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.     

Stereoselective dioxirane hydroxylations and the synthesis of tripod boronic acid esters

Methyl(trifluoromethyl)dioxirane (TFDO, 1b), a powerful yet selective oxidant, was employed to achieve in high yield the direct stereoselective hydroxylation at tert-CH of cis,cis-1,3,5-trimethylcyclohexane (4), yielding triol 7 bearing all-axial disposition of the three OH groups. Similarly, TFDO oxidation of 1,3- and of 1,4-dimethylcyclohexane gave the corresponding Z-diols 5 and 6, respectively. Triol 7 was a convenient starting material to synthesize a novel borate—that is, 1-bora-2,8,9-trioxa-3,5,7-trimethyladamantane (8)—having a peculiar cage-shaped ‘tripod’ structure. From triol 7, novel tripod arylboronic Brönsted-assisted Lewis acids (BLA) could be obtained, as exemplified by 10a and 10b.     

Synthesis and ‘double click’ density functionalization of 8-aza-7-deazaguanine DNA bearing branched side chains with terminal triple bonds

The 7-[di(prop-2-ynl)amino]prop-1-ynyl derivative of 8-aza-7-deaza-2′-deoxyguanosine (1) was synthesized from 7-iodo-8-aza-7-deaza-2′-deoxyguanosine (7) by Sonogashira cross-coupling and converted into the phosphoramidite building block 10. Oligonucleotides bearing branched side chains with terminal triple bonds were prepared by solid-phase synthesis containing single or multiple residues of 1 as 2′-deoxyguanosine surrogates. T_m measurements demonstrate that compound 1 has a positive effect on duplex stability, which is comparable to the stabilizing effect of the octa-1,7-diynylated non-branched nucleoside 2. Nucleoside 1 and corresponding oligonucleotides were functionalized by the Cu(I)-mediated 1,3-dipolar cycloaddition ‘double click’ reaction with diverse ligands (AZT 3, benzyl azide 4, 11-azidoundecanol 5 and m-dPEG™₄-azide 6). The conjugation reactions were carried out in solution and on solid support. Nucleoside 1 allowed ‘double’ functionalization of a single residue with two reporter groups. The ‘double click’ reaction proceeded smoothly even when two residues of nucleoside 1 were arranged in proximal positions. Hybridization with complementary strands led to a stable oligonucleotide duplex. Molecular modeling indicates that inspite of the crowded steric situation with four AZT ligands within closest proximal positions, all ligands are well accommodated in the major groove not disturbing the DNA helix.     

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].     

Syntheses and characterisation of mercury complexes of sulfadiazine,sulfamerazine and sulfamethazine

The triple sulfa drugs, sulfadiazine, sulfamerazine and sulfamethazine, form a large number of metal complexes in different solvent media. The present studies show the synthesis and characterization of the Hg(II) complexes of sulfadiazine 1, sulfamerazine 2 and sulfamethazine 3 in dimethylformamide solution in presence of ammonia. The compounds were characterised by spectroscopic methods and crystal structures of the complexes were determined. All the compounds, 1, 2 and 3, crystallise in monoclinic crystal systems with the space groups of C2/c, C2/c and P2₁/c, respectively. Compounds 1 and 3 have eight coordinate ‘2+6’ geometries, with two tridentate sulfonamide ions and two DMF molecules in the coordination sphere. Complex 2 has a six co-ordinate, ‘2+4’ geometry which contains a short linear N–Hg–N moiety from co-ordinated sulfonamides. The IR spectral data suggest the binding of mercury atom to the sulfonamidic nitrogen atoms in agreement with the crystal structure determination.     

‘Two-point’-bound supramolecular complexes from semi-rigidified dipyridine receptors and zinc porphyrins

Two linear compounds 1 and 2 have been designed and synthesized as new receptors for zinc porphyrins. Both compounds consist of two folded aromatic amide moieties, which are connected with an acetylene linker in 1 or directly in 2. The rigid conformations of their folded moieties are stabilized by intramolecular tri-centered hydrogen bonding, while the whole molecule adopts a ‘S’- or ‘C’-styled conformation depending on the relative orientation of the two rigid moieties. Two pyridine units are introduced at the ends of 1 and 2 for the complexation of zinc porphyrin guests. Although the ¹H NMR investigation indicated that both compounds can bind two zinc porphyrin guests at high concentrations (≥5 mM) in chloroform, the UV-vis studies revealed that, at low concentration of 1 and 2 (4 μM), both compounds complex one zinc porphyrin guest to form structurally unique ‘two-point’-bound 1:1 complexes. The association constants of the 1:1 complexes have been determined with the UV-vis titration experiments.     

Self-assembly of a new series of quadruply hydrogen bonded heterotrimers driven by the donor-acceptor interaction

This paper describes the self-assembly of a new series of heterotrimers in chloroform-d by utilizing the cooperative interaction of hydrogen bonding and donor-acceptor interaction. Compounds 1 and 11, in which an 2-ureido-4[1H]-pyrimidinone unit is connected to 34-crown-10 or 36-crown-10, were used as donor monomer, and 2 and 19, in which an 2-ureido-4[1H]-pyrimidinone unit is connected to NDI, were used as acceptor monomer, while linear compound 4, which contains two diamido-1,8-naphthyridines, was used as template. A large tri-p-(t-butyl)phenylmethoxyl group was introduced to 19 in order to compare its assembling behavior with that of 2. Mixing 4 with dimer 1·2 caused 1·2 to fully decompose and to afford 55% of ‘in-in’-oriented heterotrimer 1·4·2. Adding 4 to the solution of 2·11 or 11·19 in chloroform-d also led to full dissociation of the dimers. However, in these systems the ‘in-in’-arranged heterotrimer 2·4·11 or 11·4·19 could be produced exclusively.     

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.     

Synthesis and fluoride-induced chemiluminescent decomposition of bicyclic dioxetanes substituted with a 2-hydroxynaphthyl group

Five bicyclic dioxetanes bearing a 2-hydroxynaphthyl group, 1aA-1eA, were synthesized and their chemiluminescent decomposition was examined by the use of tetrabutylammonium fluoride (TBAF) as a base in DMSO. It was found that these dioxetanes hold completely the ‘odd/even’ relationship between the substitution pattern of hydroxy as a trigger on the naphthalene ring and their chemiluminescent efficiency, and that dioxetane 1aA exhibited chemiluminescence with the highest efficiency among those for the oxynaphthyl-substituted dioxetanes hitherto known. The significant change in chemiluminescent efficiency depending on the substitution pattern was clarified to be attributed to the marked change in singlet-chemiexcitation efficiency for charge-transfer-induced chemiluminescence (CTICL) of 1aA-1eA. In respect of the rate of CTICL-decomposition, ‘odd/even’ relationship was observed for 1aA-1dA.     

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.     

Solid-phase synthesis of backbone-cyclized β-helical peptides

This paper describes the synthesis and purification of two 22-residue cyclic peptides, cyclo{[(l-Val-d-Val)₄-(l-Val-d-Pro-Gly)]₂-} 3 and cyclo{[(d-Leu-l-Leu)₄-(d-Leu-l-Pro-Gly)]₂-} 4, that were designed to fold into double-stranded antiparallel β-helical structures. Due to intramolecular hydrogen bonding and the conformational constraints imposed by the two reverse-turn segments (d-Pro-Gly and l-Pro-Gly, respectively), the linear precursors to 3 and 4 (lin-3 and lin-4) were expected to adopt preorganized conformations that would bring the N and C termini close together and thereby favor ring closure. Precursors lin-3 and lin-4 were constructed by stepwise Boc solid-phase peptide synthesis using the commercially available alkanesulfonamide ‘safety-catch’ linker and cyclized head-to-tail via the method of cleavage-by-cyclization. The crude cyclic peptides were highly hydrophobic and contained minor impurities that could not be removed solely by reversed-phase HPLC (RP-HPLC); however, two-step purification—first by RP-HPLC with i-PrOH/water gradients, followed by gel-permeation chromatography (GPC) on Sephadex LH-20 with CHCl₃/MeOH—afforded both peptides in pure form (≥95% by ¹H NMR) and in acceptable yield (23%). Subsequent ¹H NMR experiments supported the expected structures of 3 and 4. The successful formation of the 66-membered rings of 3 and 4 is consistent with the notion of conformational preorganization in the linear precursors; furthermore, the protocols for synthesis and purification described should prove useful for preparing additional cyclic β-helical peptides, including longer peptides and peptides having polar residues.     

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.     

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.     

Nucleoside and oligonucleotide pyrene conjugates with 1,2,3-triazolyl or ethynyl linkers: synthesis,duplex stability,and fluorescence changes generated by the DNA-dye connector

Fluorescent nucleosides and oligonucleotides functionalized with pyrene were synthesized using ‘click’ chemistry or the Sonogashira cross-coupling reaction. The dye was connected to position-7 of 7-deaza-2′-deoxyguanosine or to the 2′-deoxyribofuranose moiety. Four different DNA-dye connectors with 1,2,3-triazolyl residues or triple bonds were constructed. Phosphoramidites of the pyrene conjugates (9, 14, 25) were prepared and used in solid-phase synthesis. Short linkers (2, 4) destabilize DNA, while long linkers (1) increased duplex stability. Nucleosides and oligonucleotides with single dye incorporations show linker dependent fluorescence. Linker dependent excimer emission with pyrenes in proximal positions was also observed. A ‘superchromophore’ formed by the 7-deaza-2′-deoxyguanosine ethynylpyrene conjugate shows strong red shifted fluorescence emission at 495 nm.     

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.     

Synthesis and photochromic behaviour of new methyl induced linear and angular thieno-2H-chromenes

New methyl induced linear and angular thieno-2H-chromenes 4, 5 and 6 were prepared by reaction of new methylated 6-hydroxybenzo[b]thiophenes 2 (a, b and c) and propargylic alcohols 3a and 3b, using acidic Alumina Brockmann I as catalyst and drying agent. Compounds 2 were prepared in good to excellent yields in a ‘one pot’ three step reaction from the corresponding bromo compounds 1. The photochromic behaviour of compounds 4, 5 and 6b was evaluated with the aid of a classical set of spectrokinetic parameters, and compared to reference compounds that are benzoannellated in the 5,6 and 6,7 positions of the chromene (naphthopyrans) and also to thieno-2H-chromenes 7 and 8, previously prepared, which are analogues of 5a. The resistance to fatigue (photodegradation) under continuous irradiation was also evaluated.     

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.     

Synthesis and structural characterization of copper(II) and vanadium(V) complexes of pyridyl/pyrimidyl–pyrazole derived Schiff base ligands – Metal specific adjustment of ligand binding mode

Two mononuclear copper(II) complexes [Cu(L₁)ClO₄] (1), [Cu(L₂)ClO₄] (3) and two mononuclear vanadium(V) complexes [{VO(L₁)(OCH₃)(CH₃OH)}{VO(L₁)(OCH₃)}] (2) and [VO(L₂) (OCH₃)(CH₃OH)] (4) have been synthesized using two Schiff base ligands HL₁ [N′-(2-hydroxybenzylidene)-5-methyl-1-(pyridin-2-yl)-1H-pyrazole-3-carbohydrazide] and HL₂ [1-(4,6-dimethylpyrimidin-2-yl)-N′-(2-hydroxybenzylidene)-5-methyl-1H-pyrazole-3-carbohydrazide]. These two similar ligands HL₁ and HL₂ in their ‘ketoimine’ form function as mononegative NNNO tetradentate ones towards the Cu(II) centre forming square planar part of the square pyramidal geometry. Where as the same ligands in their ‘imineol’ form behave as binegative ONO tridentate ones to form their V(V) analogues. In the asymmetric unit of 2, there are two independent V(V) complex molecules differing in their conformations as well as in coordination environment – octahedral V(V) in ‘unit A’ is hexa-coordinated while that in ‘unit B’ being penta-coordinated is square pyramidal. Vanadium atom in 4 is in octahedral geometry with NO₅ chromophore. The ligands HL₁ and HL₂ have been synthesized for the first time in our laboratory and characterized by X-ray crystallography and spectroscopy. The complexes (1, 2 and 4) are also characterized by X-ray crystallography, spectroscopic and electrochemical studies.     

Micelles catalyzed one pot regio- and chemoselective synthesis of benzo[a]phenazines and naphtho[2,3-d]imidazoles ‘in H2O’

An efficient, novel, and concise one pot regio- and chemoselective synthesis of benzo[a]phenazines (4) and naphtho[2,3-d]imidazoles (8) has been accomplished in excellent yields by nucleophilic substitution reaction of 2,3-dichloro-1,4-naphthoquinone (1) with o-phenylenediamine (2) and benzamidines (7) respectively ‘in H₂O’ using base and micelles (SDS) as catalyst. Analog reaction of 2,3-dichloro-1,4-naphthoquinone (1) with 2-aminobenzenethiol (9) under identical conditions led to formation of a mixture of benzo[b]phenothiazine (10), benzo[a]phenothiazine (11), and benzo[a]-1,4-benzothiazino-3,2-phenothiazine (12) in 17%, 23%, and 57% yields, respectively.