Individual scale factor approach for the vibrational circular dichroism similarity-guided spectral and conformational analysis of perezone and dihydroperezone.

Evaluation of DFT calculated vibrational parameters for the IR and VCD spectra similarity of perezone (1) and dihydroperezone (2) was undertaken. Conformational sets were obtained using different search engines, and the parameters needed for spectra prediction were obtained using several combinations of commonly employed functionals and basis sets, and then weighted spectra were generated and compared with observed traces to provide infrared similarity (SIR ) and enantiomeric similarity index (ESI) values. These values evidenced a poor performance of the evaluated levels of theory that were overcome when using the individual scaling factors approach, providing 16% to 139% increases of the ESI values. The best performing level of theory was the B3LYP/DGDZVP2 with ESI values of 0.722 and 0.792 for 1 and 2. Moreover, a correlation analysis showed that the irregular DFT performance arises from rotational strength deviations, which suggests to discard conformational abundance accuracy as the main source of differences. Furthermore, a similarity guided conformational analysis showed that conformations with high ESI values prefer particular orientations of the CC bonds directly attached to the stereogenic carbon atom, with more distant dihedral angles having less influence. Additionally, folded and extended conformers appear to be equally capable to yield high individual ESI values, although abundances of folded conformers just account for 16% of the total population. Nevertheless, abundance optimization showed that a high ESI similarity value of 0.834, is possible when the population of these conformers is increased to 26%, suggesting that a larger abundance of these conformers might be present in solution.

Absolute configuration assignment of stigmasterol oxiranes.

Diastereoisomeric stigmasterol oxiranes 4, 5, 8, and 9 are known phytosterol oxidation products (POPs) that have been evaluated for their cytotoxicity, although the results are of limited significance since, in most cases, they were evaluated as mixtures. Consequently, to establish biological activity hierarchy of these oxides, it is critical to evaluate individual pure POPs. Therefore, we now describe the obtention of individual molecules and their absolute configuration (AC) determination. The two acetylated C-5-C-6 oxiranes 6 and 7; the two acetylated C-22-C-23 oxides 10 and 11, obtained by means of Δ5 double bond protection-deprotection; and the four C-5-C-6, C-22-C-23 diepoxystigmasteryl acetates 19-22 were now individually gained and their AC determined by vibrational circular dichroism. Vibrational modes associated with the C-5-C-6 and the C-22-C-23 bonds were identified in dioxiranes 19-22 and used to assign the AC of monoepoxides 6, 7, 10, and 11. The AC of biological active non-acetylated molecules follows immediately. Due to the scarce spectroscopic information available for these POPs, the 1 H and 13 C NMR chemical shifts of 3-22 were assigned using 1D- and 2D-NMR experiments.

Structure and Absolute Configuration of Abietane Diterpenoids from Salvia clinopodioides: Antioxidant, Antiprotozoal, and Antipropulsive Activities.

The aerial parts of Salvia clinopodioides afforded abietanes 1a, 2a, and 3 (clinopodiolides A-C), two of which possess an unusual lactol moiety at C-19-C-20, together with an icetexane named clinopodiolide D (4a). Their structures were established by spectroscopic means, mainly 1H and 13C NMR, including 1D and 2D homo- and heteronuclear experiments. The antioxidant, antiprotozoal, and antidiarrheal effects of the isolates were evaluated. Compounds 2a and 3 showed better effects than α-tocopherol in the inhibition of lipid peroxidation with IC50 (µM) = 5.9 ± 0.1 and 2.7 ± 0.2, respectively, and moderate activity in the DPPH assay. All tested compounds showed moderate antiamoebic and antigiardial activity, as well as a good antipropulsive effect.

Absolute configuration of the diterpenoids icetexone and conacytone from Salvia ballotaeflora.

Detailed literature inspections regarding the diterpenoids icetexone (1) and conacytone (3) reveal that the absolute configuration (AC) of these natural occurring compounds is not rigorously proven, despite they were originally isolated in 1976. This task is now completed by single-crystal X-ray diffraction Flack and Hooft parameters determination after processing data collected with Cu Kα graphite monochromated radiation. The AC of both compounds is further determined by vibrational circular dichroism measurements performed on icetexone acetate (2) and conacytone triacetate (4) since the solubility of 1 and 3 is limited. Comparison of the substituent chemical shifts (SCS) induced by acetylation of 1 and 3 to afford 2 and 4, respectively, reveals that in the case of icetexone, all six SCS values of the quinone ring are in excellent agreement with the expected values, while in the case of conacytone, three agree and three do not agree due to the presence of additional acetates near the quinone ring. Density functional theory calculations performed on 3-hydroxythymoquinone (6) and its tautomer 4-hydroxy-1,2-quinone 7, on 6-hydroxythymoquinone (8) and its tautomer ortho-quinone 9, and on icetexone (1) and the claimed natural occurring ortho-quinone tautomer romulogarzone (5) indicate that 2-hydroxy-1,4-quinones are more stable, by some 11-14 kcal/mol, than their 4-hydroxy-1,2-quinone tautomers, and therefore, romulogarzone (5) is inexistent.

Absolute configuration of the ocimene monoterpenoids from Artemisia absinthium.

The absolute configuration (AC) of the naturally occurring ocimenes (-)-(3S,5Z)-2,6-dimethyl-2,3-epoxyocta-5,7-diene (1) and (-)-(3S,5Z)-2,6-dimethylocta-5,7-dien-2,3-diol (2), isolated from the essential oils of domesticated specimens of Artemisia absinthium, followed by vibrational circular dichroism (VCD) studies of 1, as well as from the acetonide 3 and the monoacetate 4, both derived from 2, since secondary alcohols are not the best functional groups to be present during VCD studies in solution due to intermolecular associations. The AC follows from comparison of experimental and calculated VCD spectra that were obtained by Density Functional Theory computation at the B3LYP/DGDZVP level of theory. Careful nuclear magnetic resonance (NMR) measurements were compared with literature values, providing for the first time systematic 1 H and 13 C chemical shift data. Regarding homonuclear 1 H coupling constants, after performing a few irradiation experiments that showed the presence of several small long-range interactions, the complete set of coupling constants for 3, which is representative of the four studied molecules, was determined by iterations using the PERCH software. This procedure even allowed assigning the pro-R and pro-S methyl group signals of the two gem-dimethyl groups present in 3.

Antidiabetic effect, antioxidant activity, and toxicity of 3',4'-Di-O-acetyl-cis-khellactone in Streptozotocin-induced diabetic rats.

Pyranocoumarins are compounds with an important pharmacological profile, such as anti-inflammatory, antioxidant, cytotoxic, antiviral, antibacterial, and hypoglycemic effects. These molecules have a widespread presence as secondary metabolites in medicinal plants used to treat Diabetes Mellitus (DM). The aim of this work was to evaluate antidiabetic activity in Streptozotocin (STZ)-induced diabetic rats and the antioxidant effects of 3',4'-Di-O-acetyl-cis-khellactone (DOAcK), as well as its toxic potential. We obtained DOAcK with an enantiomeric excess of 70% by chemical synthesis. Our results showed that this compound exerts an important antidiabetic effect: blood glucose decreased in groups treated with DOAcK by 60.9% at dose of 15mg/kg (p<0.05) compared with the diabetic control group, and demonstrated a statistically significant increase in weight gain (45.7±9.7 in the group treated with DOAcK vs. -23.0±33.1 in the group with diabetes). In a biochemical profile, DOAcK did not modify lipid metabolism and did not cause damage at the renal level. DOAcK administration increased the activities of Catalase (CAT), Glutathione Peroxidase (GPx), and Super Oxide Dismutase (SOD) to levels near those of the healthy group. Histopathological analysis exhibited morphology similar to that of the healthy group and the group treated with DOAcK. DOAcK is not mutagenic by Ames test for Salmonella typhimurium strains TA98, TA100, or TA102, and is not genotoxic by Micronucleus assay; median lethal dose (LD50) >2000mg/kg and, at this dose, no signs of toxicity or death were reported after 14days of observation. These results indicate that DOAcK can improve glucose metabolism, which may be due to the increased antioxidant activity of CAT, GPx and SOD. In addition, DOAcK is not toxic in the studies tested.

Complete 1H NMR assignments of pyrrolizidine alkaloids and a new eudesmanoid from Senecio polypodioides.

Chemical investigation of the aerial parts of Senecio polypodioides lead to the isolation of the new eudesmanoid 1ß-angeloyloxyeudesm-7-ene-4ß,9α-diol (1) and the known dirhamnosyl flavonoid lespidin (3), while from roots, the known 7ß-angeloyloxy-1-methylene-8α-pyrrolizidine (5) and sarracine N-oxide (6), as well as the new neosarracine N-oxide (8), were obtained. The structure of 1 and 8 was elucidated by spectral means. Complete assignments of the (1)H NMR data for 5, 6, sarracine (7), and 8 were made using one-dimensional and two-dimensional NMR experiments and by application of the iterative full spin analysis of the PERCH NMR software.

NMR-based conformational analysis of perezone and analogues.

Complete assignment of the (1)H NMR chemical shift and coupling constant values of perezone (1), O-methylperezone (2) and 6-hydroxyperezone (3) was carried out by total-line-shape-fitting calculations using the PERCH iterative spectra analysis software (PERCH Solutions Ltd., Kuopio, Finland). The resulting simulated spectra for the three compounds showed strong similarity to their corresponding experimental spectra. Particularly, all vicinal, allylic and homoallylic coupling constant values for the side chain of the three compounds were very similar, thus revealing that the conformation of these three molecules in solution is indeed almost identical. This fact is in agreement with extended side chain conformations over folded chain conformations because 1, 2 and 3 undergo completely different intramolecular cycloaddition reactions. In addition, results of double pulsed field gradient spin echo NOESY 1D experiments performed on perezone (1) were unable to provide evidence for folded conformers.

A new germacranolide from Ageratina vernalis.

The aerial parts of Ageratina vernalis provided the new germacranolide 1,10-epoxydeltoidin A (3), together with the known pentacyclic triterpenoid hopane-6α,22-diol (1), and the also known germacranolides deltoidin A (2) and 15-hydroxydeltoidin A (4). In addition, pTsOH catalyzed cyclization of 2 afforded the new guaianolide 5. The absolute configuration of 2, 4, and 5 was assigned by vibrational circular dichroism spectroscopy, while the complete 1H and 13C NMR data assignments of 2-5 followed from 1 D- and 2 D-NMR experiments.

A new diterpene and bioactivities of labdanes isolated from Buddleja marrubiifolia.

The new labdane [(3R*,4aR*,7S*,10aS*,10bR*)-3-ethenyl-3,4a,7,10a-tetramethyl-dodecahydro-1H-naphtho-[2,1-b]-pyran-7-yl]-methylbenzoate together with other 7 labdanes were isolated from the aerial parts of Buddleja marrubiifolia. Compound structures were elucidated by spectroscopic methods. Some compounds showed moderate to weak antimicrobial activity towards a panel of bacterial and fungal pathogens. In addition, trans-biformene (2) and ribenol acetate (8) showed to be highly cytotoxic with LC50 < 1 µg/mL, the other compounds showed moderate cytotoxic effect with a LC50 range of 6.008-15.26 µg/mL. For all isolated compounds, no inflammatory response was observed.

Nematicidal activity of furanoeremophilenes against Meloidogyne incognita and Nacobbus aberrans.

BACKGROUND: While searching for novel small molecules for new organic pesticide agents against plant-parasitic nematodes, we found that the hexane extract from the roots of Senecio sinuatos and its main secondary metabolite, 3ß-angeloyloxy-6ß-hydroxyfuranoeremophil-1(10)-ene (1), possess nematicidal activity against the second stage juvenile (J2) of Meloidogyne incognita and Nacobbus aberrans. Both species reduce yield of various vegetable crops. These results encouraged us to synthesize esters 3-9 formed by diol 2, obtained by alkaline hydrolysis of 1 and acetic anhydride, benzoic acid, 2-nitrobenzoic acid, 2-bromobenzoic acid, 4-nitrobenzoic acid, 4-bromobenzoic acid, and 4-methoxybenzoic acid, respectively. The nematicidal activity of these esters was evaluated and compared with that of the free benzoic acids. RESULTS: Natural product 1 and derivatives 2-9 were obtained and characterized by their physical and spectroscopic properties, including one-dimensional (1D) and two-dimensional (2D) nuclear magnetic resonance (NMR) experiments; X-ray diffraction analysis established their absolute configuration. The nematicidal activity of compounds 1-9 was assessed in vitro against M. incognita and N. aberrans J2 and was compared to activity shown by benzoic acid, 2-nitrobenzoic acid, 2-bromobenzoic acid, 4-nitrobenzoic acid, 4-bromobenzoic acid, and 4-methoxybenzoic acid. The esters suppressed nematodes more than free benzoic acid. Nacobbus aberrans J2 were suppressed, with compounds 5, 6, and 8 being the most active. CONCLUSION: Esters formed by 3ß,6ß-dihydroxyfuranoeremophil-1(10)-ene and ortho- or para-substituted benzoic acids containing electron acceptor groups had nematicidal activity against N. aberrans. These compound can potentially serve as a model for the development of new organic nematicidal agents. © 2022 Society of Chemical Industry.

Benzodihydrofurans from Cyperus teneriffae.

Three new benzodihydrofurans (1-3) and seven known aromatic compounds (4-10) were isolated from the roots of Cyperus teneriffae. Vibrational circular dichroism spectroscopy was used to define the absolute configuration of 1.

Absolute configuration by vibrational circular dichroism of anti-inflammatory macrolide briarane diterpenoids from the Gorgonian Briareum asbestinum.

The four new briarane diterpenoids 2-butyryloxybriarane B-3 (2), 9-acetylbriarenolide S (3), briarenolide W (4), and 12-isobriarenolide P (5), along with briarane B-3 (1) and the five known diterpenes 6-10 were isolated from the gorgonian coral Briareum asbestinum collected from the Mexican Caribbean Sea. The structures were elucidated by 1D and 2D NMR and MS measurements. Since the structure of briarane B-3 (1) was only suggested and published without any spectroscopic support, it was herein confirmed, and the supporting data are now provided. In addition, 1 provided the opportunity to explore the sensitivity of vibrational circular dichroism (VCD) to determine the configuration of a single stereogenic center in the presence of eight other stereogenic centers in a molecule possessing a highly flexible ten-member ring. A single-crystal X-ray diffraction study, in which the Flack and Hooft parameters of 1 were determined, further confirmed that briarane B-3 is (1S,2S,6S,7R,8R,9S,10S,11R,17R)-1. This paper reports for first time the use of VCD in briarane diterpenes and with the presence of chlorine atoms. Biological evaluation of seven isolated compounds evidenced a moderate anti-inflammatory activity for compounds 6 and 9 but it did not show any cytotoxic, antiviral, antibacterial, and topoisomerase inhibitory activity.

Antifeedant and cytotoxic activity of longipinane derivatives.

The polyoxygenated longipinane derivatives 1- 8 were tested as antifeedant compounds against the herbivorous insects Spodoptera littoralis, Rhopalosiphum padi, and Myzus persicae. Compounds 1-3 and 8 exhibited significant antifeedant activity against S. littoralis and M. persicae. The antifeedant activity against S. littoralis increased moderately after the C-8 hydroxy group in 3 was removed to afford 1 and increased strongly after the remaining two hydroxy groups were acetylated to afford 2. Compound 1 was active on M. persicae. Compounds 1, 3, and 4, with an unsaturated six-membered ring, exhibited an increase in post-ingestive effects on S. littoralis ranging from antifeedant in the case of 1 to toxic for compounds 3 and 4. These compounds did not have any phytotoxic effect on Lactuca sativa. When tested on a panel of tumoral cells, compounds 2 and 6 exhibited moderate selective cytotoxic effects on the p53 null lung carcinoma cells H1299, which were not affected by the drug paclitaxel. In addition, vibrational circular dichroism (VCD) was applied to the representative longipinene derivative 2 to verify its absolute configuration, and the sensitivity of the VCD methodology was evaluated by comparing spectra of the three diastereoisomers (4 R,5 S,7 R,9 R,10 R,11 R)-7,9-diacetyloxylongipin-2-en-1-one (2), (4 R,5 S,7 S,9 R,10 R,11 R)-7,9-diacetyloxylongipin-2-en-1-one, and (4 R,5 S,7 R,9 S,10 R,11 R)-7,9-diacetyloxylongipin-2-en-1-one.

Absolute configuration of eremophilanoids by vibrational circular dichroism.

The absolute configurations (AC) of natural occurring 6-hydroxyeuryopsin (1), of its acetyl derivative 2, and of eremophilanolide 8 were confirmed by comparison of the experimental vibrational circular dichroism (VCD) spectra with theoretical curves generated from density functional theory (DFT) calculations. Initial analyses were carried out using a Monte Carlo searching with the MMFF94 molecular mechanics force field. All MMFF94 conformers were further optimized using DFT at the B3LYP/6-31G(d) level of theory, followed by calculations of their vibrational frequencies at the B3LYP/6-31G(d,p); the VCD spectra of 2 and 8 were also calculated at the B3PW91/DGDZVP level of theory. Good agreement between theoretical and experimental VCD curves unambiguously verified the 4S,5R,6S absolute configuration for 1 and 2, and the 1S,4S,5R,6S,8S,10S configuration for 8.

Dihydrofurochromones from Prionosciadium thapsoides.

Chemical investigations of Prionosciadium thapsoides roots led to the isolation of the new dihydrofurochromones (S)-(+)-4'-O-angeloyl-5-O-methylvisamminol (1) and (S)-(+)-4'-O-senecioyl-5-O-methylvisamminol (2), together with the known coumarins jatamansin, buchtormin, isopteryxin, isosamidin, psoralen, and bergapten. The structures of 1 and 2 were determined by 1D and 2D NMR experiments, and their absolute configuration was established by chemical correlation with (+)-5-O-methylvisamminol (3), whose structure was secured by single-crystal X-ray diffraction analysis and its absolute configuration was established as S by vibrational circular dichroism spectroscopy in comparison to DFT B3LYP/DGDZVP calculations.

Antifeedant and phytotoxic activity of hydroxyperezone and related molecules.

The insect antifeedant and toxic activity of hydroxyperezone (1), its derivatives 2-9, along with 3-hydroxy- (10) and 6-hydroxythymoquinone (11) were studied against Spodoptera littoralis, Leptinotarsa decemlineata, and Myzus persicae. The antifeedant tests showed that L. decemlineata was the most sensitive insect, followed by M. persicae, while S. littoralis was not deterred by compounds 1-11. Leucohydroxyperezone tetraacetate (3), oxoperezinone (6), dihydroleucoperezinone diacetate (7), 3-hydroxy- (10) and 6-hydroxythymoquinone (11) showed strong activity against L. decemlineata. 1 and 7 exhibited moderate deterrent activity against M. persicae, while 1 and dihydroleucohydroxyperezone tetraacetate (4) acted as post-ingestive antifeedants to S. littoralis. The phytotoxic activity of compounds 1-11 was also evaluated. Hydroxyperezone (1) strongly inhibited seed germination at 24 h, while the activity of 3-8 and 10 was moderate. The level of radicle growth inhibition obtained with compounds 1-5 and 8-11 was significant (< 50%).

Pyrrolizidine Alkaloids.

Naturally occurring pyrrolizidine alkaloids (PAs) are isolated from plants and other sources. The interest of the scientific community in these compounds owes itself to their high toxicity and biological activity, as well as to the challenge of synthesizing their pyrrolizidine scaffold. This review encompasses a wide range of topics found in the literature from 1995 to date, including the occurrence, biosynthesis, toxicity (hepatotoxicity, genotoxicity, and tumorigenicity), biological activity, and pharmacological properties (glycosidase inhibitory activity) of these secondary metabolites. Particular attention is given to the chemistry of PAs, addressing general strategies for formal and total syntheses via amino-based substrates, pyrroles, and pyrrolidine-based derivatives.

Antifeedant and phytotoxic activity of cacalolides and eremophilanolides.

The antifeedant effect of six cacalolides and six eremophilanolides was tested against the herbivorous insects Spodoptera littoralis, Leptinotarsa decemlineata, and Myzus persicae. The test compounds included several natural products isolated from Senecio madagascariensis (14-isovaleryloxy-1,2-dehydrocacalol methyl ether, 4), S. barba-johannis (13-hydroxy-14-oxocacalohastine, 5; 13-acetyloxy-14-oxocacalohastine, 6) and S. toluccanus [6-hydroxyeuryopsin, 7; 1(10)-epoxy-6-hydroxyeuryopsin, 9; toluccanolide A, 11] and the derivatives cacalol methyl ether (1); cacalol acetate (2); 1-acetyloxy-2-methyloxy-1,2,3,4-tetradehydrocacalol acetate (3); 6-acetyloxyeuryopsin (8); 6-acetyloxy-1(10)-epoxyeuryopsin (10), and toluccanolide A acetate (12). Compound 11 and its derivative 12 exhibited moderate antifeedant activity against S. littoralis; 2, 7-10, and 12 showed strong activity against L. decemlineata, while the aphid M. persicae was moderately deterred in the presence of compounds 1, 4, 8, 10, and 12. The phytotoxic activity of 1-12 on Lactuca sativa was also evaluated. Compounds 2 and 4-12 moderately inhibited seed germination at 24 h, while compounds 1-4, 6, 9, and 10 had a significant inhibition effect on L. sativa radicle length (over 50%).

Vibrational Circular Dichroism: Recent Advances for the Assignment of the Absolute Configuration of Natural Products.

Vibrational circular dichroism (VCD) emerged during the last decade as a reliable tool for the absolute configuration (AC) determination of organic compounds. The principles, instrumentation, and methodology applied prior to early 2013 were recently reviewed by us. Since VCD is a very dynamic field, the aim of this review is to update VCD advances for the AC assignment of terpenoids, aromatic compounds, alkaloids, and other natural products for the 2013-2014 period, when VCD was applied to the AC assignment of some 70 natural products. In addition, although discovered in 2012, a brief introduction to the VCD exciton coupling approach and its applications in natural products AC assignment is presented.