Search

Recently, structural elucidation of natural products has undergone a revolution. The combined use of different modern spectroscopic methods has allowed obtaining a complete structural assignment of natural products using small amounts of sample. However, despite the extraordinary ongoing advances in spectroscopy, the mischaracterization of natural products has been and remains a recurrent problem, especially when the substance presents several stereogenic centers. The misinterpretation of NMR data has resulted in frequent reports addressing structural reassignment. In this context, a great effort has been devoted to developing quantum chemical calculations that simulate NMR parameters accurately, allowing to achieve a more precise spectral interpretation. In this work, we employed a protocol for theoretical calculations of 1 H NMR chemical shifts and coupling constants using DFT, followed by the application of the DP4+ method to revisit the structure of Heliannuol L, a member of the Heliannuol class, isolated from Helianthus annuus. Our results indicate that the originally proposed structure of Heliannuol L needs a stereochemical reassignment, placing the hydroxyl bonded to C10 in the opposite side of the methyl and hydroxyl groups bonded to C7 and C8, respectively.

Two different products were obtained by the regiodivergent reaction of benzoquinone derivatives with phenolates and anilines: 3-aryloxybenzoquinone and 2-phenylamino-3-bromobenzoquinone. Calculated density functional theory free energies of reaction values corroborate the experimental observation of the formation of the substitution product in the reaction with phenolates in acetonitrile and the product of addition/oxidation for the reaction with aniline in water. Calculated charges and Fukui functions are similar for C2 and C3 atoms, indicating an equal possibility to suffer a nucleophilic attack. The calculated energy barriers for nucleophilic attack steps indicated that the first steps of the substitution with phenolates and addition/oxidation with anilines are faster, which justifies the formation of the respective products. The natural bond order analysis for the transition states revealed that there is a strong interaction between lone pairs of N and O atoms and the π

In the early 2000s, the first articles regarding the calculation of NMR parameters for natural products appeared in the literature. Since then, modelling 1H and 13C chemical shifts and spin–spin coupling constants for this class of compounds has experienced a remarkable increase in precision, accessibility, and application, leading to considerable advances in the field. More recently, significant contributions from several authors have led to continuous growth in this research field, updating and broadening the simulation of NMR parameters, in particular with the application of new techniques for data treatment. Nowadays, such studies are routinely found in the high impact literature. In this review, we intend to cover the general guidelines and the main advances in NMR calculations of natural products published since 2012. We intend to address the bottlenecks of quantum chemical calculations of NMR parameters, including mathematical definitions, updates, and a discussion of relevant examples, and to highlight novel tools, for example DU8+, CP3, DP4, DP4+ and J-DP4. We will cover all aspects of NMR simulation focusing on natural products, from the fundamentals to the new computational toolboxes available, combining advanced quantum chemical calculations with complex upstream data processing and machine learning.

The skeleton of the helianane's family is an unsolved controversial topic. Recent synthetic studies and 13C NMR structural analysis have demanded for an amendment of helianane to the open ring curcudiol. However, some authors argue that the original helianane structure, a benzofused eight-membered ether ring system, cannot be ruled out immediately without further spectral analyses of curcudiol and helianane. The fact that this compound is extremely rare, obtained only from marine organisms, makes remote the possibility of reisolation. Therefore, we decided to approach this problem computationally. Herein, we performed a complementary quantum mechanical study in order to provide more information about the helianane's actual skeleton. Our 13C NMR chemical shifts calculations suggests that the curcudiol structure is more likely to be the correct one. In addition, we simulated the formation pathways for both products starting from the known biosynthetic precursor. The results show that curcudiol is around 8.0 kcal mol−1 more stable than the originally proposed helianane structure.

4-quinolones derivatives can present fluorescent properties, depending on their substituents and on the chemical environment (e.g., acidic medium), allowing their application as ion sensors. We theoretically evaluated the photophysical properties of previously synthesized 3-acyl-4-quinolones to verify how different substituents (R1=H, NH2 and R2 = OEt, OH, NHPh) affect their absorption profiles and the emission profile of a reference compound, PB3. All DFT and TD-DFT calculations were performed at B3LYP-D3/6-311++G(d,p) level and continuum polarization model for simulated acetonitrile as solvent. For PB2 (R1 = H, R2 = OEt), we observed hypsochromic shift compared to PB3 due to the increase of the gap between HOMO/LUMO (absence of electron-donating group), in accordance with experimental data. For R1=NH2 and R2=OH, NHPh (PB6 and PB10, respectively), the gap between HOMO/LUMO increases, resulting in a soft bathochromic shift for the simulated absorption spectra. In addition, we evaluated the effect of acid addition on the absorption and emission profile of PB3 and the results were compared with experimental data. Our thermodynamic results suggest that protonation occurs on the endocyclic carbonyl of the quinolone moiety, probably due to an increased aromatic character, as suggested by our NICS calculations. Finally, we associate the increase of the fluorescence in the acidic medium to the establishment of an intramolecular hydrogen bond and, thus, increased rigidity.

In the past, structure determination of natural products was an arduous process depending almost entirely on chemical synthesis, mainly by derivatization and degradation processes, taking years of effort. Recently, structural elucidation of natural products has undergone a revolution. Nowadays, with the combined use of different advanced spectroscopic methods, it became possible to completely assign the structure of natural products using small amounts of sample. However, despite the extraordinary ongoing advances in spectroscopy, the mischaracterization of natural products has been and remains a recurrent problem, especially in the presence of several chiral centers. The misinterpretation of NMR data has resulted in frequent reports addressing the issue of structural reassignment. In this context, a great effort has been devoted to the development of quantum chemical calculations to predict NMR parameters, and thus achieve a more accurate spectral interpretation. In this work, we applied a protocol for theoretical calculations of 1H NMR chemical shifts in order to establish the correct and unequivocal structure of Helianuol L, a member of the Heliannuol’s class, isolated from Helianthus annus. These secondary metabolites present a broad spectrum of biological activities, including the allelochemical activity, making them promising candidates as natural agrochemicals. It is worth mentioning, however, that the process of elucidating the structure of Heliannuol L was based on structural correlations with molecules already known in the literature, where few stereochemical analyses were performed. In this way, based on the fact that other compounds of the Heliannuol’s class had their structure previously reassigned, the verification of the proposed structure of Heliannuol L becomes of great importance.

Three molecules containing morpholine, 1,4-naphthoquinone, 7-chloroquinoline and 1,3,5-triazine cores, scaffolds with recognized anti-corrosive activity, were synthesized and had their anticorrosive activity evaluated through potentiodynamic polarization and electrochemical impedance studies. Both studies were conducted in a simulated production water medium containing 150,000 mg·L-1 Cl- and 5 mg·L-1 S2-. Corrosion inhibition efficiency ranged from 67% - 86%, amongst which the naphthoquinone-containing derivative (compound 1) was the most effective. These compounds act through formation of a protective film on the surface of AISI 316 stainless steel. Investigation of the molecular properties of the prepared inhibitors by DFT calculations revealed that the LUMO energy and chemical hardness of the molecules can be directly correlated with their inhibition efficiency.

This work describes the first determination of the absolute configuration (AC) of (−)-cubebin by means of electronic circular dichroism (ECD), supported by quantum chemical calculations. The comparison of experimental ECD with the corresponding quantum chemical prediction for the proper diastereoisomer resulted in the definitive assignment of the AC of the naturally occurring (−)-cubebin as (8R,8aR,9S). The challenging determination of the relative configuration (RC) of cubebin based only on experimental nuclear magnetic resonance (NMR) methods is stressed. Computation of the 13C and 1H NMR chemical shifts for all the possible diastereoisomers leads to values of mean absolute error and root mean square deviation that do not allow distinguishing among them. Thus, errors in stereochemical determination can easily occur even when using two-dimensional methods, which clearly demonstrate the complexity of this special case. To determine the RC of this bioactive natural compound with high level of confidence, it was necessary to combine the DP4+ method with X-ray crystallography. Therefore, employing the commonly used empirical methods to determine the AC of (−)-cubebin can easily lead to misassignment of its stereochemistry.

We synthesized ten enamine naphthoquinones with yields ranging from 43 to 76%. These compounds were screened for their in vitro antiproliferative activities by MTT assay against four types of human cancer cell lines: HCT116, PC3, HL60 and SNB19. The naphthoquinones bearing the picolylamine (7) and quinoline (12) moieties were the most actives (IC50 < 24 μM for all the cell lines), which were comparable or better to the values obtained for the control drugs. In silico evaluations allowed us to develop a qualitative Structure-Activity Relationship which suggest that electrostatic features, particularly the C2-C3 internuclear repulsion and the molecular dipole moment, relate to the biological response. Furthermore, Molecular Docking simulations indicate that the synthetic compounds have the potential to act as anticancer molecules by inhibiting topoisomerase-II and thymidylate synthase.

Three molecular hybrids containing 1,4-naphthoquinones, 1,3,5-triazines, morpholine and 7-chloroquinoline, which have recognized contributions to the biological activity of many drugs, were synthesized in yields ranging from 43-84%. All hybrids were obtained in three steps starting from readily available reactants: lawsone, cyanuric chloride, morpholine and 4,7-dichloroquinoline. A previous docking study was carried out to identify the binding energy and pharmacophore conformation of the promising anticancer compounds with PI3Kγ (phosphoinositide 3-kinase) and AMPK (5’ AMP-activated protein kinase). The cancer activity in human metastatic melanoma cells (SKMEL-103) were performed, and the synthetized compounds presented half maximal inhibitory concentration (IC50) values around 25 µM. The expressions of PI3K and AMPK were also determined using western blotting technique, and all molecular hybrids negatively modulated both targets.

Density functional theory calculations (ωB97X-D/6-311++G(d,p)) are employed to investigate an alternative pathway for Prins-like cyclization. Although strong acids usually catalyze this reaction, 4-amino-1,3-dioxanes are rapidly obtained in high yields without catalyst when benzenamines and acetaldehyde react at low temperatures, in aqueous medium. Considering these conditions, we applied a supermolecule model with explicit water molecules to compute the mechanism for 4-amino-1,3-dioxanes formation from the reactants. The structure of the primary solvation shell was determined by Metropolis Monte Carlo method. In the Prins-cyclization step, we found an unpredicted pathway with non-ionic transition structures or intermediates. Explicit water molecules establish a net of hydrogen bonds allowing prototropism, maintaining the electrical neutrality in the system while two protons transfer occurs. To provide data to further experimental confirmation of this hypothesis, we estimated the kinetic isotope effect for the reaction. We also investigated the use of aliphatic amines, which indicates that the reaction may be of a broader application than first observed experimentally.

Although CO2 capture by alkanolamine aqueous solutions is a well-established technology, it demands high energy penalties and water consumption. Therefore, the development of new methods for CO2 removal is still a challenge. Herein, we employed the Density Functional Theory (DFT) to explore the potential of different mixtures composed of glycerol and nitrogen-containing bases to capture CO2. By combining glycerol, CO2 and the bases, it was possible to show that aliphatic amines are able to form intermolecular hydrogen bonds with the primary hydroxyl groups of glycerol, increasing their nucleophilicity and assisting the reaction with CO2 to form glycerol carbonate as the most stable product. To confirm that glycerol carbonate would be experimentally obtained from the given mixture, we selected triethylamine (TEA) to assist glycerol (Gly) in its reaction with CO2. The resulting product was characterized by Attenuated Total Reflectance Fourier Transform Infrared spectroscopy (ATR-FTIR), 1D and 2D Nuclear Magnetic Resonance spectroscopy (1H and 13C NMR) and Thermogravimetric Analysis (TGA). The ATR-FTIR results showed that TEA is protonated after bubbling CO2 in the glycerol/TEA mixture, suggesting that the reaction with CO2 occurs after deprotonation of glycerol, forming organic carbonates, as also indicated in the NMR spectra. The combined theoretical and experimental results indicate that TEA is able to activate glycerol in its reaction with CO2 to form organic carbonates, being an alternative procedure for CO2 capture.

Prostate cancer is an important cause of death in the male population and for which there is no satisfactory chemotherapy. Herein a new series of chalcone hybrids containing 2H-1,2,3-triazole core as the ring B has been synthesized and evaluated in vitro against PC-3 prostate cancer cell line. Compounds 4a, 4c and 4e significantly reduced cell viability and showed IC50 of 28.55, 15.64 and 25.56 µM, respectively. The structure-activity relationship supported by computational chemistry points that the polarity of the molecular surface area should have some relevance to the efficiency of the compounds, in particular the ratio of the partial positive charge sites and the total molecular surface area exposed to the cell environment.

Hydrogen sulfide, H2S, stand as one of the major issues in petroleum industry. Aqueous solutions of triazines are the most utilized non-regenerative H2S scavenger. Although they present a theoretical capture capacity of 3 mol of H2S per mole of triazine, it effectively scavenges only 2 mol. Herein, we employed Density Functional Theory at CAM-B3LYP/6–311++G(2d,2p) level of calculation to rationalize the full mechanism for capture of H2S by hexahydro-1,3,5-triazines, in particular the reason why the reaction stops at the second equivalent of H2S. For the capture of the first equivalent of H2S, we found an unprecedented SN1 pathway to be less energetic than SN2, the most commonly accepted in literature. For capture of a second H2S molecule, however, both mechanisms are energetically similar. High barriers were found for the capture of the third molecule of H2S, related to the lower electrophilicity of the carbon atom bonded to nitrogen and sulfur atoms.

A clean, efficient and facile one-pot protocol was developed for the synthesis of a series of new aminonaphthoquinones derived from 2-hydroxy-1,4-naphthoquinone (lawsone) by three-component Mannich reaction using catalytic amount of p-TsOH in CH3CN, at room temperature. At the present work, we improved the yield and significantly reduced the reaction time for several Mannich reactions with different amine and aromatic aldehydes using a non-expensive, mild catalyst and suitable solvent.

Hydroxynaphthoquinones such as lawsone (2-hydroxy-1,4-naphthoquinone) have proven to be effective antifungal agents. These compounds were tested for antifungal activity against yeast standard and clinical strains by the broth microdilution method. Among the synthetic lawsone derivatives, 2-hydroxy-3-((2-hydroxyphenyl)(pyrrolidin-1-yl)methyl)naphthalene-1,4-dione, 2-hydroxy-3-(((4-nitrophenyl)amino)(phenyl)methyl)naphthalene-1,4-dione and 2-hydroxy-3-((2-hydroxyphenyl)((4-nitrophenyl)amino)methyl)naphthalene-1,4-dione showed high activity against Candida albicans ATCC 10231, with minimal inhibitory concentrations (MICs) and minimal fungicidal concentrations (MFCs) ranging from 20 to 330 and from 80 to 330 μg mL-1, respectively. Moreover, they also showed a mechanism of action on exogenous ergosterol. Therapeutic concentrations (CC50) of 2-hydroxy-3-((2-hydroxyphenyl)(pyrrolidin-1-yl)methyl)naphthalene-1,4-dione, 2-hydroxy-3-(((4-nitrophenyl)amino)(phenyl)methyl)naphthalene-1,4-dione and 2-hydroxy-3-((2-hydroxyphenyl)((4-nitrophenyl)amino)methyl)naphthalene-1,4-dione were 52.81, 52.58 and 85.94 μg mL-1, respectively, which can be considered moderate or low. In addition, docking studies showed that these compounds had similar binding energy to standard ketoconazole, which are recognized as the molecular target by van der Waals interactions. Furthermore, they are under Lipinski’s rule of 5 with a druglikeness score better than ketoconazole and nystatin. These findings suggest that 2-hydroxy-3-((2-hydroxyphenyl)(pyrrolidin-1-yl)methyl)naphthalene-1,4-dione, 2-hydroxy-3-(((4-nitrophenyl)amino)(phenyl)methyl)naphthalene-1,4-dione and 2-hydroxy-3-((2-hydroxyphenyl)((4-nitrophenyl)amino)methyl)naphthalene-1,4-dione have potential as leading compounds against human fungal infections.

Improved reaction conditions are developed for the three component Mannich reaction of lawsone (I) with aldehydes and amines to give new aminonaphthoquinones.

The multicomponent one-pot synthesis has received great importance due to its wide range of applications in pharmaceutical chemistry and combinatorial libraries for drug discovery. The Mannich reaction is a classical method for the preparation of -aminocarbonylated compounds from amine, aldehyde and an active CH bond, and it’s one of the most important reaction in organic chemistry. Our research group described the multicomponent Mannich reaction with lawsone and various aldehydes and amines in ethanol at room temperature, according to the procedure found in the literature with some modifications. It should be noticed that the reaction times ranged from 12 to 48 hours, depending on the aldehyde and the amine used. Dabiri and co-workers published Mannich reaction in aqueous medium, under reflux, using InCl3 as catalyst where reaction times varied from 4 to 7.5 hours.

Using the same previous procedure, the reaction of the aldehyde N-phenyl-1,2,3-triazole (6) with lawsone and the amines 7 and 8, was performed. Unfortunately, rather than obtaining the Mannich adducts 9, in this reaction was obtained exclusively the compound 10 and 11 (Scheme 2). Scheme 2. Synthesis of N-phenyl-1,2,3-triazole derivatives. Compounds 10 and 11 were achieved through Michael addition in the respectively Mannich adducts formed in situ and occur due to the very low reactivity of the aldehyde triazolic 6 compared to the aldehydes used in preparation of adducts 2-4. The synthesized compounds (2-4, 10 and 11) were evaluated for their in vitro antifungal activity against for C. albicans (ATCC 14053), C. glabrata (ATCC 2001) and C. krusei (ATCC 34135).

The multi-component one-pot synthesis has received great importance because of its wide range of applications in pharmaceutical chemistry for the production of structural scaffolds and combinatorial libraries for drug discovery. In this context, three component coupling (3CC) reactions have proven remarkably successful in generating molecular complexities in a single step operation. 1 The 4amidotetrahydropyran ring system is a core structure in a number of natural products 2 and generally, are prepared via Prins cyclization using acid catalysis. However, the use of Ritter amidation to terminate Prins cyclization is scarce, hence an efficient and practical methodology for the Prins-Ritter type reaction would be of great importance for the preparation of structurally diverse tetrahydropyran derivatives for the drug discovery process.

Environmentally friendly one-pot protocol was developed for the first synthesis of aminonaphthoquinones derived from 2-hydroxy-1,4-naphthoquinone (lawsone) via a multicomponent Mannich reaction in aqueous media using a catalytic amount of dodecyl benzenesulfonic acid (DBSA), exploring a Bronsted acid-surfactant catalyst (BASC) concept, at room temperature.