Fluorous Synthesis of Hydantoin-, Piperazinedione-, and Benzodiazepinedione-Fused Tricyclic and Tetracyclic Ring Systems

Fluorous proline derivatives generated from one-pot, three-component [3+2] cycloaddition of azomethine ylides are employed for different post-condensation reactions to form hydantoin-, piperazinedione-, and benzodiazepinedione-fused tricyclic and tetracyclic ring systems. The high synthetic efficiency is achieved by conducting fast microwave reactions and easy fluorous-solid phase extractions for reaction mixture purifications. Methods developed for these novel drug-like heterocyclic compounds can be applied to diversity-oriented library synthesis.     

A Novel Approach to Synthesis of Tricyclic Diterpenoid

A novel approach has been found and the first total synthesis of (±)-Salvirecognine was accomplished by using it. In which intramolecular cyclization and Friedel-Crafts alkylation took place simultaneously to afford key intermediates for synthesis of aromatic tricyclic diterpenoids OMe PPA O O O OMe 1 2 Scheme 1 As shown in Scheme 1 intramolecular cyclization and Friedel-Crafts alkylation took place simultaneously when compound 1 was treated by PPA at 125 ℃. In which the i-pr…     

Synthesis and Characterisation of Novel Tricyclic and Tetracyclic Furoindoles: Biological Evaluation as SAHA Enhancer against Neuroblastoma and Breast Cancer Cells

The dihydropyranoindole structures were previously identified as promising scaffolds for improving the anti-cancer activity of histone deacetylase inhibitors. This work describes the synthesis of related furoindoles and their ability to synergize with suberoylanilide hydroxamic acid (SAHA) against neuroblastoma and breast cancer cells. The nucleophilic substitution of hydroxyindole methyl esters with α-haloketones yielded the corresponding arylether ketones, which were subsequently cyclized to tricyclic and tetracyclic furoindoles. The furoindoles showed promising individual cytotoxic efficiency against breast cancer cells, as well as decent SAHA enhancement against cancer cells in select cases. Interestingly, the best IC₅₀ value was obtained with the non-cyclized intermediate.     

A Chiron-based Approach for the Synthesis of Tricyclic Tyrosine Analogue

A chiron approach-based enantioselective synthesis of designed tricyclic tyrosine analogue D-2 was developed. A SmI2-mediated free radical cyclization, an intramolecular Friedel-Crafts reaction and an intramolecular Mannich reaction served as key steps. These key steps were optimized and repeated in good yields. All the stereochemistries in the synthesis were established and confirmed.     

Intramolecular aldol condensation of Michael adducts of levoglucosenone and cyclododecanone

Base-promoted intramolecular aldol condensation of diastereomeric Michael adducts of levoglucosenone and cyclododecanone affords 12-hydroxy-14,20-dioxatetra-cyclo[9.6.1.1^12,17.1^13,16]icosan-18-one as a mixture of three diastereomers. The products thus obtained are promising for synthesizing 14-membered macrocyclic compounds, including cembranoids and their analogues.     

Tricyclic heterocycles as precursors to functionalized spirocyclic oximes

An efficient synthesis of functionalized spirocyclic oximes from tricyclic heterocycles is reported. This novel method accomplishes high diastereoselectivity via an intramolecular 1,3-dipolar cycloaddition with a regenerating Michael linker strategy. Ring opening of the tricyclic N-(trimethylsilyloxy)pyrrolo[3,4-c]isoxazolidine framework was found to be essential for successful N-alkylation of the tertiary amine on the polymer support. β-Elimination of the quaternary salt releases the spirocyclic oximes from the solid support in overall yields of 45–60%.     

Novel Entry to the Tricyclic Core of Stemofoline and Didehydrostemofoline

A novel approach to the tricyclic core of the Stemona alkaloids stemofoline and didehydrostemofoline has been discovered that features an intramolecular (3+2) dipolar cycloaddition of an unactivated carbon-carbon double bond with an azomethine ylide; the azomethine ylide was generated by an unprecedented reaction that occurred during a Swern oxidation of an α-(N-cyanomethyl)-β-hydroxy ester. In separate experiments, the efficacy of introducing the requisite oxygen functionality at C(8) and the 1-butenyl side chain at C(3) was established.     

A Counterion‐Directed Approach to the Diels–Alder Paradigm: Cascade Synthesis of Tricyclic Fused Cyclopropanes

An approach to the intramolecular Diels–Alder reaction has led to a cascade synthesis of complex carbocycles composed of three fused rings and up to five stereocenters with complete stereocontrol. Computational analysis reveals that the reaction proceeds by a Michael/Michael/cyclopropanation/epimerization cascade in which size and coordination of the counterion is key.     

Synthesis and Biological Evaluation of Novel Tetracyclic Benzothiazepines

6-Arylidene-2,3-dimethyl-6,7,8,9-tetrahydro-benzocyclohepten-5-one 2a–l were obtained by the condensation of 2,3-dimethyl/3-methyl benzocyclohepten-5-one 1 with appropriate aromatic aldehydes, and upon condensation with 2-aminothiophenol in ethyl alcohol yielded 1,5-benzothiazepine derivatives 3a–l, respectively. Compounds 3d and 3h were found to possess antimicrobial activity when tested against B. Subtilis. Compounds 3i and 3j were found to possess moderate anti-inflammatory activity. Compound 3b was found to possess comparable antifungal activity when compared to clotrimazole against Trichomonas species.

Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.     

An Efficient Approach to the [1,2,4]-Triazolo[3,2-d][1,5]Benzoxazepine Skeleton-A Novel Tricyclic Ring System

Unprecedented [1,2,4]-Triazolo[3,2-d][1,5]benzoxazepine skeleton was easily achieved by cycloaddition of the allene-like cations 3, derived from 4-chromanone arylhydrazones, to the triple bond of nitriles and ensuing ring enlargement. The structural assignment of one product (5d) has been ultimately accomplished by X-ray diffraction analysis.     

环十二碳酮与苯基乙二醇反应产物的分离及确定

环十二碳酮(1)与苯基乙二醇(2)在对甲苯磺酸催化下的反应粗产物具有浓郁的花香,最初我们以为这种香气来源于缩酮2-苯基-1,4-二氧杂螺[4,11]十六烷(3):但该反应粗产物经反复重结晶后得到的无色晶体却没有香气、经红外、~1H核磁等谱图及碳氢分析鉴定该无色晶体确是缩酮3.既然缩酮3没有气味,则反应粗产物的香气必然来自反应中的副产物。薄层色谱分析表明,该反应中副产物较多。我们猜测,副反应可能主要来自2。     

Synthesis and Antibacterial Activity of New Tetracyclic Triazolo-thiadiazino Fluoroquinolones

Since nalidixic acid1 was first clinically used as a potent antibacterial agent, many analogues, such as bicyclic ciprofloxacin2, tricyclic ofloxacin3, have become an important class of therapeutical compounds. Recently, novel tetracyclic fluoroquinolones having a thiazolooxazine ring with potent antibacterial activity against both G+ and G- have been reported4. In order to find better antibacterial agents for our urgent research of the multidrug resistant (MDR)5, we herein describe a facil…     

Stereoselective Cascade Cyclizations with Samarium Diiodide to Tetracyclic Indolines: Precursors of Fluorostrychnines and Brucine

A series of γ-indolylketones with fluorine, cyano or alkoxy substituents at the benzene moiety was prepared and subjected to samarium diiodide-promoted cyclization reactions. The desired dearomatizing ketyl cascade reaction forming two new rings proceeded in all cases with high diastereoselectivity, but with differing product distribution. In most cases, the desired annulated tetracyclic compounds were obtained in moderate to good yields, but as second product tetracyclic spirolactones were isolated in up to 29 % yield. The reaction rate was influenced by the substituents at the benzene moiety of the substrate as expected, with electron-accepting groups accelerating and electron-donating groups decelerating the cyclization process. In case of a difluoro-substituted γ-indolylketone a partial defluorination was observed. The intermediate samarium enolate of the tetracyclic products could be trapped by adding reactive alkylating agents as electrophiles delivering products with quarternary carbons. In the case of a dimethoxy-substituted tetracyclic cyclization product a subsequent reductive amination stereoselectively provided a pentacyclic compound that was subsequently N-protected and subjected to a regioselective elimination. The obtained functionalized pentacyclic product should be convertible into the alkaloid brucine by four well-established steps. Overall, the presented report shows that functionalized tetracyclic compounds with different substituents are rapidly available with the samarium diiodide cascade cyclization as crucial step. Hence, analogues of the landmark alkaloid strychnine, for example, with specific fluorine substitutions, should be easily accessible.     

Tetracyclic Thioxanthene Derivatives: Studies on Fluorescence and Antitumor Activity

Thioxanthones are bioisosteres of the naturally occurring xanthones. They have been described for multiple activities, including antitumor. As such, the synthesis of a library of thioxanthones was pursued, but unexpectedly, four tetracyclic thioxanthenes with a quinazoline–chromene scaffold were obtained. These compounds were studied for their human tumor cell growth inhibition activity, in the cell lines A375-C5, MCF-7 and NCI-H460. Photophysical studies were also performed. Two of the compounds displayed GI₅₀ values below 10 µM for the three tested cell lines, and structure–activity relationship studies were established. Three compounds presented similar wavelengths of absorption and emission, characteristic of dyes with a push-pull character. The structures of two compounds were elucidated by X-ray crystallography. Two tetracyclic thioxanthenes emerged as hit compounds. One of the two compounds accumulated intracellularly as a bright fluorescent dye in the green channel, as analyzed by both fluorescence microscopy and flow cytometry, making it a promising theranostic cancer drug candidate.     

Syntheses of Prekinamycin and a Tetracyclic Quinone from Common Synthetic Intermediates

Towards total synthesis of a series of kinamycin and related antibiotics via common synthetic intermediates, total synthesis of prekinamycin was achieved via Suzuki coupling of naphthaleneboronic acid and bromobenzene derivative, intramolecular Friedel? Crafts reaction of 2‐(naphthalen‐2‐yl)benzoic acid, and diazotization in ten steps from 3,5‐dimethylphenol. Synthetic studies towards kinamycin antibiotics was also examined, and the tetracyclic quinone core for kinamycins was synthesized. Palladium‐catalyzed site‐selective hydroxylation of a benzoic acid derivative with the AB‐D ring part was successfully applied to the selective D‐ring functionalizations.     

Tricyclic Pyridine Derivatives with High Affinity to the Central Benzodiazepine Receptor

Novel tricyclic heterocycles were prepared and evaluated for their affinity to the central benzodiazepine receptor. The most potent compounds with IC₅₀'s in the nanomolar range were; found among thienoquinolizines and benzo[a]quinolizines (cf. Tables 2–5). The central ring of the tricyclic ring system may be partially unsaturated (cf. Tables 2 and 4) or fully unsaturated (cf. Tables 3 and 5) without loss of the high affinity to the receptor. The position of the ester group in the pyridinone ring is crucial for good binding (cf. Tables 1 and 2). It may be replaced by a broad variety of functional groups, e.g. amides, alkyl carbamates, alkyl groups, and hydroxyalkyl groups (cf. Tables 2–5). In the benzo[a]quinolizines, shifting the halogen atom from C(10) to C(9) leads to complete loss of affinity to the benzodiazepine receptor (cf. Table 4).     

A Synthetic Approach for Constructing the 3/6/6/5‐Fused Tetracyclic Skeleton of Tenuipesine A

An efficient approach toward the 3/6/6/5‐fused tetracyclic skeleton of tenuipesine A has been accomplished. The strategy featured 1) a tandem Mitsunobu and 3,3‐rearrangement reaction yielding the key intermediate 7 with two adjacent all‐carbon quaternary centers with high d.r.; and 2) a tandem DBDMH‐mediated semipinacol rearrangement via a 1,2‐oxygen migration of an allylic hemiketal to construct the highly substituted tetrahydropyran ring.     

Synthesis,Structure, and Antimalarial Activity of Tricyclic 1,2,4-Trioxanes Related to Artemisinin

Two sets of tricyclic 1,2,4-trioxanes containing the ABC ( 10 , 11 ) and ACD ring portions ( 21 , 22 , 32 , 33 , 37 , and 38 ) of artemisinin ( 1 ) were synthesized by successive photo-oxygenation of appropriate enol-ether precursors to 1,2-dioxanes and inter- and intramolecular reaction with a carbonyl compound or oxo-substituted side-chain. The structures of 10 , 21 , and 22 were determined by X-ray analysis. The anti-malarial activity of all trioxanes, except 37 and 38 , was evaluated in vitro against chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum parasites. Trioxanes 11 and 21 were as active as artemisinin ( 1 ). It was found that neither the lactone function nor rings B and D of 1 were essential for activity. A possible pharmacophore for artemisinin-like activity, which embodies a spirocyclopentane group attached to C(3) of 1,2,4-trioxane, was proposed.