On the Valorisation of Chitin-Derived Furans by Milling.

Chitin-derived furans offer a sustainable alternative feedstock for nitrogen appended aromatic compounds. Herein, we address the challenge of using chitin-derived furans, 3-acetamido-5-acetylfuran (3A5AF) and 3-acetamido-5-furfural aldehyde (3A5F), to favour the formation of exo Diels-Alder adducts and 4­acetylaminophthalimides respectively, using a mechanochemical ball-milling technique. Mechanochemical activation is explored through the synthesis of 7-oxa-norbornene backbones with novel substitution pattern from 3A5AF in yields up to 77% and improved exo:endo selectivity compared to solution-phase reactions. The synthesis of 4­acetylaminophthalimides from 3A5F in yields up to 79% is also showcased from hydrazone derivatives.

Synthesis and antitumoral evaluation of natural product-like compounds based on tropolone and benzotropolone derivatives.

We present the preparation of a series of novel natural product-like homobarrelenones, norcaranes, and dihydrofluorenones through a diversity-oriented synthetic (DOS) strategy that combines Diels-Alder reactions and phototransformations, as well as their biological evaluation against MCF-7, HT-29, and NCI-H460 human tumor cells. Six of these demonstrated activities in the micromolar range against the three cell lines, and none were predicted as cytotoxic against human nontumor cells according to in silico studies. In addition, within the set of active derivatives, three exhibited low unspecific cytotoxicity in a sperm motility assay. The rich functionality of the new compounds makes them ideal candidates for exhaustive structure-activity relationship studies.

Energetics and electronics of polar Diels-Alder reactions at the atomic level: QTAIM and IQA analyses of complete IRC paths.

The mechanism of Diels-Alder reactions between cyclopentadiene and several cyanoethylenes was studied by means of Density Functional Theory calculations using QTAIM and IQA (Interacting Quantum Atoms) analyses along complete IRC paths. Each geometry from the IRC had its wavefunction computed and the topology of the electronic density for it was then evaluated. By means of IQA, the global energetic profile was partitioned among the various atoms in the molecule, providing insight into what atoms are the main ones responsible for the magnitude of the energy barriers. The (a)synchronicity of the reaction mechanisms featuring non-symmetrically substituted dienophiles was characterized, from QTAIM, by the electron densities and Laplacians over the LCP's as well as by the different atomic energy barriers obtained from IQA. The magnitude of the atomic barrier nicely explains the (a)synchronicity of the reaction mechanisms, and the degree of (a)synchronicity is nicely revealed by the difference between the earlier and later bond breaking and bond formations. The main conclusion is that important energetic and electronic changes are occurring before and after the position of the transition state structure, mainly for those asynchronous mechanisms, and although these provide essential insight into the reaction mechanism, most studies cannot assess this kind of information because they are focusing solely on reactants, transition states, and products. We advocate that the additional computational effort required for such analyses is more than compensated by the great amount of useful information it provides.

On the Notation of Catastrophes in the Framework of Bonding Evolution Theory: Case of Normal and Inverse Electron Demand Diels-Alder Reactions.

This paper generalizes very recent and unexpected findings [J. Phys. Chem. A, 2021, 125, 5152-5165] regarding the known "direct- and inverse-electron demand" Diels-Alder mechanisms. Application of bonding evolution theory indicates that the key electron rearrangement associated with significant chemical events (e. g., the breaking/forming processes of bonds) can be characterized via the simplest fold polynomial. For the CC bond formation, neither substituent position nor the type of electronic demand induces a measurable cusp-type signature. As opposed to the case of [4+2] cycloaddition between 1,3-butadiene and ethylene, where the two new CC single bonds occur beyond the transition state (TS) in the activated cases, the first CC bond occurs in the domain of structural stability featuring the TS, whereas the second one remains located in the deactivation path connecting the TS with the cycloadduct.

Chitosan Hydrogels Based on the Diels-Alder Click Reaction: Rheological and Kinetic Study.

The Diels-Alder reaction is recognized to generate highly selective and regiospecific cycloadducts. In this study, we carried out a rheological and kinetic study of N-furfuryl chitosan hydrogels based on the Diels-Alder click reaction with different poly(ethylene)glycol-maleimide derivatives in dilute aqueous acidic solutions. It was possible to prepare clear and transparent hydrogels with excellent mechanical properties. Applying the Winter and Chambon criterion the gel times were estimated at different temperatures, and the activation energy was calculated. The higher the temperature of gelation, the higher the reaction rate. The crosslinking density and the elastic properties seem to be controlled by the diffusion of the polymer segments, rather than by the kinetics of the reaction. An increase in the concentration of any of the two functional groups is accompanied by a higher crosslinking density regardless maleimide:furan molar ratio. The hydrogel showed an improvement in their mechanical properties as the temperature increases up to 70 °C. Above that, there is a drop in G' values indicating that there is a process opposing to the Diels-Alder reaction, most likely the retro-Diels-Alder.

Iboga Inspired N-Indolylethyl-Substituted Isoquinuclidines as a Bioactive Scaffold: Chemoenzymatic Synthesis and Characterization as GDNF Releasers and Antitrypanosoma Agents.

The first stage of the drug discovery process involves the identification of small compounds with biological activity. Iboga alkaloids are monoterpene indole alkaloids (MIAs) containing a fused isoquinuclidine-tetrahydroazepine ring. Both the natural products and the iboga-inspired synthetic analogs have shown a wide variety of biological activities. Herein, we describe the chemoenzymatic preparation of a small library of novel N-indolylethyl-substituted isoquinuclidines as iboga-inspired compounds, using toluene as a starting material and an imine Diels-Alder reaction as the key step in the synthesis. The new iboga series was investigated for its potential to promote the release of glial cell line-derived neurotrophic factor (GDNF) by C6 glioma cells, and to inhibit the growth of infective trypanosomes. GDNF is a neurotrophic factor widely recognized by its crucial role in development, survival, maintenance, and protection of dopaminergic neuronal circuitries affected in several neurological and psychiatric pathologies. Four compounds of the series showed promising activity as GDNF releasers, and a leading structure (compound 11) was identified for further studies. The same four compounds impaired the growth of bloodstream Trypanosoma brucei brucei (EC50 1-8 µM) and two of them (compounds 6 and 14) showed a good selectivity index.

Synthesis of endo-fused 5-unsubstituted Hexahydro-2H-pyrano[3,2-c]quinolinesvia Sequential Sc(OTf)3-catalyzed Cationic Imino-Diels-Alder Reaction/N-debenzylation using N-benzylanilines, 3,4-dihydro-2H-pyran and Paraformaldehyde under MW Irradiation.

BACKGROUND: Hexahydro-2H-pyrano[3,2-c]quinolines are known to have antibacterial, antifungal, and antitumor properties. Great efforts have been made to develop new synthetic methods that lead to the synthesis of valuable libraries. Extensive methodologies, low yields, excessive amounts of catalyst and expensive reactants are some of the limitations of current methodologies. AIMS AND OBJECTIVE: Developing a useful and efficient method to construct diversely substituted hexahydro-2Hpyrano[ 3,2-c]quinolines into good to excellent yields through a cationic imino-Diels-Alder/N-debenzylation methodology. METHOD: The cationic imino-Diels-Alder/N-debenzylation methodology was used for the preparation of substituted hexahydro-2H-pyrano[3,2-c]quinolines. It involves the use of Sc(OTf)3 for activation of cationic imino- Diels-Alder cycloaddition reaction of N-benzylanilines, 3,4-dihydro-2H-pyran and paraformaldehyde in MeCN; and microwave irradiation to shorten reaction time to afford new 6-benzyl-hexahydro-2H-pyrano[3,2- c]quinolines whose catalytic transfer debenzylation reactions with HCO2NH4 in the presence of Pd/C (10%) and methanol give the new 5-unsubstituted pyrano[3,2-c]quinolines in excellent yields. RESULTS: We found that optimal conditions for the preparation of hexahydro-2H-pyrano[3,2-c]quinolines were Sc(OTf)3 0.5 % and acetonitrile at 160°C for 15 min; and using paraformaldehyde obtained the 6-benzylhexahydro- 2H-pyrano [3,2-c]quinolines with excellent yields, while the N-debenzylation process using ammonium formate in the presence of Pd/C and methanol resulted in the synthesis of hexahydro-2H-pyrano [3,2-c] quinolines with quantitative yields (95-98%). CONCLUSION: We describe an efficient method to synthesize hexahydro-2H-pyrano[3,2-c]quinolines via the cationic imino-Diels-Alder/N-debenzylation methodology using Sc(OTf)3 0.5 % as Lewis Acid catalyst. Excellent yields of the products, use of MW irradiation, short times of reactions, and an efficient and highly diversified method are some of the main advantages of this new protocol.

Highly selective Diels-Alder and Heck arylation reactions in a divergent synthesis of isoindolo- and pyrrolo-fused polycyclic indoles from 2-formylpyrrole.

A highly regio-, chemo- and stereoselective divergent synthesis of isoindolo- and pyrrolo-fused polycyclic indoles is herein described, starting from 2-formylpyrrole and employing Diels-Alder and Heck arylation reactions. 3-(N-Benzyl-2-pyrrolyl)acrylates and 4-(pyrrol-2-yl)butenones underwent a highly endo-Diels-Alder cycloaddition with maleimides to furnish octahydropyrrolo[3,4-e]indoles, which served as precursors in the regioselective synthesis of aza-polycyclic skeletons via an intramolecular Heck arylation reaction. Through the latter reaction, the 3-(N-benzyl-2-pyrrolyl)acrylates give rise to 3-(pyrrolo[2,1-a]isoindol-3-yl)acrylates. A further oxidative aromatization of the polycyclic intermediates provides the corresponding polycyclic pyrrolo-isoindoles and isoindolo-pyrrolo-indoles. A theoretical study on the stereoselective Diels-Alder reactions, carried out by calculating the endo/exo transition states, revealed the assistance of non-covalent interactions in governing the endo stereocontrol.

Synthesis and structural elucidation of a phthalide analog using NMR analysis and DFT calculations.

Phtalides are secondary metabolites found in several fungi with a wide range of biological activities. A novel phthalide analog was synthesized by Diels-Alder reaction between cyclopentadiene and 3,4-dichlorofuran-2(5H)-one. Quantum mechanical calculations were used in conjunction with the spectrometric methods to determine the structure of the title compound. The calculated NMR chemical shifts for eight candidate pairs of enantiomers were compared with the experimental NMR chemical shifts applying the DP4 probability and mean absolute errors methodology. DP4 analysis using 1 H and 13 C NMR chemical shifts without assignment of the signals presented 100% probability for the correct candidate structure 3d, proving the consistency of the method even without spectra interpretation. Results from theoretical calculation and NMR spectra interpretation were in agreement to the structure of rac-(3aR,4S,4aS,5R,8S,8aR,9R,9aS)-3a,9a-dichloro-3a,4,4a,5,8,8a,9,9a-octahydro-4,9:5,8-dimethanonaphtho[2,3-c]furan-1(3H)-one.

Thermally reversible nanocellulose hydrogels synthesized via the furan/maleimide Diels-Alder click reaction in water.

The study deals with the synthesis of thermally reversible hydrogels from modified cellulose nanofibers via the Diels-Alder "click" reaction in an aqueous medium. "Never-dried" cellulose fibres derived from hardwood were submitted to shearing and surface TEMPO-oxidation before being modified with furfurylamine. The ensuing pendant furan moieties were reacted with a water-soluble bismaleimide via Diels-Alder coupling at 65 °C to produce a hydrogel, whose deconstruction was induced by the corresponding retro-Diels-Alder reaction carried out at 95 °C. Differential scanning calorimetry and rheological measurement were used to characterize the hydrogels. These aqueous cellulosic materials should provide original applications in such areas as strong paper-based artefacts and biocompatible gels.

Synthesis of Tris-Heterocycles via a Cascade IMCR/Aza Diels-Alder + CuAAC Strategy.

6-Triazolylmethyl-pyrrolo[3,4-b]pyridin-5-one tris-heterocycles were synthesized in 43-57% overall yields. The two-stage synthesis involved a cascade process (Ugi-3CR/aza Diels-Alder/N-acylation/aromatization) followed by a copper-assisted alkyne-azide [3+2] cycloaddition (CuAAC). This efficient and convergent strategy proceeded via complex terminal alkynes functionalized with a fused bis-heterocycle at the α-position. The final products are ideal candidates for SAR studies as they possess two privileged scaffolds in medicinal chemistry: 4-substituted or 1,4-substituted 1H-1,2,3-triazoles and pyrrolo[3,4-b]pyridin-5-ones.

Enantiopure 4-oxazolin-2-ones and 4-methylene-2-oxazolidinones as chiral building blocks in a divergent asymmetric synthesis of heterocycles.

Enantiopure 3-((R)- and 3-((S)-1-phenylethyl)-4-oxazoline-2-ones were evaluated as chiral building blocks for the divergent construction of heterocycles with stereogenic quaternary centers. The N-(R)- or N-(S)-1-phenylethyl group of these compounds proved to be an efficient chiral auxiliary for the asymmetric induction of the 4- and 5-positions of the 4-oxazolin-2-one ring through thermal and MW-promoted nucleophilic conjugated addition to Michael acceptors and alkyl halides. The resulting adducts were transformed via a cascade process into fused six-membered carbo- and heterocycles. The structure of the reaction products depended on the electrophiles and reaction conditions used. Alternative isomeric 4-methylene-2-oxazolidinones served as chiral precursors for a versatile and divergent approach to highly substituted cyclic carbamates. DFT quantum calculations showed that the formation of bicyclic pyranyl compounds was generated by a diastereoselective concerted hetero-Diels-Alder cycloaddition.

Synthesis of New 5-Aryl-benzo[f][1,7]naphthyridines via a Cascade Process (Ugi-3CR/Intramolecular Aza-Diels-Alder Cycloaddition)/Aromatization.

A series of eight new 5-aryl-benzo[f][1,7]naphthyridines were synthesized in 17 to 64% overall yields via an improved MW-assisted cascade-like one pot process (Ugi⁻three component reaction/intramolecular aza-Diels-Alder cycloaddition) coupled to an aromatization process from tri-functional dienophile-containing ester-anilines, substituted benzaldehydes and the chain-ring tautomerizable 2-isocyano-1-morpholino-3-phenylpropan-1-one as starting reagents, under mild conditions. The doubly activated dienophile and the aza-diene functionalities of the eight new Ugi-adducts were exploited to perform an in situ aza-Diels-Alder cycloaddition/aromatization (dehydration/oxidation) process, toward the complex polysubstituted 5-aryl-polyheterocycles, which could be taken as starting point for further SAR studies because the benzo[f][1,7]naphthyridine is the core of various bioactive products. It is relevant to emphasize that the synthesis or isolation of benzo[f][1,7]naphthyridines containing a substituted aromatic ring in the C-5 position, has not been published before.

(-)-Shikimic Acid as a Chiral Building Block for the Synthesis of New Cytotoxic 6-Aza-Analogues of Angucyclinones.

We describe the syntheses of nine new angucyclinone 6-aza-analogues, achieved through a hetero Diels-Alder reaction between the shikimic acid derivative-azadiene 13, with different naphthoquinones. The cytotoxic activity of the new synthesized compounds and five angucyclinones, previously reported, was evaluated in vitro against three cancer cell lines: PC-3 (prostate cancer), HT-29 (colon cancer), MCF-7 (breast cancer), and one non-tumoral cell line, human colon epithelial cells (CCD841 CoN). Our results showed that most 6-azadiene derivatives exhibited significant cytotoxic activities, which was demonstrated by their IC50 values (less than 10 µM), especially for the most sensitive cells, PC-3 and HT-29. From a chemical point of view, depending on the protected group of ring A and the pattern of substitution on ring D, cytotoxicity elicited these compounds, in terms of their potency and selectivity. Therefore, according to these chemical features, the most promising agents for every cancer cell line were 7a, 17, and 19c for PC-3 cells; 7a, 17, and 20 for HT-29 cells, and 19a for MCF-7 cells.

Synthesis of Polyheterocyclic Pyrrolo[3,4-b]pyridin-5-ones via a One-Pot (Ugi-3CR/aza Diels-Alder/N-acylation/aromatization/SN2) Process. A Suitable Alternative towards Novel Aza-Analogues of Falipamil.

We describe the one-pot synthesis of twenty polyheterocyclic pyrrolo[3,4-b]pyridin-5-ones via a cascade process (Ugi-3CR/aza Diels-Alder/N-acylation/aromatization) in 20 to 95% overall yields, as well as four pharmacologically promising analogues via an improved cascade process (Ugi-3CR/aza Diels-Alder/N-acylation/aromatization/SN2): two piperazine-linked pyrrolo[3,4-b]pyridin-5-ones in 33 and 34%, and a couple of Falipamil aza-analogues in 30 and 35% overall yields. It is worth highlighting the good substrate scope found, because final products are furnished with alkyl, aryl, and heterocyclic substituents. The use of chain-ring tautomerizable isocyanides (as key reagents for the Ugi-type three component reaction) allowed for a rapid and efficient assembly of the polysubstituted oxindoles, which were used in situ toward the complex products, conferring features like robustness, sustainability, and the one-pot approach to this synthetic methodology.

Electrically-Responsive Reversible Polyketone/MWCNT Network through Diels-Alder Chemistry.

This study examines the preparation of electrically conductive polymer networks based on furan-functionalised polyketone (PK-Fu) doped with multi-walled carbon nanotubes (MWCNTs) and reversibly crosslinked with bis-maleimide (B-Ma) via Diels-Alder (DA) cycloaddition. Notably, the incorporation of 5 wt.% of MWCNTs results in an increased modulus of the material, and makes it thermally and electrically conductive. Analysis by X-ray photoelectron spectroscopy indicates that MWCNTs, due to their diene/dienophile character, covalently interact with the matrix via DA reaction, leading to effective interfacial adhesion between the components. Raman spectroscopy points to a more effective graphitic ordering of MWCNTs after reaction with PK-Fu and B-Ma. After crosslinking the obtained composite via the DA reaction, the softening point (tan(δ) in dynamic mechanical analysis measurements) increases up to 155 °C, as compared to the value of 130 °C for the PK-Fu crosslinked with B-Ma and that of 140 °C for the PK-Fu/B-Ma/MWCNT nanocomposite before resistive heating (responsible for crosslinking). After grinding the composite, compression moulding (150 °C/40 bar) activates the retro-DA process that disrupts the network, allowing it to be reshaped as a thermoplastic. A subsequent process of annealing via resistive heating demonstrates the possibility of reconnecting the decoupled DA linkages, thus providing the PK networks with the same thermal, mechanical, and electrical properties as the crosslinked pristine systems.

Solvent effect on the degree of (a)synchronicity in polar Diels-Alder reactions from the perspective of the reaction force constant analysis.

In this work, we computationally evaluated the influence of six different molecular solvents, described as a polarizable continuum model at the M06-2X/6-31+G(d,p) level, on the activation barrier/reaction rate, overall energy change, TS geometry, and degree of (a)synchronicity of two concerted Diels-Alder cycloadditions of acrolein (R1) and its complex with Lewis acid acrolein···BH3 (R2) to cyclopentadiene. In gas-phase, we found that both exothermicity and activation barrier are only reduced by about 2.0 kcal mol-1, and the asynchronicity character of the mechanism is accentuated when BH3 is included. An increment in the solvent's polarity lowers the activation energy of R1 by 1.3 kcal mol-1, while for R2 the reaction rate is enhanced by more than 2000 times at room temperature (i.e., the activation energy decreases by 4.5 kcal mol-1) if the highest polar media is employed. Therefore, a synergistic effect is achieved when both external agents, i.e., Lewis acid catalyst and polar solvent, are included together. This effect was ascribed to the ability of the solvent to favor the encounter between cyclopentadiene and acrolein···BH3. This was validated by the asymmetry of the TS which becomes highly pronounced when either both or just BH3 is considered or the solvent's polarity is increased. Finally, the reaction force constant κ(ξ) reveals that an increment in the solvent's polarity is able to turn a moderate asynchronous mechanism of the formation of the new C-C σ-bonds into a highly asynchronous one. Graphical abstract A synergistic effect is achieved when both external agents, i.e., Lewis acid catalyst and polar solvent, are included together: lowered energy barriers and increased asynchronicities.

Biogenesis of Triterpene Dimers from Orthoquinones Related to Quinonemethides: Theoretical Study on the Reaction Mechanism.

The biogenetic origin of triterpene dimers from the Celastraceae family has been proposed as assisted hetero-Diels-Alder reaction (HDA). In this work, computational calculation of HDA between natural quinonemethides (tingenone and isopristimerol) and hypothetical orthoquinones has been performed at the M06-2X/6-31G(d) level of theory. We have located all the HDA transition states supporting the biogenetic route via HDA cycloadditions. We found that all reactions take place through a concerted inverse electron demand and asynchronous mechanism. The enzymatic assistance for dimer formation was analyzed in terms of the calculated transition state energy barrier.

Microbial diversification of Diels-Alder cycloadducts by whole cells of Penicillium brasilianum.

Functionalizations of cycloadducts are important steps for the use of Diels-Alder reactions in the construction of complex cyclic or polycyclic molecules from relatively simple starting materials. In the present work, we studied the ability of Penicillium brasilianum to perform microbial transformations of racemic Diels-Alder endo-cycloadducts. Thus, Diels-Alder products, obtained from reacting cyclopentadiene or 2,3-dimethylbutadiene with alkylated para-benzoquinones, were transformed by the resting cells of P. brasilianum producing new functionalized polycyclic compounds. These biotransformations yielded novel products of oxidation and ring closure, reduction of the C=C or C=O in [Formula: see text]-unsaturated system, and allylic hydroxylations. The reduction products (conjugated double bond and carbonyl group) were also synthesized, and the enantioselectivity of both in vitro and in vivo processes was evaluated. In all cases, the microbiological transformations were enantioselective. In silico docking studies of the Diels-Alder cycloadducts with P. brasilianum oxidoreductase "old yellow enzymes" shed more light on these transformations.

Novel N-allyl/propargyl tetrahydroquinolines: Synthesis via Three-component Cationic Imino Diels-Alder Reaction, Binding Prediction, and Evaluation as Cholinesterase Inhibitors.

New N-allyl/propargyl 4-substituted 1,2,3,4-tetrahydroquinolines derivatives were efficiently synthesized using acid-catalyzed three components cationic imino Diels-Alder reaction (70-95%). All compounds were tested in vitro as dual acetylcholinesterase and butyryl-cholinesterase inhibitors and their potential binding modes, and affinity, were predicted by molecular docking and binding free energy calculations (∆G) respectively. The compound 4af (IC50 = 72 µm) presented the most effective inhibition against acetylcholinesterase despite its poor selectivity (SI = 2), while the best inhibitory activity on butyryl-cholinesterase was exhibited by compound 4ae (IC50 = 25.58 µm) with considerable selectivity (SI = 0.15). Molecular docking studies indicated that the most active compounds fit in the reported acetylcholinesterase and butyryl-cholinesterase active sites. Moreover, our computational data indicated a high correlation between the calculated ∆G and the experimental activity values in both targets.