Antifungal diastereomeric furanones from Mutisia friesiana: structural determination and conformational analysis

Two diastereomeric furanones, (4S,5S)-5-(4′-methyl-3′-pentenyl)-4-hydroxy-5-methyldihydrofuran-2-one 1 and (4S,5R)-5-(4′-methyl-3′-pentenyl)-4-hydroxy-5-methyldihydrofuran-2-one 2 were isolated for the first time from the shrub Mutisia friesiana. The relative stereochemistries of 1 and 2 were ascertained from NOESY NMR data and confirmed by a combination of molecular modeling (molecular mechanics and ab initio molecular orbital calculations) and NMR data. Comparison between experimental and calculated ¹H–¹H vicinal coupling constants revealed that both furanones exist in an equilibrium of two stable conformers of the five-membered ring. Application of Mosher's method suggests that both diastereomeric furanones have the same (S)-configuration at C-(4) and are epimers at C-(5). Furanones 1 and 2 showed antifungal activity against the pathogenic fungus Cladosporium cucumerinum.     

Hyperbenzones A and B,two 1,2-seco and rearranged polycyclic polyprenylated acylphloroglucinols from Hypericum beanii

Two novel seco-polycyclic polyprenylated acylphloroglucinols (PPAPs), hyperbenzones A (1) and B (2), were isolated from the roots of Hypericum beanii, together with one known biosynthetic congener 3. Compound 1 incorporates a 6/5/5 ring system with an unprecedented spiro[bicyclo[3.3.0]octane-3,1?-cyclohexane]-2,2??dione motif. The structures of 1 and 2 were determined by a combination of high resolution electrospray ionization mass spectroscopy (HRESIMS), nuclear magnetic resonance (NMR) spectroscopic analyses, gage-independent atomic orbital (GIAO) NMR chemical shift calculation with DP4+ analyses, electronic circular dichroism (ECD) calculation, and X-ray diffraction analysis. A 1,2-seco retro-Claisen rearrangement from a bicyclo[3.3.1]nonane PPAP precursor and following chemodivergent radical cascade cyclizations are proposed as the key steps in the biosynthetic pathway to yield compounds 1 and 2. Biological investigations indicated that compounds 1 and 3 could decrease intracellular lipid accumulation in a palmitic acid-induced nonalcoholic steatohepatitis (NASH) cell model.     

Artanomadimers A–F: six new dimeric guaianolides from Artemisia anomala

A novel dimeric guaianolide with an unprecedented skeleton, named artanomadimer A (1), and five new analogues, artanomadimers B–F (2–6), were isolated from the aerial parts of Artemisia anomala. Their structures and stereochemistry were elucidated by extensive spectroscopic methods, and the absolute stereochemistry of compound 4 was confirmed by X-ray crystallographic analysis. Artanomadimer A (1) is probably formed through a Diels–Alder reaction with the new carbon–carbon bond formation of C-11/C-2′ and C-13/C-5′ based on its structure. A cytotoxic evaluation showed that compounds 1 and 6 exhibited significant inhibitory effects against the cell growth of BGC-823 tumor cell lines with IC₅₀ values of 2.71 and 6.25 μM, respectively.     

Birhodomolleins D and E,two new dimeric grayanane diterpenes with a 3-O-2′ linkage from the fruits of Rhododendron pumilum

Two dimeric grayanane diterpenes with a novel 3-O-2 linkage, birhodomolleins D (1) and E (2), were isolated and structurally elucidated from the fruits of Rhododendron pumilum. Their structures were fully determined by comprehensive analysis of spectroscopic data.     

Absolute configuration of hypothemycin and 5′-O-methylhypothemycin from Phoma sp.—a test case for solid state CD/TDDFT approach

Two metabolites, the known antitumor macrolide hypothemycin 1 and its new 5′-O-methyl ether, 5′-O-methylhypothemycin 2, and the known steroid ergosterol 3, were isolated from a Phoma sp. The structures were elucidated by means of spectroscopic data analysis, and the absolute configuration of hypothemycin 1 was confirmed by single crystal X-ray analysis in combination with the new solid-state CD/TDDFT methodology. Since the solid-state CD spectrum shows contributions from intermolecular interactions in the crystal, 1 represents a critical test case for our solid-state CD/TDDFT approach.     

Dicitrinones E and F,citrinin dimers from the marine derived fungus Penicillium citrinum HDN-152-088

Two new citrinin dimers named dicitrinones E and F (1 and 2), together with one biogenetically related known citrinin monomer (3), were isolated from the marine derived fungus Penicillium citrinum HDN-152-088. All structures including the absolute configurations were elucidated on the basis of comprehensive spectroscopic data, and assisted by ECD calculations. Among them, compounds 1 and 2 belong to the class of citrinin dimers with a rare carbon-bridged C-7/C-7′ linkage. Compound 1 displayed antioxidant activity with IC₅₀ value of 23.73 μM.     

Preparation of 2,2′-anhydronucleosides: regio- and stereoselective modifications of the base and sugar moieties

2′-Deoxy-2′-iodonucleosides 4–9, obtained from suitably protected furanoid glycals 1 and 2 with different silylated pyrimidine bases, were transformed into the corresponding 2,2′-anhydronucleosides 10–15 with inversion of the configuration at C-2′, by heating in DMF with n-dibutyltin oxide. Regio- and stereospecific opening at C-2′ of the 2,2′-ring in compounds 10, 11, and 12 with sodium azide afforded the related 2′-azido-2′-deoxynucleosides 16, 17 and 18, respectively. Action of sodium hydroxide on 12 caused the regioselective opening of the above-mentioned ring at C-2 with retention of the configuration at C-2′ giving 19. Compound 19 could be transformed straightforwardly into 18 by well-established methodology. On the other hand, compound 15 could be transformed into the related 2′,3′-anhydronucleoside 23 by a regio- and stereoselective addition at N-3–C-2′ of allyl bromide concomitant with 2,2′-ring opening and inversion of the configuration at C-2′ to afford the intermediate 2′-bromo-2′-deoxynucleoside 21, which was subsequently treated with sodium methoxide giving 23.     

Spirostaphylotrichin W,a spirocyclic γ-lactam isolated from liquid culture of Pyrenophora semeniperda, a potential mycoherbicide for cheatgrass (Bromus tectorum) biocontrol

A novel spirocyclic γ-lactam, named spirostaphylotrichin W (1), was isolated together with the well known and closely related spirostaphylotrichins A, C, D, R and V, as well as triticone E, from the liquid cultures of Pyrenophora semeniperda (anamorph: Drechslera), a seed pathogen proposed for cheatgrass (Bromus tectorum) biocontrol. Spirostaphylotrichin W was characterized as (3S*,4S*,5S*,6S*,9Z,10Z)-4,6-dihydroxy-2,3-dimethoxy-3-methyl-10-propyliden-2-azaspiro [4.5]dec-8-ene-1,7-dione, by spectroscopic and chemical methods. The relative stereochemistry of spirostaphylotrichin W was assigned using NOESY experiments and in comparison to those of spirostaphylotrichin V (2) and triticone E (6). In fact, the relative stereochemistry at C-3 was the same of that of 2, while that at C-4 and C-6 was inverted in respect to that reported, respectively, for 2 and 6. In a B. tectorum coleoptile bioassay at concentration of 10⁻³, spirostaphylotrichin A proved to be the most active compound, followed by spirostaphylotrichins C and D. Spirostaphylotrichin W and V showed mild toxicity while spirostaphylotrichin R and triticone E were not active. When tested on host and non-host plants by leaf puncture bioassay, spirostaphylotrichins A, C and D caused the appearance of necrotic spots while the other compounds were inactive.     

Bioassay and UPLC-Q-Orbitrap-MS/MS guided isolation of polycyclic polyprenylated acylphloroglucinols from St. John's wort and their neuroprotective activity

St. John’s wort (Hypericum perforatum L.) is a popular dietary supplement ingredient used for the treatment of mild-to-moderate depression in the United States and Germany. Reported studies mainly focused on the biological evaluation and mechanism study of its crude extracts or two main components (namely, hypericin and hyperforin). However, it is unclear whether other phytochemicals including polycyclic polyprenylated acylphloroglucinols (PPAPs) contributed to the neuroprotective effects of H. perforatum. Here, bioassay and ultra performance liquid chromatography–quadrupole orbitrap mass spectrometry (UPLC-Q-Orbitrap-MS/MS) guided isolation were applied to discover bioactive PPAPs from the crude extracts of H. perforatum. A new PPAP, named hyperforen A (2), along with nine known PPAPs (1 and 3–10), were identified from an ethyl acetate extract of H. perforatum. To the best of our knowledge, compound 2 represents the first PPAP with an unprecedented bicyclo[7.3.0]dodecane core. The chemical structures of the isolates were elucidated by extensive spectroscopic analysis and electronic circular dichroism calculations. Moreover, compounds 1–3, 6, and 10 (10 μM) exhibited significant neuroprotective effects against corticosterone-induced injury in PC12 cells. Fingings from the current study suggest that bioactive PPAPs from H. perforatum are promising compouds for the management of depression.     

Three new decarbonyl prenylphloroglucinols bearing unusual spirost subunits from Hypericum scabrum and their neuronal activities

Three novel polycyclic polyprenyled acylphloroglucinols,Hyperscabins A-C,were obtained from the aerial parts of Hypericum scabrum.They featured an unprecedented 5,5-spiro ketal subunit with the loss of C-2' carbonyl in the phloroglucinol ring.Their structures were characterized by extensive spectroscopic analyses,NMR calculations with DP4+analysis,calculated electronic circular dichroism(ECD) spectra and the application of modified Mosher's methods.In the assay of [3 H]-5-HT and [~3 H]-NE reuptake inhibition,compounds 1 and 2 showed good inhibito ry activity(81.8% and 83.2%) in 10 μmol/L.In addition,compound 1 significantly increased cell viability in the experiment of oxygen and glucose deprivation/deoxygenation.     

2,4-diaminothiazoles: Tautomeric structures and acetylation-substitution studies

NMR investigations on the hydrohalides of 2,4-diaminothiazole, 1, and on its 5-methyl and 5-phenyl derivatives, 2 and 3 respectively, show that they exist as a single nonaromatic tautomer with C-5 tetrahedral. This is also true for the free base 1, whereas 3 has C-5 trigonal. The di- and triacetyl derivatives of 1–3 are shown to be N,N′-di- and N,N,N′-triacetyl derivatives. Ethyl 2-cyano-3-ethoxyacrylate and 2-cyano-3-ethoxyacrylonitrile react with 1 at C-5.     

Novel indan-1,3-dione derivatives: Design,green synthesis,effect against tomato damping-off disease caused by Fusarium oxysporum and in silico molecular docking study

An effective method for synthesizing series of twenty-two new compounds 1, 2a,b, 3, 4a,b, 5a-e, 7, 8, 9, 10, 12, 13a-d, 15a,b was performed starting from reaction of 1,2,3-indenetrione thiourea, and ethyl cyanoacetate under microwave irradiation and / or 2-(1,3-dioxo-1H-inden-2(3H)-ylidene) hydrazine carbothioamide with acetic anhydride. Chemical structure of the obtained products has been established by spectroscopic techniques including FTIR, ¹H NMR, ¹³C NMR, DEPT-135, and mass spectroscopy. The designed new compounds have been successfully examined in-vitro for their antifungal activities. The relation between the structure of the synthesized compounds and their activity against tomato damping-off disease caused by Fusarium oxysporum fungi was studied and favourable results were obtained. The antifungal studies indicated that compounds 1, 7, 4a and 5a-d exerted the highest antifungal activities, while 3 and 4b recorded the lowest effect. The obtained results confirmed the possibility of the application of ethyl 6′-amino-1,3-dioxo-2′-thioxo-1,2′,3,3′-tetrahydro-1′H-spiro[indene-2,4′-pyrimidine]-5′-carboxylate 1 as a new effective regulator of the vegetative growth of tomatoes. The molecular docking analysis was performed within succinate dehydrogenase (SDH) as a target enzyme in order to rationalize the promising findings obtained for the active compounds 1, 2a,b, 5a-d, 7, 8, 9, 10, 12, and 13a.     

Eucalyptals D and E,new cytotoxic phloroglucinols from the fruits of Eucalyptus globulus and assignment of absolute configuration

Two new phloroglucinols, named eucalyptals D (1) and E (2), along with a related known compound (euglobal-In-3, 3) were isolated from the fruits of Eucalyptus globulus. Their structures were established on the basis of extensive spectroscopic studies, revealing that they share a common 3,5-diformyl-isopentyl phloroglucinol unit, but each is instead coupled to a different sesquiterpenoid skeleton (aromadendrene in 1, cadinene in 2, and a spirosesquiterpene in 3). Compound 1 possessed an unusual seven-membered D ring with an ether bridge between C-2 of the aromadendrene moiety and C-2′ of the aromatic unit. The absolute configuration of the isolates was defined by the comparison of experimental and calculated electronic circular dichroism (ECD) spectra. Compounds 1–3 exhibited significant in vitro cytotoxicities against a few human cancer cell lines (Huh-7, Jurkat, BGC-823, and KE-97) using the CellTiter-Glo^TM luminescent cell viability assay method.     

Structures of six new compounds from Ligularia brassicoides

Four new eremophilane type sesquiterpenoids, a new bakkane type sesquiterpenoid, and a new secoeremophilane type sesquiterpenoid were isolated from Ligularia brassicoides Hand.-Mass. (Asteraceae) collected in China, and were an epoxy lactone derived from 6-acyloxyeuryopsin 1, 6-acyloxy-9-oxoeuryopsin 2, 6-acyloxy-9-oxofuranoeremophilane 3, 6-acyloxyeuryopsin 4, 6-acyloxy bakkane type epoxy lactone 5, and secovirgaurenol 6-O-(2′-hydroxymethyl)acrylate (6), respectively. All but one had a 2′-hydroxymethylacryloyloxy group at C-6. This is the first study to describe the chemical constituents of this species.     

Chiral ligands derived from abrine. Part 7: Effect of O,S, N in aromatic ring substituents at C-1 on enantioselectivity induced by tetrahydro-β-carboline ligands in diethylzinc addition to aldehydes

The effect of O, S and N atoms in aromatic ring substituents at C-1 position of tetrahydro-β-carboline ligands on the enantioselectivity of diethylzinc additions to benzaldehyde was studied when esters or tertiary alcohol functions were present at C-3. A mechanism is proposed to explain why the ester ligands 2c and 2d, in which the pyridyl N atom is at C′-2 in 2c and at C′-3 in 2d, catalyzed the addition of diethylzinc to benzaldehyde to form the (R)- and (S)-enantiomers of 1-phenyl-1-propanol, respectively. An explanation was also proposed for the moderate enantioselectivity induced by tert-alcohol 3c versus the very small enantioselectivity induced by 3d, containing a 3-pyridyl function at C-1, during diethylzinc additions. A -CH₂-t-Bu substituent at C-1 leads to very high enantioselectivities.     

Meroterpenoids with diverse ring systems and dioxolanone-type secondary metabolites from Phyllosticta capitalensis and their phytotoxic activity

Twenty meroterpenoids with diverse ring systems including five new ones (1, 2, 5, 6, and 15), together with two new (23 and 24) and two known dioxolanone-type secondary metabolites were isolated from Phyllosticta capitalensis, an endophytic fungus from Cephalotaxus fortunei Hook. Compound 1 was the first example with a 9,14-seco ring A and a five-membered ring B in guignardone derivatives. Compound 2 represented a novel guignardone derivative possessing a 5/7/6/5 ring system with CH₂-7 attached to C-4 rather than C-6 in ring D. The structures of all new compounds were elucidated using spectroscopic data analyses and electronic circular dichroism comparison. The phytotoxic effects of compounds 1–24 on Lactuca sativa and Lolium perenne were evaluated. Compound 22 showed inhibition activity on the shoots growth of L. sativa and L. perenne, as well as the roots growth of L. perenne.     

Regio- and stereoselective reactions of a rhodanine derivative with optically active 2-methyl- and 2-phenyloxirane

The reaction of a rhodanine derivative (=(Z)-5-benzylidene-3-phenyl-2-thioxo-1,3-thiazolidin-4-one; 1) with (S)-2-methyloxirane (2) in the presence of SiO₂ in dry CH₂Cl₂ for 10 days led to two diastereoisomeric spirocyclic 1,3-oxathiolanes 3 and 4 with the Me group at C(2) (Scheme 2). The analogous reaction of 1 with (R)-2-phenyloxirane (5) afforded also two diastereoisomeric spirocyclic 1,3-oxathiolanes 6 and 7 bearing the Ph group at C(3) (Scheme 3). The structures of 3, 4, 6, and 7 were confirmed by X-ray crystallography (Figs. 1 and 2). These results show that oxiranes react selectively with the thiocarbonyl group (CS) in 1. Furthermore, the nucleophilic attack of the thiocarbonyl S-atom at the SiO₂-activated oxirane ring proceeds with high regio- and stereoselectivity via an S_N2-type mechanism.     

Lycocasuarines A–C,Lycopodium alkaloids from Lycopodiastrum casuarinoides

Three lycodine-type Lycopodium alkaloids (1–3) were isolated from Lycopodiastrum casuarinoides. Their structures were elucidated by spectroscopic analysis, single-crystal X-ray crystallography, and computational methods. Compound 1 possesses a rearranged five-membered ring D resulting from C-8/C-15 cleavage and a new C-7/C-15 linkage. Compound 2 is the first Lycopodium alkaloid found to bear an additional carbon (C-17) directly bonded to C-8, which is particularly unusual from a biogenetic point of view. Compounds 1–3 were evaluated for acetylcholinesterase inhibitory activities.     

Eutypellazines N−S,new thiodiketopiperazines from a deep sea sediment derived fungus Eutypella sp. with anti-VRE activities

Chemical investigation of a deep sea sediment derived fungus Eutypella sp. MCCC 3A00281 resulted in the isolation of six new thiodiketopiperazine alkaloids, namely eutypellazines N-S (1?6). Their structures were elucidated on the basis of the extensive NMR and mass spectroscopic analysis, including the ECD data for the determination of absolute configuration. The structures of eutypellazines N-P (1?3) were characteristic of unique spirocyclic skeletons, while eutypellazines N-O bearing a spirocyclic tetrahydrobenzothiophene motif were found from wide type fungus for the first time. The biogenetic generation of the spirocyclic skeletons was postulated. Compounds 3–5 exhibited inhibitory effects against vancomycin-resistant enterococci (VRE), suggesting that they may be the potential inhibitors toward drug resistant pathogenic bacteria after the structural modification.     

Synthesis of regioisomeric,stereoregular AABB-type polyamides from chiral diamines and diacids derived from natural amino acids

Two regioisomeric and stereoregular AABB-type polyamides have been synthesized using l-glutamic acid 1 and l-alaninol 4 as sources of chirality. From 4, two derivatives of chiral diamines were prepared and regioselectively condensed with pentachlorophenyl 5-oxo-(S)-2-tetrahydrofurancarboxylate 3, derived from 1. Manipulation of functional groups and convenient deprotections led to the ammonium salts of N-[1′-amino-(S)-2′-propyl]- and N-[(S)-2′-amino-1′-propyl]-5-oxo-(S)-2-tetrahydrofurancarboxyamide 11 and 15, respectively, in which the building blocks derived from 1 and 4 are linked through an amido group. Compounds 11 and 15 are, in fact, α,ω-amino acids having amino and lactone groups, and hence activated for polycondensation. Thus, polymerization of 11 took place under regio- and stereo-control to afford stereoregular poly[N-(1′-amino-(S)-2′-propyl)-carboxyamido-(S)-2-hydroxypentan-5-oic acid] (16). Similar polycondensation of 15, under the optimized conditions employed for the synthesis of 16, gave the regioisomeric polyamide 17, which exhibited a molecular weight lower than that of 16. The thermal and spectroscopic properties of optically active AABB-polyamides 16 and 17 are described.