Strained cyclophane macrocycles: impact of progressive ring size reduction on synthesis and structure

The synthesis, X-ray crystal structures, and calculated strain energies are reported for a homologous series of 11- to 14-membered drug-like cyclophane macrocycles, representing an unusual region of chemical space that can be difficult to access synthetically. The ratio of macrocycle to dimer, generated via a copper catalyzed azide-alkyne cycloaddition macrocyclization in flow at elevated temperature, could be rationalized in terms of the strain energy in the macrocyclic product. The progressive increase in strain resulting from reduction in macrocycle ring size, or the introduction of additional conformational constraints, results in marked deviations from typical geometries. These strained cyclophane macrocyclic systems provide access to spatial orientations of functionality that would not be readily available in unstrained or acyclic analogs. The most strained system prepared represents the first report of an 11-membered cyclophane containing a 1,4-disubstituted 1,2,3-triazole ring and establishes a limit to the ring strain that can be generated using this macrocycle synthesis methodology.     

One‐Pot Multimolecular Macrocyclization for the Expedient Synthesis of Macrocyclic Aromatic Pentamers by a Chain Growth Mechanism

POCl₃‐mediated one‐pot macrocyclization allows the highly selective formation of five‐residue macrocycles that are rigidified by internally placed intramolecular hydrogen bonds. Mechanistic investigation by using tailored competition experiments and kinetic simulation provides a comprehensive model, supporting a chain‐growth mechanism underlying the one‐pot formation of aromatic pentamers, whereby the successive addition of a bifunctional monomer unit onto either another monomer or the growing oligomeric backbone is faster than other types of bimolecular condensations involving oligomers longer than monomers. DFT calculations at the B3LYP/6‐31G* level reveal the five‐residue pentamer to be the most stable with respect to alternative four‐, six‐, and seven‐residue macrocycles. These novel mechanistic insights may become useful in analyzing other macrocyclization, oligomerization, and ploymerization reactions.     

Reaction pathways leading to arylene ethynylene macrocycles via alkyne metathesis

Mechanistic studies on the direct formation of arylene ethynylene macrocycles via alkyne metathesis catalyzed by a molybdenum complex are reported. Gel permeation chromatography (GPC) and matrix-assisted laser desorption ionization (MALDI) mass spectrometry on the products from metathesis of monomer 1 show the initial formation of linear oligomers and large macrocycles (n > 6), followed by their transformation into the thermodynamically most stable product distribution-mainly the cyclic hexamer. Variable temperature and scrambling experiments reveal the reversibility of macrocycle formation. Nearly identical product distributions are observed from the cross metathesis of hexacycle 2 with diphenylacetylene and from the metathesis of bis(phenylethynyl) substituted monomer 4, demonstrating that macrocycle formation is thermodynamically rather than kinetically controlled. The metathesis byproduct, 3-hexyne, is shown to inhibit the catalyst. It is suggested that the relative metathesis rates of dialkylalkynes versus diarylalkynes trap the catalyst in a nonproductive manifold, rendering it unavailable for the productive metathesis of aryl alkylalkyne substrates. This finding indicates that dialkyl-substituted alkyne byproducts should be avoided (or efficiently removed) if the metatheses of aryl substrates, especially those with electron-withdrawing groups, are to proceed to high conversion.     

芳酰胺类大环一步高效合成及其成环机理研究进展

总结了最近发现的新型芳酰胺及芳酰肼大环一步合成反应,着重探讨了由分子内三中心氢键所引导的高效一步成环反应机理.这类反应是由未成环寡聚物前体的折叠构象所构筑,不仅高效,而且反应机理新颖,提供了传统成环反应难以得到的几类刚性大环的合成方法.这些大环化合物表现出对客体识别的高度专一性,并能形成具有高通量性的跨膜孔道.     

Shape-persistent macrocycles: structures and synthetic approaches from arylene and ethynylene building blocks

Shape-persistent arylene ethynylene macrocycles have attracted much attention in supramolecular chemistry and materials science because of their unique structures and novel properties. In this Review we describe recent examples of macrocycle synthesis by cross-coupling (Sonogashira: aryl acetylene macrocycle or Glaser: aryl diacetylene macrocycle) and dynamic covalent chemistry. The primary disadvantage of the coupling methods is the kinetically determined product distribution, since a significant portion of oligomers grow beyond the length of the cyclic targets ("overshooting"). Better results have been obtained recently by a dynamic covalent approach involving reversible metathesis reactions that afford macrocycles in one step. Mechanistic studies demonstrate that macrocycle formation is thermodynamically controlled by this route. Remaining synthetic challenges include the efficient preparation of site-specifically functionalized structures and larger, more complex two- and three-dimensional molecules.     

Synthesis of cycloparaphenylene under spatial nanoconfinement

Suzuki coupling reactions between symmetrical monomers were conducted in various mesoporous silica nanoreactors grafted with palladium catalysts, enabling the selective formation of [12]cycloparaphenylene precursor with separate yield up to 25% in one-pot reactions, much higher than that in homogeneous reaction. The spatial nanoconfinement of the nanoreactors promotes the macrocyclization while limits the concomitant linear oligomer formation, offering more possibilities for the synthesis of macrocycles from symmetrical monomers in one-pot reaction.     

Accessing Improbable Foldamer Shapes with Strained Macrocycles

The alkylation of some secondary amide functions with a dimethoxybenzyl (DMB) group in oligomers of 8-amino-2-quinolinecarboxylic acid destabilizes the otherwise favored helical conformations, and allows for cyclization to take place. A cyclic hexamer and a cyclic heptamer were produced in this manner. After DMB removal, X-ray crystallography and NMR show that the macrocycles adopt strained conformations that would be improbable in noncyclic species. The high helix folding propensity of the main chain is partly expressed in these conformations, but it remains frustrated by macrocyclization. Despite being homomeric, the macrocycles possess inequivalent monomer units. Experimental and computational studies highlight specific fluxional pathways within these structures. Extensive simulated annealing molecular dynamics allow for the prediction of the conformations for larger macrocycles with up to sixteen monomers.     

Sterically Crowded Trianglimines—Synthesis,Structure, Solid‐State Self‐Assembly,and Unexpected Chiroptical Properties

The chiral, triangular‐shape hexaimine macrocycles (trianglimines), bearing bulky alkynyl or aryl substituents were synthesized and studied by means of experimental and theoretical methods. The macrocyclization reactions are driven by the extraordinary stability of the trianglimine ring and provided products with high yields. Electrostatic repulsion between imine nitrogen atoms and the substituents forced an anti conformation of the aromatic linkers. Although the DFT‐optimized structure of 7 is D₃ symmetrical, in the crystal, the macrocycle adopts a bowl‐like molecular shape. The macrocycle self‐assembles into tail‐to‐tail dimers by mutual interdigitation of aromatic moieties. In contrast, macrocycle 8 adopts a rigid pillararene‐like conformation. The nature of the substituent significantly affects the electronic properties of the linker. As a result, unexpectedly high exciton Cotton effects are observed in the electronic circular dichroism (ECD) spectra. The origin of these effects was subject of an in‐depth study.     

Synthesis of Phenylene Vinylene Macrocycles through Acyclic Diene Metathesis Macrocyclization and Their Aggregation Behavior

A series of phenylene vinylene macrocycles (PVMs) bearing substituents with various sizes and electronic properties have been synthesized through a one‐step acyclic diene metathesis macrocyclization approach and their aggregation behaviors have been investigated. In great contrast to the aggregation of the analogous phenylene ethynylene macrocycles, which aggregate only when substituted with electron‐withdrawing groups, these PVMs undergo exceptionally strong aggregation, regardless of the electron‐donating or ‐withdrawing characters of the substituents. The unusual aggregation behavior of the PVMs is further investigated with thermodynamic and computer modeling studies, which show a good agreement with the recently proposed direct through‐space interaction model, rather than the polar/π model. The high aggregation tendency of PVMs suggests the great potential of this novel class of shape‐persistent macrocycles in a variety of applications, such as ion channels, host–guest recognition, and catalysis.     

Hydrindacene‐Based Acetylenic Macrocycles with Horizontally and Vertically Ordered Functionality Arrays

The macrocyclization of 2,6‐diethynyl hydrindacenes ( 1 ) with functional groups at mutually perpendicular positions results in the formation of novel macrocycles which, as a result of the hindered rotation of the hydrindacene units, possess directionally persistent peripheral functionalities. The two hydrindacene units in the dimer macrocycle ( 2 ) have been shown to interact electronically through their respective butadiyne moieties, whereas the trimer macrocycle ( 3 ) demonstrates a moderate degree of geometrical flexibility as a result of the five‐membered hydrindacene rings. In addition, these trimer macrocycles contain a central cavity suitably sized for the inclusion of various solvent molecules. These new macrocycles can be further modified by introducing π‐conjugated side groups, such as styryl and thienyl groups, as well as by attaching a variety of peripheral ester groups.     

Cover Picture: Expanding the Toolbox of Target Directed Bio-Orthogonal Synthesis: In Situ Direct Macrocyclization by DNA Templates (Angew. Chem. Int. Ed. 7/2023)

Herein, we demonstrate for the first time that noncanonical DNA can direct macrocyclization-like challenging reactions to synthesize gene modulators. The planar G-quartets present in DNA G-quadruplexes (G4s) provide a size complementary reaction platform for the bio-orthogonal macrocyclization of bifunctional azide and alkyne fragments over oligo- and polymerization. G4s immobilized on gold-coated magnetic nanoparticles have been used as target templates to enable easy identification of a selective peptidomimetic macrocycle. Structurally similar macrocycles have been synthesized to understand their functional role in the modulation of gene function. The innate fluorescence of the in situ formed macrocycle has been utilized to monitor its cellular localization using a G4 antibody and its in cell formation from the corresponding azide and alkyne fragments. The successful execution of in situ macrocyclization in vitro and in cells would open up a new dimension for target-directed therapeutic applications.     

Synthesis and self-association of an imine-containing m-phenylene ethynylene macrocycle

The purpose of this study was to test the suitability of the imine bond as a structural unit within the backbone of phenylene ethynylene macrocycles and oligomers by determining the ability of m-phenylene ethynylene macrocycle 1 to form pi-stacked aggregates in both solution and the solid state. Macrocycle 1, with two imine bonds, was synthesized in high yield from diamine 4 and dialdehyde 5. The imine-forming macrocyclization step was carried out under a variety of conditions, with the best yield obtained simply by refluxing the reactants in methanol. The self-association behavior of 1 in various solvents was probed by (1)H NMR. The association constants (K(E)) in acetone-d(6) and tetrahydrofuran-d(8) were determined by fitting the concentration-dependent chemical shifts with indefinite self-association models. The results showed that solvophobically driven intermolecular pi-pi stacking could be preserved in the imine-containing m-phenylene ethynylene macrocycles. Interestingly, in acetone macrocycle 1 exhibited a stronger tendency to form a dimer rather than higher aggregates. We postulate that this behavior may be due to electrostatic attraction between dipolar imine groups. The solid-state packing of 1 was studied by wide- and small-angle X-ray powder diffraction (WAXD and SAXD). Bragg reflections of 1 were consistent with a hexagonal packing motif similar to our previous studies on m-phenylene ethynylene macrocycles that formed columnar liquid crystal phases.     

BOP-mediated one-pot synthesis of C5-symmetric macrocyclic pyridone pentamers

We report here, for the first time, the BOP-mediated one-pot macrocyclization that is facilitated and guided by internally placed intramolecular H-bonds to allow for the highly selective formation of five-residue cation-binding macrocycles.     

Synthesis of New Multibenzo Oxygen–Sulfur Donor Macrocycles Containing Lactams at Room Temperature

Some new oxygen–sulfur, multibenzo macrocyclic ligands containing amide groups have been prepared using the macrocyclization process with the reaction of 2,2′-thiobis-[4-methyl(2-aminophenoxy)phenyl ether] as a symmetrical diamine with appropriate dicarboxylicacid dichlorides in moderate yields. This macrocyclization led to the formation of di- and tetramide macrocycles. These reactions were routinely carried out at ambient temperature in CH₂Cl₂ as solvent in high dilution without template effect conditions. It is found that sulfur the atom affects the rigidity of the macrocycles and diastereotopicity of nuclei in the ring of these series of macrocyclic compounds.     

Syntheses of Acetylenic Oligophenylene Macrocycles Based on a Novel Dewar Benzene Building Block Approach

A general synthetic approach to strained p-phenylene-based acetylenic macrocycles is described. A key feature in this approach is exploitation of Dewar benzene as an angular p-phenylene synthon. Thus, 1,4-acetal-bridged 2,5-dichloro(Dewar benzene) 5, prepared in four steps from dimethyl acetylenedicarboxylate and 1,2-dichloroethylene, is applied as such a building block in the syntheses of strained macrocycles 13 and anti-20. For the synthesis of 13, m-phenylene units are used as spacers and modified Eglington-Glaser coupling is applied for the macrocyclization step. For the synthesis of anti-20, on the other hand, o-phenylene units are used as spacers and Sonogashira coupling is applied for the macrocyclization step. Macrocycles 13 and anti-20 are characterized crystallographically, and their strained nature is reflected mainly in the deviation of the acetylene units from linearity; the C&tbd1;C-C angles range from 168.7(3) degrees to 179.9(3) degrees in 13 and from 168.0(5) degrees to 171.4(4) degrees in anti-20. Macrocycle 13 shows unique conformational property, namely, the p-phenylene units arranged in parallel in the rectangular framework rotate freely about the long axes, as evidenced by the (1)H NMR studies. Macrocycle anti-20 exhibits a Stokes shift of 179 nm, which is exceptionally large for phenylacetylene macrocycles, presumably owing to the characteristic stacking structure.     

Self-assembled, kinetically locked, Ru(II)-based metallomacrocycles: physical, structural, and modeling studies

By using a "complex as ligand approach," the metal-ion-templated self-assembly of heterometallic tetranuclear metallomacrocycles containing kinetically locked Ru(II) centers is described. Depending on the metal-ion template employed in the self-assembly process, the final macrocycle can be kinetically labile or inert. Electrochemical studies reveal that the kinetically inert macrocycles display reversible Ru(III/II) oxidation couples. The crystal structure of a kinetically inert Ru2Re2 macrocycles reveals a structurally complex palmate anion-binding pocket. Host-guest studies carried out with the same macrocyle in organic solvents reveals that the complex functions as a luminescent sensor for anions and that binding affinity and luminescent modulation is dependent on the structural nature and charge of the guest anion. Computational density functional theory (DFT) studies support the hypothesis that the luminescence of the macrocycle is from a 3MLCT state and further suggests that the observed guest-induced luminescence changes are most likely due to modulation of nonradiative decay processes.     

Synthesis and characterization of pyridine-based polyamido-polyester optically active macrocycles and enantiomeric recognition for D- and L-amino acid methyl ester hydrochloride

Five new chiral macrocycles, 3a-e, have been prepared by the acylation cyclization of chiral diamine dihydrobromide intermediates 2a-c with 2,6-pyridinedicarbonyl dichloride in highly diluted solution at room temperature. The chiral diesters 1a-c needed for the preparation of the macrocycles were obtained from condensation of corresponding N-(Z)-L-amino acids and 2,6-bishydroxymethyl pyridine in the presence of DCC and DMAP. The enantiomeric recognition of chiral macrocycles 3a-e for D- and L-amino acid methyl ester hydrochlorides has been characterized by fluorescence spectra, which indicate that some of them exhibited significant chiral recognition for the enantiomers of D- and L-amino acid methyl ester hydrochlorides. The stoichiometry and binding constants of 3a-L-Am(2) and 3c-L-Am(2) complexes have been determined. An X-ray analysis of the chiral macrocycle 3b show that the chiral ligand is rather rigid and strained.     

Cucurbit[n]uril analogues: synthetic and mechanistic studies

[reaction: see text] The synthesis of cucurbit[n]uril analogues (18, 19, (+/-)-20, 33, 34, 35, 36, and 37) is presented. These CB[5], CB[6], and CB[7] analogues all contain bis(phthalhydrazide) walls that are incorporated into the macrocycle. The tailor-made synthesis of these CB[n] analogues proceeds by the condensation of the appropriate bis(electrophile) (4, 7, or 9) with bis(phthalhydrazide) (17), which delivers the CB[6] and CB[7] analogues in good yield, whereas the CB[5] analogue is formed in low yield. To improve the solubility characteristics of the CB[n] analogues for recognition studies in water or organic solution, the CO2Et groups were transformed to CO2H and CO2(CH2)9CH3 groups. On the basis of the results of product resubmission experiments, we conclude that these macrocycles are kinetic products. To help rationalize the good yields obtained in the CB[6] and CB[7] analogue macrocyclization reactions, we performed mechanistic studies of model methylene bridged glycoluril dimers, which suggest an intramolecular isomerization during CB[n] analogue formation.     

Total synthesis of the cyanolide A aglycon

The synthesis of the potent molluscicide cyanolide A has been achieved in 10 steps without the use of protecting groups. The synthesis features a key Sakurai macrocyclization/dimerization reaction that simultaneously forms both tetrahydropyran rings and the macrocycle of the natural product.     

Rapid construction of shape-persistent H-bonded macrocycles via one-pot H-bonding-assisted macrocyclization

The study of macrocycles has crossed many traditional disciplines such as chemistry, physics, biology, medicine and engineering with many research areas concentrating on specific and selective molecular recognition, self-organisation and its already demonstrated and other promising applications. Compared to traditional strategies to synthesize macrocycles with widely ranging structures using such as templated cyclization or dynamic covalent bond formation, one-pot H-bonding-assisted macrocyclization has been shown to provide a simple, fast and cost-efficient method to synthesize shape-persistent H-bonded macrocycles of varying types containing an internal cavity of as large as 2.9 nm in diameter. This review will summarize the recent works on such “greener” syntheses of H-bonded macrocycles that help to create a whole new dimension of research and to offer a new bottom-up strategy for constructing functional architectures and materials.