Synthesis of macrocyclic bis(phenylbenzoxazole) derivatives via tandem claisen rearrangement and their fluorescence behavior

Novel macrocyclic bis(phenylbenzoxazole) derivatives were easily synthesized from macrocyclic isobutenyl bis(amide‐ether)s by tandem Claisen rearrangement and subsequent intramolecular cyclization of the amide‐phenol intermediates. The position of substitution of the oligoethylene glycol moiety on the phenylamido groups of the macrocycles did not have a large effect on the yields of the bis(benzoxazole)s for the meta and para derivatives. The fluorescence quantum yields of most of the macrocyclic bis(benzoxa‐zole)s were lower than those of the corresponding nonmacrocyclic bis(benzoxazole) model compounds. The quantum yields of the para‐substituted macrocyclic bis(benzoxazole)s were clearly lower than those of the model compounds and decreased with increasing length of the oligoethylene chain.     

Synthesis and anti-inflammatory activity of triazole-based macrocyclic amides through click chemistry

Triazole-based macrocyclic amides 1–12 with amide group as the intrannular functionality has been synthesized through click chemistry. Triazole-based macrocyclic amides 1–12 show good anti-inflammatory activity even at low concentration (50?µg/mL) when compared to that of the reference drug prednisolone. BINOL-based chiral macrocyclic amides and pyridine-based macrocyclic amides show better anti-inflammatory activity than the other synthesized macrocyclic amides.     

New diazadi(and tri)thia‐21‐crown‐7 ethers containing 8‐hydroxyquinoline side arms

A series of macrocyclic diazadi(and tri)thiacrown ethers containing two 5‐substituent‐8‐hydroxyquinoline side arms have been synthesized from the corresponding macrocyclic diazadi(and tri)thiacrown ethers. The crown ethers were obtained by reduction of the proper macrocyclic di(and tri)thiadiamides by borane‐tetrahydrofuran or by sodium borohydride‐boron trifluoride ethyl etherate‐tetrahydrofuran. The yields for the reduction of diamides by sodium borohydride‐boron trifluoride ethyl etherate‐tetrahydrofuran were higher than those by borane‐tetrahydrofuran. The following four methods were used to prepare macrocycles bearing two 8‐hydroxyquinoline side arms: (1) Mannich reaction with 8‐hydroxyquinoline; (2) Reductive animation with 8‐hydroxyquinoline‐2‐carboxaldehyde using sodium triacetoxyborohydride as the reducing agent; (3) Cyclization of N,N'‐bis(8‐hydroxyquinolin‐2‐ylmethyl)‐1,2‐bis(2‐aminoethoxy)ethane (38) with bis(α‐chloroamide) 5 ; and ( 4 ) A step‐by‐step process wherein macrocyclic trithiadiamide 11 was reduced by lithium aluminum hydride‐tetrahydrofuran to the cyclic monoamide 36 , which smoothly reacted with 5‐chloro‐8‐hydroxyquinoline to produce monosubstituted‐macrocyclic monoamide 39 .     

含三螺吡喃单元大环分子的合成和酸致变色效应

合成了含有3个螺吡喃单元的大环分子,采用点击化学方法实现高效的闭环反应,大环分子产率为64%。 使用红外、核磁和质谱等方法检测和表征了反应中间产物和目标产物,质谱分析结果证实环化结构。 使用紫外-可见光谱仪观察到大环产物和线性螺吡喃前体分子在pH值接近4时的酸致变色效应。 与线性螺吡喃前体分子的最大紫外吸收峰位置（476 nm）相比,螺吡喃大环分子在最大紫外吸收峰位置（464 nm）发生蓝移。 螺吡喃大环分子比线性前体分子具有更大的摩尔消光系数,其pH响应性能更加优异。     

四氮大环-金属配合物与DNA作用的电化学及谱学研究

Mononuclear copper（Ⅱ）, nickel（Ⅱ） and cobalt（Ⅲ） tetracoordinate macrocyclic complexes were synthesized and spectroscopically characterized. The crystal structure of the three compounds were determined by X-ray crystallography. The electrochemical experimental results indicate that the three complexes could interact with DNA mainly by electrostatic interaction. The interaction of tetracoordinate macrocyclic cobalt（Ⅲ） complex with DNA was studied by cyclic voltammetry and UV-vis spectroscopy. The experimental results reveal that tetracoordinate macrocyc- lic cobalt（Ⅲ） complex could interact with DNA by electrostatic interaction to form a 1 ： 1 DNA association complex with a binding constant of 7.50 ×10^3 L·mol^-1.     

Estimation of Li+, K+ and Ca2+ Complexation with [12] crown-4, [15] crown-5 and [18] crown-6 Using a Na+ ISE in Dioxane-Water, Part IV*

 The (1:1) Na⁺ equilibrium constants, Ke1, of macrocyclic ethers of [12]crown-4, [12]crown-5 and [18]crown-6 were determined with a Na⁺ ISE in the presence of a second cation e.g. Li⁺, K⁺ and Ca²⁺ in dioxane/water (50/50). We estimated the (1:1) equilibrium constants, K e2 of the macrocyclic ethers with Li⁺, K⁺ and Ca²⁺ by this way. The binding selectivity of a macrocyclic ether between two cations was estimated in the same binary solvent mixture where the water hydration role is diminished. Results showed clearly the effect of macrocyclic size and cation radii in a solution. Received October 27, 1998. Revision March 22, 1999.     

Diastereoisomeric singly bridged cyclophosphazene-macrocyclic compounds

31P NMR spectroscopy and added chiral shift reagent (CSR) or chiral solvating agent (CSA) have been used to show that unsymmetrically substituted singly bridged macrocyclic phosphazene compounds exist as 1:1 diastereoisomers of two racemic mixtures, in contrast to previous work (ref 2) on symmetrically substituted diastereoisomeric analogues, which exist as meso and racemic forms. The cis-ansa cyclotriphosphazatriene-macrocycle, 1, is meso and monosubstitution of the >P(O-macrocycle)Cl group with 2-naphthol gives a racemic product (7), in which the macrocyclic ring exists in a trans-ansa configuration. Reaction of 7 with the di-secondary amine, piperazine, gives an unsymmetrically disubstituted racemic compound (8) having a cis-ansa configuration of the macrocyclic ring. Reaction of 8 with a further quantity of 1 forms a singly bridged derivative (9) with the macrocyclic rings in cis-trans configurations, and further reaction of 9 with pyrrolidine gives compound 10 with the macrocyclic rings in cis-cis configurations. Both 9 and 10 have four stereogenic centers giving rise to diastereoisomeric compounds existing as mixtures of two racemates. The results are consistent with inversion of configuration at phosphorus at each step of the reaction of >P(OR)Cl groups with nucleophile Z (i.e., Z = naphthoxy, piperazino, pyrrolidino) to form >P(OR)Z derivatives.     

Regioselective synthesis of spiropyrrolidine/spiropyrrolizidine/spirothiazolidine-grafted macrocycles through 1,3-dipolar cycloaddition methodology

Synthesis of 13- and 16-membered macrocyclic enone with alkyl ether and triazole as a linker was achieved using intramolecular aldol condensation. The newly synthesized macrocyclic enone was successfully utilized as a dipolarophile in 1,3-dipolar cycloaddition (1,3-DC). The dipole generated from isatin/acenaphthenequinone with various secondary amino acids (sarcosine, l-proline, and thiazolidine-4-carboxylic acid) were reacted with macrocyclic enone to give a new class of spiropyrrolidine-grafted macrocycles in good yield (>85%). The structures were assigned by 2D NMR spectra and the regio- and stereochemical outcome of the cycloadducts were established by a single crystal X-ray analysis.     

The Crystal and Molecular Structure of a New Macrocyclic Ligand, (H_6BDBPH)Br_6·4H_2O

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Polarographic Eiectroreduction of Some Complexes of Uranium with Macrocyclic Polyethers

Abstract

The polarographic behaviour of uranium(VI) in aqueous C. 1 N nitric acid medium, in the presence of some polyoxa macrocyclic ligands (15-crown-5, benzo-15-crown-5, 18-crown-6, dicyclohexyl-18-crown-6), at 25°C, was investigated. Both in the absence and in the presence of the polyoxa macrocyclic ligands, the reduction of hexavalent uranium in aqueous medium takes place in two steps, each of which involving the transfer of an electron. Under diffusion-controlled conditions, the two steps of the reduction in acid medium proceed reversibly. The results of the polarographic measurements enabled to estimate the ratio of the stability constants of the complex ions of U(111) and of U(IV) with macrocyclic polyethers.     

Dramatic acceleration of the Menschutkin reaction and distortion of halide leaving-group order

Compared to structurally related linear trialkylamines, a simple macrocyclic amine with an anion-binding cavity exhibits very large rate enhancements (>10(5)) for stoichiometric N-alkylation with primary alkyl, allyl, and benzyl halides in the weakly polar solvent CDCl3. There is also a major distortion of the halide leaving-group order. For example, with benzyl halides the relative leaving-group order with a control amine is Cl (1) < Br (71) < I (160), whereas the leaving-group order with the macrocyclic amine is I (0.4) < Cl (1) < Br (8.5). Reaction with the macrocyclic amine is inhibited by the addition of DMSO, which is unusual because the Menschutkin reaction is normally enhanced by the presence of a polar aprotic solvent. Competitive inhibition studies indicate that the reaction proceeds through a prereaction complex. Effective molarities for the subsequent unimolecular N-alkylation step with 4-t-butylbenzyl halides are 4-t-BuBnCl (62,000 M) > 4-t-BuBnBr (2200 M) > 4-t-BuBnI (35 M); thus, the free energy of activation is selectively decreased for organohalides having smaller and more charge dense leaving groups. Likely reasons for this selective enhancement effect are: (a) increased transition-state stabilization due to hydrogen bonding in the macrocyclic pocket and (b) reduced entropic penalty in the transition state due to an increased fraction of prereaction complexes that are oriented in a near attack conformation. The study suggests that it should be possible to develop highly reactive macrocyclic amines that selectively sense or scavenge carcinogenic haloalkanes from the atmosphere.     

A Macrocyclic Fluorophore Dimer with Flexible Linkers: Bright Excimer Emission with a Long Fluorescence Lifetime

Bright fluorescent molecules with long fluorescence lifetimes are important for the development of lifetime‐based fluorescence imaging techniques. Herein, a molecular design is described for simultaneously attaining long fluorescence lifetime (τ) and high brightness (Φ_F×?) in a system that features macrocyclic dimerization of fluorescent π‐conjugated skeletons with flexible linkers. An alkylene‐linked macrocyclic dimer of bis(thienylethynyl)anthracene was found to show excimer emission with a long fluorescence lifetime (τ≈19 ns) in solution, while maintaining high brightness. A comparison with various relevant derivatives revealed that the macrocyclic structure and the length of the alkylene chains play crucial roles in attaining these properties. In vitro time‐gated imaging experiments were conducted as a proof‐of‐principle for the superiority of this macrocyclic fluorophore relative to the commercial fluorescent dye Alexa Fluor 488.     

Synthesis and characterization of organic–inorganic macrocyclic molecular brushes with poly(ε-caprolactone) side chains

In this work, we reported the synthesis of a dodecahydroxyl-functionalized macrocyclic oligomeric silsesquioxane (MOSS). The novel 24-membered hydroxyl-functionalized MOSS was employed as a macroinitiator for the ring-opening polymerization of ε-caprolactone (CL) and the organic–inorganic macrocyclic molecular brushes with poly(ε-caprolactone) (PCL) side chains were successfully synthesized. The organic–inorganic macrocyclic molecular brushes were characterized by means of nuclear magnetic resonance spectroscopy (NMR) and gel permeation chromatography (GPC). The results of wide angle X-ray diffraction (XRD) indicate that the architecture of the organic–inorganic macrocyclic molecular brushes did not alter the structure of PCL crystals. Differential scanning calorimetry (DSC) shows that the architecture of organic–inorganic macrocyclic molecular brushes significantly affected the rearrangement of PCL crystals. Compared to linear PCL, the organic–inorganic macrocyclic molecular brushes possessed the improved thermal stability in terms of the temperatures at the maximum of degradation rate and the yields of degradation residues.     

Direct Quantitative Estimation of the Macrocyclic Effect in the Dissociation of Protoporphyrin Complexes

(Chloro)platinum(III)protoporphyrin and its closest noncyclic analogue, platinum(III)biliverdin, are synthesized; the forms and stability of the complexes in proton-donating solutions as dependent on temperature and solvent composition are studied. The macrocyclic effect (the effect of coordinated macrocyclic ligand opening) is directly estimated quantitatively; a correlation between its contribution to the rate of dissociation (or stability) of the complexes and their structures is found.     

On Phosphorylation of Dihydric Phenols with Amines of Phosphoric and Phenylphosphonic Acids

Abstract

With the aim to create macrocyclic phosphorus-containing heterocycles (new phosphorus crown-ethers) and corresponding polyesters the interaction between dihydric phenols and complete anides of phosphoric and phenylphosphonic acids was studied. It was shown that, according to reaction conditions and reagents ratio, the resulting products can have a linear structure, with oligo- (A) or polymexic (B) molecules, and a macrocyclic structure (C) alike : phospho(III)arylene crown-ethers obtained for example by the consecutive assembling of planned macrocyclic systems or by the direct interaction.     

Affinity Maturation of Macrocyclic Peptide Modulators of Lys48-Linked Diubiquitin by a Twofold Strategy

Messenger RNA display of peptides containing non-proteinogenic amino acids, referred to as RaPID system, has become one of the leading methods to express libraries consisting of more than trillion-members of macrocyclic peptides, which allows for discovering de novo bioactive ligands. Ideal macrocyclic peptides should have dissociation constants (K_D) as low as single-digit values in the nanomolar range towards a specific target of interest. Here, a twofold strategy to discover optimized macrocyclic peptides within this affinity regime is described. First, benzyl thioether cyclized peptide libraries were explored to identify tight binding hits. To obtain more insights into critical sequence information, sequence alignment was applied to guide rational mutagenesis for the improvement of their binding affinity. Using this twofold strategy, benzyl thioether macrocyclic peptide binders against Lys48-linked ubiquitin dimer (K48-Ub2) were successfully obtained that display K_D values in the range 0.3–1.2 nm , which indicate binding two orders of magnitude stronger than those of macrocyclic peptides recently reported. Most importantly, this macrocyclic peptide also showed an improved cellular inhibition of the K48-Ub2 recognition by deubiquitinating enzymes and the 26S proteasome, resulting in the promotion of apoptosis in cancer cells.     

Construction of unsymmetrical bis-urea macrocyclic host for neutral molecule and chloride-ion binding

Construction of synthetic macrocyclic host that can bind with neutral molecules and anions has potential applications in supramolecular chemistry. Herein, we have designed and synthesized blue light emitting an unsymmetrical neutral bis-urea macrocyclic host. This macrocycle can bind with neutral DMF molecule (1:1) as well as Cl⁻ ion (1:1) through noncovalent interactions. X-Ray crystal structure, ¹H NMR titrations with Job's Plot, HRMS with isotropic distribution pattern, FT-IR, and density functional theory analysis revealed the binding of bis-urea macrocyclic host with the guest molecule.     

Synthesis of New,Unnatural Macrocyclic Trichothecenes: 3-isoverrucarin A ((1″-O)(3→4)abeo-verrucarin A), verrucinol,and verrucene. 46th Communication on verrucarins and roridins

A new unnatural macrocyclic trichothecene, an analogue of verrucarine A ( 1 ), which was named 3-Isoverrucarin A ((1″-O)(3→4)abeo-verrucarin A; 3 ) was synthesized starting from anguidine ( 5 ). The two key reactions were the removal of the 4β-acetoxy group of anguidine ( 5 ) by a Barton deoxygenation and the final macrolactonization. During the cyclization procedure, two unexpected new macrocyclic by-products, which were named verrucinol ( 19 ) and verrucene ( 20 ), were formed. They represent novel types of macrocyclic trichothecenes, the macrolidic moiety of verrucene ( 20 ) consisting only of the (Z,E)-muconic-acid residue. The formation of the analogous macrolide 26 of verrucene ( 20 ) was not possible, probably because the ring strain is too strong.     

含四硫富瓦烯大环化合物的合成与研究进展

简要介绍了含有四硫富瓦烯(TTF)单元的大环化合物的分类, 概括了各类含四硫富瓦烯大环化合物的合成方法, 主要包括含有1,3-二硫杂环戊烯-2-硫酮单元的大环化合物在亚磷酸三烷基酯参与下的偶合反应, 以及带有氰乙基硫等取代基的预先合成的官能化TTF与二卤代低聚醚的反应. 综述了含四硫富瓦烯大环化合物的电化学性能及其在分子识别方面应用研究的最新进展, 提出了含四硫富瓦烯大环化合物的发展趋势.     

Slippage of a Porphyrin Macrocycle over Threads of Varying Bulkiness: Implications for the Mechanism of Threading Polymers through a Macrocyclic Ring

Threading of a polymer through a macrocyclic ring may occur directly, that is, by finding the end of the polymer chain, or by a process in which the polymer chain first folds and then threads through the macrocyclic ring in a hairpin‐like conformation. We present kinetic and thermodynamic studies on the threading of a macrocyclic porphyrin receptor ( H₂1 ) onto molecular threads that are blocked on one side and are open on the other side. The open side is modified by groups that vary in ease of folding and in bulkiness. Additionally, the threads contain a viologen binding site for the macrocyclic receptor, which is located close to the blocking group. The rates of threading of H₂1 were measured under various conditions, by recording as a function of time the quenching of the fluorescence of the porphyrin, which occurs when receptor H₂1 reaches the viologen binding site. The kinetic data suggest that threading is impossible if the receptor encounters an open side that is sterically encumbered in a similar way as a folded polymer chain. This indicates that threading of polymers through macrocyclic compounds through a folded chain mechanism is unlikely.