Synthesis of the Tricyclic Picrotoxane Motif by an Oxidative Cascade Cyclization

Cao, Jingming; Thor, Waygen; Yang, Shenkun; Zhang, Mengxun; Bao, Wenli; Zhu, Lizhi; Yang, Wei; Cheng, Yuen Kit; Lee, Chi‐Sing

doi:10.1021/acs.orglett.9b01806

Cited by 15 publications

(11 citation statements)

References 63 publications

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“…Further cyclization of B at C16 of the phenyl ring yields resonance-stabilized radical C (path a), which undergoes further oxidation to carbonium ion D and then aromatization via proton loss to give 2 . From a chemistry perspective, intermediate B , bearing a stable tertiary radical, might also undergo further oxidation to form stabilized carbocation E , as proposed by George and Lee, which might trigger an intramolecular Friedel–Crafts reaction to form carbonium ion D , followed by aromatization to give 2 .…”

mentioning

confidence: 99%

Protecting-Group-Free Total Syntheses of (±)-Norascyronones A and B

et al. 2020

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mentioning

confidence: 99%

Protecting-Group-Free Total Syntheses of (±)-Norascyronones A and B

et al. 2020

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“…Picrotoxin is a plant-derived product, with a universal efficacy as GABA A R’s chloride channel blocker. Picrotoxin is found naturally in the Anamirta Cocculus plant, although it can be synthesized chemically [ 137 , 138 ]. It has been utilized as a CNS stimulant, and antidote for poisoning by CNS depressants and barbiturates [ 139 ].…”

Section: Molecular Pharmacology Of Gaba a Receptorsmentioning

confidence: 99%

GABAA receptors: structure, function, pharmacology, and related disorders

Ghit

Assal

Al‐Shami

et al. 2021

Journal of Genetic Engineering and Biotechnology

220

115

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Background γ-Aminobutyric acid sub-type A receptors (GABAARs) are the most prominent inhibitory neurotransmitter receptors in the CNS. They are a family of ligand-gated ion channel with significant physiological and therapeutic implications. Main body GABAARs are heteropentamers formed from a selection of 19 subunits: six α (alpha1-6), three β (beta1-3), three γ (gamma1-3), three ρ (rho1-3), and one each of the δ (delta), ε (epsilon), π (pi), and θ (theta) which result in the production of a considerable number of receptor isoforms. Each isoform exhibits distinct pharmacological and physiological properties. However, the majority of GABAARs are composed of two α subunits, two β subunits, and one γ subunit arranged as γ2β2α1β2α1 counterclockwise around the center. The mature receptor has a central chloride ion channel gated by GABA neurotransmitter and modulated by a variety of different drugs. Changes in GABA synthesis or release may have a significant effect on normal brain function. Furthermore, The molecular interactions and pharmacological effects caused by drugs are extremely complex. This is due to the structural heterogeneity of the receptors, and the existence of multiple allosteric binding sites as well as a wide range of ligands that can bind to them. Notably, dysfunction of the GABAergic system contributes to the development of several diseases. Therefore, understanding the relationship between GABAA receptor deficits and CNS disorders thus has a significant impact on the discovery of disease pathogenesis and drug development. Conclusion To date, few reviews have discussed GABAA receptors in detail. Accordingly, this review aims to summarize the current understanding of the structural, physiological, and pharmacological properties of GABAARs, as well as shedding light on the most common associated disorders.

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“…14) Recently, there are reports on synthetic studies of picrotoxane-type skeleton (4), which lacks the hydroxy group in an angular position. [15][16][17] However, the applications of these methods toward the synthesis of 2 and 3 has not been explored. These backgrounds encouraged us to examine the total synthesis of 3, a method of which can also be developed for the synthesis of 1 and 2.…”

Section: Introductionmentioning

confidence: 99%

Model Synthetic Study of Tutin, a Picrotoxane-Type Sesquiterpene: Stereoselective Construction of a <i>cis</i>-Fused 5,6-Ring Skeleton

Ikeuchi

Haraguchi

Yamada

et al. 2022

CHEMICAL & PHARMACEUTICAL BULLETIN

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Picrotoxinin, coriamyrtin, and tutin are representative natural products classified as picrotoxane-type sesquiterpenes and they function as strong neurotoxins. Because they possess a cis-fused 5,6-ring skeleton with a highly congested functionalization, organic chemistry researchers have pursued the development of a stereoselective synthesis method for such skeleton. This study aims to stereoselectively synthesize the cisfused 5,6-ring skeleton with two tetrasubstituted carbons at both angular positions using a model compound. The results revealed that the desymmetrization of the 2-methyl-1,3-cyclopentanedione moiety via the DLproline-mediated intramolecular aldol reaction of a pentanal derivative bearing an isopropenyl group and the five-membered ring at the 3-and 5-position, respectively, provided the desired cis-fused skeleton. This reaction can construct four contiguous stereogenic centers of the bicyclic skeleton with the two angular positions in good yield with high stereoselectivity. Further, this reaction was applied to the kinetic resolution of the racemate using L-proline, providing the enantiomeric pure aldol product with the desired skeleton. This method can be utilized for total synthesis of picrotoxane-type sesquiterpenes.

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Synthesis of the Tricyclic Picrotoxane Motif by an Oxidative Cascade Cyclization

Cited by 15 publications

References 63 publications

Protecting-Group-Free Total Syntheses of (±)-Norascyronones A and B

Protecting-Group-Free Total Syntheses of (±)-Norascyronones A and B

GABAA receptors: structure, function, pharmacology, and related disorders

Model Synthetic Study of Tutin, a Picrotoxane-Type Sesquiterpene: Stereoselective Construction of a <i>cis</i>-Fused 5,6-Ring Skeleton

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