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Sesquitepenoids inuloxins A-D, belonging to different subgroups, were isolated from Dittrichia viscosa and showed potential biocontrol of some parasitic plants as Pelipanche, Orobanche, and Cuscuta species. The absolute configurations of the first three inuloxins A-C were previously determined by using experimental and computational chiroptical spectroscopic methods. The absolute configuration of inuloxin D remains to be established. The bioactive inuloxin E, closely related to inuloxin D, was recently isolated from the same plant organic extract. The same relative configuration of inuloxin D was assigned to inuloxin E by comparison of their NMR spectroscopic data. The absolute configurations of inuloxin D and inuloxin E are suggested in this work by analysis of the experimental and predicted chiroptical properties of the 4-O-acetyl derivative of inuloxin D.

The application of flexible biphenyls as chiroptical probes for the absolute configuration assignment to chiral natural products is described. The method is straightforward and reliable and can be applied to conformationally mobile and ECD silent compounds, not treatable by computational analysis of chiroptical data. By this approach, the (6′R) absolute configuration of the phytotoxin colletochlorin A (1) was confirmed, while the absolute configuration of the phytotoxin agropyrenol (2), previously assigned by the NMR Mosher method, was revised and assigned as (3′S,4′S). Moreover, with the biphenyl method the configurational assignment can be obtained simply by the sign of a diagnostic Cotton effect at 250 nm in the ECD spectrum, thus allowing application without the need of advanced knowledge of chiroptical spectroscopy and computational protocols.

The organic extract of the aerial parts of Dittrichia viscosa, a perennial native plant of the Mediterranean basin, showed a significant acaricidal activity against Varroa destructor, the parasite mite of Apis mellifera, commonly called honey bee. Among the metabolites isolated from the organic extract of this Asteraceae, α-costic acid showed to be one of the compounds responsible for the toxic activity exhibited by the crude plant extract on this parasite mite species. In addition to the toxic effect a clear acaricidal response has been recorded when the parasitic mite was exposed to 1 mg/mL concentration of α-costic acid while no effects have been showed on honey bees using the same compound at the same concentration. This finding suggests a potential use of α-costic acid to control Varroa mites. The possibility to reliably achieve absolute configuration of α-costic acid by DFT computational analysis of chiroptical spectra has been also demonstrated.†

Oxadiazolo[3,4-c][1,4]thiazin-3-ones are cardiovascular agents that block L-type calcium channels. Previous data of cardiac and vasorelaxant activity on guinea-pig for several derivatives indicated the two positions ortho to the thiazine's sulphur as crucial for modulating the activity; but these positions are likely susceptible to metabolic biotransformations, as indicated by in silico predictions. We designed new derivatives, and obtained three negative inotropic agents with EC50 in the low nanomolar range, more potent than all the precursors published so far. In particular, benzocondensation at the thiazine ring led to 3a (EC50 = 0.013 μM) and 3b (EC50 = 0.006 μM). Besides negative inotropy, we also observed relaxant activity on nonvascular muscle in the micromolar range. We resolved the new derivatives by chiral chromatography, and determined their absolute configuration by comparing experimental and calculated chiroptical properties (VCD, ECD and ORD): they hold the same absolute configuration-optical rotation relationship, (S)-(+)/(R)-(−). Both cardiac and nonvascular activity are majorly or mostly retained in the R-form for all the compounds, but for the nonvascular activity we observed a strong stereoselectivity for 3a, with the R-form in the nanomolar range (IC50 = 0.020 μM) and 259-fold more potent than the S-one.

We describe an effective oxidation of diltiazem (DTZ)-like molecules (a class of prochiral sulfides with potential pharmacological properties) using m-chloroperbenzoic acid (MCPBA) as oxidant either in dichloromethane or methanol. An excellent diastereomeric excess of one sulfoxide has been observed “in the absence of any chiral auxiliary”. The stereochemistry of the two diastereomeric sulfoxides has been determined by TDDFT simulations of the experimental electronic circular dichroism (ECD) spectra. A computational DFT study of the reaction mechanism shows that the attack of MCPBA on the two sulfide enantiotopic faces affords two preliminary complexes M1 and M1′. M1 is more stable than M1′ by 3.3 and 3.5 kcal mol−1 in dichloromethane and methanol, respectively, and after equilibration its population must be dominant. Two diastereomeric pathways originate from M1 and M1′ and give two diastereomeric sulfoxides with R and S configurations at the new chiral sulfur, respectively. Since TS (the transition state originating from M1) is more stable than TS′ (the energy gap is 0.7 kcal mol−1 in dichloromethane or methanol), following the Curtin–Hammett principle, the favoured path is the pro-R channel (M1→TS→M2) affording the (Rc,Rs)-2a′ product species in agreement with the observed diastereoselectivity. The M1–M1′ and TS–TS′ energy gaps are actually determined by the difference in the hydrogen bond network that features the two species even if the approaching orientation of the two molecules is governed by the interactions between the π systems of oxidant and substrate aromatic rings. The diastereomeric ratio computed on the basis of the energy difference between TS and TS′ (0.7 kcal mol−1) is 63:37, which must be compared to the experimental value 9:1. When we consider free energy differences (2.4 kcal mol−1 in vacuum and 2.9 kcal mol−1 in solution) this theoretical ratio becomes 85:15 and 89:11, respectively, in excellent agreement with the experimental value 9:1.