Efficient Synthesis of Cyclohepta[b]indoles and Cyclohepta[b]indole-Indoline Conjugates via RCM, Hydrogenation, and Acid-Catalyzed Ring Expansion: A Biomimetic Approach.

Cyclohepta[b]indoles, prevalent in natural products and pharmaceuticals, are conventionally accessed via metal or Lewis acid-mediated cycloadditions with prefunctionalized substrates. Our study introduces an innovative sequential catalytic assembly for synthesizing cyclohepta[b]indoles from readily available isatin derivatives. The process involves three catalytic sequences: ring-closing metathesis, catalytic hydrogenation, and acid-catalyzed ring expansion. The RCM of 2,2-dialkene-3-oxindoles, formed by butenyl Grignard addition to 3-allyl-3-hydroxy-2-oxindoles, yields versatile spirocyclohexene-3-oxindole derivatives. These derivatives undergo further transformations, including dibromination, dihydroxylation, epoxidation, Wacker oxidation at the double bond. Hydrogenation of spirocyclohexene-3-oxindole yields spirocyclohexane-3-oxindoles. Their subsequent acid-catalyzed ring expansion/aromatization, dependent on the acid catalyst, results in either cyclohepta[b]indoles or cyclohepta[b]indole-indoline conjugates, adding a unique synthetic dimension. The utility of this methodology is exemplified through the synthesis of an A-FABP inhibitor, showcasing its potential in pharmaceutical applications.

Cu(II)-Catalyzed Enantioselective Aza-Friedel-Crafts Reaction of 1-Naphthols and Electron-Rich Phenols with Isatin-Derived Ketimines.

New chiral ligands could be obtained by introducing proline moieties and imidazoline moieties to binaphthyl skeletons. The chiral ligands exhibited balanced rigidity and flexibility which could allow the change of the conformations during the reactions on one hand, and could provide sufficient asymmetric induction on the other. The proline moiety could act as a linker connecting the binaphthyl skeletons and the imidazoline moieties as well as a coordinating group for the central metal, and the electronic and steric properties of the imidazoline groups could be carefully fine-tuned by the use of different substituents. In the presence of Cu(II) catalyst bearing such chiral ligands, aza-Friedel-Crafts reaction of 1-naphthols and electron-rich phenols with isatin-derived ketimines provided the desired products with good to excellent yields and up to 99 % ee. The reactions showed good scalability, and excellent ee could still be obtained when the reaction was carried out in gram-scale.

New enantioenriched ß-indolyl ketones as aromatase inhibitors: Unraveling heme-ligand interactions by MD simulation and MMPBSA analysis.

A series of enantioenriched ß-indolyl ketones as aromatase inhibitors (AI) is synthesized through the Michael-type Friedel-Crafts alkylation of indole. A highly efficient bifunctionalized amino catalyst is developed to access structurally diverse ß-indolyl ketones in high yields (up to 91%) and excellent enantioselectivity (enantiomeric ratio up to 98:2). All the synthesized compounds demonstrated promising aromatase inhibitory potential, where ortho-substituted analogs (3c and 3e) were found most active with IC50 values of 0.68 and 0.90 µM, respectively. Both of these compounds exhibited significant cytotoxicity (IC50 = 0.34 and 0.37 µM) against the MCF-7 breast cancer cell line in the (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) assay. Molecular docking studies of the synthesized compounds demonstrate favorable binding interactions with the estrogens controlling CYP19A1 (3EQM) and metabolizing CYP3A4 (5VCC) enzymes. Molecular dynamic (MD) simulation analysis revealed the essentiality of heme-ligand interactions to build a stable protein-ligand complex. An average root mean square deviation of 0.35 nm observed during a 100-ns MD simulation and binding free energy in the range of -190 to -227 kJ/mol calculated by g_mmpbsa analysis authenticated the stability of the 3c-3EQM complex. ADMET and drug-likeness parameters supported the suitability of these indole derivatives as the drug lead to develop potent inhibitors for estrogen-dependent breast cancer.

Co2+ to Al3+ Substitution Induced Dual-Site Synergistic Catalysis to Friedel-Crafts Alkylation Reactions.

The dual-site synergistic effect in heterogeneous catalysis is quite interesting, and also complex because at least two substrate molecules are adsorbed or activated on the catalyst surface, which apparently needs two spatially separated and functionally independent active sites. It would become more difficult when the substrate molecules are large ones. The replacement of Al3+ in Al4 B6 O15 lattice with Co2+ leads to the formation of unsaturated Co2+ (4-fold coordination) along with oxygen vacancies (Ov ). The former one behaves as a medium-strength Lewis acid site, and can adsorb and activate molecules with a nitro group (e. g., ß-nitrostyrene). The latter one can adsorb and activate oxygen species, which further activates the indole derivatives. Next, the spatially separated dual sites on the catalyst surface can synergistically and efficiently catalyze their Friedel-Crafts alkylation reactions under mild conditions. The high durability can be proved by the as-maintained high yields, that is, 98, 93, 96, 92 and 90 % for 5 runs, respectively. The reaction kinetics obey the second-order characteristic. Annealing under hydrogen condition can further generate more surficial Ov , leading to an improvement to the catalytic activity. A simple and probably routine aliovalent doping endows such a complex synergistic catalysis involving two large substrate molecules, providing an inspired perspective of developing dual-site catalysts.

Structure Guided Design, Synthesis, and Biological Evaluation of Oxetane-Containing Indole Analogues.

The oxetane functional group offers a variety of potential advantages when incorporated within appropriate therapeutic agents as a ketone surrogate. OXi8006, a 2-aryl-3-aroyl-indole analogue, functions as a small-molecule inhibitor of tubulin polymerization that has a dual mechanism of action as both an antiproliferative agent and a tumor-selective vascular disrupting agent. Replacement of the bridging ketone moiety in OXi8006 with an oxetane functional group has expanded structure activity relationship (SAR) knowledge and provided insights regarding oxetane incorporation within this class of molecules. A new synthetic method using an oxetane-containing tertiary alcohol subjected to Lewis acid catalyzed conditions led to successful Friedel-Crafts alkylation and yielded fourteen new oxetane-containing indole-based molecules. This synthetic approach represents the first method to successfully install an oxetane ring at the 3-position of a 2-aryl-indole system. Several analogues showed potent cytotoxicity (micromolar GI50 values) against human breast cancer cell lines (MCF-7 and MDA-MB-231) and a pancreatic cancer cell line (PANC-1), although they proved to be ineffective as inhibitors of tubulin polymerization. Molecular docking studies comparing colchicine with the OXi8006-oxetane analogue 5m provided a rationale for the differential interaction of these molecules with the colchicine site on the tubulin heterodimer.

Chemoenzymatic Synthesis of Cylindrocyclophanes A and F and Merocyclophanes A and D.

Incorporating enzymatic reactions into natural product synthesis can significantly improve synthetic efficiency and selectivity. In contrast to the increasing applications of biocatalytic functional-group interconversions, the use of enzymatic C-C bond formation reactions in natural product synthesis is underexplored. Herein, we report a concise and efficient approach for the synthesis of [7.7]paracyclophane natural products, a family of polyketides with diverse biological activities. By using enzymatic Friedel-Crafts alkylation, cylindrocyclophanes A and F and merocyclophanes A and D were synthesized in six to eight steps in the longest linear sequence. This study demonstrates the power of combining enzymatic reactions with contemporary synthetic methodologies and provides opportunities for the structure-activity relationship studies of [7.7]paracyclophane natural products.

Highly Active La(III)-Based Metal-Organic Framework as a Heterogeneous Lewis Acid Catalyst for Friedel-Crafts Alkylation.

In this study, a novel La(III)-based two-dimensional (2D) metal-organic framework, [La2/3 (qptca)1/2 ] (referred to as SLX-2), from LaCl3 and 1,1' : 4',1'' : 4'',1''' : 4''',1''''-quinquephenyl]-2,2'',2'''',5''-tetracarboxylic acid (H4 qptca) was synthesized by conventional solvothermal method and thoroughly characterized by using X-ray single-crystal diffraction, powder X-ray diffraction, and thermogravimetric analyses. The 2D SLX-2 features a unique lanthanum center exposed to the skeleton and was used as an efficient Lewis acid catalyst for the Friedel-Crafts alkylation of indole and pyrrole with ß-nitrostyrene along with a wide substrate scope, giving the desired products in good-to-high yields under the optimal reaction conditions. Furthermore, the catalyst was used for twenty cycles, with nearly no effect on its activity, and the reaction was heterogeneous in nature. Moreover, compared to the previous hydrogen-bond-donating MOF catalysts for such alkylation reactions, SLX-2 showed an excellent stability toward harsh acidic and basic environment, and gave comparable catalytic activities.

Synthesis, In Silico and In Vivo Toxicity Assessment of Functionalized Pyridophenanthridinones via Sequential MW-Assisted Intramolecular Friedel-Crafts Alkylation and Direct C-H Arylation.

A rapid, efficient, and original synthesis of novel pyrido[3,2,1-de]phenanthridin-6-ones is reported. First, the key cinnamamide intermediates 8a-f were easily prepared from commercial substituted anilines, cinnamic acid, and 2-bromobenzylbromide in a tandem amidation and N-alkylation protocol. Then, these N-aryl-N-(2-bromobenzyl) cinnamamides 8a-f were subjected to a TFA-mediated intramolecular Friedel-Crafts alkylation followed by a Pd-catalyzed direct C-H arylation to obtain a series of potentially bioactive 4-phenyl-4,5-dihydro-6H,8H-pyrido[3,2,1-de]phenanthridin-6-one derivatives 4a-f in good yields. Finally, the toxicological profile of the prepared final compounds, including their corresponding intermediates, was explored through in silico computational methods, while the acute toxicity toward zebrafish embryos (96 hpf-LC50, 50% lethal concentration) was also determined in the present study.

Unexpected rearrangements and a novel synthesis of 1,1-dichloro-1-alkenones from 1,1,1-trifluoroalkanones with aluminium trichloride.

A novel reactivity of 1,1,1-trifluoroalkanones is reported, where the reaction with AlCl3 results in the formation of 1,1-dichloro-1-alkenones. The reaction scope was found to be broad, with various chain lengths and aryl substituents tolerated. For substrates containing an electron-rich aromatic ring, further reactions take place, resulting in bicyclic and/or rearrangement products.

Transition-metal-free intramolecular Friedel-Crafts reaction by alkene activation: A method for the synthesis of some novel xanthene derivatives.

In this work, new derivatives (substituted 9-methyl-9-arylxanthenes) of xanthene compounds (5a-l) of possible biological significance were synthesized by developing a new synthesis method. In order to obtain xanthene derivatives, the original alkene compounds to be used as the starting materials were synthesized in four steps using appropriate reactions. A cyclization reaction by intramolecular Friedel-Crafts alkylation was carried out in order to synthesize the desired xanthene derivatives using the alkenes as starting compounds. The intramolecular Friedel-Crafts reaction was catalyzed by trifluoroacetic acid (TFA) and provided some novel substituted 9-methyl-9-arylxanthenes with good yields at room temperature within 6-24 hours. As a result, an alkene compound was used for activation with TFA in the synthesis of xanthene through intramolecular Friedel-Crafts alkylation for the first time.

Discovery of 3-(benzofuran-2-ylmethyl)-1H-indole derivatives as potential autophagy inducers in cervical cancer cells.

In this manuscript we have documented the identification of a novel anticancer scaffold 3-(benzofuran-2-ylmethyl)-1H-indole. This scaffold has been designed by tweaking the known bisindolylmethane scaffold of natural products that display a wide range of biological activities. A series of 24 new conjugates have been synthesized and among them 5 derivatives exhibited IC50 values less than 40 µM against two cervical cancer cell lines SiHa and C33a. Further mechanistic studies of two compounds 3eb and 3ec revealed that the toxicity of these compounds was due to the effective induction of autophagy mediated cell death. The autophagy induction was confirmed by the progressive conversion of LC3I to LC3II and downregulation of p62 in cervical cancer cells.

Synthesis of novel lignan-like compounds and their antimicrobial activity.

Herein we report the preparation of 3,4-dibenzylfurans and some oxidized derivatives with lignan backbone. The compounds were prepared using the Friedel-Crafts reaction with BF3 etherate as catalyst, demethylation with iodocyclohexane, acetylation and oxidation reactions. The antimicrobial activity was evaluated through their capacity to inhibit the growth of Gram positive and Gram negative bacteria, and of the yeast Candida albicans. Among ten products assayed four furans displayed a good antimicrobial activity against Staphylococcus aureus, S. epidermidis and C. albicans; on the contrary, none of the compounds were active against Pseudomonas aeruginosa. One of them inhibited the growth of S. aureus, S. epidermidis (biofilm producer strain) and C. albicans at 16 µg/mL, showing a bactericidal activity already after one hour of treatment. In summary, the results suggest a possible use of these derivatives for general disinfection practices or antimicrobial agents in cosmesis skin-care.

Synthesis of Naphthoquinone Derivatives: Menaquinones, Lipoquinones and Other Vitamin K Derivatives.

Menaquinones are a class of isoprenoid molecules that have important roles in human biology and bacterial electron transport, and multiple methods have been developed for their synthesis. These compounds consist of a methylnaphthoquinone (MK) unit and an isoprene side chain, such as found in vitamin K1 (phylloquinone), K2, and other lipoquinones. The most common naturally occurring menaquinones contain multiple isoprene units and are very hydrophobic, rendering it difficult to evaluate the biological activity of these compounds in aqueous assays. One way to overcome this challenge has been the application of truncated MK-derivatives for their moderate solubility in water. The synthesis of such derivatives has been dominated by Friedel-Crafts alkylation with BF3∙OEt2. This attractive method occurs over two steps from commercially available starting materials, but it generally produces low yields and a mixture of isomers. In this review, we summarize reported syntheses of both truncated and naturally occurring MK-derivatives that encompass five different synthetic strategies: Nucleophilic ring methods, metal-mediated reactions, electrophilic ring methods, pericyclic reactions, and homologation and side chain extensions. The advantages and disadvantages of each method are discussed, identifying methods with a focus on high yields, regioselectivity, and stereochemistry leading to a detailed overview of the reported chemistry available for preparation of these compounds.

Design and Catalytic Application of Functional Porous Organic Polymers: Opportunities and Challenges.

This review article encompasses the progress and conventional overview of current research activities of porous organic polymers (POPs), especially in catalysis, as they have garnered colossal interest in the scientific fraternity due to their intriguing characteristic features. Various synthetic strategies with possible modification of functionality of POPs have been used to improve the catalytic efficiency towards value-added chemicals production. Accordingly, this review article is mainly focused on the design, development of various functionalized POPs by employing Friedel-Crafts alkylation, FeCl3 assisted oxidative polymerisation and polymerisation in nonaqueous medium, and a comprehensive understanding in potential catalytic applications namely, acetalization, hydrodeoxygenation (HDO), hydrogenation, coupling, photocatalytic hydrogen evolution and biomass conversion towards the production of value-added chemicals in biodiesel and chemical industries.

Different behaviors of cyclic dipeptide prenyltransferases toward the tripeptide derivative ardeemin fumiquinazoline and its enantiomer.

In nature, cyclic dipeptide prenyltransferases catalyze regioselective Friedel-Crafts alkylations of tryptophan-containing cyclic dipeptides. This enzyme class, belonging to the dimethylallyl tryptophan synthase superfamily, is known to be flexible toward aromatic prenyl acceptors, while mostly retaining its typical regioselectivity. Ardeemin fumiquinazoline (FQ) (1), a tryptophan-containing cyclic tripeptide derivative, is assembled in Aspergillus fischeri by the non-ribosomal peptide synthetase ArdA and modified by the prenyltransferase ArdB, leading to the pharmaceutically active hexacyclic ardeemin. Therefore, 1 and its enantiomer ent-ardeemin FQ (2) constitute potential substrates for aromatic prenyltransferases. In this study, we investigated the acceptance of both enantiomers by two cyclic dipeptide C2-prenyltransferases BrePT and FtmPT1 and three C3-prenyltransferases CdpNPT, CdpC3PT, and AnaPT. LC-MS analysis of the incubation mixtures and NMR analysis of the isolated products revealed that the stereochemistry at C11 and C14 in 1 and 2 has a strong influence on their acceptance by these enzymes and the regioselectivity of the prenylation reactions. 1 was very well accepted by BrePT, FtmPT1, and CdpNPT, with C2- or C3-prenylated derivatives as predominant products, which fills the prenylation gaps by tryptophan prenyltransferases reported in a previous study. 2 was a poor substrate for all the enzymes and converted with low regioselectivity and mainly prenylated at C6 and C7 of the indole moiety.

Total Synthesis of (-)-Daphenylline.

A concise and highly stereoselective total synthesis of the Daphniphyllum alkaloids (-)-daphenylline has been accomplished. The synthesis was started from (S)-carvone and proceeded via a stereoselective Mg(ClO4 )2 -catalyzed intramolecular amide addition cyclization, an intramolecular Diels-Alder reaction to construct the ABCD tetracyclic core architecture, and a Robinson annulation coupled with an oxidative aromatization sequence. Finally, the DF ring system was installed through an intramolecular Friedel-Crafts cyclization. The total synthesis of (-)-daphenylline is achieved in 19 steps in the longest reaction sequence and in 7.6 % overall yield.

Enantioselective Friedel-Crafts Alkylation Reactions of ß-Naphthols with Donor-Acceptor Aminocyclopropanes.

The enantioselective Friedel-Crafts alkylation reaction of ß-naphthols with donor-acceptor aminocyclopropane was developed. In the presence of a copper complex derived from Cu(OTf)2 and bisoxazoline, a series of γ-substituted γ-aminobutyric acid derivatives were obtained with good yields (up to 98 %) and excellent enantioselectivities (up to 98 %). Using this catalytic system, the 2-amino cyclopropane-1,1-dicarboxylate was obtained with high enantiomeric excess (up to 98 %) by an efficient kinetic resolution (s values of up to 90). The Friedel-Crafts alkylation product could be transformed into a tetracyclic 1,3-oxazine derivative.

Transition-Metal-Free Selective C-H Benzylation of Tertiary Arylamines by a Dearomatization-Aromatization Sequence.

Due to the significance of hybrid systems in drug discovery, there is an urgent need to assemble multiple biologically active ingredients into a single molecule. Here, we report a general transition-metal-free selective C-H benzylation of tertiary arylamines in good to excellent yields with a broad substrate scope and high functional-group tolerance under mild conditions. Besides arylamines, some other benzene derivatives also readily furnished the corresponding diaryl methane derivatives with this protocol. A series of control experiments and theoretical calculations indicated that this transition-metal-free reaction is a dearomatization-aromatization process.

Catalytic asymmetric synthesis of indole derivatives as novel α-glucosidase inhibitors in vitro.

Indole containing compounds have acquired conspicuous significance due to their wide spectrum of biological activities. Synthesis of a series of enantiomerically pure indole derivatives 3a-rvia Friedel-Crafts alkylation of indole 1 with enones 2a-r were described here. The products were isolated in a moderate to excellent yields (upto 89%) with excellent enantioselectivities (upto 99.9% ee). These compounds 3a-r were evaluated for their in vitro α-glucosidase inhibitory activity and some of them were identified as potent inhibitors (IC50 = 4.3 ±â€¯0.13-43.9 ±â€¯0.51 µM) with several fold higher activity than the clinically used α-glucosidase inhibitor, acarbose (IC50 = 840 ±â€¯1.73 µM). To the best of knowledge, this is the first report of the propanone substituted indole ring containing compounds by in vitro α-glucosidase enzyme inhibition.

Mutation on Gly115 and Tyr205 of the cyclic dipeptide C2-prenyltransferase FtmPT1 increases its catalytic activity toward hydroxynaphthalenes.

The fungal cyclic dipeptide prenyltransferase FtmPT1 from Aspergillus fumigatus catalyzes a regular C2-prenylation of brevianamide F (cyclo-L-Trp-L-Pro) and is involved in the biosynthesis of a number of biologically active natural products including tryprostatins, spirotryprostatins, verruculogen, and fumitremorgins. FtmPT1, like other members of the dimethylallyltryptophan synthase superfamily, was shown to have high substrate promiscuity for tryptophan-containing cyclic dipeptides and a few other aromatic substrates. A previous study demonstrated the acceptance of 1-naphthol by FtmPT1, but with very low product yield. In this study, we report the significantly increased acceptance of 1-naphthol and other hydroxynaphthalenes by FtmPT1_G115A and six FtmPT1_Y205X single mutants as well as FtmPT1_G115A_Y205C. These results provided an example for creation of biocatalysts with improved catalytic activity by site-directed mutagenesis.