Unravelling the Synthesis and Chemistry of Stable, Acyclic, and Double‐Deficient 1,3‐Butadienes: An <i>endo</i>‐Selective Diels–Alder Route to Hedgehog Pathway Inhibitors

Xin, Xiaoyi; Zimmermann, Stefan; Flegel, Jana; Otte, Felix; Knauer, Lena; Strohmann, Carsten; Ziegler, Slava; Kumar, Kamal

doi:10.1002/chem.201805823

Cited by 7 publications

(3 citation statements)

References 84 publications

(34 reference statements)

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“…However, recent advances in asymmetric synthesis have provided highly efficient and convenient protocols for achieving axially chiral molecules in an enantioselective fashion, which also provides new opportunities for in‐depth investigations into the bioactivities of a diverse range of functional molecules bearing enantio‐specific stereogenic axes 35–49 . Meanwhile, multifunctionalized urazole derivatives have demonstrated excellent biological activity against pathogens, including fungi, bacteria and viruses 50–58 . As a continuing research program in our laboratory, we are extremely interested in the potential of urazole derivatives bearing axial chiralities in the development of novel pesticides with high antiplant virus efficiency and low nontarget biological risk (Fig.…”

Section: Introductionmentioning

confidence: 99%

“…[35][36][37][38][39][40][41][42][43][44][45][46][47][48][49] Meanwhile, multifunctionalized urazole derivatives have demonstrated excellent biological activity against pathogens, including fungi, bacteria and viruses. [50][51][52][53][54][55][56][57][58] As a continuing research program in our laboratory, we are extremely interested in the potential of urazole derivatives bearing axial chiralities in the development of novel pesticides with high antiplant virus efficiency and low nontarget biological risk (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

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Development of axially chiral urazole scaffolds for antiplant virus applications againstpotato virus Y

Jin

Mou

Zou

et al. 2023

Pest Management Science

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BACKGROUND Potato virus Y (PVY) was first discovered by Smith in 1931 and is currently ranked as the fifth most significant plant virus. It can cause severe damage to plants from the family Solanaceae, which results in billions of dollars of economic loss worldwide every year. To discover new antiviral drugs, a class of multifunctional urazole derivatives bearing a stereogenic CN axis were synthesized with excellent optical purities for antiviral evaluations against PVY. RESULTS The absolute configurations of the axially chiral compounds exhibited obvious distinctions in antiviral bioactivities, with several of these enantio‐enriched axially chiral molecules showing excellent anti‐PVY activities. In particular, compound (R)‐9f exhibited remarkable curative activities against PVY with a 50% maximal effective concentration (EC50) of 224.9 μg mL−1, which was better than that of ningnanmycin (NNM), which had an EC50 of 234.0 μg mL−1. And the EC50 value of the protective activities of compound (R)‐9f was 462.2 μg mL−1, which was comparable to that of NNM (442.0 μg mL−1). The mechanisms of two enantiomer of the axially chiral compounds 9f were studied by both molecule docking and defensive enzyme activity tests. CONCLUSION Mechanistic studies demonstrated that the axially chiral configurations of the compounds played significant roles in the molecule PVY‐CP (PVY Coat Protein) interactions and could enhance the activities of the defense enzymes. The (S)‐9f showed only one carbon–hydrogen bond and one π–cation interaction between the chiral molecule and the PVY‐CP amino acid sites. In contrast, the (R)‐enantiomer of 9f exhibited three hydrogen bonding interactions between the carbonyl groups and the PVY‐CP active sites of ARG157 and GLN158. The current study provides significant information on the roles that axial chiralities play in plant protection against viruses, which will facilitate the development of novel green pesticides bearing axial chiralities with excellent optical purities. © 2023 Society of Chemical Industry.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Development of axially chiral urazole scaffolds for antiplant virus applications againstpotato virus Y

Jin

Mou

Zou

et al. 2023

Pest Management Science

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“…Urazole is a heteroatom-rich five-membered heterocycle bearing three nitrogen and two oxygen atoms. This unique structural motif has received considerable interest in developing bioactive molecules as potential medicines (Figure a) . For example, 1-acetyl-4-phenyl-1,2,4-triazolidine-3,5-dione (APTD) is in clinical studies as a potential hypolipidemic medicine .…”

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confidence: 99%

Carbene-Catalyzed Atroposelective Annulation and Desymmetrization of Urazoles

Jin

Huang

et al. 2021

Org. Lett.

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Thermally Activated Geometrical Regioselective E→Z Isomerization‐Enabled Cascade Sequences of Conjugated Dienals: Experimental and DFT Studies

Saha

Banerjee

Malo

et al. 2023

Chemistry A European J

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The geometrical regioselective E → Z isomerization of a conjugated alkene under thermal activation poses a challenge due to microscopic reversibility. Herein we report that such reversibility issues can be circumvented by integrating E → Z isomerization with subsequent cyclization cascade. Thus, linearly conjugated dienals in a mixture of toluene‒alcohol (2:1) solvents or only with alcohol at 60‐70 °C can be converted to γ‐alkoxybutenolides in moderate to good yields. The intermediary 2Z,4E‒isomer can be isolated, which includes the first example of isolating the regioselective isomerization product under thermal conditions. Density functional theory (DFT) studies have been employed to shed light on the feasibility of geometrical alkene isomerization and ensuing cascade sequences. It has been observed that the regioselective 2E,4E → 2Z,4E isomerization of dienal is a thermodynamically facile (ΔG < 0) process. The thermodynamic plausibility of the subsequent cascade reaction from the Z‐isomer to the anticipated product in the presence of a polar protic solvent (here MeOH) is also explicated. Out of the two probable pathways, the "hemiacetal pathway" involving a relay proton transfer is kinetically more feasible due to the diminished activation barrier than the conjugate addition pathway.

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Unravelling the Synthesis and Chemistry of Stable, Acyclic, and Double‐Deficient 1,3‐Butadienes: An endo‐Selective Diels–Alder Route to Hedgehog Pathway Inhibitors

Cited by 7 publications

References 84 publications

Development of axially chiral urazole scaffolds for antiplant virus applications againstpotato virus Y

Development of axially chiral urazole scaffolds for antiplant virus applications againstpotato virus Y

Carbene-Catalyzed Atroposelective Annulation and Desymmetrization of Urazoles

Thermally Activated Geometrical Regioselective E→Z Isomerization‐Enabled Cascade Sequences of Conjugated Dienals: Experimental and DFT Studies

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