pH Dependent Chiroptical Properties of (1<i>R</i>,2<i>R</i>)- and (1<i>S</i>,2<i>S</i>)-<i>trans</i>-Cyclohexane Diesters and Diamides from VCD, ECD, and CPL Spectroscopy

Diesters of (1<i>R</i>,2<i>R</i>)- and (1<i>S</i>,2<i>S</i>)-cyclohexanediols and diamides of (1<i>R</i>,2<i>R</i>)- and (1<i>S</i>,2<i>S</i>)-diaminocyclohexane with <i>p</i>-hydroxycinnamic acid have been known for some time to exhibit intense bisignate electronic circular dichroism (ECD) spectra in CH₃OH. It was also known that added NaOH causes a bathochromic shift of ∼50 nm in CH₃OH, and an even higher one in DMSO. We have measured vibrational circular dichroism (VCD) spectra both for neutral compounds and in the presence of NaOH and other bases. The VCD and IR spectra in the mid-IR region for CD₃OD and DMSO-<i>d</i>₆ solution exhibit high sensitivity to the charged state for the diesters. They possess two strong bisignate features in the presence of bases in the mid-IR, which are interpreted in terms of vibrational exciton couplets, while this phenomenon is less evident in diamides. VCD allied to density functional theory (DFT) calculations allows one to shed some light on the spectral differences of diesters and diamides by studying their conformational properties. Optical rotatory dispersion (ORD) curves confirm the ECD data. Circularly polarized luminescence (CPL) data have been also acquired, which are rather intense in basified solution: the CPL spectra are monosignate and are as intense in the diester and in the diamide case

Importance and Difficulties in the Use of Chiroptical Methods to Assign the Absolute Configuration of Natural Products: The Case of Phytotoxic Pyrones and Furanones Produced by <i>Diplodia corticola</i>

α-Pyrones and furanones are metabolites produced by <i>Diplodia corticola</i>, a pathogen of cork oak. Previously, the absolute configuration (AC) of diplopyrone was defined by chiroptical methods and Mosher’s method. Using X-ray and chiroptical methods, the AC of sapinofuranone C was assigned, while that of the (4<i>S,</i>5<i>S</i>)-enantiomer of sapinofuranone B was established by enantioselective total synthesis. Diplofuranone A and diplobifuranylones A–C ACs are still unassigned. Here electronic and vibrational circular dichroism (ECD and VCD) and optical rotatory dispersion (ORD) spectra are reported and compared with density functional theory computations. The AC of the (4<i>S</i>,5<i>S</i>)-enantiomer of sapinofuranone B and sapinofuranone C is checked for completeness. The AC of diplobifuranylones A–C is assigned as (2<i>S</i>,2′<i>S</i>,5′<i>S</i>,6′<i>S</i>), (2<i>S</i>,2′<i>R</i>,5′<i>S</i>,6′<i>R</i>), and (2<i>S</i>,2′<i>S</i>,5′<i>R</i>,6′<i>R</i>), respectively, with the Mosher’s method applied to define the absolute configuration of the carbinol stereogenic carbon. The AC assignment of sapinofuranones is problematic: while diplofuranone A is (4<i>S</i>,9<i>R</i>), sapinofuranones B and C are (4<i>S</i>,5<i>S</i>) according to ORD and VCD, but not to ECD. To eliminate these ambiguities, ECD and VCD spectra of a di-<i>p</i>-bromobenzoate derivative of sapinofuranone C are measured and calculated. For phytotoxicity studies, it is relevant that all six compounds share the <i>S</i> configuration for the stereogenic carbon atom of the lactone moiety

Mode Robustness in Raman Optical Activity

By reformulating Raman and ROA invariants we provide ground for the definition of robust modes in ROA spectroscopy. Introduction of two parameters defining robustness helps characterization and assignment of ROA bands. Application and use of robustness parameters to [<i>n</i>]­helicenes and oxirane/thiirane derivatives are presented

Absolute Configurations of Fungal and Plant Metabolites by Chiroptical Methods. ORD, ECD, and VCD Studies on Phyllostin, Scytolide, and Oxysporone

The absolute configuration (AC) of the bioactive metabolites phyllostin (<b>1</b>) and scytolide (<b>2</b>), two hexahydro-1,4-benzodioxines produced by <i>Phyllosticta cirsii</i>, and oxysporone (<b>3</b>), a dihydrofuropyranone recently isolated from a strain of <i>Diplodia africana</i>, has been assigned by computational analysis of their optical rotatory dispersion (ORD), electronic circular dichroism (ECD), and vibrational circular dichroism (VCD) spectra. Computational prediction of ORD, ECD, and VCD allowed us to assign (3<i>S,</i>4a<i>R,</i>8<i>S,</i>8a<i>R</i>) AC to naturally occurring (−)-<b>1</b>, while (4a<i>R,</i>8<i>S,</i>8a<i>R</i>) AC was assigned to (−)-<b>2</b> employing only ECD and VCD, because in this case ORD analysis turned out to be unsuitable for AC assignment. Theoretical prediction of both ORD and ECD spectra of <b>3</b> led to assignment of (4<i>S,</i>5<i>R,</i>6<i>R</i>) AC to (+)-<b>3</b>. In this case a satisfactory agreement between experimental and calculated VCD spectra was obtained only after taking into account solvent effects. This study shows that in the case of flexible and complex natural products only a concerted application of more than a single chiroptical technique permits unambiguous assignment of absolute configuration

DataSheet1_Neurodegeneration: can metabolites from Eremurus persicus help?.docx

The number of patients affected by neurodegenerative diseases is increasing worldwide, and no effective treatments have been developed yet. Although precision medicine could represent a powerful tool, it remains a challenge due to the high variability among patients. To identify molecules acting with innovative mechanisms of action, we performed a computational investigation using SAFAN technology, focusing specifically on HuD. This target belongs to the human embryonic lethal abnormal visual-like (ELAV) proteins and plays a key role in neuronal plasticity and differentiation. The results highlighted that the molecule able to bind the selected target was (R)-aloesaponol-III-8-methyl ether [(R)-ASME], a metabolite extracted from Eremurus persicus. Notably, this molecule is a TNF-α inhibitor, a cytokine involved in neuroinflammation. To obtain a suitable amount of (R)-ASME to confirm its activity on HuD, we optimized the extraction procedure. Together with ASME, another related metabolite, germichrysone, was isolated. Both ASME and germichrysone underwent biological investigation, but only ASME confirmed its ability to bind HuD. Given the multifactorial nature of neurodegenerative diseases, we decided to investigate ASME as a proteasome activator, being molecules endowed with this kind of activity potentially able to counteract aggregations of dysregulated proteins. ASME was able to activate the considered target both in enzymatic and cellular assays. Therefore, ASME may be considered a promising hit in the fight against neurodegenerative diseases.</p