Giulia Mazzoccanti

A study on the amino acid‐mediated intramolecular cyclization of diketoaldehyde 2 to form bicyclic ketocarbaldehyde 1, a potentially useful intermediate in the synthesis of some polycyclic diterpenes, is hereafter presented. This cyclization exhibits a peculiar enantio‐selectivity if compared to similar intramolecular cyclizations due to its product being the (S)‐enantiomer when using d‐amino acids. Our findings reveal that the transformation proceeds through two irreversible steps: the cyclization and the subsequent dehydration process. The reaction enantiomeric excess (e.e.) was optimized by systematically varying the amino acids, solvents, and acids used. Aldol intermediates were successfully isolated. The structure of the most abundant one was confirmed by X‐ray analysis, which supported the proposed reaction mechanism. NMR and MS were employed to monitor in real‐time the formation and the evolution of these intermediates. This approach allowed us to detect the key species that contribute to the enantioselectivity and yield of the final product. Additionally, the transition state energies associated with the formation of the eight possible aldol intermediates were examined through computational studies, further elucidating the mechanistic pathway of this enantioselective cyclization.

1,2-Diphenylethylenediamine (DPEDA) is a privileged chiral scaffold being used in the construction of a broad variety of organocatalysts and ligands for enantioselective organic reactions. This molecule gave a significant contribution in the synthesis of structurally different bi/multifunctional organocatalysts. DPEDA played an essential role in the development of organocatalysts capable of yielding important information on the different reaction mechanisms, like enamine, iminium, hydrogen-bonding and anion-binding catalysis. The aim of the present review is to highlight and summarize the achievements reached in the last 20 years (2004–2024) in the chemistry of DPEDA-based organocatalysts for asymmetric synthesis.

The optical purity of cannabichromene (CBC, 1a) is affected by the matrix in which it is generated by thermolysis from its native carboxylated form (cannabichromenic acid, CBCA, 1b). Thus, thermolysis at 130 °C in planta caused a marked decrease of the enantiomeric excess (ee), while, under the same conditions, only a modest decrease of optical purity was observed when thermolysis was carried out in extracto. To rationalize these puzzling observations, the kinetics of thermal (100 °C) racemization of enantiopure cannabichromene (1a) was evaluated by enantioselective ultrahigh performance liquid chromatography in solvents (decalin and isopropyl alcohol, neat and acidified with TFA) and surfaces (native and silanized borosilicate glass) of complementary polarity. Optical stability was more than halved in isopropanol compared to decalin (t_1/2 50 h vs 135 h), but acidification had no effect on racemization. However, contact with a solid surface dramatically accelerated the process, with a t_1/2 of only 6 h on both glass surfaces. The overall extent of racemization of enantiopure CBC (1a) was compared under conditions commonly used for decarboxylation (heating at 130 °C) between a decalin solution and a thin film on three different surfaces (native and silanized borosilicate glass and powdered blank cannabis biomass). In line with the kinetic data, a significant erosion of enantiopurity was observed on all solid surfaces compared to the solution. These observations suggest that discrepancies in the reported enantiomeric purity of natural CBC could be not only of biogenetic derivation but also be associated with the decarboxylation protocol of cannabichromenic acid (1b). These findings, while relevant for the exploitation of the bioactivity of natural CBC for human health, should also prompt the adoption of a standardized decarboxylation protocol for the studies on the configurational status of CBC (1a) in cannabis and, in general, of cannabinochromanoids in nature.

Two different types of chiral stationary phases, based on Pirkle's design, were created by attaching chiral selectors to 3‐mercapto silica gel. To prepare the enantiomeric selectors, 3,5‐dinitrobenzoyl and naphthyl groups were sequentially added to a chiral 1,2‐diaminocyclohexane core. The chiral selectors demonstrated enantioselectivity towards ibuprofen enantiomers in solution, as confirmed by ¹H NMR spectroscopy, and in initial HPLC testing, the enantiomeric selectors showed enantioselectivity for selected racemic solutes (viz., α = 1.27 for1,1′‐bi‐(2‐naphthol)). Molecular docking studies revealed that the chiral selectors had a bent structure and a cleft‐like cavity where the analyte could be held during complexation while establishing H‐bonding and π–π stacking interactions.

SARS-CoV-2 and HCoV-OC43 belong to the same β genus of the Coronaviridae family. SARS-CoV-2 was responsible for the recent COVID-19 pandemic, and HCoV-OC43 is the etiological agent of mild upper respiratory tract infections. SARS-COV-2 and HCoV-OC43 co-infections were found in children with respiratory symptoms during the COVID-19 pandemic. The two β-coronaviruses share a high degree of homology between the 3CLpro active sites, so much so that the safer HCoV-OC43 has been suggested as a tool for the identification of new anti-SARS-COV-2 agents. Compounds 5 and 24 inhibited effectively both Wuhan and British SARS-CoV-2 patient isolates in Vero E6 cells and the HCoV-OC43 in MRC-5 cells at low micromolar concentrations. The inhibition was apparently exerted via targeting the 3CLpro active sites of both viruses. Compounds 5 and 24 at 100 μM inhibited the SARS-CoV-2 3CLpro activity of 61.78 and 67.30%, respectively. These findings highlight 5 and 24 as lead compounds of a novel class of antiviral agents with the potential to treat SARS-COV-2 and HCoV-OC43 infections.

The absolute configuration of three chiral eugenol derivatives was assigned by a multi‐step methodology based on enantioselective HPLC combined with spectroscopic and theoretical calculations. Milligram amounts of enantiopure forms used for stereochemical characterization were isolated by HPLC on the immobilized amylose‐based chiral stationary phase Chiralpak IG using normal phase elution conditions. The absolute configuration was indirectly determined for one of the three compounds by ¹H NMR via methoxy‐α‐trifluoromethyl‐α‐phenylacetic acid derivatization (Mosher's acid). Comparison of the experimental and predicted electronic circular dichroism spectra confirmed the stereochemical assignment by Mosher's method and extended the absolute configuration assignment to two other chiral compounds.

A novel C3‐symmetric multi–amino catalyst was synthesized and evaluated in the asymmetric Michael addition to produce warfarin and its analogues. The multi–amino catalyst turned out to be efficient up to 1 % molar without the use of acidic additives providing the desired product in 82 % yield and maintaining good level of enantioselectivity. ESI‐MS experiments together with data supplied by theoretical models allowed us the understand the operating mechanism of the catalyst, clarifying the role of the amine functions and confirming the catalyst's multifunctionality. The presence of three active catalytic sites makes it easy its anchoring to silica as solid support for applications in heterogeneous phase catalysis.