space. This perspective highlights past and ongoing studies in our group that involve new methods development as well as specific synthetic library preparations and applications in chemical biology, with the goal to enhance the use of alkene and cyclopropane peptide bond isosteres.

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Alcohols as Replacements of the Central Amide in β-Turns, Synthesis of Pro-Aib Hydroxyethylene Isostere and Analysis in Model β-Turn Peptides

Cited by 11 publications

References 21 publications

Design of Pseudodiproline Dimers as Mimetics of Pro-Pro Units: Stereocontrolled Synthesis, Configurational Relevance, and Structural Properties

Design of Pseudodiproline Dimers as Mimetics of Pro-Pro Units: Stereocontrolled Synthesis, Configurational Relevance, and Structural Properties

Applications of γ,δ-Unsaturated Ketones Synthesized by Copper-Catalyzed Cascade Addition of Vinyl Grignard Reagents to Esters

Peptide-Like Molecules (PLMs): A Journey from Peptide Bond Isosteres to Gramicidin S Mimetics and Mitochondrial Targeting Agents

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