Computer-aided molecular modeling and design of DNA-inserting molecules

Summary Intercalators are molecules capable of sliding between base pairs without disturbing the overall stacking pattern. In addition, there may exist molecules capable of inserting into a base pair thereby disrupting the hydrogen bonds and replacing them with new hydrogen bonds. A molecule probably capable of inserting, i.e., an insertor, is the diketopiperazine cyclo-[Gly-Gly] (1). A barbiturate (2), alloxan (3), a pyrimidine derivative (4) and a hydantoin (5) were also studied as possible insertors. Furthermore, molecules such as ethyleneurea (6), succinimide (7), as well as a malonamide derivative (8) and oxamide derivatives (9–11) were studied in order to investigate the arrangement and the number of hydrogen bonds necessary for insertion. Molecules 12–14 were designed and studied for their capacity to act as bisinsertors and/or bisintercalators. These molecules feature two diketopiperazine moieties which are connected via a diphenyl(thio)ether, i.e., 12 and 13, or a bisphenol A spacer, i.e., 14. The latter molecule (14) seems a promising candidate as a bisinsertor.     

Group-theoretical Foundations for the Concept of Mandalas as Diagrammatical Expressions for Characterizing Symmetries of Stereoisomers

Group-theoretical foundations for the concept of mandalas have been formulated algebraically and diagrammatically in order to reinforce the spread of the unit-subduced-cycle-index (USCI) approach (S. Fujita, Symmetry and Combinatorial Enumeration in Chemistry, Springer-Verlag, Berlin-Heidelberg, 1991). Thus, after the introducton of right coset representations (RCR) (H\)G and left coset representations (LCR) G(/H) for the group G and its subgroup H, a regular body of G-symmetry is defined as a diagrammatical expression for a right regular representation (C ₁\)G, which is an extreme case of RCRs. The |G| substitution positions of the regular body as a reference are numbered in accord with the numbering of the elements of G and segmented into |G|/|H| of H-segments, which are governed by the RCR (H\)G. By regarding each H-segment as a substitution position, the H-segmented regular body is reduced into a reduced regular body, which can be regarded as a secondary skeleton for generating a molecule. The reference regular body (or H-segmented one) is operated by every symmetry operations of G to generate regular bodies (or H-segmented ones), which are placed on the vertices of a hypothetical regular body of G-symmetry. The resulting diagram (a nested regular body) is called a mandala (or a reduced mandala), which is a diagrammatical expression for specifying the G-symmetry of a molecule. The effect of a K-subduction on the regular bodies of a mandala (or a reduced mandala) results in the K-assemblage of the mandala (or the reduced mandala), where the resulting K-assemblies governed by the LCR G(/K) construct a |G|/|K|-membered orbit, which corresponds to a molecule of K-symmetry. The sphericity of the RCR (or the LCR) is used to characterize symmetrical properties of substitution positions and those of stereoisomers. The fixed-point vector for each mandala (or reduced mandala) in terms of row view and the number of fixed points of K-assembled mandalas (or K-assembled reduced mandalas) in terms of column view are compared to accomplish combinatorial enumeration of stereoisomers. The relationship between a mandala and a reordered multiplication table is discussed.     

Synthesis of novel 3-phenyl-2-oxido/sulfido-1,3,4,2-benzoxadiazaphosphepines

An efficient and facile synthetic approach towards a series of novel 3-phenyl-2-oxido/sulfido-2,3-dihydro-1,3,4,2-benzoxadiazaphosphepines 2–7 was described. The method depended on the cyclocondensation of equimolar ratios of salicylaldehyde phenylhydrazone (1) with different examples of phosphorus halides and phosphorus sulfides in toluene containing triethylamine as a catalyst. In the same manner, the fusion of salicylaldehyde phenylhydrazone (1) with triethyl phosphate in the presence of DBU afforded the 2-ethoxy-1,3,4,2-benzoxa-diazaphosphepine 8, while a fusion of compound 1 with diethyl phosphite and tris(2-chloroethyl)phosphite led to the formation of new examples of 1,2-benzoxaphospholes 9 and 10, respectively. Interestingly, the reaction of compound 1 with diethyl ethoxycarbonyl phosphonate in ethanol containing DBU as a catalyst furnished the chromeno[3,4-d][1,2,3]diazaphosphole derivative 12 as a regioselective product.     

Polyphosphoric Acid–Mediated,One-Pot,Novel Reactions to Build Polymethoxyarylnaphthalene Lignans

The one-pot reaction of succinic anhydride with 1,2-dimethoxybenzene furnished two structurally complicated polymethoxyarylnaphthalene lignans, polymethoxyarylnaphthol 1 as the minor product and polymethoxynaphtho[1,2-b]oxacycloheptatrienone 2 as the major product, in the presence of a small amount of polyphosphoric acid (PPA) as catalyst at 140°C and yielded 2 as a single product in good yield when a large amount of PPA as solvent was employed at 60–80°C. The novel structures of 1 and 2 were elucidated from ¹H NMR, ¹³C NMR, infrared (IR), and Electrospray ionization–mass spectrometry (ESI-MS) and further confirmed by x-ray diffractions. The possible mechanisms for the formation of 1 and 2 were also proposed.     

The Effect of Very Bulky Groups on the Equilibrium of Penta- and Hexacoordinated Phosphoranes 1

The synthesis of dithio-diphenol 4 and sulfonyl-diphenol 5, both with very bulky groups, provided starting materials for reaction sequences that led to the formation of the very stable hexacoordinated phosphorane 2 and sensitive pentacoordinated phosphorane 3. Hexacoordination was established in 2 by an intramolecular donor interaction at the phosphorus center from an oxygen atom of the sulfonyl group present as part of the eight-membered ring. The solid state structures of 2 and 3 were established by X-ray analysis, as was that of phosphite 1 formed in the reaction sequence leading to 2. In solution, 2 has two forms existing in a dynamic equilibrium between a pentacoordinated and the more dominant hexacoordinated form as determined by ³¹P and ¹⁹F NMR spectroscopy. The high stability of 2 with respect to hydrolysis and alcoholysis reactions suggests that an associative process is responsible as the controlling reaction mechanism.     

Cyanothioacetamide in Heterocyclic Chemistry: Synthesis of Thiopyran,Pyridinethione, Thienopyridine,Pyridothienotriazine and Pyridothienopyrimidine Derivatives

Abstract

Cyanothioacetamide (1) reacted with α- and β-naphthaldehyde 2a,b to afford the corresponding 3-naphthyl-2-thiocarboxamidopropenonitriles 3a,b. Compounds 3a,b structures could be elucidated via their reactions with acrylonitrile, ethyl acrylate (4a,b). N-arylmaleimides 6a-c and ethyl acetoacetate (8). The isolated products could be represented as the thiopyran, thiopyranopyrrolidine and pyridinethione derivatives 5a-d, 7a-f and 9a,b respectively. Pyridinethiones 9a,b had been used as the starting materials in the present study in addition to the next ones to synthesize several new thienopyridines, pyridothienotriazine and pyridothienopyrimidines 12a-f, 15a,b, 16b, 17–19a,b respectively through their reactions with the corresponding reagents.

All structures of the newly synthesized heterocyclic compounds were established on the basis of the data of IR, ¹H NMR and elemental analyses.     

Supramolecular system composed of B12 model complex and organic photosensitizer: impact of the corrin framework of B12 on the visible-light-driven dechlorination without the use of noble metals

The visible-light-driven dechlorination system without the use of a noble metal has been developed. We screened the combination of cobalt catalysts having square-planar monoanionic ligands (hydrophobic B₁₂ model complex 1/imine-oxime type complex 2) and typical red dyes (Rose Bengal 3/Rhodamine B 4/Nile Red 5) for the construction of a dehalogenation system via a noble-metal-free and visible-light-driven process. The combination of the hydrophobic B₁₂ model complex 1 and Rose Bengal 3 exhibited the highest catalytic activity to 1,1-bis(4-chlorophenyl)-2,2,2-trichloroethane (DDT) to form the monodechlorinated compound, 1,1-bis(4-chlorophenyl)-2,2-dichloroethane, as the major product. The prolonged photocatalysis of DDT by the B₁₂–Rose Bengal system afforded the tri-dechlorinated compound, trans-4,4′-dichlorostilbene, as the major product. Furthermore, we investigated the mechanism of the dehalogenation cycle using various methods such as UV–vis spectroscopy and laser flash photolysis. Finally, we clarified the advantage of using the hydrophobic B₁₂ model complex 1 as an electron acceptor as well as a cobalt catalyst in the organic dye-involved photocatalysis.     

Radical scavenging activities of flavonoids from roots of Akschindlium godefroyanum

Chemical constituents of crude ethyl acetate extract of roots of Akschindlium godefroyanum (Kuntze) H. Ohashi were investigated and seven flavonoids were isolated. Their structures were identified based on spectroscopic methods as well as by comparison with spectral data reported in the literature as six flavanonols and a flavonol including 7,4′-dihydroxy-5,3′-dimethoxyflavanonol (1), neophellamuretin (2), taxifolin (3), erycibenin D (4), geraldol (5), fustin (6) and garbanzol (7). Compounds 2, 4 and 7 were found in the genus Akschindlium for the first time. Compounds 3, 5 and 6 appeared to have free radical scavenging activities using DPPH assay with IC₅₀ of 21, 40 and 15 μg/mL, respectively.     

Chemical composition and antioxidant activity of a polar extract of Thymelaea microphylla Coss. et Dur.

Thymelaea microphylla Coss. et Dur. (Thymelaeaceae) is a rare medicinal plant endemic to Algeria. In order to continue our studies on this species, herein we report the isolation and characterisation of 20 compounds from a hydroalcoholic extract (EtOH–H₂O 7:3) of the aerial parts. They include monoterpene glucosides (1–3), phenolic acid derivatives (4, 8 and 9), phenylpropanoid glucosides (5 and 6), flavonoids (7, 10 and 11), a benzyl alcohol glucoside (12), ionol glucosides (13–16), lignans (17–19) and a bis-coumarin (20). All the structures were elucidated by spectroscopic methods including 1D and 2D NMR experiments, as well as ESI-MS analysis. Moreover, the extract of T. microphylla showed a significant and concentration-dependent free radical-scavenging activity in vitro, correlated to the presence of phenolic and chlorogenic acid derivatives (8, 9 and 4).     

Practical Preparation of Trimethoprim: A Classical Antibacterial Agent

An efficient, simple, and mild preparation of the classical antibacterial agent trimethoprim (1) was achieved in 85% overall yield from 3,4,5-trimethoxybenzaldehyde (2). First, the addition of propenenitrile (3) with dimethylamine almost quantitatively afforded 3-dimethylaminopropanenitrile (7). Then, by condensation of 7 with 2 as well as the continuous replacement of 3-dimethylamino group with aniline in situ, the key intermediate 3-anilino-2-(3,4,5-trimethoxybenzyl)propenenitrile (9) was obtained in an excellent yield of 91% with a one-pot procedure. Finally, the cyclization of 9 with guanidine nitrate furnished 1 in yields as good as 95% in the presence of the excessive sodium methoxide.

Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications® to view the free supplemental file.     

Total Synthesis of Angucyclines. XVII. First Synthesis of Antibiotic 100‐1, a Deoxydisaccharide Angucycline Antibiotic of the Urdamycinone B‐Type

Two routes to the deoxydisaccharide angucycline antibiotic 100‐1 (3) are described. Key steps comprise the regioselective oxidation/bromination of the 1,5‐diacetoxyolivose C‐saccharide 7 to the bromoquinone 8. Diels–Alder reaction of the bromoquinone with the diene 9 followed by HBr elimination afforded the urdamycinone B precursor 11 as a diastereomeric mixture. Selective protection as the TBDMS ether 13, acetylation and deprotection of the silyl ether afforded the alcohol 15 which was selectively glycosylated to the α‐rhamnal glycoside 17 in 72% yield (at 70% conversion) using benzoyl rhamnal (16) as the glycoside donor and scandium triflate as the promotor. The silyl group at C‐3 of the aglycone was then transformed into a hydroxyl group. Zemplén deacylation and photooxidation of the benzylic position at C‐1 then converted the two diastereoisomers into the natural product 3 and the C‐3 diastereoisomer 20. At this stage the diastereomers 3 and 20 were separated. Alternatively and more easily, the diastereomers were separated at the stage of the urdamycinone B analogues 21a and 21b, followed by a similar reaction sequence to the natural disaccharide 3.     

PEG-400 mediated an efficient eco-friendly synthesis of new isoxazolyl pyrido[2,3-d]pyrimidines and their anti-inflammatory and analgesic activity

Abstract

Polyethylene glycol-400 (PEG-400) has been developed as an efficient and eco-friendly reaction medium for the synthesis of new isoxazolyl pyrido[2,3-d]pyrimidine derivatives 11 from isoxazolyl cyanoacetamide synthon 7. Compound 7 was employed with various aromatic aldehydes 8 and malononitrile 9 in the presence of triethylamine (Et₃N) to afford the corresponding (E)-6-amino-1-(3-methyl-5-styrylisoxazol-4-yl)-2-oxo-4-phenyl-1,2-dihydro- pyridine-3,5-dicarbonitrile 10 at room temperature by using PEG-400 as a solvent medium as well as catalyst. The intermediate 10 on treatment with thiourea in the presence of PEG-400 at 90?°C to give the target compounds isoxazolyl pyrido[2,3-d]pyrimidines 11 in good to excellent yields. The newly synthesized compounds 10 and 11 were characterized by IR, ¹H NMR, ¹³C NMR, and HRMS analysis. The target compounds 11a-x was screened for their anti-inflammatory and analgesic activities. Among the tested compounds, the compounds 11s, 11t, 11u, 11v, 11w, and 11x showed significant anti-inflammatory and potent analgesic activities as that of reference drugs. The advantages of this protocol are operational simplicity, catalyst free, environmental safety, wide substrate scope, good yields, and PEG-400 can be recovered and reused. Most significant of all, this protocol is green.     

Copper(I) bromide complexes of two 15-memberd O2S2-macrocycles with different sulfur-to-sulfur separations: dimer and one-dimensional coordination polymer

Abstract

A comparative study on the exo-coordination-based networking of 15-membered O₂S₂-macrocycle isomers (L¹ and L²) induced by interdonor distances is reported. In copper(I) bromide complexation, the isomer L¹ incorporating a shorter sulfur-to-sulfur separation yielded a discrete dimer complex [(μ-Cu₂Br₂)(L¹)₂] (1) in which two macrocycles are bridged by a Cu₂Br₂ square cluster. While, the reaction of copper(I) bromide with the isomer L² incorporating a longer sulfur-to-sulfur separation afforded a double-stranded one-dimensional (1D) coordination polymer {[(μ₄-Cu₂Br₂)(L²)₂]·CH₂Cl₂}_n (2) as a kinetic product which converted to [(μ₄-Cu₂Br₂)(L²)₂]_n (3) with different 1D connectivity pattern as a thermodynamic product. The results indicate as examples of programmed self-assembly that the proposed interdonor distances and the ligand isomerism play decisive roles cooperatively in the topologies of the supramolecular products via different coordination modes.     

ORGANISCHE PHOSPHORVERBINDUNGEN 80 HERSTELLUNG VON TRIAZOLYLMETHYL-PHOSPHONATEN UND VON TRIAZOLYL-METHYLPHOSPHONIUMSALZEN UND DEREN VERWENDUNG IN DER WITTIG-HORNER REAKTION

Abstract

Attempts to prepare 1H-1,2,4-triazol-1-ylmethylphosphonates (4 and 5) by a Mannichtype reaction or by transesterification of 1-hydroxymethyl-1H-1,2,4-triazol 1 with tertiary phosphites failed. On the other hand 4 and 5 are obtained by a Michaelis-Becker reaction from 1-chloromethyl-1H-1,2,4-triazol 3 and sodium phosphites in high yield. The Michaelis-Arbuzov reaction is less suited for the preparation of 4 and 5. 3 is obtained in good yield as a water clear liquid, b.p. 52–54°C/0.2 torr, from the interaction of 1 with thionyl chloride followed by treatment with a base. On standing at 0° or 20°C it decomposes within hours and yields the unsymmetrical methylen-bis(triazol) 3a in addition to other products. However an acetonitrile solution of 3 is stable for months. Heating this solution with tertiary phosphines gives triazolylsubstituted phosphoniumsalts 6 to 8. The Wittig-Horner reaction with 4 to 6 gives the olefinically substituted triazols 9–12 as a Z/E mixture in high yield. Alkylation of 4 with methyl-and ethyl iodide gives the corresponding alkylated diethyl-1H-1,2,4-triazol-1-yl-ethyl-1-and-propyl-1-phosphonates 14 and 15 which on hydrolysis with HCI yield 1H-1,2,4-triazol-1-yl-ethyl-1-and propyl-1-phosphonic acids 17 and 18, respectively. Hydrolysis of 4 gives the unsubstituted 1H-1,2,4-triazol-1-ylmethyl-phosphonic acid, 16.     

New peripherally tetra-[trans-3,7-dimethyl-2,6-octadien-1-ol] substituted metallophthalocyanines: synthesis,characterization and catalytic activity studies on the oxidation of phenolic compounds

In this paper, we elucidated the synthesis, characterization, and investigation of catalytic activity studies of new metallophthalocyanines 4 and 5 as the catalyst for phenolic compounds oxidation by trying different types of oxygen sources. The structural characterization of the products was made by a combination of elemental analysis, FT-IR, LC-MS/MS (for phthalonitrile derivative 3), MALDI-TOF mass spectral data (for metallophthalocyanines 4–7), UV–vis spectroscopy (for metallophthalocyanines 4–7), ¹H NMR and ¹³C NMR spectroscopies (for compounds 3 and 6). The synthetic routes for the (trans-3,7-dimethyl-2,6-octadien-1-ol) substituted phthalonitrile derivative 3 and corresponding metallophthalocyanines 4–7 are outlined in Scheme 1. The MPc complexes 4–7 were synthesized via cyclotetramerization of compound 3 in the presence of the corresponding anhydrous metal salts (CoCl₂ for 4, CuCl₂ for 5, Zn(CH₃COO)₂ for 6 and MnCl₂ for 7) in dry n-pentanol as solvent and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as strong base at reflux temperature under nitrogen gas. Phthalocyanines and their metal complexes, in general, display poor solubility in most of the organic solvents, however, the synthesized metallophthalocyanine complexes 4–7 were highly soluble in common organic solvents because of the introduction of the methyl groups on alkyl chains of peripheral arms. The catalytic activity of compounds 4 and 5 was evaluated for the oxidation of phenolic compounds such as 4-nitrophenol, o-chlorophenol, 2,3-dichlorophenol, and p-methoxyphenol. CoPc 4 displayed good catalytic performance with a full oxidation of 4-nitrophenol into the corresponding benzoquinone and hydroquinone with the highest TON and TOF values within 3 h.     

One-Pot,Facile, Highly Efficient,and Green Synthesis of Acridinedione Derivatives Using Vitamin B1

An efficient methodology for the synthesis of acridinedione derivatives 4a–o has been achieved by one-pot, multicomponent condensation of dimedone 1, various amines 2a–d, and substitute aromatic aldehydes 3a–k, in the presence of the easily available, inexpensive, and nontoxic catalyst vitamin B₁ (VB₁) as a versatile biodegradable. Synthesis of acridine-type compounds was performed in good yields in water as green solvent. Its high-yield efficiency; clean, ecofriendly, simple workup procedure; and easy purification are regarded as the main advantages of this method besides its green solvent. The synthesized compounds are characterized using spectroscopic analyses (FTIR, ¹H NMR, ¹³C NMR, and high-resolution mass spectrometry) techniques.     

Synthesis and Characterization of the products from reaction of Metal Carbonyls [M(CO)6 (M Cr,Mo, W), Re(CO)5Br,Mn(CO)3Cp] with Salicylaldehyde Methanesulfonylhydrazone

Five new complexes, [M(CO)₅(salmsh)] (M?=?Cr;?1,?Mo;?2,?W;?3), [Re(CO)₄Br(salmsh)], 4, and [Mn(CO)₃ (salmsh)], 5, have been synthesized by the photochemical reaction of metal carbonyls with salicylaldehyde methanesulfonylhydrazone (salmsh). The complexes have been characterized by elemental analyses, EI mass spectrometry, FT-IR and ¹H NMR spectroscopy. The spectroscopic studies show that salmsh behaves as a monodentate ligand coordinating via the imine N donor atom in 1–4 and as a tridentate ligand in 5.     

Synthesis of the Methyl Glycosides of a Di- and Two Trisaccharide Fragments Specific for the Shigella flexneri Serotype 2a O-Antigen

ABSTRACT

The stereocontrolled synthesis of methyl α-D-glucopyranosyl-(1→4)-α-L-rhamnopyranoside (EC, 1), methyl α-L-rhamnopyranosyl-(1→3)-[α-D-glucopyranosyl-(1→4)]-α-L-rhamnopyranoside (B(E)C, 3) and methyl α-D-glucopyranosyl-(1→4)-α-L-rhamnopyranosyl-(1→3)-2-acetamido-2-deoxy-β-D-glucopyranoside (ECD, 4) is described; these constitute the methyl glycosides of branched and linear fragments of the O-specific polysaccharide of Shigella flexneri serotype 2a. Emphasis was put on the construction of the 1,2-cis EC glycosidic linkage resulting in the selection of 2,3,4,6-tetra-O-benzyl-α-D-glucopyranosyl fluoride (8) as the donor. Condensation of methyl 2,3-O-isopropylidene-4-O-trimethylsilyl-α-L-rhamnopyranoside (11) and 8 afforded the fully protected αE-disaccharide 20, as a common intermediate in the synthesis of 1 and 3, together with the corresponding βE-anomer 21. Deacetalation and regioselective benzoylation of 20, followed by glycosylation with 2,3,4-tri-O-benzoyl-α-L-rhamnopyranosyl trichloroacetimidate (15) afforded the branched trisaccharide 25. Full deprotection of 20 and 25 afforded the targets 1 and 3, respectively. The corresponding βE-disaccharide, namely, methyl β-D-glucopyranosyl-(1→4)-α-L-rhamnopyranoside (βEC, 2) was prepared analogously from 21. Two routes to trisaccharide 4 were considered. Route 1 involved the coupling of a precursor to residue E and a disaccharide CD. Route 2 was based on the condensation of an appropriate EC donor and a precursor to residue D. The former route afforded a 1:2 mixture of the αE and βE condensation products which could not be separated, neither at this stage, nor after deacetalation. In route 2, the required αE-anomer was isolated at the disaccharide stage and transformed into 2,3,4,6-tetra-O-benzyl-α-D-glucopyranosyl-(1→4)-2,3-di-O-benzoyl-α-L-rhamnopyranosyl trichloroacetimidate (48) as the EC donor. Methyl 2-acetamido-2-deoxy-4,6-O-isopropylidene-β-D-glucopyran-oside (19) was preferred to its benzylidene analogue as the precursor to residue D. Condensation of 19 and 48 and stepwise deprotection of the glycosylation product afforded the target 4.     

Novel Photochemical Synthesis of Spiro-1,2,6,8,9 Pentaza-4-thia(4,4)nonane via Rearrangement of Aliphatic Arylazo Compounds

Irradiation of N-phenyl-2-phenylazo-3-oxo-3-[(4-phenyl-5-aryl)-1,2,4-triazol-3-yl)thio]butanamides 4 _a–c gave the corresponding title spiro compounds 5 _a–c as end products via tandem rearrangement and cyclization of 4 _a–c in their excited states.