Search

2-Pyridone is characterized by a very wide range of reactivity of a different nature, ranging from electrophilic aromatic substitution, CH–metal-mediated reactions, and NH/OH functionalization of both possible lactam/lactim tautomers, through cycloaddition, to nucleophilic addition and transformation of the tautomeric C=O/C–OH moiety. The high availability of 2-pyridones and the possibility of their far-reaching functionalization additionally increased their values. Therefore, they are very useful building blocks for the synthesis of structurally diverse piperidine and pyridine compounds, including naturally occurring 2-pyridones. This review reports on the use of simple 2-pyridones in the synthesis of alkaloids and alkaloids-inspired compounds based on the piperidine or pyridine framework.1 Introduction2 Structure, Availability, and Reactivity of 2-Pyridones3 Monocyclic Piperidine Alkaloids from 2-Pyridones4 Polycyclic Alkaloids, Their Derivatives, and Alkaloid-Inspired Compounds from 2-Pyridones4.1 New Ring Formation Involving C/N Atoms of the 2-Pyridone Ring4.1.1 Indolizine-Fused 2-Pyridones: Camptothecins and Related Compounds4.1.2 Other Indolizines from 2-Pyridones4.1.3 Compounds Bearing the Quinolizine Ring System4.2 New Ring Formation Involving C/C Atoms of the 2-Pyridone Ring4.2.1 C-2/C-3 Ring Fusion4.2.2 C-3/C-4 Ring Fusion4.2.3 C-4/C-5 Ring Fusion4.2.4 C-5/C-6 Ring Fusion4.2.5 C-2/C-4 Ring Bridge4.2.6 C-2/C-6 Ring Bridge4.2.7 C-3/C-5 Ring Bridge4.2.8 C-3/C-6 Ring Bridge4.2.9 C-4/C-6 Ring Bridge5 Conclusion

Indolo[2,3-a]quinolizidine 1 (Scheme 1) has an interesting history. First synthesized by Keufer1 in 1950, this tetracyclic amine was subsequently prepared by several others,2–7 only later to be dis...

An efficient synthesis of 6-oxo-1,2,3,4,5,7,12,12b-octahydroindolo[2,3-α]quinolizine from 2-acetylpyridine and phenylhydrazine is described. This derivative of the natural alkaloid desbromoarborescidine A is an important entry point to the sarpagine-vobasine family of plant alkaloids.

A common strategy was developed to access both indolizino[8,7-b]indole and indolo[2,3-a]quinolizine derivatives from tryptamine-N-ethynylpropiolamide substrates in a switchable fashion via tuning both the electronic effects and steric effects.

Ent-homocyclopiamine B (1), a new prenylated indole alkaloid bearing an alicyclic nitro group along with 2-methylbutane-1,2,4-triol (2) were isolated from an endophytic fungus Penicillium concentricum of the liverwort Trichocolea tomentella (Trichocoleaceae). The structure of 1 was elucidated through extensive spectroscopic analyses and comparison with data reported for a structurally related nitro-bearing Penicillium metabolite, clopiamine C (3), which contain an indolizidine ring instead of the quinolizine ring in 1. The new compound, ent-homocyclopiamine B, exhibited slight growth inhibition against Gram-positive bacteria. Based on the reported biosynthesis of related compounds and the isolation of the mevalonic acid derived compound 2-methyl-1,2,4-butanetriol (2), we proposed that ent-homocylopiamine B (1) was biosynthesized from lysine and prenyl group-producing mevalonic pathway.

Octahydroindolo[2,3-a]quinolizine ring system forms the basic framework comprised of more than 2000 distinct family members of natural products. Despite the potential applications of this privileged substructure in drug discovery, efficient, atom-economic and modular strategies for its assembly, is underdeveloped. Here we show a one-step build/couple/pair strategy that uniquely allows access to diverse octahydroindolo[2,3-a]quinolizine scaffolds with more than three contiguous chiral centers and broad distribution of molecular shapes via desymmetrization of the oxidative-dearomatization products of phenols. The cascade demonstrates excellent diastereoselectivity, and the enantioselectivity exceeded 99% when amino acids are used as chiral reagents. Furthermore, two diastereoselective reactions for the synthesis of oxocanes and piperazinones, is reported. Phenotypic screening of the octahydroindolo[2,3-a]quinolizine library identifies small molecule probes that selectively suppress mitochondrial membrane potential, ATP contents and elevate the ROS contents in hepatoma cells (Hepa1–6) without altering the immunological activation or reprogramming of T- and B-cells, a promising approach to cancer therapy., Methods enabling the synthesis of diverse collections of nature-inspired compounds with potential medicinal use are sought after in drug design. Here, the authors report a build/couple/pair strategy to efficiently construct chiral polycyclic scaffolds and show their diversification for drug discovery screening.

The cascade oxidative annulation reactions of aryl imidazoles with two molecules of alkynes via multiple C-H activation proceed efficiently in the presence of [Cp*RhCl2]2 and Cu(OAc)2·H2O to give substituted benzo[ij]imidazo[2,1,5-de]quinolizine-based polyheteroaromatic compounds. This method is compatible with various functional groups, which are very useful for further synthetic transformations.

Tetrahydroberberine (systematic name: 9,10-dimethoxy-5,8,13,13a-tetrahydro-6H-benzo[g][1,3]benzodioxolo[5,6-a]quinolizine), C20H21NO4, a widely distributed naturally occurring alkaloid, has been crystallized as a racemic mixture about an inversion center. A bent conformation of the molecule is observed, with an angle of 24.72 (5)° between the arene rings at the two ends of the reduced quinolizinium core. The intermolecular hydrogen bonds that play an apparent role in crystal packing are 1,3-benzodioxole –CH2...OCH3and –OCH3...OCH3interactions between neighboring molecules.

The stereoselective synthesis of (−)-protoemetinol has been accomplished through nine steps from a known homoallylic amine. The key steps of the synthesis involve the efficient preparation of an aza-Claisen rearrangement (ACR) precursor using cross metathesis and amide enolate-induced ACR followed by acid-catalyzed transannulation for the elaboration of the benzo[α]quinolizine skeleton and three stereogenic centers. This unique synthetic route envisages a unified and versatile strategy for the synthesis of 2,3-disubstituted benzo[α]quinolizidine.

Highly active antiretroviral therapy (HAART) has been widely adopted to control the HIV-1 infection successfully. HIV-1 integrase (IN) inhibitors are primary drugs in HAART regimens targeting integration step in the HIV-1 life cycle. However, due to the emergence of viral resistance and cross-resistance amongst drugs, there is a pressing need for new and potent IN inhibitors. This review covers the three patents describing spirocyclic and phosphate substituted quinolizine derivatives as novel HIV-1 IN inhibitors for the discovery of new anti-HIV-1 drug candidates. Areas covered: This review is focused on spirocyclic and phosphate substituted quinolizine derivatives bearing the same metal chelation scaffold as novel HIV-1 IN inhibitors. Expert opinion: Generally, privileged structure-based optimizations have emerged as an effective approach to discover newly antiviral agents. More generally, due to the similar Mg2+ catalytic active centers of endoribonucleases, some divalent metal ion chelators were found to be versatile binders targeting multiple metalloenzymes. Therefore, privileged structure-based scaffold re-evolution is an important tactic to identify new chemotypes, to explore unknown biological activities, or to provide effective ligands for multiple targets by modifying the existing active compounds.

International audience; Benzo[a]quinolizine is an important heterocyclic framework that can be found in numerous bioactive compounds. The general scheme for the synthesis of these compounds was based on the preparation of the appropriate dihydroisoquinolines by Bischler-Napieralski cyclization with good yields, followed by the Pemberton method to form the oxazinones or pyridones derivatives via acyl-ketene imine cyclocondensation. All the synthesized compounds were assayed in vitro for their ability to inhibit mitochondrial respiratory chain. Most of the tested compounds were able to inhibit the integrated electron transfer chain, measured as NADH oxidation, which includes complexes I, III and IV, in the low micromolar range. Oxazino[2,3-a]isoquinolin-4-ones displayed greater activity than their pyrido[2,1-a]isoquinolin-4-ones analogs. Indeed, the presence of a furan ring in C₂ position of oxazino[2,3-a]isoquinolin-4-ones provided the compound (1g) with the most potent biological activity. Therefore, these compounds and especially the oxazinone derivatives are in the tendency of the new less toxic antitumor agents that target mitochondrial electron transport chain in a middle range potency.

The cerium(IV) ammonium nitrate (CAN)-catalyzed sequential multicomponent reaction between tryptamine, α,β-unsaturated aldehydes, and β-dicarbonyl compounds affords highly substituted indolo[2,3-a]quinolizines in a single synthetic operation. Two rings are generated through the creation of two C-C and two C-N bonds by a domino process comprising initial β-enaminone formation, followed by individual Michael addition, 6-exo-trig cyclization, iminium formation, and Pictet-Spengler steps. Furthermore, the reaction is diastereoselective and affords exclusively compounds with a trans relationship between the H-2 and H-12b protons. The use of amines bearing a less nucleophilic side chain aromatic ring (5-bromotryptamine, 3,4-dimethoxyphenylethylamine) prevents the Pictet-Spengler final step and leads to N-indolylethyl or N-phenylethyl-1,4-dihydropyridines, which are cyclized to the corresponding indolo[2,3-a]quinolizines or benzo[a]quinolizines in the presence of HCl in methanol/water. Treatment of the fused quinolizine derivatives with sodium triacetoxyborohydride led to the corresponding indolo[2,3-a]quinolizidines or benzo[a]quinolizidines, possessing four stereogenic centers, as mixtures of two diastereomers.

Starting from Boc-protected tryptamine and (S)-tetrahydro-5-oxo-2-furancarboxylic acid, facile enantioselective total synthesis of desbromoarborescidines A-C and the formal synthesis of (S)-deplancheine have been accomplished via a common intermediate (S)-indolo[2,3-a]quinolizine. Synthesis of enantiomerically pure (S)-acetoxyglutarimide, stereoselective reductive intramolecular cyclization, hydroxyl group-assisted in situ N-Boc-deprotection, selective deoxygenation of the xanthate ester, and lactam hydrolysis followed by an appropriate exchange of nitrogen regioselectivity in intramolecular cyclization were the decisive steps.

An expedited method was developed for the enantioselective synthesis of dodecahydrobenz[a]indolo[3,2-h]quinolizine containing five contiguous stereogenic centers with high enantioselectivities (99% ee). The methodology comprises a domino organocatalytic double Michael reaction and Pictet-Spengler-lactamization reaction. The structures and absolute configurations of the appropriate products were confirmed by X-ray analysis.

The aminobenzo[a]quinolizines were investigated as a novel class of DPP-IV inhibitors. The stereochemistry of this class plays an important role in the bioactivity. In this study, the mechanisms of how different configuration of three chiral centers of this class influences the binding affinity were investigated by molecular dynamics simulations, free energy decomposition analysis. The S configuration for chiral center 3* is decisive for isomers to maintain high bioactivity; the chirality effect of chiral center 2* on the binding affinity is largely dependent, while the S configuration for chiral center 2* is preferable to R configuration for the bioactivity gain; the effect of chiral center 11b* on the binding affinity is insignificant. The chirality specificity for three chiral centers is responsible for distinction of two van der Waals contacts with Tyr547 and Phe357, and of H-bonding interactions with Arg125 and Glu206. Particularly, the Arg125 to act as a bridge in the H-bonding network contributes to stable H-bonding interactions of isomer in DPP-IV active site.

Pingbeimunone A (1), a new compound, together with the known ussuriedine (2), benzo[7,8]fluoreno[2,1-b]quinolizine cevane-3,6,16,20-tetrol (3), ebeiedinone (4), pingbeimine C (5) and verticine (6) were isolated from Fritillaria ussuriensis. The structure was elucidated on the basis of spectral analysis (IR, NMR and MS spectroscopy). In addition, their AChE inhibitory activities were also tested.

Phosphane-free Pd0-catalyzed intramolecular aromatic amination was studied. o-Halophenethylamines and 3-(o-halophenyl)propylamines were found to be transformed into indolines and quinolines in a catalytic system based on Pd(OAc)2 and Cu(OAc)2 in the presence of K2CO3. Application of the method to substrates containing isoquinoline rings – the 1-(o-bromobenzyl)-3,4-dihydroisoquinolines 6, the 1-(o-bromobenzyl)-1,2,3,4-tetrahydroisoquinolines 7, and the 1-(o-bromophenethyl)isoquinolines 9 – provided the indolo[2,1-a]isoquinoline and dibenzo[a,f]quinolizine ring systems 8 and 10. Extension of the method to β-carbolines (compounds 11, 12, and 17) produced the benz[f]indolo[2,3-a]indolizine-13-ones 15 and the benz[f]indolo[2,3-a]quinolizine 18. The benzo[f]pyrido[3,4-a]indolizine and indolo[f]pyrido[3,4-a]indolizin-12-one ring systems 27 and 31 were built in a similar manner. It was also found that under an atmosphere of CO the same catalytic system produced the corresponding benzolactams, the isoquino[2,1-a][2,7]naphthyridine 34 and the indolo[2,3-a]pyrido[g]quinolizin-8-one 36 [(±)-dihydronauclefine] in good yields.

This review summarizes recent medicinal chemistry investigations in vitro and in vivo in search for new phenothiazines of promising biological activities. New phenothiazine derivatives (over 50 main structures) contain dialkylaminoalkyl, cycloaminoalkyl and aminoalkyl substituents and their acyl and sulfonyl derivatives, and other substituents with varied the monocyclic (pyrazole, thiazole, oxadiazole, thiadiazole, tetrazole) and bicyclic (quinolizine, pyrazolopyrimidine, thiazolopyridine, azabicyclononane and spiro[chromanpyrimidine] heterocycles linked directly or via the alkyl chain with the thiazine nitrogen atom or with the benzene ring. The modifications of the tricyclic ring system with the bicyclic homoaromatic ring (naphthalene) and monocyclic and bicyclic azine rings (pyridine, pyrimidine, pyrazine and quinoline) led to compounds of significant biological activities. Recently obtained phenothiazines exhibit promising antibacterial, antifungal, anticancer, antiviral, anti-inflammatory, antimalarial, antifilarial, trypanocidal, anticonvulsant, analgesic, immunosuppressive and multidrug resistance reversal properties. These activities were the results of the actions of phenothiazines on biological systems via the interaction of the pharmacophoric substituent (in some cases of strict length), via the interaction of the multicyclic ring system (π-π interaction, intercalation in DNA) and via the lipophilic character allowing the penetration through the biological membranes. The activities were examined by using various biological systems such as cell lines, bacteria, viruses, parasites, laboratory mice, rats and rabbits, and monolayer and bilayer membranes. Some mechanisms of the actions are discussed. This review shows current tendency in the phenothiazine synthesis (without synthetic routes) and reveals the phenothiazine core to be very potent pharmacophoric moiety which can be a rich source of new compounds having desirable biological activities.

Cyclization of 2-(4-R-piperidino)benzaldehydes with 5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one proceeding via tert-amino effect mechanism is stereoselective. Relative configuration of (3R*,4aS*,5R*)-2,3,4,4a,5,6-hexahydro-1H-benzo[c]quinolizine was established on the base of NMR spectroscopy data and X-ray analysis.

To some of the quinolizine derivatives described earlier (1 and 2) we have been able to assign a cis or trans structure on the strength of a stereoselective synthesis. Infrared spectral data and differences in the rate of dehydrogenation, combined with a study of the conformations possible, allowed such assignment for other compounds in this series.

The preparation of some derivatives of 1,3,4,6,7,1 1b-hexahydro-9,10-dimethoxy-2H-benzo[a]quinolizine and 1,2,3,4,6,7,12,12b-octahydroindolo-[2,3-a]quinolizine substituted with two alkyl groups, either in the 1- or the 3-position is described. Two reaction routes were followed for each of the two types of compounds and some of the numerous intermediates have been isolated.

The preparation of a number of 2-substituted 1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-2H-benzo[a]quinolizines and 1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinolizines is described. Starting from 3-substituted valerolactones, the preparation required five stages (see Reaction Scheme I). A number of the 3-substituted valerolactones used were conveniently prepared by reduction of the corresponding glutaric acid derivatives, e.g. the anhydrides, with sodium borohydride. The final stage is a stereoselective reduction, leading to cis or trans isomers. The synthesis and data of one of the end-products, 1,3,4,6,7,11b-hexahydro -9,10-dimethoxy-2-phenyl-2H-benzo[a]quinolizine, are compared with those reported for this compound by Tomimatsu.

The condensation between 2-(2-oxocyclohexyl)propionic acid and β-arylethylamines, followed by dehydrogenation leads to 1-β-arylethylcarbostyrils in high yields, thus facilitating the Bishler-Napieralski pathway to dibenzo[a,f]quinolizines. An illustration is presented with the synthesis of 6,7,12,13-tetrahydro-9,10-dimethoxy-11bH-dibenz[a, f]quinolizine and 6,7,12,12b,13,14-hexahydrobenz[f]indolo[2,3-a]quinolizine. The octahydro-2-quinolone derivatives could not be reduced to the perhydro compounds, but resulted in a cyclised compound.

The influence of the nitrogen lone pair delocalisation with the adjacent aromatic ring in the trans-quinolizidine conformation of the title compound on the proton and carbon-13 n.m.r. spectral parameters distinguishes the assignment criteria for these compounds from the previously studied benzo-substituted quinolizidines.

Cyclopenta[a]quinolizine, a novel tricyclic pseudoazulene, was prepared by reaction of cyclopentadienyllithium with oxazolo[3,2-a]pyridinium or substituted pyridinium salts. Structural analysis (X-ray analysis, NMR and UV spectroscopy) and DFT calculations confirm its highly dipolar nature (due to delocalization of the negative charge around the five-membered ring) combined with partial localization of bonds in both six-membered rings.

We report a highly diastereoselective approach for the synthesis of a functionalized dodecahydrobenz[a]indolo[3,2-h]quinolizine ring system that is present as the heterocyclic core of the manadomanzamine alkaloids. We have achieved complete control over the relative and absolute stereochemistries at the three contiguous stereocentres at ring positions 1, 10 and 24 in only two linear synthetic steps. The introduction of useful functionality to the heterocyclic skeleton is significant as this may allow for future derivatization, and application of this route in an asymmetric synthesis of the manadomanzamine natural products.

The cyclization via the mechanism of “tert-amino effect” of 2-(4-R-piperidino)benzaldehydes with cyclic active methylene components (Meldrum’s acid, 1,3-cyclohexanedione, and N,N-disubstituted barbituric acids) proceeded stereoselectively giving spiro-joined 2,3,4,4a,5,6-hexahydro-1H-benzo[c]quinolizines with axially oriented hydrogen atoms in the positions 3 and 4a of the benzo[c]quinolizine ring.

A highly efficient total synthesis of (+/-)-yohimbenone and a formal synthesis of (+/-)-emetine is described. The key element of the synthesis consists of a conjugate addition-dipolar cycloaddition of 2,3-bis(phenylsulfonyl)-1,3-butadiene with an appropriate oxime. The resulting cycloadducts are cleaved reductively to provide azapolycyclic scaffolds with strategically placed functionality for further manipulation to the target compounds.

A three-step synthesis of (±)-harmacine is described from the readily available 4,4-diethoxybutan-1-amine via an acid-mediated acyl iminium ion cyclisation. The synthesis of the homologous (±)1,2,3,4,6,7,12,12b-octahydroindole[2,3-a]quinolizine from 5,5-diethoxypentan-1-amine is also described. Although similar, the two systems required very different cyclisation conditions.

In a search for novel DPP-IV inhibitors, 2-aminobenzo[a]quinolizines were identified as submicromolar HTS hits. Due to the difficult synthetic access to this compound class, 1,3-disubstituted 4-aminopiperidines were used as model compounds for optimization. The developed synthetic methodology and the SAR could be transferred to the 2-aminobenzo[a]quinolizine series, leading to highly active DPP-IV inhibitors.

We present a facile and highly stereoselective approach to the indolo[2,3-a]quinolizine ring system from a readily available, non-racemic chiral template. We demonstrate the potential for application of this methodology to natural product synthesis through conversion of the template to some representative indole alkaloids with high enantiomeric purity in both enantiomeric series. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

4-Hetaryl and 4-tosyl-1,2,3,3a,4,5-hexahydropyrrolo[l,2-a]quinoline-4-carbonitriles were prepared in two steps by the condensation of 2-(l-pyrrolidinyl)benzaldehydes with substituted acetonitriles XCH 2 CN (X = hetaryl, tosyl), followed by the thermal cyclization of the corresponding arylidene derivatives. Similarly, starting from 2-(l-piperidinyl)benzaldehydes 5-hetaryl and 5-tosyl-2,3,4,4a,5,6-hexahydro-1H-pyrido[l,2-a]qumoline-5-carbonitriles were obtained. For the hetaryl-substituted derivatives the cyclization step was found to be assisted by protons. In addition 4,5,5a,6,7,8-hexahydro-1H-pyrazolo[3,4-e]indolizine and l,4,5,5a,6,7,8,9-octahydro-pyrazolo[4,3-c]quinolizine derivatives were prepared by the same method starting from 5-(1-pyrrolidinyl)-and 5-(1-piperidinyl)-3-methyl-l-phenylpyrazole-4-carbaldehydes. The relative configuration between the bridgehead hydrogen and the cyano group was assigned as trans on the basis of x-ray crystallographic data.

The scope of the lanthanide mediated, sequential hydroamination/C–C cyclization reaction was determined for the formation of tricyclic and tetracyclic aromatic nitrogen heterocycles. An array of ring sizes was explored to determine the diastereoselectivity. The electronic characteristics of the aromatic ring was also varied to determine how it affected the cascade reaction. It was found that the benzo[a]quinolizine and the pyrido[2,1,a]isoindolizine ring systems formed with the highest diastereoselectivity (>20:1), regardless of the electronic characteristics of the aromatic ring. Additionally, a tetracyclic indole nitrogen heterocycle was formed with a 2.3:1 diastereomeric ratio. A novel procedure for substrate preparation is also presented.

Fluorescently labeled histamine H(1) receptor antagonists were synthesized starting from N-demethylmepyramine by introduction of omega-aminoalkyl chains (2-8 methylene groups in length) followed by derivatization of the terminal NH(2) group with various fluorophores (fluorescein, naphthofluorescein, rhodamine, tetramethylrhodamine, BODIPY, dansyl, and nitrobenzoxadiazole (NBD)). On the isolated guinea pig ileum and in a Ca(2+) assay on U373MG human glioblastoma cells the highest H(1) antagonistic activities were found in 5- and 6-carboxyfluorescein labeled compounds with hexa- and octamethylene spacers and in an analogous NBD-aminohexanoyl derivative (pA(2) or pK(B) values in the range: 8.3-9.0; compared to 9.3-9.4 for mepyramine).

Synthesis of indole alkaloid related compounds using Schiff base formation, intramolecular cyclization (or N-alkylation), and Pictet–Spengler reaction as a cascade one pot condensation has been reported. The cascade chemistry has been applied to the synthesis of (±)-harmicine as a key step.

A convenient ipso substitution method for the preparation of benzo[c]quinolizine (2) and 4-hydroxy-3-(2'-pyridyl)coumarin (3) has been developed. The intramolecular nucleophilic substitution reaction of 3-oxo-2-(2'-pyridyl)-(2-halophenyl)propanoate (1) in refluxing xylenes gives initially benzo[c]quinolizine, while further heating results in the formation of 4-hydroxycoumarin. A mechanism has been proposed to rationalize the two competitive reaction pathways, and the role of HCl is discussed. Under optimized conditions, seven benzo[c]quinolizines and five coumarins were prepared in moderate to good yields.

The article contains sections titled: Overview of the Universe of Sponges Metabolites of Calcarea (Calcareous Sponges) General Characteristics of Calcarea Fatty Acids Sterols Non-Nitrogenous Derivatives of Species of the Genus Leucetta Imidazole Alkaloids and Zinc Complexes Isolated from the Genera Leucetta, Leucosolenia, and Clathrina αω-Bis Long-Chain Aminoalcohols Nitrogen-Containing Macrolides and Cyclic Peptides Other Nitrogen-Containing Compounds of Calcarea Metabolites of Hexactinellida Classification and Membrane Constituents of Demospongiae Classification Some Physical Observations on Demosponges Shape and Size Consistency Color and Odor Diversity of Membrane Constituents: Some Examples Phospholipids and “Demospongic Acids” Fatty Acids with 5,9 Dienic Structure Other Mono- and Polyunsaturated Fatty Acids Branched Fatty Acids Isoprenic Acids Cyclopropanic Acids Brominated Acids 2-O Substituted Acids Sulfur Derivatives of Demospongic Acids Intracellular Localization and Biological Activity of Demospongic Acids Brief Reminder About Conventional Sterols Unconventional Sterols Produced by Changes in the Tetracyclic System Unconventional Sterols Produced by Polymethylation of the Side Chain Sterols with Degraded Side Chains Sterols and Stanols with Cyclopropanic and Cyclopropenic Side Chains Secosterols Polyhydroxylated Steroids and Derivatives, Peroxysterols Sulfated Sterols Chlorinated Sterols and Sterones Nitrogen-Containing Sterols Glycolipids Secondary Metabolites of Homoscleromorpha Fatty Acids, Polyketides and Oxylipins of Plakinastrella and Plakortis Cyclic Peroxides and Peroxylactones from Plakinastrella and Plakortis Glycosides Polyhydroxylated Sterols of Oscarella lobularis Alkaloids and Other Original Nitrogen Derivatives of Plakortis and Corticium Secondary Metabolites of Astrophorida Acetylenic Fatty Acids of Stelletta Cyclitol Derivatives Glycolipids: Caminosides and Pachymosides Triterpenes of Malabaricane and Isomalabaricane: Sesterterpenes Triterpenic Glycosides and Steroidal Glycosides Substituted Tetramic Acids and Derived Glycosides Erylusamines, Erylusine, and Erylusidine Cyclic Depsipeptides, Peptolides, and Macrolactones Nitrogen-Containing Terpenes Bengazoles and Bengamides Atypical Nitrogenous Derivatives Phosphorus-Containing Derivatives Aromatic and Heteroaromatic Sulfated Derivatives Isotactic Polymethoxydienes of Myriastra clavosa Keywords: A-nor-sterols; acetylenic derivatives; Actinobacteria; Agelasida; aragonite; Astrophorida; brominated acids; Calcarea; calcite; carotenoids; Chondrosida; Cyanobacteria; cyclic peptides; cyclic peroxides; cyclopropanic acids; Demospongiae; demospongic acids; Dendroceratida; depsipeptides; 3,5-dibromotyrosine derivatives; Dictyoceratida; diterpenes; fatty acids; galactosylceramides; glycolipids; glycosides; guanidine derivatives; Hadromerida; Halichondrida; Haplosclerida; Hexactinellida; Homoscleromorpha; Hopanoids; imidazole alkaloids; indole alkaloids; isonitriles; isoprenic acids; isoquinoline alkaloids; Litchfield matrix; Lithistida; macrolides; meroterpenes; nitrogen-containing terpenes; peroxylactones; phosphorus-containing derivatives; Poecilosclerida; polybromodiphenyl ethers; polyethers; Poribacteria; δ-Proteobacteria; pyridine derivatives; pyridoacridine alkaloids; pyrrole derivatives; quinolizine derivatives; quinone derivatives; secosterols; sesquiterpenes; sesterterpenes; Silicispongia; Spirophorida; squalenoids; steroids; sulfated sterols; sulfur-containing derivatives; triterpenes; Verongida; zinc complexes

The article contains sections titled: Secondary Metabolites of Hadromerida and Chondrosida Perforating Power of Clionaidae lyso-Phospholipids and Sulfated Sphingosines of Spirastrella abata Brominated Acetylenic Derivatives of Diplastrella Cyclic Peroxides Terpenes Unconventional Sterols Macrolactones: Latrunculins and Spongistatins Atypical Glycosides of Latrunculia corticata Other Nitrogen-Free Toxins Peptides and Depsipeptides Pyrrole Derivatives and other Nitrogen-Containing Heterocycles Atypical Nucleosides Secondary Metabolites of Lithistida Particular Characteristics of Lithistid Sponges Unusual Halogenated Fatty Acids Nitrogen-Containing Sesquiterpenes of Theonella Specific Glycolipids of Theonella swinhoei, Discodermia calyx and D. dissoluta Long-Chain Polyacetylenic Derivatives of Theonella sp 3β-Methoxysterols of Jereicopsis graphidiophora 4-Methylene Sterols and Sterones of Theonella Macrolides Examples of Acetogenins: Discodermolide, Calyculins, and Onnamides Linear Amides and Peptides Mono- and Bicyclic Peptides Symbiotic Origin of Some Polypeptides Cyclic and Linear Depsipeptides Atypical Nitrogenous Derivatives Secondary Metabolites of Spirophorida Atypical Sterols of Cinachyra, Microscleroderma, and Scleritoderma Cinachyrolide A, Enigmazole A Microsclerodermins and Aciculitins Examples of Atypical Derivatives of Some Sponges of the Tetillidae Secondary Metabolites of Agelasida Sterols Diterpenes and Carotenoids Gracilioethers of Agelas gracilis Merosesquiterpenes and Nitrogen-Containing Meroditerpenes Galactosylceramides and Glycolipids Oroidin and Related C11N5 Bromopyrrole Alkaloids Oroidin Series Agelastatin A Series Other Series Pyrrole-2-carboxylic Acid Derivatives Other Examples of Nitrogen-Containing Heterocycles Betaines Secondary Metabolites of Halichondrida A-nor-Steroids and Other Nonconventional Sterols Conventional Terpenes Nitrogen-Containing Terpenes: Isonitriles and Related Derivatives Other Terpenes Long-Chain Linear Polyamines and α,ω-bis-isothiocyanates Polyethers: Halichondrins, Okadaic, and Glycookadaic Acids Various Lipids Linear Peptides of the Genera Auletta and Cymbastela Depsipeptides and Cyclic Peptides Unusual Amino Acids and Betaines Pyrrole, Imidazole, Pyridine, Isoquinoline, and Indole Derivatives Pyrrole Derivatives Imidazole Derivatives Pyridine and Isoquinoline Derivatives Indole Derivatives Heterocycles Related to the Oroidin Family Atypical Halogenated and Sulfur-Containing Derivatives Keywords: A-nor-sterols; acetylenic derivatives; Actinobacteria; Agelasida; aragonite; Astrophorida; brominated acids; Calcarea; calcite; carotenoids; Chondrosida; Cyanobacteria; cyclic peptides; cyclic peroxides; cyclopropanic acids; Demospongiae; demospongic acids; Dendroceratida; depsipeptides; 3,5-dibromotyrosine derivatives; Dictyoceratida; diterpenes; fatty acids; galactosylceramides; glycolipids; glycosides; guanidine derivatives; Hadromerida; Halichondrida; Haplosclerida; Hexactinellida; Homoscleromorpha; Hopanoids; imidazole alkaloids; indole alkaloids; isonitriles; isoprenic acids; isoquinoline alkaloids; Litchfield matrix; Lithistida; macrolides; meroterpenes; nitrogen-containing terpenes; peroxylactones; phosphorus-containing derivatives; Poecilosclerida; polybromodiphenyl ethers; polyethers; Poribacteria; δ-Proteobacteria; pyridine derivatives; pyridoacridine alkaloids; pyrrole derivatives; quinolizine derivatives; quinone derivatives; secosterols; sesquiterpenes; sesterterpenes; Silicispongia; Spirophorida; squalenoids; steroids; sulfated sterols; sulfur-containing derivatives; triterpenes; Verongida; zinc complexes

The article contains sections titled: Secondary Metabolites of Haplosclerida Acetylenic Derivatives 1-Glyceryl Ethers from the Assemblage Ceratodictyon/Spongiosum/Haliclona/Cymaeformis Atypical Fatty Acids Terpenes and Meroterpenes Triterpenic Glycosides Hopanoids, Steroids and Sterosides Macrolides, Depsipeptides, and Cyclic Peptides Aminoalcohols and Glycosphingolipids (Cerebrosides) Manzamines and Related Derivatives Quinolizidine and 1-Oxaquinolizidine Derivatives Pyridine Derivatives and 3-alkylpyridinium Salts Pyridoacridine Alkaloids Pyrroloquinones and Other Examples of Nitrogen-Containing Heterocycles Quinones and Sulfated Hydroquinones Very Long-Chain Linear Sulfated Derivatives Thiocyanatins: α,ω-Dithiocyanates of Oceanapia sp Some Information on Freshwater Haplosclerid Sponges Secondary Metabolites of Poecilosclerida Sterols, Steroids, and Sterosides Terpenes and Triterpenic Glycosides Polybrominated Acetogenins and Oxylipins Long-Chain Acetylenic Derivatives: Raspailynes Glycolipids Brominated Aromatic Derivatives of Hamigera tarangaensis Macrolides Chondropsins: Cyclic Depsipeptides of Chondropsis sp Eurypamides (Microciona eurypa), Microcionamides (Clathria abietina) and Other Cyclic Peptides Linear Amides and Peptides Examples of Some Atypical Sulfur-Containing Derivatives Pyrrole and Indole Derivatives Pyridines, Quinolizines, and Pyridoacridines Guanidine Derivatives Pyrroloiminoquinones and Pyrroloquinones Azasugars and Cyclic Amines Other Examples of Polycyclic Alkaloids Phosphorus- and Arsenic-Containing Derivatives, Betaines Keywords: A-nor-sterols; acetylenic derivatives; Actinobacteria; Agelasida; aragonite; Astrophorida; brominated acids; Calcarea; calcite; carotenoids; Chondrosida; Cyanobacteria; cyclic peptides; cyclic peroxides; cyclopropanic acids; Demospongiae; demospongic acids; Dendroceratida; depsipeptides; 3,5-dibromotyrosine derivatives; Dictyoceratida; diterpenes; fatty acids; galactosylceramides; glycolipids; glycosides; guanidine derivatives; Hadromerida; Halichondrida; Haplosclerida; Hexactinellida; Homoscleromorpha; Hopanoids; imidazole alkaloids; indole alkaloids; isonitriles; isoprenic acids; isoquinoline alkaloids; Litchfield matrix; Lithistida; macrolides; meroterpenes; nitrogen-containing terpenes; peroxylactones; phosphorus-containing derivatives; Poecilosclerida; polybromodiphenyl ethers; polyethers; Poribacteria; δ-Proteobacteria; pyridine derivatives; pyridoacridine alkaloids; pyrrole derivatives; quinolizine derivatives; quinone derivatives; secosterols; sesquiterpenes; sesterterpenes; Silicispongia; Spirophorida; squalenoids; steroids; sulfated sterols; sulfur-containing derivatives; triterpenes; Verongida; zinc complexes

Benzo[a]quinolizine is an important heterocyclic framework that can be found in numerous bioactive compounds. The general scheme for the synthesis of these compounds was based on the preparation of the appropriate dihydroisoquinolines by Bischler-Napieralski cyclization with good yields, followed by the Pemberton method to form the oxazinones or pyridones derivatives via acyl-ketene imine cyclocondensation. All the synthesized compounds were assayed in vitro for their ability to inhibit mitochondrial respiratory chain. Most of the tested compounds were able to inhibit the integrated electron transfer chain, measured as NADH oxidation, which includes complexes I, III and IV, in the low micromolar range. Oxazino[2,3-a]isoquinolin-4-ones displayed greater activity than their pyrido[2,1-a]isoquinolin-4-ones analogs. Indeed, the presence of a furan ring in C₂ position of oxazino[2,3-a]isoquinolin-4-ones provided the compound (1g) with the most potent biological activity. Therefore, these compounds and especially the oxazinone derivatives are in the tendency of the new less toxic antitumor agents that target mitochondrial electron transport chain in a middle range potency.

The dehydrogenative coupling of imidazo[1,2-a]pyridine derivative has been achieved for the first time. In cases in which the most-electron-rich position of the electron-excessive heterocycle was blocked by a naphthalen-1-yl substituent, neither oxidative aromatic coupling nor reaction under Scholl conditions enabled the fusion of the rings. The only method that converted the substrate into the corresponding imidazo[5,1,2-de]naphtho[1,8-ab]quinolizine was coupling in the presence of potassium in anhydrous toluene. Moreover, we discovered new, excellent conditions for this anion-radical coupling reaction, which employed dry O2 from the start in the reaction mixture. This method afforded vertically fused imidazo[1,2-a]pyridine in 63 % yield. Interestingly, whereas the fluorescence quantum yield (Φfl) of compound 3, despite the freedom of rotation, was close to 50 %, the Φfl value of flat naphthalene-imidazo[1,2-a]pyridine was only 5 %. Detailed analysis of this compound by using DFT calculations and a low-temperature Shpol′skii matrix revealed phosphorescence emission, thus indicating that efficient intersystem-crossing from the lowest-excited S1 level to the triplet manifold was the competing process with fluorescence. Po raz pierwszy otrzymano nowy typ związku heterocyklicznego - imidazo[1,2-a]pirydyne sprzezoną w pozycjach 3 i 5 z naftalenem. Udowodniono, ze spośrod wszystkich metod wewnątrzcząsteczkowego odwodornienia tylko sprzeganie z wytworzeniem aniono-rodnikow prowadzi do oczekiwanego produktu. Opracowano przy tym nowe warunki prowadzenia tej reakcji, w ktorych suchy tlen jest obecny od początku w ukladzie reakcyjnym. Dokladne zbadanie wlaściwości optyczne obu związkow zarowno w roztworze jak i w matrycach Szpolskiego oraz poprzez obliczenia kwantowo-mechaniczne wykazaly, ze za niską wydajnośc kwantową fluorescencji odpowiedzialne jest przejście miedzysystemowe na nisko lezący stan trypletowy.

Efficient, stereocontrolled total synthesis of the title compound is described, starting from enantiopure intermediates. A key step was the diastereoselective catalytic hydrogenation of a pentacyclic oxazepinohexahydroindolo[2,3- a ]quinolizine derivative.

Novel synthetic routes to nitrogen-bridged derivatives of pyrrolo[2,1,5-cd]indolizine and pyrrolo[2,1,5-de]quinolizine were developed starting from 2-acyl-N-(acylmethyl)pyridinium halides. Thus, 2-benzoyl-N-phenacylpyridinium bromide (1) afforded 3,4-diphenylpyrrolo[2,1,5-cd]indolizines (4) via 1,3-dipolar cycloaddition, to yield 3,5-dibenzoylindolizines (3), followed by intramolecular McMurry coupling. Similarly, 2-(1,3-dioxolan-2-yl)-N-phenacylpyridinium bromide (5) gave 3-phenylpyrrolo[2,1,5-cd]indolizine (7) together with the unexpected product 3-phenyl-4-hydroxypyrrolo[2,1,5-cd]indolizines (8). However, 2-acetyl-N-phenacylpyridinium bromide (13) or 2-benzoyl-N-acetonylpyridinium bromide (16) underwent a tandem reaction of aldol condensation and 1,3-dipolar cycloaddition to form 3-phenyl-5H-pyrrolo[2,1,5-de]quinolizin-5-ones (15) or 5-phenyl-3H-pyrrolo[2,1,5-de]quinolizin-3-ones (17) in a single step. These novel procedures are general and can be carried out under convenient conditions.

N-Allyl enamines can undergo a [3,3] sigmatropic rearrangement known as a 3-aza-Cope (or amino-Claisen) reaction. We explored a 3-aza-Cope reaction involving 1,3 allylic migration from nitrogen to carbon in N-allyl enammonium quaternary salts, exemplified by benzo[a]quinolizine 8 and pyrrolo[2,1-a]isoquinoline 13, with an interest in stereochemistry and mechanism. Salts 8 and 13 were accessed, respectively, through stereospecific allylation of hydroxy amines 4 and 11a/11b to give 7 and 12a/12b, which were dehydrated with trifluoroacetic acid. Allylic migration in these tricyclic tetrahydroisoquinolines occurred with high stereospecificity, with the major products 9 (from 8) and 15a (from 13) apparently deriving from a concerted suprafacial [3,3] rearrangement. The rearrangement of 8 to 9 was facile at 23 degrees C (t(1/2) = ca. 5 h) and was98% stereospecific, whereas the rearrangement of 13 to 15a/15b required heating between 50 and 100 degrees C, with ca. 90-95% stereospecificity (t(1/2) = ca. 0.3 h at 100 degrees C). A deuterium-labeling experiment with 21 ((2)H-13) confirmed that allylic inversion accompanies the 1,3 migration en route to major isomer 22a ((2)H-15a), supporting the predominance of a concerted [3, 3] sigmatropic mechanism. However, the 5-10% loss of stereospecificity in the rearrangements of the pyrroloisoquinolines 13 and 21, reflected by formation of minor isomers 15b and 22b, respectively, indicates a minor nonconcerted reaction pathway.

Three types of dihydroberberine derivatives such as spirobenzylisoquinoline, benzindenoazepine and cyclopropanated quinolizine species were synthesized from dihydroberberine for the investigation on their anti-tumor activity. Among them, cyclopropanated quinolizine species were more effective than spirobenzylisoquinoline and benzindenoazepine against P-388 and L-1210 leukemia cell.

A chiral synthesis of functionalized benzo[a]quinolizine derivative (5) has been accomplished starting from a chiral lactone 7. The key feature is the efficient control of the stereochemistry of ring juncture of the functionalized benzo[a]quinolizine derivative 5 by the N-acyliminium ion cyclization of chiral lactam 11b.

Methyl 3α-1,2,3,4,6,7,12,12bβ-cotahydroindolo[2,3- a ]quinolizine-1α-carboxylate ( 6 ), a key intermediate for the synthesis of tacamine-type indole alkaloids, was prepared in six simple steps from methyl 5-(1′-hydroxyethyl)nicotinate ( 7 ). The last step was the catalytic hydrogenation of the two ethylidene isomers 14 and 15 , both of which gave the target ester stereoselectively.