Controlling Diastereoselectivity in Dearomatizing Diels-Alder Reactions of Nitroarenes with 2-Trimethylsilyloxycyclohexadiene.

Dearomative Diels-Alder cycloadditions between nitroarenes and 2-trimethylsilyloxycyclohexadiene are carried out under high pressure at room temperature in the absence of any chemical promoter. Reactions are performed with different arenes, including the highly aromatic naphthalenes and quinolines. They lead to 3D-scaffolds with exquisite exo-diastereoselectivity. The exo approach is characterized by lower distortion of the substrates in a late TS and by more favorable orbital interactions presumably between the nitro group and the dienic part, explaining the stereoselectivity.

Interception and Synthetic Application of Diradical and Diene Forms of Dual-Nature Azabicyclic o-Quinodimethanes Generated by 6p-Azaelectrocyclization.

We demonstrate that 2-alkenylarylaldimines and ketimines undergo thermal 6p-azaelectrocyclization to generate a wide range of azabicyclic o-quinodimethanes (o-QDMs). These o-QDMs exist as a hybrid of a diene and a benzylic diradical. The diradical nature was confirmed by their ability to undergo dimerization and react with H-atom donor, 2,2,6,6-Tetramethylpiperidin-1-yl)oxyl (TEMPO) and O2. In addition, the interception of the diradicaloid o-QDMs by H-atom transfer was used to synthesize five tetrahydroisoquinoline alkaloids and related bioactive molecules. The diene form can undergo [4 + 2] cycloaddition reactions with different dienophiles to generate bridged azabicycles in high endo:exo selectivity. The azabicyclic o-QDMs can be generated for [4 + 2] cycloaddition from a wide range of electronically and sterically varied 2-alkenylarylimines, including mono, di, tri and tetrasubstituted alkenes, and imines derived from arylamine, alkylamine (1°, 2°, 3°), benzylamine, benzylsulfonamide and Boc-amine.

Catalytic Enantioselective [4+2] Cycloadditions of Salicylaldehyde Acetals with Enol Ethers.

A readily accessible conjugate-base-stabilized carboxylic acid (CBSCA) catalyst facilitates highly enantioselective [4+2] cycloaddition reactions of salicylaldehyde-derived acetals and cyclic enol ethers, resulting in the formation of polycyclic chromanes with oxygenation in the 2- and 4-positions. Stereochemically more complex products can be obtained from racemic enol ethers. Spirocyclic products are also accessible.

Chiral NHC-Catalyzed [4+2] Cycloadditions: Highly Diastereo/Enantioselective Access to Spiro[cyclohex-4-ene-1,3'-indoles] and DFT Calculations.

A highly efficient NHC-catalyzed cycloaddition of (E)-alkenylisatins and γ-chloroenals with a broad substrate scope has been developed to provide spiro[cyclohex-4-ene-1,3'-indole] in good yields (up to 99 % yield) with excellent diastereo- and enantioselectivities (up to >20 : 1 d.r., >99 % ee) under mild conditions without the use of metal and additives. Based on computational investigations, the role of the NHC on the diastereo- and enantioselectivity is discussed.

Sugar-Assisted Kinetic Resolutions in Metal/Chiral Amine Co-Catalyzed α-Allylations and [4+2] Cycloadditions: Highly Enantioselective Synthesis of Sugar and Chromane Derivatives.

Functionalized triose-, furanose and chromane-derivatives were synthesized by the titled reactions. The sugar-assisted kinetic resolution/C-C bond-forming cascade processes generate a functionalized sugar derivative with a quaternary stereocenter in a highly enantioselective fashion (up to >99 % ee) by using a simple combination of metal and chiral amine co-catalysts. Notably, the interplay between the chiral sugar substrate and the chiral amino acid derivative allowed for the construction of a functionalized sugar product with high enantioselectivity (up to 99 %) also when using a combination of racemic amine catalyst (0 % ee) and metal catalyst.

[4+2]-Cycloaddition to 5-Methylidene-Hydantoins and 5-Methylidene-2-Thiohydantoins in the Synthesis of Spiro-2-Chalcogenimidazolones.

Novel hydantion and thiohydantoin-based spiro-compounds were prepared via theDiels-Alder reactions between 5-methylidene-hydantoins or 5-methylidene-2-thiohydantoins and 1,3-dienes (cyclopentadiene, cyclohexadiene, 2,3-dimethylbutadiene, isoprene). It was shown that the cycloaddition reactions proceed regioselectively and stereoselectively with the formation of exo-isomers in the reactions with cyclic dienes andthe less sterically hindered products in the reactions with isoprene. Reactions of methylideneimidazolones with cyclopentadiene proceed viaco-heating the reactants; reactions with cyclohexadiene, 2,3-dimethylbutadiene, and isoprene require catalysis by Lewis acids. It was demonstrated that ZnI2 is an effective catalyst in the Diels-Alder reactions of methylidenethiohydantoins with non-activated dienes. The possibility of alkylation and acylation of the obtained spiro-hydantoinsat the N(1)nitrogen atoms with PhCH2Cl or Boc2O and the alkylation of the spiro-thiohydantoinsat the S atoms with MeI or PhCH2Cl in high yields have been demonstrated. The preparativetransformation of spiro-thiohydantoins into corresponding spiro-hydantoinsin mild conditions by treating with 35% aqueous H2O2 or nitrile oxide has been carried out. The obtained compounds show moderate cytotoxicity in the MTT test on MCF7, A549, HEK293T, and VA13 cell lines. Some of the tested compounds demonstrated some antibacterial effect against Escherichia coli (E. coli) BW25113 DTC-pDualrep2 but were almost inactive against E. coli BW25113 LPTD-pDualrep2.

Metalla-Claisen Rearrangement in Gold-Catalyzed [4+2] Reaction: A New Elementary Reaction Suggested for Future Reaction Design.

We report here computational evidence for a metalla-Claisen rearrangement (MCR) in the case of gold-catalyzed [4+2] cycloaddition reaction of yne-dienes. The [4+2] reaction starts from exo cyclopropanation, followed by MCR and reductive elimination. The cyclopropane moiety formed in the first step is crucial for a low barrier of the MCR step. In addition, the importance of an appropriate combination of the tether group and the terminal substituent on alkyne in the yne-diene substrates was studied. The mechanism of rhodium-catalyzed [4+2] reaction of yne-dienes was also investigated to see whether an MCR mechanism is involved or not. The findings and new understanding hereby reported represent an important advance in the catalysis field.

Design and Manipulation of a Minimalistic Hydrocarbon Nanocar on Au(111).

Nanocars are carbon-based single-molecules with a precise design that facilitates their atomic-scale control on a surface. The rational design of these molecules is important in atomic and molecular-scale manipulation to advance the development of molecular machines, as well as for a better understanding of self-assembly, diffusion and desorption processes. Here, we introduce the molecular design and construction of a collection of minimalistic nanocars. They feature an anthracene chassis and four benzene derivatives as wheels. After sublimation and adsorption on an Au(111) surface, we show controlled and fast manipulation of the nanocars along the surface using the tip of a scanning tunneling microscope (STM). The mechanism behind the successful displacement is the induced dipole created over the nanocar by the STM tip. We utilized carbon monoxide functionalized tips both to avoid decomposition and accidentally picking the nanocars up during the manipulation. This strategy allowed thousands of maneuvers to successfully win the Nanocar Race II championship.

Promoting Solar-driven Hydrogen Peroxide Production over Thiazole-based Conjugated Polymers via Generating and Converting Singlet Oxygen.

Solar-driven synthesis of hydrogen peroxide (H2 O2 ) from water and air provides a low-cost and eco-friendly alternative route to the traditional anthraquinone method. Herein, four thiazole-based conjugated polymers (Tz-CPs: TTz, BTz, TBTz and BBTz) are synthesized via aldimine condensation. BBTz exhibits the highest H2 O2 production rate of 7274 µmol g-1 h-1 in pure water. Further, the reaction path is analyzed by electron paramagnetic resonance (EPR), in situ diffuse reflectance infrared Fourier transform (DRIFT) and theoretical calculation, highlighting the prominent role of singlet oxygen (1 O2 ). The generation of 1 O2 occurs through the oxidation of superoxide radical (⋅O2 - ) and subsequent conversion into endoperoxides via [4+2] cycloaddition over BBTz, which promotes charge separation and reduces the barrier for H2 O2 production. This work provides new insight into the mechanism of photocatalytic O2 reduction and the molecular design of superior single-polymer photocatalysts.

Syntheses of Anthracene-Centered Large PAH Diimides and Conjugated Polymers.

Polycyclic aromatic hydrocarbon (PAH) structures with suitable electron-withdrawing groups are useful building blocks for developing optical and electron-transporting materials. Here, we report the application of a double benzannulation process to the syntheses of PAH diimides with enlarged π-frameworks featuring a central anthracene moiety. The preparations are realized by copper-catalyzed [4+2] cycloaddition of ethynyl-substituted aromatic dicarboximide to 2,5-bis(phenylethynyl)terephthalaldehyde, followed by intramolecular photocyclization or direct arylation via Heck cross coupling. A central symmetric benzo[1,2-k:4,5-k']-bis(fluoranthene)-3,4,12,13-tetracarboxyl diimide (BFDI) is acquired, with the single crystal structure revealing its completely planar polycyclic skeleton. Such a shape-persistent PAH expectedly exhibits a tendency to stack face-to-face and forms J-aggregates. Moreover, BFDI can be difunctionalized site-selectively at the reactive 9 and 10 positions of the anthracene unit and then applied to prepare conjugated polymers. When coupled with 1,4-diketopyrrolo[3,4-c]-pyrrole (DPP) via thiophene and dithiophene linkers, two polymers with significantly broadened absorption bands extended to the near-infrared regime are obtained, evidencing the effective π-conjugative extension ability of BFDI unit.

Byproduct formation during the biosynthesis of spinosyn A and evidence for an enzymatic interplay to prevent its formation.

Biosynthesis of spinosyn A in Saccharopolyspora spinosa involves a 1,4-dehydration followed by an intramolecular [4 + 2]-cycloaddition catalyzed by SpnM and SpnF, respectively. The cycloaddition also takes place in the absence of SpnF leading to questions regarding its mechanism of catalysis and biosynthetic role. Substrate analogs were prepared with an unactivated dienophile or an acyclic structure and found to be unreactive consistent with the importance of these features for cyclization. The SpnM-catalyzed dehydration reaction was also found to yield a byproduct corresponding to the C11 = C12 cis isomer of the SpnF substrate. This byproduct is stable both in the presence and absence of SpnF; however, relative production of the SpnM product and byproduct could be shifted in favor of the former by including SpnF or the dehydrogenase SpnJ in the reaction. This result suggests a potential interplay between the enzymes of spinosyn A biosynthesis that may help to improve the efficiency of the pathway.

Lewis Acid-Catalyzed Formal (4+2)-Cycloaddition between Cross-Conjugated Azatrienes and Styrylmalonates: The Way to Functionalized Quinolizidine Precursors.

Quinolizidine and azaphenalene alkaloids are common in nature and exhibit a pharmaceutical activity, which stirs up increased interest in expanding the range of methods for the synthesis of the corresponding derivatives. In this work, we attempted to adapt our previously presented method for the synthesis of tetrahydropyridines to the preparation of potential precursors for these heterocycles as a separate development of a necessary intermediate stage. To this end, we studied the reactions of ß-styrylmalonates with N-protected cross-conjugated azatrienes in the presence of Sn(OTf)2. Moreover, the regioselectivity of the process involving unsymmetrically substituted azatrienes was estimated. The diene character of vinyltetrahydropyridines was studied in detail with the participation of PTAD. Finally, for the Ts-protected highly functionalized vinyltetrahydropyridines synthesized, a detosylation method to give new desired azadiene structures as precursors of the quinolizidine core was suggested.

A Ring Opening-Annulation Reaction of Anthra[1,2-d][1,2,3]triazine-4,7,12(3H)-trione in the Presence of Pyridines as an Efficient Approach to the Construction of Naphtho[2,3-H]pyrido(quinolino)[2,1-b]quinazoline System.

The [1,2,3]triazin-4(3H)-one ring is a synthetically important molecular platform for a variety of chemical transformations. Despite this, currently, there has been little research on the reaction of the thermal opening of the [1,2,3]triazin-4(3H)-one nucleus. In this work, we describe the synthetic potential of anthra[1,2-d][1,2,3]triazine-4,7,12(3H)-trione in the reaction of the thermal opening of a cycle following the [4+2]-cycloaddition reaction with a number of pyridine derivatives and quinoline. It is shown that this method is effective for the synthesis of the 6H-naphtho[2,3-H]pyrido(quinolino)[2,1-b]quinazoline-6,9,14-trione system. We also investigate the influence of the position of substituents in the structure of pyridine on the formation characteristics of the target products.

Catalytic Enantioselective de novo Construction of Chiral Arenes through Desymmetrizing Oxidative [4+2]-Cycloaddition.

Central chirality in arene derivatives arising out of unsymmetrically substituted arene ring is a fascinating yet rarely explored research topic. Here, we report a desymmetrization approach to centrally chiral unfunctionalized arenes, which is enabled by the enantioselective de novo construction of the arene ring. This operationally simple protocol is based on a [4+2]-cycloaddition between polycyclic meso-cyclohexenediones and α,ß-unsaturated aldehydes, and doesn't usually require any external oxidant. Catalyzed by a diphenylprolinol silyl ether, this reaction proceeds via dienamine intermediate and greatly simplifies the access to diversely substituted chiral arenes with outstanding enantioselectivities.

Development of Dipolarophiles for Catalytic Asymmetric Cycloadditions through Pd-π-Allyl Zwitterions.

The development of new and efficient methodology for the construction of optically active molecules is of great interest in both synthetic organic and medicinal chemistry fields. To this end, the personal account summarizes our studies on the development of electron-deficient alkenes, allenes, and alkynes containing single activator as new dipolarophiles for Pd-catalyzed asymmetric cycloaddition reactions. These new dipolarophiles can participate in Pd-catalyzed asymmetric [3+2] and [4+2] cycloadditions through Pd-π-allyl 1,3- and 1,4-zwitterions in-situ generated by the reaction of Pd(0) catalyst with vinyl aziridines, vinyl epoxides, vinyl cyclopropanes, 4-vinyl-1,3-dioxan-2-ones, and vinyl benzoxazinanones. These [3+2] and [4+2] cycloadditions provide efficient approaches to a wide range of enantiomerically enriched five- and six-membered ring compounds containing contiguous chiral centers with high to excellent chemo-, diastereo-, and enantioselectivities. The utilities of these protocols are demonstrated by transformation of the cycloadducts into other useful chiral building blocks. DFT calculations reveal the dissimilar reactivity of different electron deficient alkenes and rationalize the mechanism and stereo-control of the reaction. A Pd-catalyzed inverse [3+2] cycloaddition is disclosed.

Fused chromeno and quinolino[1,8]naphthyridines: Synthesis and biological evaluation as topoisomerase I inhibitors and antiproliferative agents.

The synthesis of 1,8-naphthyridine derivatives fused with other heterocycles, such as chromenes and quinolines, as well as their behaviour as topoisomerase I inhibitors is studied. The preparation is carried out through a direct and simple process as an intramolecular [4 + 2] cycloaddition reaction between functionalized aldimines, obtained by the condensation of 2-aminopyridine and unsaturated aldehydes, and olefins. In particular, while no clear inhibitory activity is observed for chromeno[4,3-b][1,8]naphthyridine fused heterocycles, a very different result is observed for quinolino[4,3-b][1,8]naphthyridine derivatives. Experimental assays indicated that quinolino[4,3-b][1,8]naphthyridines inhibited the topoisomerase I enzymatic reaction behaving like a poison, as occurs with the natural TopI inhibitor, camptothecin. Furthermore, the cytotoxic effect on cell lines derived from human lung adenocarcinoma (A549), human ovarian carcinoma (SKOV3), and on non-cancerous lung fibroblasts cell line (MRC5) was also screened.

Construction of hybrid polycyclic quinolinobenzo[a]phenazinone architectures using solid-state melt reaction (SSMR).

An efficient and versatile protocol for the synthesis of hybrid polycyclic quinolinobenzo[a]phenazinones has been developed under SSMR condition via intramolecular domino Knoevenagel-hetero-Diels-Alder reaction involving the generation of two new six membered fused rings and three contiguous stereogenic centers.

A One-Pot Approach to Novel Pyridazine C-Nucleosides.

The synthesis of glycosides and modified nucleosides represents a wide research field in organic chemistry. The classical methodology is based on coupling reactions between a glycosyl donor and an acceptor. An alternative strategy for new C-nucleosides is used in this approach, which consists of modifying a pre-existent furyl aglycone. This approach is applied to obtain novel pyridazine C-nucleosides starting with 2- and 3-(ribofuranosyl)furans. It is based on singlet oxygen [4+2] cycloaddition followed by reduction and hydrazine cyclization under neutral conditions. The mild three-step one-pot procedure leads stereoselectively to novel pyridazine C-nucleosides of pharmacological interest. The use of acetyls as protecting groups provides an elegant direct route to a deprotected new pyridazine C-nucleoside.

Stereoselective [4+2] Cycloaddition of Singlet Oxygen to Naphthalenes Controlled by Carbohydrates.

Stereoselective reactions of singlet oxygen are of current interest. Since enantioselective photooxygenations have not been realized efficiently, auxiliary control is an attractive alternative. However, the obtained peroxides are often too labile for isolation or further transformations into enantiomerically pure products. Herein, we describe the oxidation of naphthalenes by singlet oxygen, where the face selectivity is controlled by carbohydrates for the first time. The synthesis of the precursors is easily achieved starting from naphthoquinone and a protected glucose derivative in only two steps. Photooxygenations proceed smoothly at low temperature, and we detected the corresponding endoperoxides as sole products by NMR. They are labile and can thermally react back to the parent naphthalenes and singlet oxygen. However, we could isolate and characterize two enantiomerically pure peroxides, which are sufficiently stable at room temperature. An interesting influence of substituents on the stereoselectivities of the photooxygenations has been found, ranging from 51:49 to up to 91:9 dr (diastereomeric ratio). We explain this by a hindered rotation of the carbohydrate substituents, substantiated by a combination of NOESY measurements and theoretical calculations. Finally, we could transfer the chiral information from a pure endoperoxide to an epoxide, which was isolated after cleavage of the sugar chiral auxiliary in enantiomerically pure form.

Molecular Basis for Two Stereoselective Diels-Alderases that Produce Decalin Skeletons*.

Enzymes catalyzing [4+2] cycloaddition have attracted increasing attention because of their key roles in natural product biosynthesis. Here, we solved the X-ray crystal structures of a pair of decalin synthases, Fsa2 and Phm7, that catalyze intramolecular [4+2] cycloadditions to form enantiomeric decalin scaffolds during biosynthesis of the HIV-1 integrase inhibitor equisetin and its stereochemical opposite, phomasetin. Computational modeling, using molecular dynamics simulations as well as quantum chemical calculations, demonstrates that the reactions proceed through synergetic conformational constraints assuring transition state-like substrates folds and their stabilization by specific protein-substrate interactions. Site-directed mutagenesis experiments verified the binding models. Intriguingly, the flexibility of bound substrates is largely different in two enzymes, suggesting the distinctive mechanism of dynamics regulation behind these stereoselective reactions. The proposed reaction mechanism herein deepens the basic understanding how these enzymes work but also provides a guiding principle to create artificial enzymes.