Synthesis of an Oxazole–Pyrrole–Piperazine Scaffold as an α‐Helix Mimetic

Moisan, Lionel; Odermatt, Severin; Gombosuren, Naran; Carella, Alexandre; Rebek, Julius

doi:10.1002/ejoc.200701164

Cited by 45 publications

(21 citation statements)

References 39 publications

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“…1 Such reactions have also found widespread use in the synthesis of highly substituted heterocycles not accessible by other means, 2 in the divergent synthesis of screening libraries, 3 and recently in bioconjugation reactions. 4 To date, our own studies have focused largely on the fundamental cycloaddition reactions of 1,2,4,5-tetrazines, 5 1,2,4-triazines, 6 1,3,5-triazines, 7 1,3,4-oxadiazoles, 8 and occasionally 1,2-diazines, 9 often followed by subsequent key transformations that now constitute general synthetic strategies for the preparation of five-membered 10 as well as six-membered heterocyclic ring systems.…”

Section: Introductionmentioning

confidence: 99%

Inverse Electron Demand Diels–Alder Reactions of 1,2,3-Triazines: Pronounced Substituent Effects on Reactivity and Cycloaddition Scope

2011

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A systematic study of the inverse electron demand Diels–Alder reactions of 1,2,3-triazines is disclosed, including an examination of the impact of a C5 substituent. Such substituents were found to exhibit a remarkable impact on the cycloaddition reactivity of the 1,2,3-triazine without altering, and perhaps even enhancing, the intrinsic cycloaddition regioselectivity. The study revealed that not only may the reactivity be predictably modulated by a C5 substituent (R = CO2Me > Ph > H), but that the impact is of a magnitude to convert 1,2,3-triazine (1) and its modest cycloaddition scope into a heterocyclic azadiene system with a reaction scope that portends extensive synthetic utility, expanding the range of participating dienophiles. Significantly, the studies define a now powerful additional heterocyclic azadiene, complementary to the isomeric 1,2,4-triazines and 1,3,5-triazines, capable of dependable participation in inverse electron demand Diels–Alder reactions, extending the number of complementary heterocyclic ring systems accessible with implementation of the methodology.

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Section: Introductionmentioning

confidence: 99%

Inverse Electron Demand Diels–Alder Reactions of 1,2,3-Triazines: Pronounced Substituent Effects on Reactivity and Cycloaddition Scope

2011

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“…1 Such reactions have also found widespread use in the synthesis of highly substituted heterocycles not easily accessed by other means, 2 in the divergent 3 synthesis of screening libraries, 4 and recently for use in bioconjugation reactions. 5 The most widely studied of these reactions in our own efforts enlist 1,2,4,5-tetrazines, 6 1,2,4- or 1,3,5-triazines, 7,8 1,3,4-oxadiazoles, 9 and occasionally 1,2-diazines, 10 often followed by key transformations that now constitute general strategies for the preparation of five-membered 11 as well as six-membered heterocyclic ring systems (Figure 1).…”

mentioning

confidence: 99%

Scope of the Inverse Electron Demand Diels–Alder Reactions of 1,2,3-Triazine

Anderson

Boger

2011

Org. Lett.

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“…Chronologically, scaffolds 1 , 4-6 2 , 7 3 , 8-10 4 , 11,12 5 , 13 6 , 14 7 , 15 and 8 16 (Figure 1) were reported as mimics of helical secondary structures, and are typical of ones in the literature. 17-19 Our interest in the concept of “universal mimics”, wherein several secondary structures are represented in one conformational ensemble, 20 led us to wonder if scaffolds that had been described only as α-helical mimics might also be able to access conformers that match other secondary structures.…”

Section: Introductionmentioning

confidence: 69%

Evaluating minimalist mimics by exploring key orientations on secondary structures (EKOS)

Xin

Pérez

et al. 2013

Org. Biomol. Chem.

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Peptide mimics that display amino acid side-chains on semi-rigid scaffolds (not peptide polyamides) can be referred to as minimalist mimics. Accessible conformations of these scaffolds may overlay with secondary structures giving, for example, “minimalist helical mimics”. It is difficult for researchers who want to apply minimalist mimics to decide which one to use because there is no widely accepted protocol for calibrating how closely these compounds mimic secondary structures. Moreover, it is also difficult for potential practitioners to evaluate which ideal minimalist helical mimics are preferred for a particular set of side-chains. For instance, what mimic presents i, i+4, i+7 side-chains in orientations that best resemble an ideal α-helix, and is a different mimic required for a i, i+3, i+7 helical combination? This article describes a protocol for fitting each member of an array of accessible scaffold conformations on secondary structures. The protocol involves: (i) use quenched molecular dynamics (QMD) to generate an ensemble consisting of hundreds of accessible, low energy conformers of the mimics; (ii) representation of each of these as a set of Cα and Cβ coordinates corresponding to three amino acid side-chains displayed by the scaffolds;(iii) similar representation of each combination of three side-chains in each ideal secondary structure as a set of Cα and Cβ coordinates corresponding to three amino acid side-chains displayed by the scaffolds; and, (iv) overlay Cα and Cβ coordinates of all the conformers on all the sets of side-chain “triads” in the ideal secondary structures and express the goodness of fit in terms of root mean squared deviation (RMSD, Å) for each overlay. We refer to this process as Exploring Key Orientations on Secondary structures (EKOS). Application of this procedure reveals the relative bias of a scaffold to overlay on different secondary structures, the “side-chain correspondences” (eg i, i+4, i+7 or i, i+3, i+4) of those overlays, and the energy of this state relative to the minimum located. This protocol was tested on some of the most widely cited minimalist α-helical mimics (1 – 8 in the text). The data obtained indicates several of these compounds preferentially exist in conformations that resemble other secondary structures as well as α-helices, and many of the α-helical conformations have unexpected side-chain correspondences. These observations imply the featured minimalist mimics have more scope for disrupting PPI interfaces than previously anticipated. Finally, the same simulation method was used to match preferred conformations of minimalist mimics with actual protein/peptide structures at interfaces providing quantitative comparisons of predicted fits of the test mimics at protein-protein interaction sites.

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Synthesis of an Oxazole–Pyrrole–Piperazine Scaffold as an α‐Helix Mimetic

Cited by 45 publications

References 39 publications

Inverse Electron Demand Diels–Alder Reactions of 1,2,3-Triazines: Pronounced Substituent Effects on Reactivity and Cycloaddition Scope

Inverse Electron Demand Diels–Alder Reactions of 1,2,3-Triazines: Pronounced Substituent Effects on Reactivity and Cycloaddition Scope

Scope of the Inverse Electron Demand Diels–Alder Reactions of 1,2,3-Triazine

Evaluating minimalist mimics by exploring key orientations on secondary structures (EKOS)

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