Alkaline metal ion-enhanced chemiluminescence of bicyclic dioxetanes bearing a hydroxyaryl group with an ‘even’ substitution pattern

Bicyclic dioxetane 5 bearing a 3-hydroxynaphthalen-2-yl group and its analogs 14 and 15 decomposed to give light with efficiencies of only 0.002-0.005% in a tetrabutylammonium fluoride (TBAF)/THF system, which was as expected for dioxetanes with a so-called ‘even’ substitution pattern. However, the chemiluminescence efficiencies (Φ^CL) markedly increased when these dioxetanes were decomposed with alkaline metal t-butoxide in THF. This enhancement of Φ^CL by alkaline metal ion was most likely due to the highly ordered conformation of an aromatic ring by chelate formation of the metal ion with both an oxido anion and oxygen atom of a tetrahydrofuran ring in an intermediary dioxetane like 12. Alkaline metal ion-enhanced chemiluminescence was similarly observed for dioxetane 6 bearing a 2-hydroxyphenyl group.     

Rotamer-dependent chemiluminescence in the intramolecular charge-transfer-induced decomposition of bicyclic dioxetanes bearing a hydroxyaryl group

Base-induced chemiluminescent decomposition of acylamino-substituted dioxetane 1b bearing a 3-hydroxyphenyl group proceeded according to dual phase kinetics due to syn-anti isomerism of the aryl group. For dioxetane 7 bearing a 6-hydroxynaphthalen-2-yl group, syn- and anti-rotamers were each isolated and their structures were determined by X-ray single crystallographic analysis. Both rotamers underwent base-induced decomposition accompanied by the emission of red light to exclusively give the same keto imide 8. However, a marked difference in chemiluminescence efficiency was observed between anti-7 and syn-7.     

The absolute axial configurations of knipholone and knipholone anthrone by TDDFT and DFT/MRCI CD calculations: a revision

Triggered by a seemingly inconsistent twisting direction in the atroposelective ring cleavage reaction of biaryl lactones by using the ‘lactone concept’, the absolute axial configurations of the most important phenylanthraquinones, knipholone (1), and knipholone anthrone (2) were reassigned on the basis of renewed quantum chemical circular dichroism (CD) calculations using advanced, higher-level methods, viz. a time-dependent DFT (TDDFT) and a multireference configurational interaction approach (DFT/MRCI). Additional confirmation of the new configurational assignment of 1 and 2 was achieved by their stereochemically unambiguous interconversion, and further corroborated by the transformation of 1 into an ‘leuco’ phenylanthracene derivative 3, i.e., a compound with a substantially different chromophore, whose absolute configuration was independently assigned again by quantum chemical CD calculations. Accordingly, the dextrorotatory enantiomer of knipholone, (+)-1, and its anthrone, (+)-2, has the P-configuration, while the laevorotatory forms, (−)-1 and (−)-2 (which likewise exist in nature), are M-configured. From this new configurational assignment, the absolute axial stereostructures of a whole series of further naturally occurring phenylanthraquinones may now be deduced.     

Chiral β-diketonate ligands of ‘pseudo planar chiral’ topology: enantioselective synthesis and transition metal complexation

A practical enantioselective synthesis of chiral β-diketonate ligands 1a-1d, which are of ‘pseudo planar-chiral’ topology, is described. Additionally, the first chiral bis(diketonates) 2a-2c, ligands of C₂-symmetry that are isoelectronic with respect to related salen ligand systems, have been prepared. Protocols for the metallation of ligands 1a-1d, 2b and 2c are reported.     

A Wacker-Cook synthesis of isoflavones: formononetine

A total synthesis of the isoflavone formononetine 1 by an oxidative Pd-mediated cyclization of α-methylenedeoxybenzoins 4a-c is described. Substrates 4a-c were rapidly assembled using ‘protected cyanohydrin’ chemistry.     

A simple synthesis of 4-(2-aminoethyl)-5-hydroxy-1H-pyrazoles

A simple four-step synthesis of 4-(2-aminoethyl)-5-hydroxy-1H-pyrazoles 8 (or their 1H-pyrazol-3(2H)-one tautomers 8′) as the pyrazole analogues of histamine was developed. First, enamino lactam 3 was prepared as the key intermediate in two steps from 2-pyrrolidinone (1). Next, acid-catalysed ‘ring switching’ transformations of 3 with monosubstituted hydrazines 4 gave N-[(1-substituted 5-hydroxy-1H-pyrazol-4-yl)ethyl]benzamides 7a-k and N-[2-(2-heteroaryl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)ethyl]benzamides 7′l-o. Benzamides 7a-k and 7′l-o were finally hydrolysed by heating in 6 M hydrochloric acid to furnish 1-substituted 4-(2-aminoethyl)-5-hydroxy-1H-pyrazoles 8a-k and 4-(2-aminoethyl)-2-heteroaryl-1H-pyrazol-3(2H)-ones 8′l-o in good overall yields.     

Enantioselective syntheses of two 5, 9E diastereomers of 223V, an alkaloid from the poison frog Dendrobates pumilio

Enantioselective syntheses of two 5, 9E diastereomers (1 and 2) of 223V (3) are described. Neither corresponded on GC-MS and GC-FTIR analyses to alkaloid 223I, previously tentatively proposed to be a 5,8-disubstituted indolizidine of the unusual 5, 9E relative stereochemistry. Synthetic (−)-(5, 9Z)-5-n-propyl-8-n-butylindolizidine (3) corresponds on GC-MS and GC-FTIR analyses to the natural indolizidine 223V found in a pumilio from ‘Split Hill’, Panama.     

Gas-phase pyrolysis of benzimidazole derivatives: novel route to condensed heterocycles

Gas-phase pyrolysis of N-(1H-benzimidazol-2-yl)-N′-arylidenehydrazines 1a-e gave the corresponding arylnitriles 2a-e, 2-aminobenzimidazole 3, 2,4,5-triphenylimidazole 4, 1,3-diphenyl-8H-2,3a,8-triazacyclopenta[a]indene 5, and 5,11-diphenyl-6H,12H-dibenzimidazo[1,2-a];1’,2’-d]pyrazine 6. The kinetics and analysis of the products of reaction are reported and used to elucidate the mechanism of the elimination process.     

Design and synthesis of fluorescent 6-aryl[1,2-c]quinazolines serving as selective and sensitive ‘on-off’ chemosensor for Hg in aqueous media

Three fluorescent quinazolines thiophen-2-yl-5,6-dihydrobenzo-[4,5]imidazo[1,2-c]quinazoline (1), pyridin-3-yl-5,6-dihydrobenzo-[4,5]imidazo-[1,2-c]quinazoline (2) and phenyl-5,5′,6,6′-dihydrobenzo-[4,4′,5,5′]imidazo-[1.1′,2-c,2′-c]quinazoline (3) have been synthesized. Structures of 1 and 3 have been authenticated crystallographically. Quinazolines 1-3 exhibit highly selective ‘on-off’ switching for Hg²⁺ ions. The fluorescence intensity displayed a linear relationship with respect to Hg²⁺ concentration (0.1-1.0 μM; R² = 0.99) with detection limit of 2.0 × 10⁻⁷ M.     

A new fluorescent sensor for the detection of pyrophosphate based on a tetraphenylethylene moiety

We have developed a new fluorescent sensor 1-2Zn based on a tetraphenylethylene (TPE) moiety for the detection of PPi. This TPE-based chemosensor showed ‘turn-on’ fluorescence emission according to the concentration of PPi. The fluorescence enhancement upon binding of PPi to 1-2Zn resulted from the restriction of intramolecular rotation of phenyl rings in 1-2Zn.     

‘One-pot’ four-step synthesis of cerpegin

Cerpegin (1) was synthesized through a ‘one-pot’ reaction in 71% overall yield. Lithiation of commercially available 2-methoxynicotinic acid (2) as its lithium salt using LTMP, followed by addition of acetone at low temperature and a specific acidic treatment of the intermediate 3 thus obtained, gave the 1,1-dimethyl-3,4-dioxo-1,3,4,5-tetrahydrofuro[3,4-c]pyridine (4). The latter was finally selectively alkylated using methyl iodide and caesium carbonate to afford cerpegin (1).     

Total synthesis of prolycopene, a novel 7,9,7′,9′-tetra-cis(Z) carotenoid and main pigment of the tangerine tomato Lycopersicon esculentum

A total synthesis of the 7,9,7′,9′-tetra-cis(Z) isomer of lycopene, also known as ‘prolycopene’, produced as the major carotenoid pigment in fruits of the tangerine tomato Lycopersicon esculentum (‘Tangella’) is described. The synthesis is based on: (i) a modified Sonogashira coupling reaction between the E-alkenyl bromide 6 and the Z-enynol 7, leading to the 2Z-trienynol 8, followed by (ii) a Wittig reaction between the phosphonium salt 4 and the C₁₀-triene dialdehyde 5 producing the symmetrical 9,9′-Z isomer of the bis-acetylene 3 and (iii) semi-hydrogenation of 3 in the presence of Lindlar's catalyst, and chromatography.     

Synthesis and characterisation of novel 3′-O- and 5′-O- modified azobenzene-thymidine phosphoramidites and their oligonucleotide conjugates as colorimeter DNA probes and FRET quenchers

The synthesis of two new ‘first generation’ azobenzene based thymidine phosphoramidites 1 and 2 having the chromophore (DABCYL) covalently incorporated as an ester in the 3′-O- and 5′-O-positions of the deoxyribose, and the incorporation of these molecules into 16-mer Chronic Myeloid Leukaemia (CML) antisense oligonucleotides, giving 7 and 8, respectively, is described. These compounds were designed as highly coloured probes, and to participate in a Fluorescence Resonance Energy Transfer (FRET) mechanism in the design of novel molecular beacons.     

Synthesis of functionalized tetracene dicarboxylic imides

For the first time, a synthesis of tetracene dicarboxylic imides was established with 1,2,3,4-tetrahydrotetracene (1) instead of tetracene as the starting material. Mono-bromination of 1 by CuBr₂ followed by a Friedel-Crafts reaction, oxidation, and imidization gave the tetrahydrotetracene carboxylic imides 5a-b. Subsequent oxidative dehydrogenation of 5a-b with DDQ afforded the functional tetracene dicarboxylic imide monobromides 6a-b, which can be further functionalized to provide functional materials such as the ‘donor-acceptor’ type compounds 7a-b.     

Donnazoles A and B from Axinella donnani sponge: very close derivatives from the postulated intermediate ‘pre-axinellamine’

Two novel dimeric pyrrole-aminoimidazole (PAI) alkaloids (−) donnazoles A-B (1-2) were isolated from the marine sponge Axinella donnani collected off the Mauritius Island. Their structures were elucidated mainly by 2D NMR. Both compounds bear the crucial substituted cyclopentane of ‘pre-axinellamine’, the hypothetical common intermediate of all dimeric PAIs. Additionally, the essential trans-6,7 ring junction of palau′amine’s congeners is already established in 1 and 2. The absolute configurations of 1 and 2 were deduced via NOE correlations in combination with the comparison of their circular dichroism data with the one of (−) sceptrin. The absolute configuration of (−) donnazoles A (1) and B (2) is coherent with the absolute configuration of the known dimeric members of PAI alkaloids.     

Natural anti-HIV agents. Part 3: Litseaverticillols A-H, novel sesquiterpenes from Litsea verticillata

Bioassay directed-fractionation led to the identification of litseaverticillols A-H (1-8) from the leaves and twigs of Litsea verticillata Hance. These new sesquiterpenes possess a unique skeleton that was recently designated as ‘litseane’. The structures of these compounds were determined by spectroscopic means including 1D and 2D NMR data. Structural configurations were determined by ROESY experiments. Mosher ester reactions and optical rotation measurements established the sesquiterpenes 1-8 as racemates. Isolates 1-8 inhibited HIV-1 replication in HOG.R5 cells with IC₅₀ values ranging from 2 to 15 μg/ml (8-58 μM) while affecting the growth of HOG.R5 at concentrations 2-3-fold higher. Based on this data, structure-activity relationships can be discerned, suggesting compounds of this class are good candidates for analog production.     

Base-induced decomposition of dioxetanes bearing a 3-hydroxyphenyl moiety substituted with a proton-donating group at the 4-position: effect of intramolecular hydrogen bonding on decomposition rate and chemiluminescence efficiency

Bicyclic dioxetanes bearing a 3-hydroxyphenyl moiety substituted with an amidomethyl group (3a-c) or a hydroxymethyl group (4) were synthesized. On treatment with tetrabutylammonium fluoride in CH₃CN, they decomposed rapidly with accompanying emission of blue light. Their decomposition rates and chemiluminescence efficiencies were found to be affected by the intramolecular hydrogen bonding between the phenoxy anion and the adjacent proton-donating group.     

Change in conformation upon complexation of double-armed terephthalamide hosts: dynamic molecular recognition of ditopic guests with strong CD signaling

Conformation of novel terephthalamide hosts 1 changes from anti to syn upon complexation with a bidentate guest (2 or 3). Chiral sense in the helical syn-form of the double-armed host molecules 1 is biased by the asymmetric centers on the chiral guest [(R,R)/(S,S)-2a], which can be detected by the drastic change in circular dichroism (CD) spectrum thanks to the exciton coupling of two chromophores (‘arms’) linked to the amide nitrogens. Asymmetric centers on the host molecule also exhibit preference for the twisting direction upon change in geometry from the anti- to syn-form. Thus, the achiral guests (2b or 3) can also be detected by modulation of CD spectrum upon complexation with the chiral host [(R,R)-1a].     

Three different fluorescent responses to transition metal ions using receptors based on 1,2-bis- and 1,2,4,5-tetrakis-(8-hydroxyquinolinoxymethyl)benzene

The dipod 1,2-bis(8-hydroxyquinolinoxymethyl)benzene (3) and tetrapod 1,2,4,5-tetrakis(8-hydroxyquinolinoxymethyl)benzene (5) have been synthesized through nucleophilic substitution of respective 1,2-bis(bromomethyl)benzene (2) and 1,2,4,5-tetra(bromomethyl)benzene (4) with 8-hydroxyquinoline (1). For comparison, 1,3,5-tris(8-hydroxyquinolinoxymethyl)benzene derivatives (7a and 7b) have been obtained. The complexation behavior of these podands towards Ag⁺, Co²⁺, Ni²⁺, Cu²⁺, Zn²⁺, and Cd²⁺ metal ions has been investigated in acetonitrile by fluorescence spectroscopy. The sterically crowded 1,2,4,5-tetrapod 5 displays unique fluorescence ‘ON-OFF-ON’ switching through fluorescence quenching (λ_max 395 nm, switch OFF) with <1.0 equiv of Ag⁺ and fluorescence enhancement (λ_max 495 nm, switch ON) with >3 equiv Ag⁺ and can be used for estimation of two different concentrations of Ag⁺ at two different wavelengths. The addition of Cu²⁺, Ni²⁺, and Co²⁺ metal ions to tetrapod 5 causes fluorescence quenching, i.e., ‘ON-OFF’ phenomena at λ_max 395 nm for <10 μM (1 equiv) of these ions but addition of Zn²⁺ and Cd²⁺ to tetrapod 5 results in fluorescence enhancement with a gradual shift of λ_em from 395 to 432 and 418 nm, respectively. Similarly, dipod 3 behaves as an ‘ON-OFF-ON’ switch with Ag⁺, an ‘ON-OFF’ switch with Cu²⁺, and an ‘OFF-ON’ switch with Zn²⁺. The placement of quinolinoxymethyl groups at the 1,3,5-positions of benzene ring in tripod 7a-b leads to simultaneous fluorescence quenching at λ_max 380 nm and enhancement at λ_max 490 nm with both Ag⁺ and Cu²⁺. This behavior is in parallel with 8-methoxyquinoline 8. The rationalization of these results in terms of metal ion coordination and protonation of podands shows that 1,2 placement of quinoline units in tetrapod 5 and dipod 3 causes three different fluorescent responses, i.e., ‘ON-OFF-ON’, ‘ON-OFF’, and ‘OFF-ON’ due to metal ion coordination of different transition metal ions and 1, 3, and 5 placement of three quinolines in tripod 7, the protonation of quinolines is preferred over metal ion coordination. In general, the greater number of quinoline units coordinated per metal ion in 5 compared with the other podands points to organization of the four quinoline moieties around metal ions in the case of 5.     

Reevaluation of Bruice’s proximity orientation

Ab initio molecular orbital calculations at HF/6-31G, HF/6-31G (d,p) and DFT at B3LYP/6-31G (d,p) levels and molecular mechanics calculations of thermodynamic and kinetic parameters for Bruice’s systems 1-6 indicate that the remarkable acceleration in the cyclization of di-carboxylic semi-esters 1-6 is solely the result of a strain effect and not proximity orientation stemming from the ‘reactive rotamer effect’.