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

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 cis-fused 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 DL-proline-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.

A new picrotoxane-type sesquiterpene from Dendrobium nobile Lindl.

A picrotoxane-type sesquiterpene, dendroterpene E (1), together with five benzene derivatives (2-6), were isolated from the stems of Dendrobium nobile Lindl. Their structures were elucidated by spectroscopic analysis and X-ray diffraction analysis. Compound 1 was a new picrotoxane-type sesquiterpene with a C-9/C-1/O/C-11 oxetane ring, which was first encountered in this type of compounds. Compounds 1-3 exhibited inhibitory activities against α-glycosidase.

Austrobuxusin N, a new picrotoxane terpenoid glycoside, from the Australian endemic plant Austrobuxus swainii (Beuzev. & C.T. White) Airy Shaw.

A new picrotoxane terpenoid glycoside, austrobuxusin N (1), together with four known compounds, austrobuxusin A-D (2-5), were isolated from the leaves of the Australian endemic plant Austrobuxus swainii (Beuzev. & C.T. White) Airy Shaw. The chemical structure of 1 was elucidated by 1D- and 2D-NMR spectroscopy, along with MS data. The sugar moiety in 1 was determined to be ß-D-glucose by acid hydrolysis and subsequent comparison of its specific rotation with that of standard. The relative configuration of the aglycone was assigned by ROESY NMR experiment and density functional theory (DFT) calculation of NMR data coupled with DP4 analysis. Cytotoxicity test revealed that compound 1 exhibited 71% inhibition against Caco-2 cell line at the concentration of 166 µM.[Formula: see text].

Picrotoxane sesquiterpene and α-pyrone derivative from Dendrobium signatum and their free radical scavenging potency.

One new picrotoxane sesquiterpene (1) and one new α-pyrone derivative (4), together with nine known compounds, were isolated from the aerial parts of Dendrobium signatum. The structures of the new compounds were elucidated based on the interpretation of 1D and 2D NMR, HRESIMS and electronic circular dichroism (ECD) data. The absolute configuration of 1 was confirmed by single-crystal X-ray diffraction data. The new α-pyrone 4 exhibited promising ABTS scavenging activity with IC50 value of 0.7 µM.

Ten picrotoxane-type sesquiterpenoids from the stems of Dendrobium wardianum Warner.

Ten undescribed picrotoxane-type sesquiterpenoids, dendrowardins A-J, together with two known ones, were isolated from the stems of Dendrobium wardianum Warner (Orchidaceae). Dendrowardins A-D feature the unusual 5,2-δ-lactone and additionally dendrowardins C-D are the first examples containing the 11,10-γ-lactone moiety. The structures were established using spectroscopic methods and by comparison with literature data. Further, dendrowardin E, amotin, and aduncin exhibited significant effects of promoting the proliferation on human lens epithelial cells (HLECs) induced by D-galactose.

Four New Picrotoxane-Type Sesquiterpenes From Dendrobium nobile Lindl.

Four picrotoxane-type sesquiterpenes, dendroterpene A-D (1-4), together with four known compounds (5-8), were isolated from the stems of Dendrobium nobile Lindl. Their structures were elucidated by spectroscopic analysis, X-ray diffraction analysis, analysis of the ECD data according to the Klyne's lactone sector rule, and quantum ECD calculation. Compounds 1 and 2 are two new picrotoxane-type sesquiterpenes with a new carbon skeleton containing a formamide group, which may be derived from the previously reported dendrobiumane B skeleton by the C(9)-C(11) carbon bond cleavage. Compounds 3, 5, 6, and 8 exhibited inhibitory activity against α-glycosidase. Compounds 5 and 6 were cytotoxic against SGC-7901, K562, A549, BEL-7402, and Hela cell lines.

New sesquiterpenoids from the stems of Dendrobium nobile and their neuroprotective activities.

Three new sesquiterpenoids, (+)-(1R,2S,3R,4S,5R,6S,9R)-3,11,12-trihydroxypicrotoxane-2(15)-lactone (1), (-)-(1S,2R,3S,4R,5S,6R,9S,12R)-3,11,13-trihydroxypicrotoxane-2(15)-lactone (2), and (+)-(1R,5R,6S,8R,9R)-8,12-dihydroxy-copacamphan-3-en-2-one (3), together with five known compounds, were isolated from the n-butanol soluble fraction of a 95% EtOH extract of the stems of Dendrobium nobile. Their structures were determined by extensive spectroscopic analysis. Particularly, to solve difficult stereochemical problems, electronic circular dichroism calculations, NMR data calculations, and a single-crystal X-ray diffraction were performed. Interestingly, compounds 1 and 2 were picrotoxinin-type sesquiterpenoids with an unusual C15,2-lactone ring. All new sesquiterpenoids (1-3) showed a significant neuroprotective activity against H2O2-induced oxidative damage in PC12 cells. Notably, at 25 and 50 µM, compounds 1 and 2 showed the best protective effects, even better than the positive control (vitamin E).

Picrotoxane sesquiterpenoids from the stems of Dendrobium nobile and their absolute configurations and angiogenesis effect.

Five picrotoxane sesquiterpenoids belonging to the unusual dendrobine-type (1 and 4) and the picrotoxinin-type (2, 3, and 5) were isolated from the stems of Dendrobium nobile Lindl. Their structures were established by spectroscopic analyses and physical properties. Compound 1 was a new dendrobine analogue. Although the planar structure of 2 and 3 had been reported, their absolute configurations were first determined by single-crystal X-ray diffraction and circular dichroism. Compound 2 exhibited angiogenesis effect against sunitinib-induced damage on intersegmental blood vessels in Tg (flk1: EGFP) and Tg (fli1: nEGFP) transgenic zebrafish at concentrations of 3.13, 6.25, 12.50, and 25.00µM.

Picrotoxane Sesquiterpene Glycosides and a Coumarin Derivative from Coriaria nepalensis and Their Neurotrophic Activity.

Two picrotoxane sesquiterpene lactone glycosides, nepalactones A (1) and B (2), and one new coumarin, nepalarin (3), were isolated from the root barks of the poisonous plant Coriarianepalensis. Their structures were elucidated via HRESIMS and 1D and 2D NMR spectroscopic analyses, and further verified via transformation methods. In addition, compounds 1-3 and five semisynthetic congeners (1a-e) were assayed for the activity to induce neurite outgrowth in rat pheochromocytoma (PC12) cells. As a result, nepalactone A derivative 1c and nepalarin (3) significantly enhanced nerve growth factor (NGF)-mediated neurite outgrowth in PC12 cells.

A new picrotoxane sesquiterpene from the berries of Baccaurea ramiflora with antifungal activity against Colletotrichum gloeosporioides.

Three picrotoxane sesquiterpenes including one new glycoside and two known constituents, sapidolide A (2) and picrotoximaesin (3), were isolated from the berries of Baccaurea ramiflora. The structure of the new sesquiterpene glycoside, ramifloside (1), was elucidated as 2-one-6α-hydroxy-13-nor-11-picrotoxen-3(15ß)-olide 10-O-ß-D-glucopyranoside on the basis of extensive spectroscopic analysis. Compounds 1-3 exhibited antifungal activity against Colletotrichum gloeosporioides with MICs of 12.5, 12.5 and 50 µg/mL.