Bicyclic Derivatives Research Articles

Synthesis of bicyclic proline derivatives by the aza-Cope-Mannich reaction: formal synthesis of (±)-acetylaranotin.

Herein we suggest an approach to oxygenated bicyclic amino acids based on an aza-Cope-Mannich rearrangement. Seven distinct amino acid scaffolds analogous to the natural products were prepared on a gram scale with precise control of stereochemistry. Successful implementation of our strategy resulted in the formal synthesis of acetylaranotin.

ChemInform Abstract: Catalyst‐Free Cascade Reaction of Heterocyclic Ketene Aminals with N‐Substituted Maleimide to Synthesise Bicyclic Pyrrolidinone Derivatives.

AbstractThe title reaction provides a facile access to a wide variety of bicyclic pyrrolidine derivatives.

Isolation and SAR studies of bicyclic iminosugars from Castanospermum australe as glycosidase inhibitors

We report the isolation and structural determination of fourteen iminosugars, containing five pyrrolizidines and five indolizidines, from Castanospermum australe. The structure of a new alkaloid was elucidated by spectroscopic methods as 6,8-diepi-castanospermine (13). Our side-by-side comparison between bicyclic and corresponding monocyclic iminosugars revealed that inhibition potency and spectrum against each enzyme are clearly changed by their core structures. Castanospermine (10) and 1-deoxynojirimycin (DNJ) have a common d-gluco configuration, and they showed the expected similar inhibition potency and spectrum. In sharp contrast, 6-epi-castanospermine (12) and 1-deoxymannojirimycin (manno-DNJ) both have the d-manno configuration but the α-mannosidase inhibition of 6-epi-castanospermine (12) was much better than that of manno-DNJ. 6,8-Diepi-castanospermine (13) could be regarded as a bicyclic derivative of talo-DNJ, but it showed a complete loss of α-galactosidase A inhibition. This behavior against α-galactosidase A is similar to that observed for 1-epi-australine (6) and altro-DMDP.

One-pot synthesis of bicyclic sugar oxazolidinone from d-glucosamine

Herein we report a one-pot and efficient method for the synthesis of a 1,2-cis fused furanoside bicyclic oxazolidinone derivative of d-glucosamine via pyranose to furanose conversion and concomitant cyclization involving the N-Troc group.

SYNTHESIS AND BIOLOGICAL EVALUATION OF SOME NOVEL FUSED THIAZOLO[3,2A]PYRIMIDINES AS POTENTIAL ANALGESIC AND ANTI-INFLAMMATORY AGENTS.

Some novel bicyclic thiazolopyrimidine derivatives bearing various substituents have been synthesized through one-pot three-component method. Structures of the target compounds were confirmed by elemental analysis and spectral data. Some selected members of the newly synthesized compounds were investigated for their analgesic and anti-inflammatory activities and revealed pronounced anti-inflammatory activity greater than that of indomethacin (reference drug).

Exploitation of in situ generated sugar-based olefin keto-nitrones: synthesis of carbocycles, heterocycles, and nucleoside derivatives.

Application of intramolecular 1,3-dipolar nitrone cycloaddition reaction on carbohydrate-derived precursors containing an olefin functionality at C-1 or C-3 or C-5 and a nitrone moiety at C-2 or C-3 as appropriate has resulted in the formation of structurally new cycloaddition products containing furanose-fused oxepane, thiepane, azepane, cyclopentane, cycloheptane, tetrahydrofuran, and pyranose-fused tetrahydrofuran rings. The structure and stereochemistry of these products have been characterized by spectral as well as single-crystal X-ray analyses. Two of the compounds have been transformed to the bicyclic nucleoside derivatives applying Vorbrüggen reaction conditions.

Solvent- and Catalyst-Free Synthesis of Nitrogen-Containing Bicycles through Hemiaminal Formation/Diastereoselective Hetero-Diels-Alder Reaction with Diazenes.

A solvent- and catalyst-free synthesis of nitrogen-containing bicyclic derivatives through a three-bond forming process is reported. Starting from dienals and readily available diazenes, the strategy involving the hemiaminal formation/hetero-Diels-Alder reaction affords the bicyclic products in a highly diastereoselective manner. This simple and green procedure has been applied to a selection of substrates, giving rise to 12 examples of nitrogen-containing bicyclic architectures. These products underwent various synthetic transformations. A sequence involving the cleavage of the hydrazine allowed the preparation of a hydantoin motif bearing an aminopropyl side chain, which is a structure found in natural products. A mechanism has also been suggested to explain the observed selectivities.

1,2-Hydroboration and 1,1-Carboboration of Alkynyl(ferrocenyl)vinylsilanes. Novel Siloles

Abstract Alkynyl(ferrocenyl)vinylsilanes containing up to three alkynyl units were prepared and treated with 9-borabicyclo[3.3.1]nonane (9-BBN). All reactions proceeded in the beginning by regioselective 1,2-hydroboration of the vinyl group, with boron attached to the terminal carbon. This was followed by intra-molecular 1,1-carboboration, leading to fused silacarbacycles, depending on the number of C≡C bonds. Thus, new siloles and even fused siloles became available. The solution-state structures were revealed by multinuclear NMR techniques (1H, 11B, 13C, 29Si NMR), complemented by calculated single-molecule structures and calculated NMR parameters at the B3LYP/6-311+G(d,p) level of theory. In one case, the solid-state structure of a bicyclic derivative was determined.

Reactivity of TpMe2-Containing Hydride–Iridafurans with Alkenes, Alkynes, and H2

The TpMe2-containing hydride-iridafurans 2a,b (TpMe2 = hydrotris(3,5-dimethylpyrazolyl)borate) cleanly reacted with ethylene to give the bicyclic derivatives 6a,b. Formation of the latter complexes is a reversible process, and it is proposed to occur by an electrocyclic ring closure that takes place between C2H4 and the 16e unsaturated intermediates A, resulting from hydride migration to the α carbon of the metallacycle. Similar reactions were observed with a variety of alkynes RC≡CR (R = H, Ph, CO2Me) and R′C≡CH (R′= CO2Me, Ph, CMe3), with the regioselectivity observed for the latter substrates depending on the nature of R′. In the case of Me3SiC≡CH the structure of an unexpected byproduct indicates that an alkyne–vinylidene rearrangement has taken place on the metal coordination sphere during the reaction, and this observation suggests that in the mechanism of all these coupling processes the corresponding π adducts are active intermediates. Finally, complexes 2a,b reacted with H2 to give products derived from the hydrogenation of their alkenyl arms.

Pyridoxine-derived bicyclic amido-, ureido-, and carbamato-pyridinols: synthesis and antiangiogenic activities

We recently developed an efficient and practical synthesis for a novel series of pyridoxine-derived 6-amido-2,4,5-trimethylpyridin-3-ols and found that this novel scaffold has outstanding activity to inhibit angiogenesis measured by the quantitative chick embryo chorioallantoic membrane (CAM) assay. As an effort to extend the scope of the amidopyridinol scaffold, we here report the synthesis and antiangiogenic activities of a series of bicyclic versions of the amidopyridinol including five- and six-membered cyclic amide-, cyclic urea-, and cyclic carbamate-fused pyridinols. The six membered bicyclic derivatives were prepared by the reported procedures, and the five-membered ring-fused ones were synthesized by new synthetic methods developed in this study. CAM assays showed that both six- and five-membered lactam-fused pyridinols have activities comparable to sunitinib malate, the positive control, in inhibition of vascular endothelial growth factor-induced angiogenesis. On the other hand, the urea and the carbamate derivatives showed modest to moderate antiangiogenic activities. In summary, some bicyclic aminopyridinols can provide a good platform for structural exploitation in future medicinal chemistry work.

Palladium-catalysed cyclisation of alkenols: Synthesis of oxaheterocycles as core intermediates of natural compounds.

The study of Pd-catalysed cyclisation reactions of alkenols using different catalytic systems is reported. These transformations affect the stereoselective construction of mono- and/or bicyclic oxaheterocyclic derivatives depending on a starting alkenol. The substrate scope and proposed mechanism of Pd-catalysed cyclisation reactions are also discussed. Moreover, the diastereoselective Pd-catalysed cyclisation of appropriate alkenols to tetrahydrofurans and subsequent cyclisation provided properly substituted 2,5-dioxabicyclo[2.2.1]heptane and 2,6-dioxabicyclo[3.2.1]octane, respectively. Such bicyclic ring subunits are found in many natural products including ocellenynes and aurovertines.

Theoretical studies on two novel series of energetic cyclic nitramines

Density functional theory calculations at the B3LYP/6-31G** theoretical level were performed for two series of guanidine-fused bicyclic skeleton derivatives (B-B7 and C-C7). The heats of formation (HOFs) were calculated via isodesmic reaction; the detonation properties were evaluated using the Kamlet–Jacobs equations; the bond dissociation energies were also analyzed to investigate the thermal stability of the cyclic nitramines. The results show that all the derivatives have high positive HOFs; compounds containing –N3 groupshave the highest HOFs, while compounds containing –NF2 groups have the highest density and detonation properties. Taking both of the detonation properties and thermal stabilities into consideration, compounds B1, B2, B5, C3, and C5 can be considered as the potential candidate of high-energy density compounds.

ChemInform Abstract: Bicyclic Hybrid Sugars as Glycosidase Inhibitors: Synthesis and Comparative Study of Inhibitory Activities of Fused Oxa‐Oxa, Oxa‐Aza, and Oxa‐Carbasugar Hybrid Molecules.

AbstractSome new bicyclic sugar derivatives are prepared.

Synthesis and antiviral activity of new phenylimidazopyridines and N-benzylidenequinolinamines derived by molecular simplification of phenylimidazo[4,5-g]quinolines

Continuing our program of research concerning the antiviral activity of a wide series of new angular and linear azolo bicyclic and tricyclic derivatives, now we have simplified and modified the 4-chloro-2-(4-nitrophenyl)-3H-imidazo[4,5-g]quinoline 1, which previously resulted the most active derivative, through either the elimination of the central ring or the opening of the imidazole ring, obtaining various imidazopyridines and N-benzylidenequinolinamines respectively.Title compounds were tested in cell-based assays for cytotoxicity and antiviral activity against representatives of two DNA virus families as wells as against representatives of RNA virus families containing single-stranded, either positive-sense (ssRNA+) or negative-sense (ssRNA−), and double-stranded genomes (dsRNA). Some imidazo[4,5-b]pyridines emerged as new derivatives endowed with antiviral activity against Vaccinia Virus (VV) at concentrations ranging from 2 to 16 μM. In particular, compound 2b demonstrate to be about 10 times more potent than Cidofovir, used as reference drug. Similarly, the imidazo[4,5-c]pyridines and N-benzylidenequinolinamines derivatives resulted active against Bovine Viral Diarrhoea virus (BVDV), at concentrations ranging from 1.2 to 28 μM. Above all compounds 1, 3a and 3f showed an EC50 of the same order of magnitude of the reference drug, the 2′-C-methyl-guanosine. Moreover, several N-benzylidenequinolinamines showed an interesting activity against Respiratory Syncytial Virus (RSV) at concentrations between 12 and 26 μM.

Effect of the structure, solid state and lipophilicity on the solubility of novel bicyclic derivatives

Novel bicyclic derivatives have been synthesized. The solubility of drug-like substances in phosphate buffer рН 7.4 has been measured within the range of (9.02·10−5 to 1.05·10−4)mol/l. The relationship between the chemical nature and the structure of the aryl substituents and the solubility parameter was investigated. The fusion temperatures, enthalpies and entropies have been determined experimentally. The influence of thermophysical characteristics and lipophilicity on the solubility was studied using regression analysis. The calculations by the solubility/lipophilicity equation showed an overall improvement of the predictions equal to 0.5 log units. It was concluded that the solvation has a considerable influence on the solubility of the compounds under consideration. It was also determined that the alkyl- and halogen-derivatives solubility values correlate with HYBOT descriptors characterizing the (donor+acceptor) properties of the substances. The thermodynamic parameters of the solubility process were calculated using the temperature dependences. The study also revealed that the solubility of the bicyclic compounds is characterized by high endothermicity of the processes and negative entropies.

Solubility and Solution Thermodynamics of Novel Bicyclic Derivatives of 1,3-Selenazine in Biological Relevant Solvents

Drug-like N-substituted 1-selena-3-azaspiro[5,5]undec-2-en-2-amine hydrobromides (1:1) have been synthesized. Phenyl, isopropylphenyl, and fluorophenyl substituents were used. The solubility of the obtained compounds in pharmaceutically relevant solvents within the temperature range from (298.15 to 318.15) K has been measured using the isothermal saturation technique. All of the compounds studied appear to have poor solubility of ∼10–6 mole fraction in phosphate buffer pH 7.4 and hexane. The solubility values enlarge substantially to ∼10–2 and 10–4 mole fraction, respectively, in octanol and muriatic buffer solution pH 2.0. The solubility of the selenazines in aqueous media was shown to increase as the number of protonated forms grew. The high solubility of the compounds in octanol was found to depend on the formation of intermolecular solvent–solute hydrogen bonds. Thermodynamic solubility functions for the substances in the solvents studied have been calculated. The solubility in all of the systems with...

Stereoselective Formation of Tetrahydrofuran Rings via [3 + 2] Annulation: Total Synthesis of Plakortone L

The [3 + 2] annulation of 2,3-O-isopropylidene-aldehydo-aldose with methallyl ether leads to the stereoselective formation of a substituted tetrahydrofuran system, which is converted to a bicyclic lactone derivative via consecutive deprotection, oxidative cleavage of the terminal diol, oxidation of the resulting lactol, and Barton-McCombie deoxygenation. The efficiency of this process was demonstrated by the first total synthesis of Plakortone L.

Novel synthesis of dihydropyrimidines for α-glucosidase inhibition to treat type 2 diabetes: In vitro biological evaluation and in silico docking

A convenient and efficient new method has been established for the synthesis of dihydropyrimidines by inexpensive and non-toxic N-acetyl glycine (NAG) catalysed reaction of aromatic aldehydes with ethyl acetoacetate and urea/thiourea. This method is applicable for various substituted aldehydes as well as urea and thiourea. It has also been used to synthesize bicyclic oxygen-bridged pyrimidine derivatives (4d, 4j). The biological assay revealed that the majority of compounds synthesized displayed modest inhibitory activity against α-glucosidase at low micro-molar concentrations. Molecular docking studies were also performed on the most active compound, 4f (with IC50 value 112.21±0.97μM), to show the enzyme – inhibitor interactions.

Stimuli-responsive host-guest systems based on the recognition of cryptands by organic guests.

CONSPECTUS: As the star compounds in host-guest chemistry, the syntheses of crown ethers proclaimed the birth of supramolecular chemistry. Crown ether-based host-guest systems have attracted great attention in self-assembly processes because of their good selectivity, high efficiency, and convenient responsiveness, enabling their facile application to the "bottom-up" approach for construction of functional molecular aggregates, such as artificial molecular machines, drug delivery materials, and supramolecular polymers. Cryptands, as preorganized derivatives of crown ethers, not only possess the above-mentioned properties but also have three-dimensional spatial structures and higher association constants compared with crown ethers. More importantly, the introduction of the additional arms makes cryptand-based host-guest systems responsive to more stimuli, which is crucial for the construction of adaptive or smart materials. In the past decade, we designed and synthesized crown ether-based cryptands as a new type of host for small organic guests with the purpose of greatly increasing the stabilities of the host-guest complexes and preparing mechanically interlocked structures and large supramolecular systems more efficiently while retaining or increasing their stimuli-responsiveness. Organic molecules such as paraquat derivatives and secondary ammonium salts have been widely used in the fabrication of functional supramolecular aggregates. Many host molecules including crown ethers, cyclodextrins, calixarenes, cucurbiturils, pillararenes, and cryptands have been used in the preparation of self-assembled structures with these guest molecules, but among them cryptands exhibit the best stabilities with paraquat derivatives in organic solvents due to their preorganization and additional and optimized binding sites. They enable the construction of sophisticated molecules or supramolecules in high yields, affording a very efficient way to fabricate stimuli-responsive functional supramolecular systems. This Account mainly focuses on the application of cryptands in the construction of mechanically interlocked molecules such as rotaxanes and catenanes, and stimuli-responsive host-guest systems such as molecular switches and supramolecular polymers due to their good host-guest properties. These cryptands are bicyclic derivatives of crown ethers, including dibenzo-24-crown-8, bis(m-phenylene)-26-crown-8, dibenzo-30-crown-10, and bis(m-phenylene)-32-crown-10. The length of the third arm has a very important influence on the binding strength of these cryptands with organic guests, because it affects not only the size fit between the host and the guest but also the distances and angles that govern the strengths of the noncovalent interactions between the host and the guest. For example, for bis(m-phenylene)-32-crown-10-based cryptands, a third arm of nine atoms is the best. The environmental responsiveness of these cryptand-based host-guest systems arises from either the crown ether units or the third arms. For example, a dibenzo-24-crown-8 unit introduces potassium cation responsiveness and an azobenzene group on the third arm imbues photoresponsiveness. We believe that studies on stimuli-responsive host-guest systems based on cryptands and organic guests will contribute significantly to future research on molecular devices, supramolecular polymers, and other functional supramolecular materials.

Two-fold tandem acyl-group shift/cyclization via gold catalysis

A complex cascade involving allendiynes in the presence of a cationic gold catalyst is described. The process features two sequential acylgroup shift/cyclization steps eventually delivering a bicyclic furan derivative from the acyclic precursor. A controlled sequence of molecular events can thus readily deliver the desired heterocycle with a remarkable selectivity.