Total Synthesis of Dalesconol A by Pd(0)/Norbornene-Catalyzed Three-Fold Domino Reaction and Pd(II)-Catalyzed Trihydroxylation.

Herein, we describe a concise total synthesis of dalesconol A through a "polycyclization/oxidation" approach. In the polycyclization stage, a Pd(0)/NBE-catalyzed 3-fold domino reaction and a subsequent intramolecular Michael addition have been utilized for the one-step assembly of the heptacyclic molecular skeleton. In the late stage of oxidation state adjustments, a stepwise sequence including site-selective benzylic oxidation, Pd(II)-catalyzed oxime ether directed trihydroxylation, and desaturation has been adopted to introduce the oxygen functionalities and furnish the synthesis of dalesconol A. With the advantage of the late-stage amidation of three C-H bonds in a single step, the amino analogue of dalesconol A has also been obtained with high efficiency.

Recent advances in total syntheses of natural products containing the benzocycloheptane motif.

Covering: 2010 to 2020Benzocycloheptane is a fundamental and unique structural motif found in pharmaceuticals and natural products. The total syntheses of natural products bearing the benzocycloheptane subunit are challenging and there are only a few efficient approaches to access benzocycloheptane. Thus, new methods and innovative strategies for preparing such natural products need to be developed. In this review, recent progress in the total syntheses of natural products bearing the benzocycloheptane motif is presented, and key transformations for the construction of benzocycloheptane are highlighted. This review provides a useful guide for those engaged in the syntheses of natural products containing the benzocycloheptane motif.

Pegylated triarylmethanes: Synthesis, antimicrobial activity, anti-proliferative behavior and in silico studies.

We describe herein the synthesis, characterization and biological studies of novel PEGylated triarylmethanes. Non-symmetrical and symmetrical triarylmethanes series have been synthesized by Friedel-Crafts hydroxyalkylation or directly from bisacodyl respectively followed by a functionalization with PEG fragments in order to increase bioavailability and biological effectiveness. The antimicrobial activity was investigated against Gram-positive and Gram-negative foodborne pathogens and against Candida albicans, an opportunistic pathogenic yeast. The anti-biocidal activity was also studied using Staphylococcus aureus as a reference bacterium. Almost all PEGylated molecules displayed an antifungal activity comparable with fusidic acid with MIC values ranging from 6.25 to 50 µg/mL. Compounds also revealed a promising antibiofilm activity with biofilm eradication percentages values above 80% for the best molecules (compounds 4d and 7). Compounds 7 and 8b showed a modest antiproliferative activity against human colorectal cancer cell lines HT-29. Finally, in silico molecular docking studies revealed DHFR and DNA gyrase B as potential anti-bacterial targets and in silico predictions of ADME suggested adequate drug-likeness profiles for the synthetized triarylmethanes.

Synthesis and Properties of NitroHPHAC: The First Example of Substitution Reaction on HPHAC.

Hexapyrrolohexaazacoronene (HPHAC) is one of the N-containing polycyclic aromatic hydrocarbons in which six pyrroles are fused circularly around a benzene. Despite the recent development of HPHAC analogues, there is no report on direct introduction of functional groups into the HPHAC skeleton. This work reports the first example of nitration reaction of decaethylHPHAC. The structures of nitrodecaethylHPHAC including neutral and two oxidized species (radical cation and dication), intramolecular charge transfer (ICT) character, and global aromaticity of the dication are discussed.

Divergent Biomimetic Total Syntheses of Ganocins†A-C, Ganocochlearins†C and D, and Cochlearol†T.

A divergent synthetic approach to six Ganoderma meroterpenoids, namely ganocins A-C, ganocochlearins C and D, and cochlearol T, has been developed for the first time. This synthetic route features a two-phase strategy which includes early-stage rapid construction of a common planar tricyclic intermediate followed by highly selective late-stage transformations into various Ganoderma meroterpenoids. Key to the strategy are a bioinspired intramolecular hetero-Diels-Alder reaction and Stahl-type oxidative aromatization, allowing efficient formation of the common tricyclic phenol intermediate. A nucleophilic dearomatization of the phenol unit, combined with a regioselective 1,4-reduction of the resulting dienone, enabled rapid access to ganocins B and C. Additionally, site-selective Mukaiyama hydration, followed by an intramolecular oxa-Michael addition/triflation cascade, served as a key strategic element in the chemical synthesis of ganocin A.

Synthesis, Characterization, and Cycloaddition Reactivity of a Monocyclic Aromatic 1,2,3,5-Tetrazine.

Herein we disclose the synthesis and full characterization of the first monocyclic aromatic 1,2,3,5-tetrazine, 4,6-diphenyl-1,2,3,5-tetrazine. Initial studies of its cycloaddition reactivity, mode, regioselectivity, and scope illustrate that it participates as the 4π-component of well-behaved inverse electron demand Diels-Alder reactions where it preferentially reacts with electron-rich or strained dienophiles. It was found to exhibit an intrinsic reactivity comparable to that of the isomeric 3,6-diphenyl-1,2,4,5-tetrazine, display a single mode of cycloaddition with reaction only across C4/N1 (no N2/N5 cycloaddition observed), proceed with a predictable regioselectivity (dienophile most electron-rich atom attaches to C4), and manifest additional reactivity complementary to the isomeric 1,2,4,5-tetrazines. It not only exhibits a remarkable cycloaddition reactivity, surprisingly good stability (e.g., stable to chromatography, long-term storage, presence of H2O even as reaction co-solvent), and broad cycloaddition scope, but it also displays powerful orthogonal reactivity with the 1,2,4,5-tetrazines. Whereas the latter reacts at extraordinary cycloaddition rates with strained dienophiles (tetrazine ligation), the new and isomeric 1,2,3,5-tetrazine displays similarly remarkable cycloaddition rates and efficiencies with amidines (1,2,3,5-tetrazine/amidine ligation). The crossover reactivities (1,2,4,5-tetrazines with amidines and 1,2,3,5-tetrazines with strained dienophiles) are sufficiently low to indicate they may be capable of use concurrently without competitive reactions.

Vinyl Carbocations Generated under Basic Conditions and Their Intramolecular C-H Insertion Reactions.

Here we report the surprising discovery that high-energy vinyl carbocations can be generated under strongly basic conditions, and that they engage in intramolecular sp3 C-H insertion reactions through the catalysis of weakly coordinating anion salts. This approach relies on the unconventional combination of lithium hexamethyldisilazide base and the commercially available catalyst, triphenylmethylium tetrakis(pentafluorophenyl)borate. These reagents form a catalytically active lithium species that enables the application of vinyl cation C-H insertion reactions to heteroatom-containing substrates.

Impact of consumption of repeatedly heated cooking oils on the incidence of various cancers- A critical review.

Repeated heating of vegetable oils at high temperatures during cooking is a very common cooking practice. Repeatedly heated cooking oils (RCO) can generate varieties of compounds, including polycyclic aromatic hydrocarbons (PAH), some of which have been reported as carcinogenic. RCO is one of the commonly consumed cooking and frying medium. These RCO consumption and inhalation of cooking fumes can pose a serious health hazard. Taking into account exploratory study, the present review aims to provide the consumption of RCO and its fumes cause the high incidence of genotoxic, mutagenic, tumorogenic and various cancers. The information on RCO and its fumes were collected through a library database and electronic search (ScienceDirect, PubMed, and Google Scholar). Remarkable studies demonstrated that the health adverse effects of RCO and its cooking fumes have been often attributed to their detrimental properties and ease to genotoxic, mutagenic and carcinogenic activities. RCO and its cooking fumes were found to enhance the incidence of aberrant cells, including breaks, fragments, exchanges and multiple chromosomal damages and micronuclei in a dose-dependent manner. Furthermore, the large consumption of RCO has been associated with a number of malignancies, including lung, colorectal, breast, and prostate cancers. The present review provides additional insights into the polluting features of PAHs produced various cancers via cooking activities in indoor environments.

Exploring the size of the lipophilic unit of the soluble epoxide hydrolase inhibitors.

Soluble epoxide hydrolase (sEH) inhibitors are potential drugs for several diseases. Adamantyl ureas are excellent sEH inhibitors but have limited metabolic stability. Herein, we report the effect of replacing the adamantane group by alternative polycyclic hydrocarbons on sEH inhibition, solubility, permeability and metabolic stability. Compounds bearing smaller or larger polycyclic hydrocarbons than adamantane yielded all good inhibition potency of the human sEH (0.4 ≤ IC50 ≤ 21.7 nM), indicating that sEH is able to accommodate inhibitors of very different size. Human liver microsomal stability of diamantane containing inhibitors is lower than that of their corresponding adamantane counterparts.

The Gas-Phase Formation Mechanism of Dibenzofuran (DBF), Dibenzothiophene (DBT), and Carbazole (CA) from Benzofuran (BF), Benzothiophene (BT), and Indole (IN) with Cyclopentadienyl Radical.

Benzofuran (BF), benzothiophene (BT), indole (IN), dibenzofuran (DBF), dibenzothiophene (DBT), and carbazole (CA) are typical heterocyclic aromatic compounds (NSO-HETs), which can coexist with polycyclic aromatic hydrocarbons (PAHs) in combustion and pyrolysis conditions. In this work, quantum chemical calculations were carried out to investigate the formation of DBF, DBT, and CA from the reactions of BF, BT, and IN with a cyclopentadienyl radical (CPDyl) by using the hybrid density functional theory (DFT) at the MPWB1K/6-311+G(3df,2p)//MPWB1K/6-31+G(d,p) level. The rate constants of crucial elementary steps were deduced over 600-1200 K, using canonical variational transition state theory with a small-curvature tunneling contribution (CVT/SCT). This paper showed that the production of DBF, DBT, and CA from the reactions of BF, BT, and IN with CPDyl involved six elementary steps: the addition reaction, ring closure, the first H shift, C-C cleavage, the second H shift, and elimination of CH3 or H. The cleavage of the C-C bond was regarded as the rate-determining step for each pathway due to the extremely high barrier. The 1-methyl substituted products were more easily formed than the 4-methyl substituted products. The main products were DBF and 1-methyl-DBF, DBT and 1-methyl-DBT, and CA and 1-methyl-CA for reactions of BF, BT, and IN with CPDyl, respectively. The ranking of DBF, DBT, and CA formation potential was as follows: DBT and methyl-DBT formation > DBF and methyl-DBF formation > CA, and methyl-CA formation. Comparison with the reaction of naphthalene with CPDyl indicated that the reactions of CPDyl attacking a benzene ring and a furan/thiophene/pyrrole ring could be inferred to be comparable under high temperature conditions.

Titanocene-Mediated Dinitrile Coupling: A Divergent Route to Nitrogen-Containing Polycyclic Aromatic Hydrocarbons.

A general synthetic strategy for the construction of large, nitrogen-containing polycyclic aromatic hydrocarbons (PAHs) is reported. The strategy involves two key steps: (1) a titanocene-mediated reductive cyclization of an oligo(dinitrile) precursor to form a PAH appended with di(aza)titanacyclopentadiene functionality; (2) a divergent titanocene transfer reaction, which allows final-step installation of one or more o-quinone, diazole, or pyrazine units into the PAH framework. The new methodology enables rational, late-stage control of HOMO and LUMO energy levels and thus photophysical and electrochemical properties, as revealed by UV/vis and fluorescence spectroscopy, cyclic voltammetry, and DFT calculations. More generally, this contribution presents the first productive use of di(aza)metallacyclopentadiene intermediates in organic synthesis, including the first formal [2 + 2 + 2] reaction to form a pyrazine ring.

Revisiting Polyarenes and Related Molecules: An Update of Synthetic Approaches and Structure-Activity-Mechanistic Correlation for Carcinogenesis.

A major proportion of basic cause for human cancer has been linked to widespread environmental pollutants including analogs of polyarenes. Search of an effective therapy can be started with the understanding of the generation of such "carcinogens" and their biological interactions. This review is to discuss the syntheses, structural activities, mechanistic and biological studies of polyarenes such as polycyclic aromatic hydrocarbons (PAHs), polycyclic azaarenes (PAAs) and their thia-analogs (PASH). It also summarizes the mechanism of mutagenicity and tumorigenicity via metabolic interventions producing diol epoxide complexes and eventually formation of DNA adducts. It suggests that inhibition of oxidative reactions and formation of diols and epoxides and unspecific intracellular activation of cytochrome P450 enzymes could be approaches in therapy against such mutagenicity and tumorigenicity. Thus, this review reflects that understanding of molecular mechanisms and activations along with a clinical and translational medicine approach would require achieving both prevention and treatment of this atrocity.

Total Synthesis of Tetarimycin A, (±)-Naphthacemycin A9, and (±)-Fasamycin A: Structure-Activity Relationship Studies against Drug-Resistant Bacteria.

Making use of a reductive olefin coupling reaction and Michael-Dieckmann condensation as two key operations, we have completed a concise total synthesis of tetarimycin A, (±)-naphthacemycin A9, and (±)-fasamycin A in a highly convergent and practical protocol. Synthetic procedures thus developed have also been applied to provide related analogues for structure-activity relationship studies, thereby coming to the conclusion that the free hydroxyl group at C-10 is essential for exerting inhibitory activities against a panel of Gram-positive bacteria, including drug-resistant strains VRE and MRSA.

Total Synthesis of Norsampsones A and B, Garcinielliptones N and O, and Hyperscabrin A.

The asymmetric total synthesis of five decarbonyl polycyclic polyprenylated acylphloroglucinols norsampsnes A (3) and B (4), garcinielliptones O (5) and N (6), and hyperscabrin A (7) is described. The synthesis to construct the core substituted cyclohexanone ring of these natural products was achieved by a key Dieckmann condensation. The chirality of the molecules was introduced by the stereoselective alkylation with Evans' oxazolidinones. The synthesis could be run on grams scale, and the Dieckmann condensation was investigated through the DFT calculations to help improve the yield of garcinielliptone O (5). Determination of the absolute configuration of garcinielliptones O (5) and N (6) was also achieved.

Fluorine-Containing Dibenzoanthracene and Benzoperylene-Type Polycyclic Aromatic Hydrocarbons: Synthesis, Structure, and Basic Chemical Properties.

Intramolecular photocyclization of stilbene derivatives (Mallory reaction) is one of the efficient methods for building polycyclic aromatic hydrocarbon (PAH) frameworks, and is also expected to be applicable to synthesis of fluorine-containing PAHs (F-PAHs). In this study, dibenzoanthracene-type (4a) and benzoperylene-type (4b) F-PAHs were synthesized using the Mallory reaction of the 1,4-distyrylbenzene-type π-conjugated molecule (3a), which was prepared by addition-defluorination of available octafluorocyclopentene (OFCP) and aryllithium in three steps. The structure of 4a originating from π⁻π interaction was characterized by X-ray crystallographic analysis. The absorption maxima of UV-Vis spectra and emission maxima of photoluminescence spectra of the PAHs were positioned at a longer wavelength compared to those of the corresponding unsubstituted PAHs, presumably due to the electron-withdrawing nature of perfluorocyclopentene (PFCP) units. The effect of PFCP units in F-PAHs was also studied by time-dependent density functional theory (TD-DFT) calculation.

Allylation of Orthoquinones Towards Annulated Polycyclic Aromatic Systems.

Promising results of an efficient and convenient strategy for the annulation of polycyclic aromatic compounds (PACs), employing orthoquinones as starting material and comprising allylation, pinacol rearrangement, ring-closing metathesis (RCM), and one-pot reduction followed by Wagner-Meerwein rearrangement, are presented. The strategy involves introducing triallylborane prepared in situ in the allylation step. Moreover, a novel expedient method for the preparation of 9,10-diallylphenanthrene was introduced.

Site-Directed Dimerization of Bowl-Shaped Radical Anions to Form a σ-Bonded Dibenzocorannulene Dimer.

Designed site-directed dimerization of the monoanion radicals of a π-bowl in the solid state is reported. Dibenzo[a,g]corannulene (C28 H14 ) was selected based on the asymmetry of the charge/spin localization in the C28 H14.- anion. Controlled one-electron reduction of C28 H14 with Cs metal in diglyme resulted in crystallization of a new dimer, [{Cs+ (diglyme)}2 (C28 H14 -C28 H14 )2- ] (1), as revealed by single crystal X-ray diffraction study performed in a broad range of temperatures. The C-C bond length between two C28 H14.- bowls (1.560(8) Å) measured at -143 °C does not significantly change upon heating of the crystal to +67 °C. The single σ-bond character of the C-C linker is confirmed by calculations. The trans-disposition of two bowls in 1 is observed with the torsion angles around the central C-C bond of 172.3(5)° and 173.5(5)°. A systematic theoretical evaluation of dimerization pathways of C28 H14.- radicals confirmed that the trans-isomer found in 1 is energetically favored.

Efficient Enantioselective Syntheses of (+)-Dalesconol A and B.

We herein report the first enantioselective syntheses of immunosuppressants (+)-dalesconol A and B in a highly efficient and concise manner, which features an efficient palladium-catalyzed enantioselective dearomative cyclization-kinetic resolution cascade to install the chiral all-carbon quaternary center, an effective sterically hindered Stille coupling, a powerful 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) oxidation to furnish all requisite unsaturation, and a tandem hydrolysis-ring closure sequence.

Polycyclic Aromatic Hydrocarbons via Iron(III)-Catalyzed Carbonyl-Olefin Metathesis.

Polycyclic aromatic hydrocarbons are important structural motifs in organic chemistry, pharmaceutical chemistry, and materials science. The development of a new synthetic strategy toward these compounds is described based on the design principle of iron(III)-catalyzed carbonyl-olefin metathesis reactions. This approach is characterized by its operational simplicity, high functional group compatibility, and regioselectivity while relying on FeCl3 as an environmentally benign, earth-abundant metal catalyst. Experimental evidence for oxetanes as reactive intermediates in the catalytic carbonyl-olefin ring-closing metathesis has been obtained.

Synthesis and Chiroptical Properties of Hexa-, Octa-, and Deca-azaborahelicenes: Influence of Helicene Size and of the Number of Boron Atoms.

Four members of a new class of cycloborylated hexa-, octa-, and deca-helicenes (1 a-d) have been prepared in enantiopure form, along with two cycloplatinated deca-helicenes (1 d', 1 d1 ), further extending the family of cycloplatinated hexa- and octa-helicenes reported previously. The azabora[n]helicenes display intense electronic circular dichroism and large optical rotations; the dependence of the optical activity on the size of the helix (n=6, 8, 10) and the number of boron atoms (1 or 2) has been examined in detail both experimentally and theoretically. The photophysical properties (nonpolarized and circularly polarized luminescence) of these new fluorescent organic helicenes have been measured and compared with the corresponding organometallic phosphorescent cycloplatinated derivatives (1 a1 -d1 ).