NMR Chemical Shift Calculations Research Articles

Macrosphelides from Antarctic fungus Pseudogymnoascus sp. (strain SF-7351) and their neuroprotective effects on BV2 and HT22 cells

Strategies for reducing inflammation in neurodegenerative diseases have attracted increasing attention. Herein, we discovered and evaluated the neuroprotective potential of fungal metabolites isolated from the Antarctic fungus Pseudogymnoascus sp. (strain SF-7351). The chemical investigation of the EtOAc extract of the fungal strain isolate revealed a novel naturally occurring epi-macrosphelide J (1), a novel secondary metabolite macrosphelide N (2), and three known compounds, namely macrosphelide A (3), macrosphelide B (4), and macrosphelide J (5). Their structures were established unambiguously using spectroscopic methods, such as one-dimensional and two-dimensional nuclear magnetic resonance (1D and 2D-NMR) spectroscopy, high-resolution electrospray ionization mass spectrometry (HR-ESI-MS), and gauge-including atomic orbital (GIAO) NMR chemical shift calculations, with the support of the advanced statistical method DP4+. Among the isolated metabolites, the absolute configuration of epi-macrosphelide J (1) was further confirmed using single-crystal X-ray diffraction analysis. The neuroprotective effects of the isolated metabolites were evaluated in lipopolysaccharide (LPS)-induced BV2 and glutamate-stimulated HT22 cells. Only macrosphelide B (4) displayed substantial protective effects in both BV2 and HT22 cells. Molecular mechanisms underlying this activity were investigated using western blotting and molecular docking studies. Macrosphelide B (4) inhibited the inflammatory response by reducing the nuclear translocation of NF-κB (p65) in LPS-induced BV2 cells and induced the Nrf2/HO-1 signaling pathway in both BV2 and HT22 cells. The neuroprotective effect of macrosphelide B (4) is related to the interaction between Keap1 and p65. These results suggest that macrosphelide B (4), present in the fungus Pseudogymnoascus sp. (strain SF-7351), may serve as a candidate for the treatment of neurodegenerative diseases.

Discovery of pyranonaphthoquinones and an eighteen-membered ring macrolide from the rhizospheric soil-derived fungus Phialocephala sp. YUD18001 by OSMAC strategy

Two new pyranonaphthoquinones, phialoyxinones A (1) and B (2), a new eighteen-membered ring lactone, phialoyxtone (3), and five known pyranonaphthoquinone derivatives were identified from the fungus Phialocephala sp. YUD18001, which was isolated from the rhizospheric soil associated with Gastrodia elata. Their structures were unequivocally established by a comprehensive interpretation of the spectroscopic data, with the stereochemistry for 1–3 was defined by a combination of TDDFT calculations, and the DP4+ probability analysis based on NMR chemical shift calculations. All of the new compounds 1–3 were evaluated for cytotoxicity and acetylcholinesterase inhibitory, compound 2 exhibited in vitro cytotoxic activities against five human cancer cell lines (HL-60, SMMC-7721, A549, MCF-7 and SW480) with IC50 values ranging from 11.80 to 19.32 μM. Compounds 2 and 3 exhibited moderate AChE inhibitory activities. A putative biosynthetic pathway for the pyranonaphthoquinones was proposed.

Interaction of Methylenecycloalkanes with BF3·THF Catalyzed by 2TiCl2

The Cp2TiCl2-catalyzed interaction of methylenecycloalkanes with BF3·THF in tetrahydrofuran was carried out for the first time with the formation of target 1-fluoro-1-boraspirocarbocycles and also isomerization products of a starting monomer (1-methylcycloalk-1-enes). The structure of reaction products was elucidated using one(1H, 13C Dept, 11B, 19F) and two-dimensional (COSY, HSQC, HMBC) NMR spectroscopy, mass spectrometry combined with quantum-chemical calculations of 13C NMR chemical shifts.

Sarcoeleganolides H–K, new anti-thrombotic cembranes from soft coral Sarcophyton elegans

Chemical investigation of soft coral the Sarcophyton elegans collected from the South China Sea led to the identification of four new cembranes, namely sarcoeleganolides H–K (1–4). Their structures and absolute configurations were established by 1D and 2D NMR spectroscopy, quantum chemical calculations of NMR chemical shifts and electronic circular dichroism (ECD) data analysis. Moreover, compound 2 exhibited moderate anti-thrombotic activity in zebrafish.

Hosimosines A-E, structurally diverse cytisine derivatives from the seeds of Ormosia hosiei Hemsl. et Wils

Ormosia hosiei Hemsl. et Wils (Fabaceae family) is an arbor species endemic to China. The seeds of O. hosiei have been used as traditional Chinese medicine to treat hernia, abdominal pain, blood stasis and amenorrhea. Cytisine-like and angustifoline type alkaloids were main components identified from this plant. In our research on the bioactive alkaloids from the promising Chinese medicinal plants, four new angustifoline type alkaloids (1–4) and a new cytisine-like alkaloid (5), named hosimosine A-E, together with 13 known analogues (6–18) were isolated from the seeds of O. hosiei. Their structures were elucidated by the extensive spectroscopic methods, especially the interpretation of NMR spectra and specific rotations, along with the methods of NMR and ECD calculation. Compounds 1–4 were identified as two pairs of epimers, whose relative configurations were deduced from density functional theory (DFT) calculations of NMR chemical shifts and DP4+ analysis, and absolute configurations were determined by comparison of their experimental and theoretical ECD spectra. Compound 5 displayed two sets of NMR data caused by the existence of tautomeric forms. Compounds 14, 17 and 18 were determined to be enantiomers of literature compounds. Some of the isolates exhibited moderate cytotoxic effects against HepG2, A2780 and MCF-7 cells.

Sesquiterpenoids from the roots of Aucklandia costus and their anti-inflammatory activities

Five undescribed sesquiterpenoid dimers, aucklandiolides A–E (1–5), one new sesquiterpenoid glycoside, β-cyclocostunolide-15-β-D-glucopyranoside (6), and seventeen known analogues (7–23) were isolated from the roots of Aucklandia costus. Their structures were elucidated by comprehensive HRESIMS and NMR spectroscopic data analysis, and their configurations were confirmed by the computational calculations of ECD and NMR chemical shifts. Aucklandiolides A and B are the first examples of dimeric sesquiterpenoids with a unique 6/6/6/5/6/6 ring system originated from a proposed Diels–Alder cycloaddition between two eudesmane sesquiterpenoids. Besides, compounds 9–11, 20, and 22 showed significant inhibition of nitric oxide production in LPS-stimulated RAW 264.7 cells at a concentration of 20 μM.

NMR Fingerprints of Formyl Phloroglucinol Meroterpenoids and Their Application to the Investigation of Eucalyptus gittinsii subsp. gittinsii.

NMR fingerprints provide powerful tools to identify natural products in complex mixtures. Principal component analysis and machine learning using 1H and 13C NMR data, alongside structural information from 180 published formyl phloroglucinols, have generated diagnostic NMR fingerprints to categorize subclasses within this group. This resulted in the reassignment of 167 NMR chemical shifts ascribed to 44 compounds. Three pyrano-diformyl phloroglucinols, euglobal In-1 and psiguadiols E and G, contained 1H and 13C NMR data inconsistent with their predicted phloroglucinol subclass. Subsequent reinterpretation of their 2D NMR data combined with DFT 13C NMR chemical shift and ECD calculations led to their structure revisions. Direct covariance processing of HMBC data permitted 1H resonances for individual compounds in mixtures to be associated, and analysis of their 1H/13C HMBC correlations using the fingerprint tool further classified components into phloroglucinol subclasses. NMR fingerprinting HMBC data obtained for six eucalypt flower extracts identified three subclasses of pyrano-acyl-formyl phloroglucinols from Eucalyptus gittinsii subsp. gittinsii. New, eucalteretial F and (+)-eucalteretial B, and known, (-)-euglobal VII and eucalrobusone C, compounds, each belonging to predicted subclasses, were isolated and characterized. Staphylococcus aureus and Plasmodium falciparum screening revealed eucalrobusone C as the most potent antiplasmodial formyl phloroglucinol to date.

New Bisabolane-Type Sesquiterpenoids from Curcuma longa and Their Anti-Atherosclerotic Activity.

To explore the sesquiterpenoids in Curcuma longa L. and their activity related to anti-atherosclerosis. The chemical compounds of the rhizomes of C. longa were separated and purified by multiple chromatography techniques. Their structures were established by a variety of spectroscopic experiments. The absolute configurations were determined by comparing experimental and calculated NMR chemical shifts and electronic circular dichroism (ECD) spectra. Their anti-inflammatory effects and inhibitory activity against macrophage-derived foam cell formation were evaluated by lipopolysaccharide (LPS) and oxidized low-density lipoprotein (ox-LDL)-injured RAW264.7 macrophages, respectively. This study resulted in the isolation of 10 bisabolane-type sesquiterpenoids (1-10) from C. longa, including two pairs of new epimers (curbisabolanones A-D, 1-4). Compound 4 significantly inhibited LPS-induced nitric oxide (NO), interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and prostaglandin E2 (PGE2) production in RAW264.7 cells. Furthermore, compound 4 showed inhibitory activity against macrophage-derived foam cell formation, which was represented by markedly reducing ox-LDL-induced intracellular lipid accumulation as well as total cholesterol (TC), free cholesterol (FC), and cholesterol ester (CE) contents in RAW264.7 cells. These findings suggest that bisabolane-type sesquiterpenoids, one of the main types of components in C. longa, have the potential to alleviate the atherosclerosis process by preventing inflammation and inhibiting macrophage foaming.

Solid-State 19F NMR Chemical Shift in Square-Planar Nickel-Fluoride Complexes Linked by Halogen Bonds.

The halogen bond (XB) is a highly directional class of noncovalent interactions widely explored by experimental and computational studies. However, the NMR signature of the XB has attracted limited attention. The prediction and analysis of the solid-state NMR (SSNMR) chemical shift tensor provide useful strategies to better understand XB interactions. In this work, we employ a computational protocol for modeling and analyzing the 19F SSNMR chemical shifts previously measured in a family of square-planar trans NiII-L2-iodoaryl-fluoride (L = PEt3) complexes capable of forming self-complementary networks held by a NiF···I(C) halogen bond [Thangavadivale, V.; Chem. Sci. 2018, 9, 3767-3781]. To understand how the 19F NMR resonances of the nickel-bonded fluoride are affected by the XB, we investigate the origin of the shielding in trans-[NiF(2,3,5,6-C6F4I)(PEt3)2], trans-[NiF(2,3,4,5-C6F4I)(PEt3)2], and trans-[NiF(C6F5)(PEt3)2] in the solid state, where a XB is present in the two former systems but not in the last. We perform the 19F NMR chemical shift calculations both in periodic and molecular models. The results show that the crystal packing has little influence on the NMR signatures of the XB, and the NMR can be modeled successfully with a pair of molecules interacting via the XB. Thus, the observed difference in chemical shift between solid-state and solution NMR can be essentially attributed to the XB interaction. The very high shielding of the fluoride and its driving contributor, the most shielded component of the chemical shift tensor, are well reproduced at the 2c-ZORA level. Analysis of the factors controlling the shielding shows how the highest occupied Ni/F orbitals shield the fluoride in the directions perpendicular to the Ni-F bond and specifically perpendicular to the coordination plane. This shielding arises from the magnetic coupling of the Ni(3d)/F(2p lone pair) orbitals with the vacant σNi-F* orbital, thereby rationalizing the very highly upfield (shielded) resonance of the component (δ33) along this direction. We show that these features are characteristic of square-planar nickel-fluoride complexes. The deshielding of the fluoride in the halogen-bonded systems is attributed to an increase in the energy gap between the occupied and vacant orbitals that are mostly responsible for the paramagnetic terms, notably along the most shielded direction.

Discovering the Solid-State Secrets of Lorlatinib by NMR Crystallography: To Hydrogen Bond or not to Hydrogen Bond

Lorlatinib is an active pharmaceutical ingredient (API) used in the treatment of lung cancer. Here, an NMR crystallography analysis is presented whereby the single-crystal X-ray diffraction structure (CSD: 2205098) determination is complemented by multinuclear (1H, 13C, 14/15N, 19F) magic-angle spinning (MAS) solid-state NMR and gauge-including projector augmented wave (GIPAW) calculation of NMR chemical shifts. Lorlatinib crystallises in the P21 space group, with two distinct molecules in the asymmetric unit cell, Z′ = 2. Three of the four NH2 hydrogen atoms form intermolecular hydrogen bonds, N30-H…N15 between the two distinct molecules and N30-H…O2 between two equivalent molecules. This is reflected in one of the NH21H chemical shifts being significantly lower, 4.0 ppm compared to 7.0 ppm. Two-dimensional 1H–13C, 14N-1H and 1H (double-quantum, DQ)-1H (single-quantum, SQ) MAS NMR spectra are presented. The 1H resonances are assigned and specific HH proximities corresponding to the observed DQ peaks are identified. The resolution enhancement at a 1H Larmor frequency of 1 GHz as compared to 500 or 600 MHz is demonstrated.

NMR and DFT studies of monounsaturated and ω-3 polyunsaturated free fatty acids in the liquid state reveal a novel atomistic structural model of DHA

Structures of low-energy conformers of caproleic acid (CA; 10:1 cis-9), oleic acid (OA; 18:1 cis-9), α-linolenic acid (ALA; 18:3 cis-9,12,15 ω-3), eicosapentaenoic acid (EPA; 20:5 cis-5,8,11,14,17 ω-3), and docosahexaenoic acid (DHA; 22:6 cis-4,7,10,13,16,19 ω-3) in the liquid state, based on detailed 1D NOE and density functional theory calculations of 1H NMR chemical shifts are presented. Transient 1D NOE experiments with variable mixing time showed significant through-space proximity of the CH2–COOH protons and the terminal CH3– groups. Variable temperature 1H NMR experiments revealed strong intermolecular centro-symmetric cyclic hydrogen bond interactions of the carboxylic groups of the monounsaturated oleic and caproleic acids (δ(COOH) ∼ 12.0–12.4 ppm), ALA and EPA (δ(COOH) ∼ 11.0 ppm). On the contrary, the carboxylic proton of DHA is strongly shielded with δ(COOH) ∼ 8.5 ppm. DFT calculations were interpreted in terms of aggregates of dimerized fatty acids with parallel and antiparallel interdigitated structures. The antiparallel arrangement was found to be in excellent agreement with experimental 1D NOE NMR data. For the dimeric DHA, a flip-flop process between a classical intermolecular centro-symmetric hydrogen bond through carboxylic groups and a novel intramolecular hydrogen bond between the carboxylic group and the terminal ω-3 double bond is demonstrated.

Phenylpropanoids and a diarylpentanol from Stellera chamaejasme with acetylcholinesterase inhibitory activity

The chemical investigation on the roots of Stellera chamaejasme led to the identification of five undescribed compounds, including three lignans (1, 2, and 3b), one coumarin (4), one diarylpentanoid (5), and eight known analogues (3a, 6–10, and 11a/11b). Among them, two pairs of enantiomers were separated by chiral resolution. The structures of all compounds were elucidated by NMR spectroscopy and HRESIMS data analyses, quantum chemical calculations of NMR chemical shifts and ECD, as well as single-crystal X-ray diffraction analyses. All isolates were tested for their inhibitory activities against AChE, and compound 2 showed the most potent inhibitory activity, with an inhibition rate of 88.0% at 100 μM. In addition, the possible interaction mechanism of 2 against AChE was predicted by molecular docking.

Improving the accuracy of 31P NMR chemical shift calculations by use of scaling methods.

Calculation of 31P NMR chemical shifts for a series of tri- and tetracoordinate phosphorus compounds using several basis sets and density functional theory (DFT) functionals gave a modest fit to experimental chemical shifts, but an excellent linear fit when plotted against the experimental values. The resultant scaling methods were then applied to a variety of "large" compounds previously selected by Latypov et al. and a set of stereoisomeric and unusual compounds selected here. No one method was best for all structural types. For compounds that contain P-P bonds and P-C multiple bonds, the Latypov et al. method using the PBE0 functional was best (mean absolute deviation/root mean square deviation (MAD/RMSD) = 6.9/8.5 ppm and 6.6/8.2 ppm, respectively), but for the full set of compounds gave higher deviations (MAD/RMSD = 8.2/12.3 ppm), and failed by over 60 ppm for a three-membered phosphorus heterocycle. Use of the M06-2X functional for both the structural optimization and NMR chemical shift calculation was best overall for the compounds without P-C multiple bonds (MAD/RMSD = 5.4/7.1 ppm), but failed by 30-49 ppm for compounds having any P-C multiple-bond character. Failures of these magnitudes have not been reported previously for these widely used functionals. These failures were then used to screen a variety of recommended functionals, leading to better overall methods for calculation of these chemical shifts: optimization with the M06-2X functional and NMR calculation with the PBE0 or ωB97x-D functionals gave values for MAD/RMSD = 6.9/8.5 ppm and 6.8/9.1 ppm, respectively, over an experimental chemical shift range of -181 to 356 ppm. Due to the unexplained failures observed, we recommend use of more than one method when looking at novel structures.

Relativistic Effects from Heavy Main Group p-Elements on the NMR Chemical Shifts of Light Atoms: From Pioneering Studies to Recent Advances

This review represents a compendium of computational studies of relativistic effects on the NMR chemical shifts of light nuclei caused by the presence of heavy main group p-block elements in molecules. The narration starts from a brief discussion of the relativistic theories and quantum chemical methods for the calculation of NMR chemical shifts at the relativistic level of the electronic theory. The main part of the review contains a survey on the relativistic calculations of NMR shielding constants of the most popular NMR-active light nuclei such as 1H, 13C, 19F, 29Si, 15N, and 31P of compounds containing heavy p-elements. A special focus is placed on the relativistic effects initiated by the 16th and 17th group elements. Different factors governing the behavior of the relativistic effects on the chemical shifts of light atoms are discussed. In particular, the stereochemistry of the relativistic “heavy atom on the light atom” effect and the influence of the spin–orbit relativistic effects on the vibrational contributions to the shielding constants of light nuclei are considered.

New efficient pecS-n (n = 1, 2) basis sets for quantum chemical calculations of 31P NMR chemical shifts.

The basis sets that are used in the quantum chemical calculations of 31P NMR chemical shifts have always been one of the most important factors of accuracy. Regardless of what high-quality approach is employed, using basis sets of insufficient flexibility in the important angular regions may give poor results and lead to misassignments of the signals in the 31P NMR spectra. In this work, it was found that the existing nonrelativistic basis sets for phosphorus atom of double- and triple-ζ quality, specialized for the 31P NMR chemical shifts calculations, are essentially undersaturated in the d-angular space that occurred to play a significant role in the overall accuracy of these calculations. This problem has been thoroughly investigated, and new pecS-n (n = 1, 2) basis sets for phosphorus chemical shifts calculations were proposed. The exponents and contraction coefficients for the pecS-n basis sets were generated with the property-energy consistent method that has been introduced in our earlier paper, and has been proven useful in the creation of efficient property-oriented basis sets. New basis sets were optimized using the GIAO-DFT method with the B97-2 functional. Extensive benchmark calculations showed that the pecS-1 and pecS-2 basis sets provide very good accuracy, characterized by the corrected mean absolute percentage errors against the experiment of about 7.03 and 4.42 ppm, respectively. In particular, the accuracy of 31P NMR chemical shifts calculations achieved with the pecS-2 basis set is one of the most favorable accuracies for today. We believe that our new pecS-n (n = 1, 2) basis sets for phosphorus atom will prove useful in modern large-scale quantum chemical calculations of 31P NMR chemical shifts.

GIAO NMR Calculation-Driven Stereochemical Assignment of Marine Macrolide Natural Products: Assessment of the Performance of DP4 and DP4+ Analyses and Assignment of the Relative Configuration of Leptolyngbyalide A–C/Oscillariolide Macrolactone

Abstract The stereochemical assignment of marine macrolide natural products by quantum chemical calculations is often hampered by the generation of an intractable number of conformers in molecular mechanics conformation searches. In this study, we assessed in detail the application of GIAO NMR chemical shift calculation and DP4-type statistical analyses to the stereochemical assignment of two marine macrolide natural products, whose relative configurations had been incorrectly assigned in the originally proposed structures. We also examined how DP4+ probability was affected by cumulative Boltzmann population level of molecular mechanics-derived conformers. Finally, GIAO NMR chemical shift calculation/DP4-type statistical analysis was applied to leptolyngbyalide A–C/oscillariolide macrolactone, whose relative configuration has not been assigned so far.

Tropine-based dicationic molten salt: An active catalyst in the acceleration of one-pot synthesis of spiro-2-amino-4H-pyran-oxindoles and bis-2-amino-4H-pyrans

A suitable dicationic molten salt based on tropine ([(Tropine)2C3H5OH].2Cl) was prepared and characterized by FT-IR, 1H-NMR, 13C-NMR, FESEM, CHN, MS and TGA analysis methods. To determine the accurate structure of the catalyst the potential energy surfaces of possible pathways have been explored and the corresponding energy barriers and some of the required NMR chemical shifts have been calculated. On the basis of the Curtin-Hammett principle, Min4bb seems likely to be the main structure and by the comparison of the experimental and calculated NMR chemical shifts, its structure has been elucidated. The calculations have been performed at the DFT (B3LYP) computational levels with a combination of 6-31+G(d,p) and 6-311G(d,p) basis sets. In continue the application of reagent was investigated in the acceleration of the synthesis of bis-2-amino-4H-pyrane and spiro-2-amino-4H-pyran-oxindole derivatives. The considerable features of the introduced procedure are included easy preparation of the catalyst, use of small amounts of the catalyst and simple work-up method. Also, the catalyst can be easily recovered and recycled for at least 5 times.

AlCl3-Catalyzed Cascade Reactions of 1,2,3-Trimethoxybenzene and Adipoyl Chloride: Spectroscopic Investigations and Density Functional Theory Studies.

The reaction of 1,2,3-trimethoxybenzene with adipoyl chloride in the presence of AlCl3 gave two isomeric cyclopentene derivatives, 1,6-bis(2,3,4-trimethoxyphenyl)hexane-1,6-dione, and two demethylation products of aryl methyl ethers. The cyclopentene derivatives including unconjugated or conjugated enones are products formed in a cascade reaction resulting from first the Friedel-Crafts acylation reaction and then aldol condensation. All compounds were optimized by density functional theory calculated using two functional levels, B3LYP and M06-2X, with the 6-311+G(d,p) basis set. The structural properties were established, natural bond orbital analysis of donor-acceptor interactions was carried out, and charges on the atoms and quantum chemical reactivity identifiers were determined to compare the strength of the intramolecular hydrogen bonds formed and their stabilities. To compare the experimental 1H and 13C NMR chemical shifts with the calculated values, NMR chemical shift calculations were carried out using the gauge-invariant atomic orbital method.

Antimicrobial secondary metabolites from an endophytic fungus Aspergillus polyporicola

Two new nucleoside derivatives, kipukasins O (1) and P (2), one new cyclohexenone derivative, arthropsadiol D (5), and one new natural product, (+)-2,5-dimethyl-3(2H)-benzofuranone (6), together with eleven known compounds (3, 4, 7–15), were obtained from the culture broth of the endophytic fungus Aspergillus polyporicola R2 isolated from the roots of Synsepalum dulcificum. Among them, the absolute configuration of compound 5 was determined by quantum chemical calculations of NMR chemical shifts and ECD spectrum. The antimicrobial activities of these compounds were evaluated. Compound 11 exhibited obvious inhibitory activity against MRSA, Staphylococcus aureus, Salmonella typhimurium, Botrytis cinerea, and Fusarium graminearum with MIC values of 4, 4, 4, 32, and 16 μg/mL, respectively. Compound 12 exhibited antibacterial activity against S. typhimurium and MRSA with MIC values of 4 and 16 μg/mL. Compound 6 exhibited antifungal activity against F. graminearum with MIC value of 32 μg/mL.

Cyclic enaminones and a 4-quinazolinone from an unidentified actinomycete of the family Micromonosporaceae

Four novel cyclic enaminones, designated RD4123A-D (1-4), and a new 4-quinazolinone metabolite, RD4123E (5), were isolated from the culture extract of an unidentified actinomycete strain RD004123, which belongs to the family Micromonosporaceae. Structures of 1-5 were determined by spectroscopic analyses using NMR, MS, and electronic circular dichroism (ECD), combined with quantum chemical calculations of ECD and NMR chemical shifts and biosynthetic consideration. Compounds 1-5 showed weak to modest cytotoxicity against murine leukemia P388 cells, while being inactive against bacteria and fungi.