Search Results (23)

Hydroxymethyl 1,3-diol motifs are common structural motifs in natural products, particularly in polypropionates with important therapeutic potential. However, general and complementary methods for their regio- and diastereoselective synthesis remain limited. In this study, we expanded a second-generation epoxide-based methodology involving the regioselective cleavage of TIPS-monoprotected cis- and trans-2,3-epoxy alcohols using alkenyl Grignard reagents. Regioselective ring opening of cis-epoxides provided anti-1,3-diols, while trans-epoxides afforded the corresponding syn-1,3-diols. The use of cis-propenylmagnesium bromide and vinyl Grignard reagents enabled direct access to cis- and terminal homoallylic 1,3-diols, respectively, with moderate to good yields (46–88%) and excellent regioselectivities (95:5). In contrast, reactions with trans-propenyl Grignard reagent led to partial alkene isomerization, limiting their synthetic utility. To address this, a complementary two-step approach employing propynyl alanate addition followed by sodium/ammonia reduction was incorporated, providing access to trans-homoallylic 1,3-diols with high diastereoselectivity. All 1,3-diols were characterized by NMR spectroscopy, confirming regioselective epoxide opening. These combined strategies offer a practical and modular platform for the synthesis of syn- and anti-hydroxymethylated 1,3-diols and their application to the construction of polypropionate-type fragments, supporting future efforts in the total synthesis of polyketide natural products. Full article

Biliverdin IXβ reductase (BLVRB) has emerged as a promising therapeutic target for thrombocytopenia due to its involvement in reactive oxygen species (ROS) mechanisms. During the pursuit of inhibitors targeting BLVRB, olsalazine (OSA) became apparent as one of the most potent candidates. However, the direct application of OSA as a BLVRB inhibitor faces challenges, as it is prone to degradation into 5-aminosalicylic acid through cleavage of the diazenyl bond by abundant azoreductase (AzoR) enzymes in gut microbiota and eukaryotic cells. To overcome this obstacle, we devised olsalkene (OSK), an inhibitor where the diazenyl bond in OSA has been substituted with an alkene bond. OSK not only matches the efficacy of OSA but also demonstrates improved stability against degradation by AzoR, presenting a promising solution to this limitation. Furthermore, we have found that both OSK and OSA inhibit BLVRB, regardless of the presence of nicotinamide adenine dinucleotide phosphate, unlike other known inhibitors. This discovery opens new avenues for investigating the roles of BLVRB in blood disorders, including thrombocytopenia. Full article

Studies have shown that the incorporation of fluorine into materials can improve their properties, but C–F bonds are not readily formed in nature. Although some researchers have studied the reaction of fluorinating alkenes catalyzed by hypervalent iodine, far too little attention has been paid to its reaction mechanism. This study aimed to explore the mechanism of the hypervalent iodine-catalyzed 1,4-difluorination of dienes. We found that the catalyst is favorable for the activation of C1=C2 double bonds through halogen bonds, and then two HFs interact with one F atom in the catalyst via hydrogen bonds, resulting in the cleavage of I–F bonds and the formation of [F–H∙∙∙F]⁻. Subsequently, the catalyst interacts with C1, and the roaming [F–H···F]⁻ attacks C4 from the opposite side of the catalyst. After the fluorination step is completed, the nucleophile F⁻ substitutes the catalyst via the S_N2 mechanism. Our calculations demonstrated that the interaction between HF and F⁻ is favorable for the stabilization of the transition state within the fluorination process for which the presence of two HFs in the reaction is the best. We also observed that [F–H∙∙∙F]⁻ attacking C4 from the opposite side of the catalyst is more advantageous than attacking from the same side. This study therefore offers a novel perspective on the mechanism of the hypervalent iodine-catalyzed fluoridation of dienes. Full article

Density functional theory (DFT) characterizations were employed to resolve the structural and energetic aspects and product selectivities along the mechanistic reaction paths of the nickel-catalyzed three-component unsymmetrical bis-allylation of alkynes with alkenes. Our putative mechanism initiated with the in situ generation of the active catalytic species [Ni(0)L₂] (L = NHC) from its precursors [Ni(COD)₂, NHC·HCl] to activate the alkyne and alkene substrates to form the final skipped trienes. This proceeds via the following five sequential steps: oxidative addition (OA), β-F elimination, ring-opening complexation, C-B cleavage and reductive elimination (RE). Both the OA and RE steps (with respective free energy barriers of 24.2 and 24.8 kcal·mol⁻¹) contribute to the observed reaction rates, with the former being the selectivity-controlling step of the entire chemical transformation. Electrophilic/nucleophilic properties of selected substrates were accurately predicted through dual descriptors (based on Hirshfeld charges), with the chemo- and regio-selectivities being reasonably predicted and explained. Further distortion/interaction and interaction region indicator (IRI) analyses for key stationary points along reaction profiles indicate that the participation of the third component olefin (allylboronate) and ^tBuOK additive played a crucial role in facilitating the reaction and regenerating the active catalyst, ensuring smooth formation of the skipped triene product under a favorably low dosage of the Ni(COD)₂ catalyst (5 mol%). Full article

Previous biomimetic studies clearly proved that equatorial ligands significantly influence the redox potential and thus the stability/reactivity of biologically important oxoiron intermediates; however, no such studies were performed on Fe^IIIOIPh species. In this study, the influence of substituted pyridine co-ligands on the reactivity of iron(III)-iodosylbenzene adduct has been investigated in sulfoxidation and epoxidation reactions. Selective oxidation of thioanisole, cis-cyclooctene, and cis- and trans-stilbene in the presence of a catalytic amount of [Fe^II(PBI)₃](OTf)₂ with PhI(OAc)₂ provide products in good to excellent yields through an Fe^IIIOIPh intermediate depending on the co-ligand (4R-Py) used. Several mechanistic studies were performed to gain more insight into the mechanism of oxygen atom transfer (OAT) reactions to support the reactive intermediate and investigate the effect of the equatorial co-ligands. Based on competitive experiments, including a linear free-energy relationship between the relative reaction rates (logk_rel) and the σ_p (4R-Py) parameters, strong evidence has been observed for the electrophilic character of the reactive species. The presence of the [(PBI)₂(4R-Py)Fe^IIIOIPh]³⁺ intermediates and the effect of the co-ligands was also supported by UV-visible measurements, including the color change from red to green and the hypsochromic shifts in the presence of co-ligands. This is another indication that the title iron(III)-iodosylbenzene adduct is able to oxygenate sulfides and alkenes before it is transformed into the oxoiron form by cleavage of the O−I bond. Full article

The mechanisms of sulfoxidation and epoxidation mediated by previously synthesized and characterized iron(III)-iodosylbenzene adduct, Fe^III(OIPh) were investigated using para-substituted thioanisole and styrene derivatives as model substrates. Based on detailed kinetic reaction experiments, including the linear free-energy relationships between the relative reaction rates (logk_rel) and the σ_p (4R-PhSMe) with ρ = −0.65 (catalytic) and ρ = −1.13 (stoichiometric), we obtained strong evidence that the stoichiometric and catalytic oxidation of thioanisoles mediated by Fe^III(OIPh) species involves direct oxygen transfer. The small negative slope −2.18 from log k_obs versus E_ox for 4R-PhSMe gives further clear evidence for the direct oxygen atom transfer mechanism. On the contrary, with the linear free-energy relationships between the relative reaction rates (logk_rel) and total substituent effect (TE, 4R-PhCHCH₂) parameters with slope = 0.33 (catalytic) and 2.02 (stoichiometric), the stoichiometric and catalytic epoxidation of styrenes takes place through a nonconcerted electron transfer (ET) mechanism, including the formation of the radicaloid benzylic radical intermediate in the rate-determining step. On the basis of mechanistic studies, we came to the conclusion that the title iron(III)-iodosylbenzene complex is able to oxygenate sulfides and alkenes before it is transformed into the oxo-iron form by cleavage of the O−I bond. Full article

Piperonal is a compound of key industrial importance due to its attractive olfactory and biological properties. It has been shown that among the fifty-six various fungal strains tested, the ability to cleave the toxic isosafrole into piperonal through alkene cleavage is mainly found in strains of the genus Trametes. Further studies involving strains isolated directly from different environments (decaying wood, fungal fruiting bodies, and healthy plant tissues) allowed the selection of two Trametes strains, T. hirsuta Th2_2 and T. hirsuta d28, as the most effective biocatalysts for the oxidation of isosafrole. The preparative scale of biotransformation with these strains provided 124 mg (conv. 82%, isolated yield 62%) and 101 mg (conv. 69%, isolated yield 50.5%) of piperonal, respectively. Due to the toxic impact of isosafrole on cells, preparative scale processes with Trametes strains have not yet been successfully performed and described in the literature. Full article

The experimental studies on the thermal properties and decomposition course of a novel class of potential anticancer drugs (1–5) containing in their heterobicyclic structures the asymmetrical triazine template were performed with the use of differential scanning calorimetry (DSC) and simultaneous thermogravimetry/differential scanning calorimetry (TG/DTG/DSC) coupled online with Fourier transform infrared spectroscopy (FTIR) and quadrupole mass spectrometry (QMS) in inert and oxidizing conditions. All the compounds were thermally characterized in detail for the first time in this article. The DSC studies proved that the melting points of the tested compounds depended on the position and type of the substituent at the phenyl moiety, whereas they did not depend on the furnace atmosphere. All the tested polynitrogenated heterocycles proved to be molecules with high thermal stability in both atmospheres, and most of them (1, 3–5) were more stable in oxidizing conditions, which indicated the formation of a more thermally stable form of the compounds when interacting with oxygen. The simultaneous TG/FTIR/QMS analyses confirmed that their pyrolysis process occurred in one main stage resulting in the emission of volatiles such as NH₃, HNCO, HCN, CO, CO₂, H₂O, NO₂, aromatic amine derivatives, alkenes (for compounds 1–5), and HCl (for the compound 5). On the other hand, the oxidative decomposition process was more complicated and proceeded in two main stages leading to the emission of NH₃, CO₂, CO, HCN, HNCO, H₂O, some aromatics (for compounds 1–5), HCl (for compounds 3–5) as well as the additional volatiles such as N₂, NO₂, NH₂OH, and (CN)₂. The type of the formed volatiles indicated that the decomposition process of the studied heterocycles under the influence of heating was initiated by the radical mechanism. Their decomposition was related to the symmetric cleavage of C–N and C–C bonds (inert conditions) and additional reaction of the volatiles and residues with oxygen (oxidizing conditions). Full article

The molecular mechanisms of three intramolecular rearrangements (I, the rearrangement of allyloxycycloheptatriene to yield tricyclic ketones; II, the cycloaddition of a nitrone-alkene to render two tricyclic isoxazolidines; and III, the decomposition of N-carbamoyl-L-proline in tetrahydro-1H-pyrrolo[1,2-c]imidazole-1,3(2H)-dione plus water, or tetrahydro-1H,3H-pyrrolo[1,2-c]oxazole-1,3-dione plus ammonia) have been studied by means of the bonding evolution theory (BET). The thermal rearrangement I is composed by a sigmatropic rearrangement coupled to an intramolecular Diels–Alder reaction. The sigmatropic reaction comprises four steps: (1) rupture of an O-C single chemical bond, (2) transformation of a C-O single to double bond, (3) creation of pseudo-radical centers on carbon atoms coupled with a double C-C bond evolving to single and the other C-C double bond migration, and (4) formation of the new C-C single bond. For the Diels–Alder reaction, the process can be described as an initial formation of up to four monosynaptic V(C) basins in two successive steps, coupled with the loss of the double bond character of the three initial double bonds, followed by the consecutive formation of two new C-C bonds, with the new double C-C bond formation sensed in between the formation of the first and the second C-C bonds. For reaction II, the bond forming process is described by the depopulation of N-C and C-C double bonds with the creation of a V(N) and two V(C) monosynaptic basins, followed by an O-C and C-C bond-forming processes via the creation of V(O,C) and V(C,C) disynaptic basins. Finally, for the thermal decomposition III, the reaction mechanism for the water elimination takes place in four events which can be summarized as follows: (1) the depopulation of V(N) with the formation of C-N, (2) the rupture of the C-O bond with transfer of its population to V(O), (3) the restoration of an N nitrogen lone pair via H-N bond cleavage, and (4) the formation of O-H illustrating the water molecule release. For the case of deamination, the events (1) and (2) correspond to the breaking and forming process of H-O and H-N bonds, respectively, while last events deal with the C-O bond formation and the elimination of the NH₃ molecule. Full article

The creation of new bonds via C-F bond cleavage of readily available per- or oligofluorinated compounds has received growing interest. Using such a strategy, a myriad of valuable partially fluorinated products can be prepared, which otherwise are difficult to make by the conventional C-F bond formation methods. Visible light photoredox catalysis has been proven as an important and powerful tool for defluorinative reactions due to its mild, easy to handle, and environmentally benign characteristics. Compared to the classical C-F activation that proceeds via two-electron processes, radicals are the key intermediates using visible light photoredox catalysis, providing new modes for the cleavage of C-F bonds. In this review, a summary of the visible light-promoted C-F bond cleavage since 2018 was presented. The contents were classified by the fluorosubstrates, including polyfluorinated arenes, gem-difluoroalkenes, trifluoromethyl arenes, and trifluoromethyl alkenes. An emphasis is placed on the discussion of the mechanisms and limitations of these reactions. Finally, my personal perspective on the future development of this rapidly emerging field was provided. Full article

We have developed a photochemical ATRA/ATRC reaction that is mediated by halogen bonding interactions. This reaction is caused by the reaction of malonic acid ester derivatives containing bromine or iodine with unsaturated compounds such as alkenes and alkynes in the presence of diisopropylethylamine under visible light irradiation. As a result of various control experiments, it was found that the formation of complexes between amines and halogens by halogen-bonding interaction occurs in the reaction system, followed by the cleavage of the carbon–halogen bonds by visible light, resulting in the formation of carbon radicals. In this reaction, a variety of substrates can be used, and the products, cyclopentenes and cyclopentanes, were obtained by intermolecular addition and intramolecular cyclization. Full article

The basidiomycete Pleurotus sapidus produced a dye-decolorizing peroxidase (PsaPOX) with alkene cleavage activity, implying potential as a biocatalyst for the fragrance and flavor industry. To increase the activity, a daughter-generation of 101 basidiospore-derived monokaryons (MK) was used. After a pre-selection according to the growth rate, the activity analysis revealed a stable intraspecific variability of the strains regarding peroxidase and alkene cleavage activity of PsaPOX. Ten monokaryons reached activities up to 2.6-fold higher than the dikaryon, with MK16 showing the highest activity. Analysis of the PsaPOX gene identified three different enzyme variants. These were co-responsible for the observed differences in activities between strains as verified by heterologous expression in Komagataella phaffii. The mutation S371H in enzyme variant PsaPOX_high caused an activity increase alongside a higher protein stability, while the eleven mutations in variant PsaPOX_low resulted in an activity decrease, which was partially based on a shift of the pH optimum from 3.5 to 3.0. Transcriptional analysis revealed the increased expression of PsaPOX in MK16 as reason for the higher PsaPOX activity in comparison to other strains producing the same PsaPOX variant. Thus, different expression profiles, as well as enzyme variants, were identified as crucial factors for the intraspecific variability of the PsaPOX activity in the monokaryons. Full article

The synthesis of a molecularly diverse library of tetrasubstituted alkenes containing a barbiturate motif is described. Base-induced condensation of N¹-substituted pyrimidine-2,4,6(1H,3H,5H)-triones with 5-(bis(methylthio)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione gave 3-substituted 5-(methylthio)-2H-pyrano[2,3-d]pyrimidine-2,4,7(1H,3H)-triones (‘pyranopyrimidinones’), regioselectively. A sequence of reactions involving ring-opening of the pyran moiety, displacement of the methylthio group with an amine, re-formation of the pyran ring, and after its final cleavage with an amine, gave tetrasubstituted alkenes (3-amino-3-(2,4,6-trioxotetrahydropyrimidin-5(2H)-ylidene)propanamides) with a diversity of substituents. Cleavage of the pyranopyrimidinones with an aniline was facilitated in 2,2,2-trifluoroethanol under microwave irradiation. Compounds were tested against Escherichia coli, Staphylococcus aureus, the yeast Schizosaccharomyces pombe, and the pathogenic fungus Candida albicans. No compounds exhibited activity against E. coli, whilst one compound was weakly active against S. aureus. Three compounds were strongly active against S. pombe, but none was active against C. albicans. Full article

We report studies on radical-initiated fragmentations of model 1,5-dideoxyhomoribofuranose derivatives with bromo, chloro, and tosyloxy substituents on C2. The effects of stereochemical inversion at C2 were probed with the corresponding arabino epimers. In all cases, the elimination of bromide, chloride, and tosylate anions occurred when the 3-hydroxyl group was unprotected. The isolation of deuterium-labeled furanone products established heterolytic cleavage followed by the transfer of deuterium from labeled tributylstannane. In contrast, 3-O-methyl derivatives underwent the elimination of bromine or chlorine radicals to give the 2,3-alkene with no incorporation of label in the methyl vinyl ether. More drastic fragmentation occurred with both of the 3-O-methyl-2-tosyloxy epimers to give an aromatized furan derivative with no deuterium label. Contrasting results observed with the present anhydroalditol models relative to our prior studies with analogously substituted nucleoside models have demonstrated that insights from biomimetic chemical reactions can provide illumination of mechanistic pathways employed by ribonucleotide reductases (RNRs) and the MoaA enzyme involved in the biosynthesis of molybdopterin. Full article

Alkene cleavage is a possibility to generate aldehydes with olfactory properties for the fragrance and flavor industry. A dye-decolorizing peroxidase (DyP) of the basidiomycete Pleurotus sapidus (PsaPOX) cleaved the aryl alkene trans-anethole. The PsaPOX was semi-purified from the mycelium via FPLC, and the corresponding gene was identified. The amino acid sequence as well as the predicted tertiary structure showed typical characteristics of DyPs as well as a non-canonical Mn²⁺-oxidation site on its surface. The gene was expressed in Komagataella pfaffii GS115 yielding activities up to 142 U/L using 2,2′-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid) as substrate. PsaPOX exhibited optima at pH 3.5 and 40 °C and showed highest peroxidase activity in the presence of 100 µM H₂O₂ and 25 mM Mn²⁺. PsaPOX lacked the typical activity of DyPs towards anthraquinone dyes, but oxidized Mn²⁺ to Mn³⁺. In addition, bleaching of β-carotene and annatto was observed. Biotransformation experiments verified the alkene cleavage activity towards the aryl alkenes (E)-methyl isoeugenol, α-methylstyrene, and trans-anethole, which was increased almost twofold in the presence of Mn²⁺. The resultant aldehydes are olfactants used in the fragrance and flavor industry. PsaPOX is the first described DyP with alkene cleavage activity towards aryl alkenes and showed potential as biocatalyst for flavor production. Full article