Marcin Górecki

Absolute Configuration Determination by Quantum Mechanical Calculation of Chiroptical Spectra: Basics and Applications to Fungal Metabolites

BACKGROUNDnQuantum mechanical simulations of chiroptical properties, such as electronic circular dichroism (ECD), optical rotation (OR), and vibrational circular dichroism (VCD), have rapidly become very popular to assign the absolute configuration of novel natural products.nnnOBJECTIVEnWe review the application of the ECD/OR/VCD computational methodology to chiral metabolites of fungal origin. First, we summarize the fundamentals of the three spectroscopies; then, we focus on the specific experimental and computational issues allied to the application of their calculations.nnnMETHODSnWe surveyed the entire literature describing the use of ECD/OR/VCD computations for fungal metabolites, and catalogued all papers according to the method employed and to the structural family of compounds. Then, we chose several examples to illustrate the use of the techniques and highlight the practical application of the computational approach.nnnRESULTSnOur literature survey demonstrates that the simulation of ECD/OR/VCD spectra is nowadays widespread and accessible also to non-experts, although a good computational practice is necessary to avoid wrong assignments. ECD is still the most common technique used in the context of fungal metabolites. OR and VCD may be profitably employed when the compound of interest lacks chromophoric groups. Our examples illustrate that the combination of two or more chiroptical methods is strongly advisable in some cases, especially in the presence of high conformational flexibility, where a single technique does not lead to a safe conclusion.nnnCONCLUSIONnThe ECD/OR/VCD computational approach is a reliable and versatile method to assign the absolute configuration of fungal metabolites and related natural products.

Incensfuran: isolation, X-ray crystal structure and absolute configuration by means of chiroptical studies in solution and solid state

A new cembrane diterpene named incensfuran (1), biogenetically derived from incensole (2), was isolated from crude extracts of the Boswellia papyrifera Hochst. The structure of incensfuran (1) was elucidated by 1D and 2D NMR study, and its absolute configuration was determined by single crystal X-ray diffraction analysis and electronic and vibrational circular dichroism spectroscopy (ECD, VCD). Moreover semisynthesis of incensfuran (1) was achieved after treatment of incensole (2) with BF3·OEt2. In addition epoxidation of incensfuran (1) provided expoxide analog 3 with 80% yield.

Induced circularly polarized luminescence for revealing DNA binding with fluorescent dyes

HIGHLIGHTSCPL application to DNA/organic dyes binding is described for the first time.Strengths and possible artefacts of the CPL approach are discussed.CPL reveals the most relevant information in the case of thiazole orange/DNA intercalation or external binding.For the DAPI/DNA system, dye aggregates produce CPL artefacts connected to photoselection.CPL can be a useful complement to other measurements for advanced analysis of DNA binding ABSTRACT To the best of our knowledge this is the first report on the application of induced circularly polarized luminescence (CPL) for sensing the binding of fluorescent dyes to double stranded DNA. Using Thiazole Orange (TO) and 4′,6‐diamidino‐2‐phenylindole (DAPI) as models, we show utility and limitations of CPL in DNA binding studies. The results obtained indicate that CPL can be used as a new chiroptical tool for this purpose, however, special attention while recording CPL data must be used, in order to exclude measurement artefacts caused by linear polarization components.

Polyoxygenated cyathane diterpenoids from the mushroom Cyathus africanus , and their neurotrophic and anti-neuroinflammatory activities

In a previous study, we reported ten new polyoxygenated cyathane diterpenoids, neocyathins A–J, and their anti-neuroinflammatory effects from the liquid culture of the medicinal Basidiomycete Cyathus africanus. In the present study, eight new highly polyoxygenated cyathane diterpenoids, named neocyathins K–R (1–8), were isolated from the solid culture of C. africanus cultivated on cooked rice, together with three known congeners (9–11). The structures and the absolute configurations of the new compounds were elucidated through comprehensive NMR and HRESIMS spectroscopic data, electronic circular dichroism (ECD) data, and chemical conversion. Compounds 1 and 2 represent the first reported naturally occurring compounds with 4,9-seco-cyathane carbon skeleton incorporating an unprecedented medium-sized 9/7 fused ring system, while the 3,4-seco-cyathane derivative (3) was isolated from Cyathus species for the first time. All compounds were evaluated for their neurotrophic and anti-neuroinflammatory activity. All the isolates at 1–25u2009μM displayed differential nerve growth factor (NGF)-induced neurite outgrowth-promoting activity in PC-12 cells, while one of the compounds, allocyathin B2 (11), inhibited NO production in lipopolysaccharide (LPS)-stimulated microglia BV-2 cells. In addition, molecular docking studies showed that compound 11 generated interactions with the inducible nitric oxide synthase (iNOS) protein.

Stereochemical analysis of β-keto sulfoxides by circular dichroism

Three β-keto sulfoxides (1-3) were synthesized in enantiopure form and investigated by means of circular dichroism (CD) spectroscopy, both in electronic and vibrational range (ECD, VCD), in combination with quantum chemical calculations. For compound 2, the X-ray structure was available; thus, the ECD in the solid state was also considered to reveal the differences between the molecular species in both states. Despite the simplicity of all β-keto sulfoxides under investigation (29 atoms), reproducing even the major spectral VCD features failed for two compounds, making the use of VCD not ideal to assign their absolute configuration in a reliable way. We demonstrated, however, that the use of ECD spectroscopy, both in solution and solid state, can easily, unambiguously, and without any complication simulate all bands by applying the standard protocol for calculations. This study may stimulate the debate on the need of the use of two chiroptical methods simultaneously in the determination of absolute configurations.

Pyriculins A and B, two monosubstituted hex‐4‐ene‐2,3‐diols and other phytotoxic metabolites produced by Pyricularia grisea isolated from buffelgrass (Cenchrus ciliaris)

Pyricularia grisea has been identified as a foliar pathogen on buffelgrass (Cenchrus ciliaris) in North America and was studied as a potential source of phytotoxins for buffelgrass control. Two monosubstituted hex-4-ene-2,3-diols, named pyriculins A and B, were isolated from its culture filtrate organic extract together with (10S,11S)-(-)-epipyriculol, trans-3,4-dihydro-3,4,8-trihydroxy-1(2H)-napthalenone, and (4S)-(+)-isosclerone. Pyriculins A and B were characterized by spectroscopic (essentially nuclear magnetic resonance [NMR], High-resolution electrospray ionization mass spectrometry [HRESIMS]) and chemical methods such as (4E)-1-(4-hydroxy-1,3-dihydroisobenzofuran-1-yl)hex-4-ene-2,3-diols. The relative and absolute configuration of these compounds was determined by a combination of spectroscopic (NMR, electronic circular dichroism [ECD]) and computational tools. When bioassayed in a buffelgrass coleoptile and radicle elongation test, (10S,11S)-(-)-epipyriculol proved to be the most toxic compound. Seed germination was much reduced and slowed with respect to the control and radicles failed to elongate. All five compounds delayed germination, but only (10S,11S)-(-)-epipyriculol was able to prevent radicle development of buffelgrass seedlings. It had no effect on coleoptile elongation, while the other four compounds caused significantly increased coleoptile development relative to the control.

Phytotoxic Activity of Metabolites Isolated from Rutstroemia sp.n., the Causal Agent of Bleach Blonde Syndrome on Cheatgrass (Bromus tectorum)

A fungal pathogen soon to be described as Rutstroemia capillus-albis (Rutstroemiaceae, Helotiales, Leotiomycetes) has been identified as the causal agent of ‘bleach blonde syndrome’ on the invasive annual grass weed Bromus tectorum (cheatgrass) in western North America. This apparently common but previously undescribed disease causes premature senescence and sterility, but does not affect seed germination or seedling emergence and growth. This study investigated whether the new species produces phytotoxins that could be implicated in pathogenesis. The compounds 9-O-methylfusarubin, 9-O-methylbostrycoidin, 5-O-methylnectriafurone, trans-methyl-p-coumarate and terpestacin were isolated from the solid culture of this fungus. The undescribed absolute stereochemistry at C-3 of 9-O-methylfusarubin and at C-1’ of 5-O-methylnectriafurone were assigned by applying electronic and vibrational circular dichroism (ECD and VCD) combined with computational methods and the advanced Mosher’s method, respectively. The first three listed compounds are naphtoquinone pigments, while terpestacin is a sesterterpene, and trans-methyl-p-coumarate could be the product of an unusual fungal phenylpropanoid biosynthesis pathway. In a juvenile plant immersion bioassay, both 9-O-methylfusarubin and terpestacin proved to be highly toxic at 10−4 M, causing wilting and plant death within 10 days. This finding suggests that these two compounds could play a role in pathogenesis on B. tectorum.

Broad-Range Spectral Analysis for Chiral Metal Coordination Compounds: (Chiro)optical Superspectrum of Cobalt(II) Complexes

Chiroptical broad-range spectral analysis extending from UV to mid-IR was employed to study a family of Co(II) N-(1-(aryl)ethyl)salicylaldiminato Schiff base complexes with pseudotetrahedral geometry associated with chirality-at-metal of the Δ/Λ type. While common chiral organic compounds have well-separated absorption and circular dichroism spectra (CD) in the UV/vis and IR regions, chiral Co(II) complexes feature an almost unique continuum of absorption and CD bands, which cover in sequence the UV, visible, near-IR (NIR), and IR regions of the electromagnetic spectrum. They can be collected in a single (chiro)optical superspectrum ranging from the UV (230 nm, 5.4 eV) to the mid-IR (1000 cm-1, 0.12 eV), which offers a fingerprint of the structure and stereochemistry of the metal complexes. Each region of the superspectrum contributes to one piece of information: the NIR-CD region, in combination with TDDFT calculations, allows a reliable assignment of the metal-centered chirality; the UV-CD region facilitates the analysis of the Δ/Λ diastereomeric equilibrium in solution; and the IR-VCD region contains a combination of low-lying metal-centered electronic states (LLES) and ligand-centered vibrations and displays characteristically enhanced and monosignate VCD bands. Circular dichroism in the NIR and IR regions is crucial to reveal the presence of d-d transitions of the Co(II) core which, due to the electric-dipole forbidden character, would be otherwise overlooked in the corresponding absorption spectra.

Chiral [MnIIMnIII3M'] (M' = NaI, CaII, MnII) and [MnIIMnIII6NaI2] clusters built from an enantiomerically pure Schiff base: synthetic, chiroptical and magnetic properties

From the reaction of manganese halides with the chiral Schiff bases obtained by condensation of o-vanillin and (R)- or (S)-phenylglycinol, 11 complexes based on pentanuclear cages with trigonal bipyramidal [MnII MnIII 3 M] (M=NaI , CaII , MnII ) or enneanuclear [MnII MnIII 6 NaI 2 ] cores were synthesized. Structural, supramolecular chirality, and optical properties were explored. The magnetic properties of related systems were reviewed, and the magnetic response of the new systems was rationalized to the bond parameters.

Synthesis and structure analysis of ferrocene‐containing pseudopeptides

Ferrocene with its aromaticity and facile redox properties is an attractive moiety to be incorporated into functional moieties. Medicinal applications of ferrocene are well known and ferrocene itself shows cytotoxic and antianemic properties. In this article, we will describe the synthesis and the structure analysis of two pseudopeptides containing a ferrocene moiety as N‐terminal group. After purification, Fc‐l‐Phe‐d‐Oxd‐OBn [l‐Pheuf8fel‐phenylalanine; d‐Oxduf8fe(4R,5S)‐4‐Methyl‐5‐carboxy‐oxazolidin‐2‐one] appears as bright brown solid that spontaneously forms brown needles. The X‐ray diffraction of the crystals shows the presence of strong π interactions between the ferrocenyl moiety and the phenyl rings, while no Nuf8ffH•••Ouf8feC hydrogen bonds are formed. This result is confirmed by FT‐IR and 1H NMR analysis. In contrast, both FT‐IR and 1H NMR analysis suggest that Fc‐(l‐Phe‐d‐Oxd)2‐OBn forms a turn conformation stabilized by intramolecular Nuf8ffH•••Ouf8feC hydrogen bonds in solution. Chiroptical spectroscopies (ECD and VCD) substantially confirmed the absence of a well‐defined folded structure. The presence of the Fc moiety is responsible for specific ECD signals, one of which displayed pronounced temperature dependence and is directly related with the helicity assumed by the Fc core. Solid‐state ECD spectra were recorded and rationalized on the basis of the X‐ray geometry and quantum‐mechanical calculations.