Macrobicyclic Compounds Research Articles

Multistep synthesis, reactivity and X-ray structure of the anisole-terminated iron(II) polyhalogenoclathrochelates and their monoribbed-functionalized macrobicyclic derivatives

Multistep synthetic pathway towards a series of the anisoleboron-capped ribbed-functionalized iron(II) cage complexes was developed. Their hexachloroclathrochelate precursor was obtained by the template condensation of three dichloroglyoximate chelating ligand synthons with two molecules of 4-methoxyphenylboronic acid as a Lewis-acidic cross-linking agent on the iron(II) ion as a matrix. It easily underwent a stepwise nucleophilic substitution with S2- and O2-dinucleophilic aliphatic (ethanedithiolate) or aromatic (pyrocatecholate) agents, forming the stable X2 (X = S or O)-six-membered ribbed substituent(s) at a quasiaromatic cage framework. Performing these reactions under the different reaction conditions (i.e., at various hexachloroclathrochelate-to-nucleophile molar ratios, a wide range of temperatures and a series of the solvents) allowed to control a predominant formation of its mono-, di- or triribbed-substituted macrobicyclic derivatives. Thus obtained iron(II) di- and tetrachloroclathrochelates can undergo their post-synthetic transformations with active nucleophilic agents. The latter complexes underwent a further nucleophilic substitution with the anionic derivative of n-butanthiol, thus giving the hexasulfide macrobicyclic compound with two functionalizing n-alkyl substituents in one of its three chelate α-dioximate fragments and two apical biorelevant anisole substituents. The obtained iron(II) clathrochelates, possessing a low-spin electronic d6 configuration, were characterized using elemental analysis, MALDI-TOF mass spectrometry, UV–Vis, 1H and 13C{1H} NMR spectroscopies, and by the single-crystal X-ray diffraction experiments for the hexachloroclathrochelate precursor, its dichlorotetrasulfide macrobicyclic derivative and the monoribbed-functionalized hexasulfide cage complex. In all their molecules, the encapsulated iron(II) ion is situated in the centre of its FeN6-coordination polyhedron, the geometry of which is intermediate between a trigonal prism and a trigonal antiprism with the distortion angles φ from 21.4 to 23.4°. Halogen bonding between the polyhalogenoclathrochelate molecules in their crystals is observed.Graphical abstract

Syntheses of Atypically Fluorinated Peptidyl Macrocycles through Sequential Vinylic Substitutions

AbstractSmall peptides containing combinations of cysteine, tyrosine, histidine, and serine residues react with octafluorocyclopentene (OFCP) to afford atypically structured macrocycles through successive vinylic substitutions. The reactions proceed rapidly in air at 0 °C and are tolerant of spectating tryptophan, asparagine, glutamine, and threonine residues. Hexapeptides of consensus sequence YXCXXC displace four fluorine atoms from OFCP to generate fluorinated macrobicyclic compounds that display dual‐turn surfaces. The method provides facile access to a wide range of previously unknown heterocyclic structures.

In,in-Cyclophanes with Bridgehead Methyl Groups.

Two in,in-cyclophanes that contain methyl groups in their central cavities have been synthesized, and their X-ray structures have been determined. One of these molecules contains a very short nonbonded contact between a hydrogen atom and a methyl group, and the other is the first example of a macrobicyclic compound that contains two inwardly directed methyl groups.

Synthesis of N- and O-Containing Macrobicycles with Central Biphenyl Moiety via Pd(0)-Catalyzed Amination Reactions

Background: Simple, efficient and enough versatile approaches to macrobicycles and macrotricycles, which are of great interest for the coordination of metal cations, were proposed in early 1990s using nucleophilic substitution reactions. Our research group was the first to begin a wide-range synthesis of N- and Ocontaining macrocycles using Pd-catalyzed amination reactions. Objective: The goal of the present research is to develop the catalytic synthesis of nitrogen- and oxygen containing macrobicycles organized around the central biphenyl moiety. Method: The method employed is the Pd(0)-catalyzed amination reactions which led to the formation of the first macrocycle comprising 3,3'-disubstituted biphenyl followed by the modification with two bromobenzyl moieties and the second Pd(0)-catalyzed macrocyclization which afforded target macrobicycles. Results: Macrocycles with the endocyclic 3,3'-disubstituted biphenyl moiety and diazadioxa, diazatrioxa, and tetraamine linkers were synthesized in 26-44% yields using Pd(0)-catalyzed amination reactions. They were modified with two 3-bromobenzyl substituents and introduced in the second Pd(0)-catalyzed macrocyclization to give macrobicycles in 8-27% yields. The result was shown to be dependent on the structure of the reacting compounds. The reaction with diazacrown ether provided a macrotricyclic derivative. Conclusion: An approach to a variety of N- and O-containing macrobicyclic compounds comprising a central biphenyl moiety and two oxadiamine (polyamine) chains via two consecutive Pd(0)-catalyzed amination reactions was elaborated.

Pd(0)-Сatalyzed Amination in the Synthesis of Planar-Chiral Macrobicyclic Compounds Comprising 1,5-Disubstituted Anthraquinone Moiety

Pd(0)-Сatalyzed Amination in the Synthesis of Planar-Chiral Macrobicyclic Compounds Comprising 1,5-Disubstituted Anthraquinone Moiety

Steric control of the in/out sense of bridgehead substituents in macrobicyclic compounds: isolation of new "crossed chain" variants of in/out isomers.

Isomers of the cage like dibridgehead diphosphine P((CH2)14)3P (1) are treated with Ph3PAu(2,6-C6H3(Trip)2) (2 equiv.; Trip = 2,4,6-C6H2(iPr)3). With out,out-1, workup gives out,out-1·(Au(2,6-C6H3(Trip)2))2 (46%), as confirmed by a crystal structure. With in,out-1, crystallization affords not in,out-1·(Au(2,6-C6H3(Trip)2))2, but rather an out,out isomer in which one of the (CH2)14 segments threads through the macrocycle formed by the other two. Implications for mechanisms of interconversion of in,out isomers are analyzed.

Dicarboxylate recognition properties of a dinuclear copper(II) cryptate.

A ditopic polyamine macrobicyclic compound with biphenylmethane spacers was prepared, and its dinuclear copper(II) complex was studied as a receptor for the recognition of dicarboxylate anions of varying chain length in H2O/MeOH (50:50 (v/v)) solution. The acid-base behavior of the compound, the stability constants of its complexes with Cu(2+) ion, and the association constants of the copper(II) cryptate with succinate (suc(2-)), glutarate (glu(2-)), adipate (adi(2-)), and pimelate (pim(2-)) were determined by potentiometry at 298.2 ± 0.1 K in H2O/MeOH (50:50 (v/v)) and at ionic strength 0.10 ± 0.01 M in KNO3. The association constants of the same cryptate as receptor for aromatic dicarboxylate substrates, such as phthalate (ph(2-)), isophthalate (iph(2-)), and terephthalate (tph(2-)), were determined through competition experiments by spectrophotometry in the UV region. Remarkably high values of association constants in the range of 7.34-10.01 log units were found that are, to the best of our knowledge, the highest values of association constants reported for the binding of dicarboxylate anions in aqueous solution. A very well defined peak of selectivity was observed with the binding constant values increasing with the chain length and reaching the maximum for substrates with four carbon atoms between the carboxylate groups. Single-crystal X-ray diffraction determinations of the cascade complexes with adi(2-) and tph(2-) assisted in the understanding of the selectivity of the cryptate toward these substrates. The Hirshfeld surface analyses of both cascade complexes suggest that the establishment of several van der Waals interactions between the substrates and the walls of the receptor also contributes to the stability of the associations.

Synthesis of macrobicyclic compounds containing diazacrown ether moieties and ortho-aminobenzylic spacers

N,N´-Bis(2-bromobenzyl) diaza-15-crown-5 and -diaza-18-crown-6 ethers were obtained in high yields. Palladium-catalyzed amination of these compounds with equimolar amounts of linear polyamines and oxadiamines afforded a large number of macrobicyclic compounds. It was found that the structure of starting compounds is crucial for the formation of the target cryptands and that their yields can substantially be increased by using larger catalyst loadings.

ChemInform Abstract: A One‐Step, Versatile Synthesis of Dibenzo [n.2.2] Macrobicyclic Compounds via a Conformation‐Directed Macrocyclization Reaction.

AbstractA highly efficient synthesis of bridged bicyclic compounds based on reductive alkyltin of anthracene dicarboxylate (I) is presented.

A One-Step, Versatile Synthesis of Dibenzo [n.2.2] Macrobicyclic Compounds via a Conformation-Directed Macrocyclization Reaction

A series of dibenzo [n.2.2] bicyclic compounds (n = 2-20) were prepared in one step and good yields starting from dimethyl anthracene-9,10-dicarboxylate. Reduction of the aromatic diester using lithium/naphthalene led to a bis-enolate that was cyclized with a variety of bis-electrophiles. The ease of the cyclization is probably due to the puckered conformation of the intermediate formed after the first alkylation step, in which the newly introduced chain that will become the bridge portion occupies a pseudoaxial position, positioning the leaving group close to the enolate nucleophile in the macrocyclization step.

Water Encapsulation in a Polyoxapolyaza Macrobicyclic Compound

A new heteroditopic macrobicyclic compound (t(2)pN(5)O(3)) containing two separate polyoxa and polyaza compartments was synthesized in good yield through a [1 + 1] "tripod-tripod coupling" strategy. The X-ray crystal structure of H(3)t(2)pN(5)O(3)(3+) revealed the presence of one encapsulated water molecule accepting two hydrogen bonds from two protonated secondary amines and donating a hydrogen bond to one amino group. The acid-base behavior of the compound was studied by potentiometry at 298.2 K in aqueous solution and at ionic strength 0.10 M in KCl. The results revealed unusual protonation behavior, namely a surprisingly low fourth protonation constant contrary to what was expected for the compound. (1)H NMR and DOSY experiments, as well as molecular modeling studies, showed that the water encapsulation and the conformation observed in the solid state are retained in solution. The strong binding of the encapsulated water molecule, reinforced by the cooperative occurrence of a trifurcated hydrogen bond at the polyether compartment of the macrobicycle, account for the very low log K(4)(H) value obtained.

Dicarboxylate Recognition by Two Macrobicyclic Receptors: Selectivity for Fumarate over Maleate

Two ditopic polyamine macrobicyclic compounds have been studied as receptors for the recognition of dicarboxylate anions of varying chain length in aqueous solution. One of the receptors consists of two tris(2-aminoethyl)amine-derived binding subunits separated by p-xylyl spacers, while the other is a heteroditopic compound, combining two different head units, a tren-derived and a 2,4,6-triethylbenzene-derived one, also separated by p-xylyl spacers. The acid-base behavior of the compounds as well as their binding ability with oxalate (oxa(2-)), malonate (mal(2-)), succinate (suc(2-)), glutarate (glu(2-)), maleate (male(2-)) and fumarate (fum(2-)) anions were studied by potentiometry at 298.2 K in aqueous solution and at ionic strength 0.10 M in KTsO. NMR studies were also performed to obtain structural information in solution on the supermolecules formed by association of the protonated macrobicycles with the dicarboxylate substrates. The results revealed that both compounds are able to form stable associations with the dianionic substrates in competitive aqueous solution, with unprecedented selectivity for fum(2-) over other dicarboxylate competitors, including its cis isomer male(2-). In addition it was found that although the selectivity pattern is unaffected by the introduction of the 2,4,6-triethylbenzene head unit, the affinity toward dicarboxylates is significantly reduced. Therefore, the comparison between the binding behavior of these two receptors showed the effect of the increased rigidity and lipophilicity of the receptor with the 2,4,6-triethylbenzene head unit in the binding properties and the selectivity pattern.

A polyoxapolyaza macrobicyclic receptor for the recognition of zwitterions

A polyoxapolyaza heteroditopic macrobicyclic compound (btpN(4)O(3)) was synthesized. The acid-base behaviour of the compound as well as its binding ability for zwitterionic amino acids were studied by potentiometry at 298.2 ± 0.1 K in H(2)O-MeOH (50:50 v/v) and at I = 0.10 ± 0.01 M in NMe(4)TsO. The H(n)btpN(4)O(3)(n+) showed preference for amino acids containing tetrahedral anionic groups.

Recognition of Oxalate by a Copper(II) Polyaza Macrobicyclic Complex

A new polyamine macrobicyclic compound was synthesised through a [1+1] "tripod-tripod coupling" strategy and using a Schiff base condensation reaction, followed by sodium borohydride reduction. The resulting compound is a heteroditopic cage (btpN(7)) in which one of the head units is appropriate for the coordination of copper(II), whereas the other head is available for additional hydrogen-bonding and electrostatic interactions with substrates. The acid-base behaviour of the new compound, the stability constants of its complex with the Cu(2+) ion and the association constants of the copper(II) cryptate with oxalate (oxa(2-)), malonate (mal(2-)), succinate (suc(2-)), maleate (male(2-)) and fumarate (fum(2-)) were determined by potentiometry at 298.2 K in aqueous solution and at an ionic strength of 0.10 mol dm(-3) in KNO(3). These studies revealed a clear preference of the receptor [CuH(h)btpN(7)H(2)O]((2+h)+) for oxa(2-) over the other dicarboxylate substrates. This arises from co-operativity between metal-anion coordination and electrostatic and hydrogen-bonding interactions, in accordance with the ideal size of this dicarboxylate, which allow it to take full advantage of the potential binding sites of the receptor. A qualitative indicator-displacement study, in agreement with the potentiometric studies, demonstrated that the copper cryptate receptor can be used as a selective visual sensor for oxalate.

Synthesis of macrobicyclic compounds containing aza-crown ether fragments and study of their complexation with zinc and cadmium nitrates

N-(3,5-Dibromobenzyl) derivatives of 1-aza-15-crown-5 and 1-aza-18-crown-6 were synthesized in high yields and their palladium-catalyzed amination reactions with various linear polyamines were studied. As a result, macrobicyclic compounds were obtained in yields up to 56%. The complexation of some macrocycles with zinc and cadmium nitrates was studied by NMR titration.

Cryptands by One-Pot Homoacetylenic Cu-Catalyzed Coupling – Synthesis, Structure and Properties

This review presents the synthesis of macrobicyclic compounds built from triphenylmethane, triphenylphosphine oxide units and other three-dimensional molecules with an aromatic core, as well as some fullerene precursors and buta-1,3-diynediyl spacers. The dependence of the coupling yield on the solvent, catalysts (Cu+ and/or Cu2+) and presence of oxygen is also addressed. The formation of inclusion complexes of these cage molecules with appropriately sized neutral guests such as solvent molecules (acetonitrile, benzene, dichloromethane, chloroform), cubane, benzyl cyanide and structural information of the host derivatives are also reviewed.

Reactions of Unsaturated Azides; Part 22: The Alkyne Azide Click Chemistry as a Synthetic Tool for the Generation of Cage-Like Triazole Compounds

The applicability of the copper(I)-catalyzed click reaction of terminal trialkynes with triazides to the synthesis of cage-like triazole compounds was determined. A number of starting materials were prepared and several monotriazoles as well as macrocyclic bistriazoles were obtained from the triazide trialkyne reaction. Finally, a tristriazole macrobicyclic compound was synthesized from the previously formed triazole precursors.

Synthesis and characterization of new metal-free and nickel(II) phthalocyanines containing hexaazadioxa macrobicyclic moieties

Novel symmetrically tetrasubstituted metal-free and metallophthalocyanines (5) and (6) which contain four hexaazadioxamacrobicycles on peripheral positions, have been synthesized. Macrobicyclic compound 3 and has been prepared by reaction of (1,3,6,9,11,14- hexaazatricyclo[12.2.1.16,9])octadecane (1) with 1,2-bis(2-iodoethoxy)-4,5-dibromobenzene (2). Compound 4 has been synthesized by reaction of compound 3 with CuCN in dry DMF. The target symmetrical phthalocyanines were separated by column chromatography and characterized by elemental analyses, 1H, 13C–NMR, IR, UV–Visible and FAB mass spectroscopies.

Synthesis of proton-ionizable acyclic, macrocyclic and macrobicyclic compounds containing one or two triazole groups

New acyclic, macrocyclic and macrobicyclic compounds containing one or two proton-ionizable triazole groups are prepared and characterized. The series includes six podands, a macrocycle with one triazole and one pyridine unit in the ring, a bis-triazolo macrocycle with four pentafluorobenzyl substitutents, and two bis(crown ethers) with a triazolo group connecting the two polyether rings. The solid-state structure and solubility in supercritical carbon dioxide are determined for the bis-triazolo macrocycle with pendant pentafluorobenzyl groups.

Phosphorus Macrocycles and Cryptands

AbstractFor Abstract see ChemInform Abstract in Full Text.