Search Results (47)

Tocopheramines are a class of antioxidants which are distinguished from tocopherols (vitamin E) by the presence of an amino group instead of the phenolic hydroxyl group. α-Tocopheramine is intensively studied for biomedical applications but also as a stabilizer for synthetic and natural polymers, in particular for cellulose solutions and spinning dopes for cellulosic fibers. This study addresses a fundamental difference in the oxidation chemistry of α-tocopheramine and its tocopherol counterpart: while the formation of the ortho-quinone methide (o-QM) involving C-5a is one of the most fundamental reactions of α-tocopherol, the corresponding ortho-iminoquinone methide (o-IQM) derived from α-tocopheramine has been elusive so far. Synthesis of the transient intermediate succeeded initially via 5a-hydroxy-α-tocopheramine, and its occurrence was confirmed by dimerization to the corresponding spiro-dimer and by trapping with ethyl vinyl ether. Eventually, suitable oxidation conditions were found which allowed for the generation of the o-IQM directly from α-tocopheramine. The underlying oxidation chemistry of α-tocopherol and α-tocopheramine is concisely discussed. Full article

The regioselectivity and the molecular mechanism of the Diels–Alder reactions between N-(2,2,2-trichloroethylidene)carboxamides and dicyclohexylcarbodiimide were explored based on the ωB97xd/6-311G(d) (PCM) calculations. It was found that the reaction course is determined by polar local interactions. It is interesting that the most favored reaction channel is realized not via classical single-step Diels–Alder mechanism, but according to the stepwise scheme with the intervention of the zwitterionic intermediate. The details of the electron density redistribution along the reaction coordinate were explained using the ELF technique. Full article

Due to the importance of biaryls as natural products, drugs, agrochemicals, dyes, or organic electronic materials, a green alternative biaryl synthesis has been developed based on easy-to-prepare and cheap copper(I)-exchanged zeolite catalysts. Cu^I-USY proved to efficiently catalyze the direct homocoupling of either phenols or aryl boronic acids under simple and practical conditions. The Cu^I-USY-catalyzed oxidative homocoupling of phenols could conveniently be performed under air either in warm methanol or water with good to high yields. In methanol, a small amount of Cs₂CO₃ was required, while none was necessary in water. The homocoupling of aryl boronic acids was best performed also in warm methanol, without an additive. These mild conditions showed good functional-group tolerance, leading to a variety of substituted (hetero)biaryls (28 examples). The heterogeneous Cu^I-USY catalyst could readily be recovered and reused. Interestingly, the homocoupling of vinyl boronic acids was successfully coupled to a Diels–Alder reaction, even in a one-pot process, allowing access to highly functionalized cyclohexenes. Full article

The hetero-Diels–Alder (HDA) reaction between the ambident heterodiene 3-methylene-2,4-chromandione (MCDO) and non-symmetric methyl vinyl ether (MVE) is investigated using the molecular electron density theory (MEDT) at the B3LYP/6-311G(d,p) computational level. The aim of this study is to gain insight into its molecular mechanism and to elucidate the factors that control the selectivity found experimentally. DFT-based reactivity indices reveal that MCDO exhibits strong electrophilic characteristics, while MVE displays a strong nucleophilic character. Meanwhile, the Parr function explains the ortho regioselectivity of this HDA reaction. The highly polar nature of this HDA reaction, supported by the high global electron density transfer (GEDT) taking place at the transition state structures (TSs), accounts for the very low activation energy associated with the most favorable TS-4on. The ambident nature of MCDO allows for the formation of two constitutional isomeric cycloadducts. In the case of MVE, pseudocyclic selectivity is attained using a thermodynamic control. This polar HDA reaction displays an endo stereoselectivity and a complete ortho regioselectivity. A comparative relative interacting atomic energy (RIAE) analysis of the two diastereomeric structures TS-4on and TS-6on indicates a high degree of likeness, which explains the low pseudocyclic selectivity under kinetic control. Full article

The molecular mechanism of the reaction between 2-methoxyfuran and ethyl (Z)-3-phenyl-2-nitroprop-2-enoate was investigated using wb97xd/6-311+G(d,p)(PCM) quantum chemical calculations. It was found that the most probable reaction mechanism is fundamentally different from what was previously postulated. In particular, six possible zwitterionic intermediates were detected on the reaction pathway. Their formation is determined by the nature of local nucleophile/electrophile interactions. Additionally, the channel involving the formation of the exo-nitro Diels–Alder cycloadduct was completely ruled out. Finally, the electronic nature of the five- and six-membered nitronates as potential TACs was evaluated. Full article

In this paper, an alternative and efficient copper(I)-catalyzed synthesis of 2-sulfonyliminocoumarins is developed through a three-component reaction of ortho-hydroxybenzyl alcohol, alkynes, and p-toluenesulfonyl azide. The proposed route for access to the 2-iminocoumarin ring involves a [4 + 2] hetero-Diels-Alder reaction between ortho-quinone methide and ketenimine intermediates generated in situ. Full article

Radiolabeled peptides are valuable tools for diagnosis or therapies; they are often radiofluorinated using an indirect approach based on an F-18 prosthetic group. Herein, we are reporting our results on the F-18 radiolabeling of three peptides using two different methods based on click reactions. The first one used the well-known CuAAC reaction, and the second one is based on our recently reported hetero-Diels–Alder (HDA) using a dithioesters (thia-Diels–Alder) reaction. Both methods have been automated, and the ¹⁸F-peptides were obtained in similar yields and synthesis time (37–39% decay corrected yields by both methods in 120–140 min). However, to obtain similar yields, the CuAAC needs a large amount of copper along with many additives, while the HDA is a catalyst and metal-free reaction necessitating only an appropriate ratio of water/ethanol. The HDA can therefore be considered as a minimalist method offering easy access to fluorine-18 labeled peptides and making it a valuable additional tool for the indirect and site-specific labeling of peptides or biomolecules. Full article

An investigation of phenolic glycosides extracted from Salix germplasm revealed that arbusculoidin (benzyl 1-O-β-d-glucopyranosyl-1-hydroxy-6-oxo-2-cyclohexenyl carboxylate) and its enolic 6-glycoside isomer, isoarbusculoidin, are widespread across the Salix family. An analysis of natural hybrid species and progeny from a willow breeding programme demonstrated that the putative biosynthetic pathway leading to the salicinoid family of phenolic glycosides runs in parallel to a “benzyl”-based pathway to arbusculoidin. The introduction of a known Diels–Alder reaction trait from Salix dasyclados, as well as an acylation trait, into progeny containing both salicyl- and benzyl- pathways caused the formation of all possible hetero-cyclodimers from mixtures of reactive dienone (acyl)glycosides that participated in cross-over reactions. In addition to providing access to new analogues of the anti-cancer dimer miyabeacin, the analysis of the breeding progeny also indicated that these dienone (acyl)glycosides are stable in planta. Although the immediate biosynthetic precursors of these compounds remain to be defined, the results suggest that the (acyl)glycosylation reactions may occur later in the pathway than previously suggested by in vitro work on cloned UGT enzymes. Full article

Thiochalcones undergo cycloaddition reactions in THF solution at 60 °C with the synthetically unexplored 1-phenyl-4H-phosphinin-4-one 1-oxide in a highly regio- and stereoselective manner, yielding hitherto unknown bicyclic P,S-heterocycles containing fused thiopyran and phosphinine rings. The stereochemical structures of two of the obtained (4+2)-cycloadducts were unambiguously assigned by means of the X-ray single-crystal analysis. Based on these assignments, a concerted mechanism of the hetero-Diels–Alder reaction via the preferred endo approach of the heterodiene from the less hindered P=O side of the phosphininone molecule is postulated to explain the established rac-(4RS,8SR,9SR,10SR)-configured (4+2)-cycloadducts isolated as major products. Full article

This paper developed a method for preparing ultrasound-responsive microgels based on reversible addition fragmentation chain transfer-hetero Diels–Alder (RAFT-HAD) dynamic covalent bonding. First, a styrene cross-linked network was successfully prepared by a Diels–Alder (DA) reaction between phosphoryl dithioester and furan using double-ended diethoxyphosphoryl dithiocarbonate (BDEPDF) for RAFT reagent-mediated styrene (St) polymerization, with a double-ended dienophile linker and copolymer of furfuryl methacrylate (FMA) and St as the dienophile. Subsequently, the microgel system was constructed by the HDA reaction between phosphoryl disulfide and furan groups using the copolymer of polyethylene glycol monomethyl ether acrylate (OEGMA) and FMA as the dienophore building block and hydrophilic segment and the polystyrene pro-dienophile linker as the cross-linker and hydrophobic segment. The number of furans in the dienophile chain and the length of the dienophile linker were regulated by RAFT polymerization to investigate the effects of the single-molecule chain functional group degree, furan/dithioester ratio, and hydrophobic cross-linker length on the microgel system. The prepared microgels can achieve the reversible transformation of materials under force responsiveness, and their preparation steps are simple and adaptive to various potential applications in biomedical materials and adaptive electrical materials. Full article

The 1,8-Diazaanthracene-2,9,10-triones, their 5,8-dihydro derivatives, and 1,8-diazaanthracene-2,7,9,10-tetraones, structurally related to the diazaquinomycin family of natural products, were synthesized in a regioselective fashion employing Diels–Alder strategies. These libraries were studied for their cytotoxicity in a variety of human cancer cell lines in order to establish structure–activity relationships. From the results obtained, we conclude that some representatives of the 1,8-diazaanthracene-2,9,10-trione framework show potent and selective cytotoxicity against solid tumors. Similar findings were made for the related 1-azaanthracene-2,9,10-trione derivatives, structurally similar to the marcanine natural products, which showed improved activity over their natural counterparts. An enantioselective protocol based on the use of a SAMP-related chiral auxiliary derived was developed for the case of chiral 5-substituted 1,8-diazaanthracene-2,9,10-triones, and showed that their cytotoxicity was not enantiospecific. Full article

The 5,8-disubstituted indolizidines are the largest family of indolizidines isolated from the skin of amphibians. These compounds exhibit interesting biological activities such as noncompetitive blockers of nicotinic receptors. In this paper, we present a short, simple, and general synthesis of these alkaloids based on the hetero Diels–Alder reaction between suitable monoactivated dienes and Δ¹-pyrroline as the dienophile. The selectivity of the process is explained based on computational studies. Concise synthesis of the indolizidine alkaloid 181B from a hetero Diels–Alder reaction was accomplished in four steps. Full article

Acyl(imidoyl)ketenes are highly reactive heterocumulenes that enable diversity-oriented synthesis of various drug-like heterocycles. Such ketenes, bearing heterocyclic substituents, afford angularly fused pyridin-2(1H)-ones in their [4+2]-cyclodimerization reactions. We have utilized this property for the development of a new synthetic approach to pharmaceutically interesting pyrido[2,1-b][1,3]benzothiazol-1-ones via the [4+2]-cyclodimerization of acyl(1,3-benzothiazol-2-yl)ketenes generated in situ. The thermal behaviors of 3-aroylpyrrolo[2,1-c][1,4]benzothiazine-1,2,4-triones and 3-benzoylpyrrolo[2,1-b][1,3]benzothiazole-1,2-dione (two new types of [e]-fused 1H-pyrrole-2,3-diones reported by us recently) have been studied by thermal analysis and HPLC to elucidate their capability to be a source of acyl(1,3-benzothiazol-2-yl)ketenes. As a result, we have found that only 3-aroylpyrrolo[2,1-c][1,4]benzothiazine-1,2,4-triones are suitable for this. The experimental results are supplemented with computational studies that demonstrate that thermolysis of 3-aroylpyrrolo[2,1-c][1,4]benzothiazine-1,2,4-triones proceeds through an unprecedented cascade of two thermal decarbonylations. Based on these studies, we discovered a novel mode of thermal transformation of [e]-fused 1H-pyrrole-2,3-diones and developed a new pot, atom, and step economic synthetic approach to pyrido[2,1-b][1,3]benzothiazol-1-ones. The synthesized drug-like pyrido[2,1-b][1,3]benzothiazol-1-ones are of interest to pharmaceutics, since their close analogs show significant antiviral activity. Full article

Hetero Diels-Alder (HDA) reactions with the participation of E-2-aryl-1-cyano-1-nitroethenes and methylenecyclopentane were evaluated on the basis of experimental as well as quantumchemical data. It was found that contrary to most known HDA reactions, title processes are realised under non-catalytic conditions and with full regiocontrol. The DFT study shows, without any doubt, the polar but single-step reaction mechanism. Deeper exploration using Bonding Evolution Theory (BET) techniques gives a clear image of the sequences of electron density reorganisation along the reaction coordinate. The first C4-C5 bond is created in phase VII by merging two monosynaptic basins, while the second O1-C6 bond is created in the last phase by a donation of the nonbonding electron density of O1 to C6. Based on the research, we can conclude that the analysed reaction proceeds according to a two-stage one-step mechanism. Full article

In the current literature, many non-covalent interaction (NCI) donors have been proposed that can potentially catalyze Diels-Alder (DA) reactions. In this study, a detailed analysis of the governing factors in Lewis acid and non-covalent catalysis of three types of DA reactions was carried out, for which we selected a set of hydrogen-, halogen-, chalcogen-, and pnictogen-bond donors. We found that the more stable the NCI donor–dienophile complex, the larger the reduction in DA activation energy. We also showed that for active catalysts, a significant part of the stabilization was caused by orbital interactions, though electrostatic interactions dominated. Traditionally, DA catalysis was attributed to improved orbital interactions between the diene and dienophile. Recently, Vermeeren and co-workers applied the activation strain model (ASM) of reactivity, combined with the Ziegler-Rauk-type energy decomposition analysis (EDA), to catalyzed DA reactions in which energy contributions for the uncatalyzed and catalyzed reaction were compared at a consistent geometry. They concluded that reduced Pauli repulsion energy, and not enhanced orbital interaction energy, was responsible for the catalysis. However, when the degree of asynchronicity of the reaction is altered to a large extent, as is the case for our studied hetero-DA reactions, the ASM should be employed with caution. We therefore proposed an alternative and complementary approach, in which EDA values for the catalyzed transition-state geometry, with the catalyst present or deleted, can be compared one to one, directly measuring the effect of the catalyst on the physical factors governing the DA catalysis. We discovered that enhanced orbital interactions are often the main driver for catalysis and that Pauli repulsion plays a varying role. Full article