Chiral Macrocycles as Reagents and Catalysts

Ionophores, whether of natural or synthetic origin, encapsulate their ionic “guests” using noncovalent bonding. This encapsulation process resembles, at least superficially, the bonding of a substrate by an enzyme-active site. The analogy to enzymes can be extended further if the ionophore is provided with functional groups that can react with a suitable guest molecule bound in the cavity of the ionophore. We have embedded in the periphery of a macrocycle a 1,4-dihydropyridine, a mimic of the coenzyme NADH. The macrocycle, in addition to having (weak) ionophoric properties, is chiral. The strategy has led to compounds that react as artificial hydrogenases and which are capable of distinguishing, in a predictable fashion, between the prochiral faces of suitable carbonyl substrates. Ancillary developments from this approach have been many. A remarkably general method for the preparation of a wide variety of macrocycles has been developed which depends on some remarkable chemical idiosyncrasies of the cesium ion. In attempts to exploit the chemical possibilities of these macrocycles, unusual chemistry, possibly relevant to the action of the enzyme, 3-phosphoglyceraldehyde dehydrogenase, has been uncovered. In a similar vein, study of macrocycles has led to variants of the aldol condensation on chiral templates. Finally, catalytic CC bond formation mediated by transition metals is revealed to be an area in which chiral macrocycles can play a useful role by acting as chiral ligands for the transition metal.     

Tuning the (Chir)Optical Properties and Squeezing out the Inherent Chirality in Polyphenylene-Locked Helical Carbon Nanorings

Distorting linear polyaromatic hydrocarbons (PAHs) out of planarity affects their physical properties and breaks their symmetry to induce inherent chirality. However, the chirality cannot be achieved in large distorted PAHs-based macrocycles due to a low racemization barrier for isomerization. Herein, we report the precise synthesis and tuning size-dependent (chir)optical properties of a new class of chiral PAHs-containing conjugated macrocycles (cyclo[n]paraphenylene-2,6-anthrylene, [n]CPPAn_2,6 ; n=6–8). Their inherent chiralities were squeezed out in small anthrylene-based macrocycles. Efficient resolutions for chiral enantiomers with (P)/(M)-helicity of small [6-7]CPPAn s were achieved by HPLC. Interestingly, these macrocycles showed enriched size-dependent physical, chiral, and (chir)optical properties. Theoretical calculations indicate that these macrocycles have high strain energy (E_strain=60.8 to 73.4 kcal/mol) and very small E_gap (∼3.0 eV). Notably, these enantiomers showed strong chiroptical properties and dissymmetry factors (|g_abs| and |g_lum|∼0.01 for an enantiomer of [6]CPPAn_2,6 ), which can give them potential applications in optically active materials.     

Nanoscale metal coordination macrocycles fabricated by using "dimeric" dipyrrins

Covalently linked dipyrrin (dipyrromethene) dimers have afforded nanoscale [2+2]-type neutral coordination macrocycles with a diagonal of about 1.6 nm. Two moieties of the achiral dipyrrin-Zn(II) complex yield the chiral coordination macrocycles as minor species, as well as major meso stereoisomers by the covalent linkages. Tetrahedral Zn(II) coordination by using acyclic ligands enables the dipyrrin-metal complex units to readily rotate and pass through the cavity of the nanorings in order to reveal the transitions between the chiral and achiral isomers.     

Substrate‐Induced Dimerization Assembly of Chiral Macrocycle Catalysts toward Cooperative Asymmetric Catalysis

An artificial system of substrate‐induced dimerization assembly of chiral macrocycle catalysts enables a highly cooperative hydrogen‐bonding activation network for efficient enantioselective transformation. These macrocycles contain two thiourea and two chiral diamine moieties and dimerize with sulfate to form a sandwich‐like assembly. The macrocycles then adopt an extended conformation and reciprocally complement the hydrogen‐bonding interaction sites. Inspired by the guest‐induced dynamic assembly, these macrocycles catalyze the decarboxylative Mannich reaction of cyclic aldimines containing a sulfamate heading group. The imine substrate can be activated toward nucleophilic attack of β‐ketoacid by a cooperative hydrogen‐bonding network enabled by sulfamate‐induced dimerization assembly of the macrocycle catalysts. Highly efficient (>95 % yield in most cases) and enantioselective (up to 97.5:2.5 er) transformation of a variety of substrates using only 5 mol % macrocycle was achieved.     

Synthesis of Novel C2—Symmetric Chiral Polyamide Macrocycles Containing Pyridyl Side—arm

Three novcl C2-symmetic macrocycles containing pyridyl units have been prepared by the cyclic condensation of chiral diamide intermediates with 2,6-pyridinedicarbonyl dichloride in highly diluted solution at room temperature.     

Selective Synthesis of Conjugated Chiral Macrocycles: Sidewall Segments of (−)/(+)‐(12,4) Carbon Nanotubes with Strong Circularly Polarized Luminescence

Carbon nanotubes (CNTs) have unusual physical properties that are valuable for nanotechnology and electronics, but the chemical synthesis of chirality‐ and diameter‐specific CNTs and π‐conjugated CNT segments is still a great challenge. Reported here are the selective syntheses, isolations, characterizations, and photophysical properties of two novel chiral conjugated macrocycles ([4]cyclo‐2,6‐anthracene; [4]CAn_2,6 ), as (?)/(+)‐(12,4) carbon nanotube segments. These conjugated macrocyclic molecules were obtained using a bottom‐up assembly approach and subsequent reductive elimination reaction. The hoop‐shaped molecules can be directly viewed by a STM technique. In addition, chiral enantiomers with (?)/(+) helicity of the [4]CAn_2,6 were successfully isolated by HPLC. The new tubular CNT segments exhibit large absorption and photoluminescence redshifts compared to the monomer unit. The carbon enantiomers are also observed to show strong circularly polarized luminescence (g_lum≈0.1). The results reported here expand the scope of materials design for bottom‐up synthesis of chiral macrocycles and enrich existing knowledge of their optoelectronic properties.     

Synthesis of a Series of Novel Chiral Aromatic Heterocyclic Macrocycles Containing L-Amino Acid and 2,5-Bisphenyl-1,3,4-triazole Subunits

An array of novel chiral aromatic heterocyclic macrocycles, which may show potential enantiomeric recognition to variable D- and L-amino acids, were synthesized in acceptable yield. The desired macrocycles 3a–c and 4a–c were obtained via the condensation reaction of chiral diamine intermediates 2a–c with 2,5-bis(o-chloroformylphenyl)-1,3,4-triazole 5 in a presence of Et₃N in a highly diluted dichloromethane solution at room temperature.     

Triptycene‐Based Chiral Macrocyclic Hosts for Highly Enantioselective Recognition of Chiral Guests Containing a Trimethylamino Group

A new class of chiral macrocyclic arene composed of three chiral 2,6‐dihydroxyltriptycene subunits bridged by methylene groups was designed and synthesized. Structural studies showed that the macrocyclic molecule adopts a hex‐nut‐like structure with a helical chiral cavity and highly fixed conformation. Efficient resolution was achieved through the introduction of chiral auxiliaries to give a couple of enantiopure macrocycles, which exhibited high enantioselectivity towards three pairs of chiral compounds containing a trimethylamino group.     

Formation of Metal‐Assisted Stable Double Helices in Dimers of Cyclic Bis‐Tetrapyrroles that Exhibit Spring‐Like Motion

Bidipyrrin‐bridged macrocycles, prepared from Ni^II‐bridged dipyrrin‐based nanorings by intramolecular oxidative biaryl coupling reactions, yielded [2+4]‐type Zn^II‐assisted stable twisted‐ring dimers comprising two double helices. These [2+4]‐type metal complexes can be optically resolved by chiral HPLC and exhibit tunable electronic and optical properties as a result of spring‐like motions. The double helices behave as glue to connect two macrocycles and as the screws of hinges to form thermally responsive synchronized spring systems.     

Designed folding of pseudopeptides: the transformation of a configurationally driven preorganization into a stereoselective multicomponent macrocyclization reaction

The efficient synthesis of large-ring pseudopeptidic macrocycles through a multicomponent [2+2] reductive amination reaction is described. The reaction was entirely governed by the structural information contained in the corresponding open-chain pseudopeptidic bis(amidoamine) precursors, which have a rigid (R,R)-cyclohexane-1,2-diamine moiety. A remarkable match/mismatch relationship between the configurations of the chiral centers of the cyclic diamine and those of the peptidic frame was observed. The macrocyclic tetraimine intermediates have been studied in detail by NMR spectroscopy, circular dichroism (CD), and molecular modeling, and the results support the appropriate preorganization induced by the match combination of the chiral centers. We have also synthesized the corresponding open-chain bis(imine) model compounds. The structural studies (NMR spectroscopy, CD, modeling) of these systems showed an intrinsically lower reactivity of the mismatch combination, even when the product of the reaction was acyclic. In addition, a synergistic effect between the two chiral substructures for the correct folding of the molecules was observed. Finally, X-ray analysis of the HCl salt of one of the macrocycles showed an interesting pattern; the macrocyclic rings stack in columnar aggregates leaving large interstitial channels filled with water-solvated chloride anions.     

Chiral Macrocycle-Enabled Counteranion Trapping for Boosting Highly Efficient and Enantioselective Catalysis

The tight binding enabled by tailor-made macrocycles can be manipulated for tuning the catalysis process. In parallel to well-developed crown ether-based cation-binding catalysis, a macrocycle-enabled counteranion trapping strategy is presented for boosting highly efficient and enantioselective catalysis. A set of bis-diarylthiourea macrocycles containing two BINOL moieties were designed and synthesized. They possess a well-confined chiral cavity and strong binding affinities towards disulfonate anions. Caused by the tight binding, just 1 mol % macrocycle in combination with 1 mol % ethanedisulfonic acid can promote excellent conversion and up to 99 % ee in the Friedel–Crafts reaction of indoles with imines. The acid or the macrocycle alone do not afford any reactivity. The high catalytic efficiency and excellent stereocontrol was ascribed to large, complexation-induced acidity enhancement and tight ion-pairing facilitated by cave-like macrocyclic cavity.     

Recent Advances in the Synthesis and Applications of Nitrogen-Containing Macrocycles

Macrocyclic nitrogen-containing compounds are versatile molecules. Supramolecular, noncovalent interactions of these macrocycles with guest molecules enables them to act as catalysts, fluorescent sensors, chiral or nonchiral selectors, or receptors of small molecules. In the solid state, they often display a propensity to form inclusion compounds. All of these properties are usually closely connected with the presence of nitrogen atoms in the macrocyclic ring. As most of the reviews published so far on macrocycles were written from the viewpoint of functional groups, synthetic methods, or the structure, search methods for literature reports in terms of the physicochemical properties of these compounds may be unobvious. In this minireview, the emphasis was put on the synthesis and applications of nitrogen-containing macrocyclic compounds, as they differ from their acyclic analogs, and at the same time are the driving force for further research.     

Conjugated macrocycles: concepts and applications

One of the most important objectives in materials, chemical, and physical sciences is the creation of large conjugated macrocycles with well-defined shapes, since such molecules are not only theoretically and experimentally interesting but also have potential applications in nanotechnology. Fully unsaturated macrocycles are regarded as models for infinitely conjugated π systems with inner cavities, and exhibit unusual optical and magnetic behavior. Macrocycles have interior and exterior sites, and site-specific substitution at both or either site can afford attractive structures, such as 1D, 2D, and 3D supramolecular nanostructures. These nanostructures could be controlled through the use of π-extended large macrocycles by a bottom-up strategy. Numerous shape-persistent π-conjugated macrocycles have been synthesized, but only a few are on the nanoscale. This Review focuses on nanosized π-conjugated macrocycles (>1 nm diameter) and giant macrocycles (>2 nm diameter), and summarizes their syntheses and properties.     

Enantiomerically pure phenanthroline or bipyridine containing macrocycles: a new class of ligands for asymmetric catalysis

New enantiomerically pure phenanthroline- and bipyridine-containing macrocycles have been synthesized by combination of the coordinating unit to inexpensive and readily available chiral templates. The catalytic properties of their Cu(I) complexes have been studied in the cyclopropanation of alkenes as test reaction. A simple structural modification of the chiral cavity allowed us to successfully control the trans or cis diastereoselectivity of the reaction.     

Chiral Macrocycle‐Enabled Counteranion Trapping for Boosting Highly Efficient and Enantioselective Catalysis

The tight binding enabled by tailor‐made macrocycles can be manipulated for tuning the catalysis process. In parallel to well‐developed crown ether‐based cation‐binding catalysis, a macrocycle‐enabled counteranion trapping strategy is presented for boosting highly efficient and enantioselective catalysis. A set of bis‐diarylthiourea macrocycles containing two BINOL moieties were designed and synthesized. They possess a well‐confined chiral cavity and strong binding affinities towards disulfonate anions. Caused by the tight binding, just 1 mol % macrocycle in combination with 1 mol % ethanedisulfonic acid can promote excellent conversion and up to 99 % ee in the Friedel–Crafts reaction of indoles with imines. The acid or the macrocycle alone do not afford any reactivity. The high catalytic efficiency and excellent stereocontrol was ascribed to large, complexation‐induced acidity enhancement and tight ion‐pairing facilitated by cave‐like macrocyclic cavity.     

Macrocycles All Aflutter: Substitution at an Allylic Center Reveals the Conformational Dynamics of [13]‐Macrodilactones

The shapes adopted by large‐ring macrocyclic compounds play a role in their reactivity and their ability to be bound by biomolecules. We investigated the synthesis, conformational analysis, and properties of a specific family of [13]‐macrodilactones as models of natural‐product macrocycles. The features of our macrodilactones enabled us to study the relationship between stereogenic centers and planar chirality through the modular synthesis of new members of this family of macrocycles. Here we report on insights gained from a new [13]‐macrodilactone that is substituted at a position adjacent to the alkene in the molecule. Analysis of the compound, in comparison to an α‐substituted regioisomer, by using X‐ray crystallography, NMR coupling constants, and reaction‐product characterization in concert with computational chemistry, revealed that the alkene unit is dynamic. That is, the data support a model in which the alkene in our [13]‐macrodilactones oscillates between two conformations. A difference in reactivity of one conformation compared to the other leads to manifestation of this dynamic behavior. The results underscore the local conformational dynamics observed in some natural‐product macrocycles, which could have implications for biomolecule binding.     

Phosphorylated macrocycles: structures,complexing properties,and molecular recognition

Procedures were developed for functionalization of macrocycles by introducing a phosphonic group either directly linked to the aromatic rings (in the case of cyclophanes or calixarenes) or as a pendant arm. For these compounds to be used as artificial receptors for amino alcohols and amino acids, the host molecule must possess not only negative charges arising from the phosphonate moieties but also a hydrophobic binding site, such as electron-rich aromatic residues. We designed inter alia new dissymmetric macrocycles capable of being involved in three binding modes with guest molecules, viz., hydrogen bonding, electrostatic attraction, and π-cation interactions. The NMR characterization of the macrocycles, their stereochemistry in solution and in the solid state, and the use as chiral receptors for biologically relevant molecules are described. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1313–1330, June, 2005.     

Inherently Chiral Macrocyclic Oligothiophenes: Easily Accessible Electrosensitive Cavities with Outstanding Enantioselection Performances

Linear conjugated oligothiophenes of variable length and different substitution pattern are ubiquitous in technologically advanced optoelectronic devices, though limitations in application derive from insolubility, scarce processability and chain‐end effects. This study describes an easy access to chiral cyclic oligothiophenes constituted by 12 and 18 fully conjugated thiophene units. Chemical oxidation of an “inherently chiral” sexithiophene monomer, synthesized in two steps from commercially available materials, induces the formation of an elliptical dimer and a triangular trimer endowed with electrosensitive cavities of different tunable sizes. Combination of chirality with electroactivity makes these molecules unique in the current oligothiophenes literature. These macrocycles, which are stable and soluble in most organic solvents, show outstanding chiroptical properties, high circularly polarized luminescence effects and an exceptional enantiorecognition ability.     

Allenes in molecular materials

This Minireview provides a critical account of the development of allene-containing advanced functional materials, starting with the design and synthesis of stable and enantiopure building blocks. A variety of systems, including shape-persistent macrocycles, foldamers, polymers, charge-transfer chromophores, dendrimers, liquid crystals, and redox-switchable chiral chromophores are discussed from the viewpoint of their syntheses, properties, and potential applications. The goal of this Minireview is to inspire new uses of enantiopure allenes for the rational design of advanced materials.     

Rules of Macrocycle Topology: A [13]‐Macrodilactone Case Study

Shape is an inherent trait of a molecule that dictates how it interacts with other molecules, either in binding events or intermolecular reactions. Large‐ring macrocyclic compounds in particular leverage their shape when they are selectively bound by biomolecules and also when they exhibit macrocyclic diastereoselectivity. Nonetheless, rules that link structural parameters to the conformation of a macrocycle are still rudimentary. Here we use a structural investigation of a family of [13]‐macrodilactones as a case study to develop rules that can be applied generally to macrocycles of different sizes and with a variety of functionality. A characteristic “ribbon” shape is adopted by the [13]‐macrodilactones in the absence of stereogenic centres, which exhibits planar chirality. When one stereogenic centre at key positions on the backbone is incorporated into the structure, the planar chirality is dictated by the configuration of the centre. In cases where two stereogenic centres are present, their relationships can either reinforce the characteristic ribbon shape or induce alternative shapes to be adopted. The rules established in the case study are then applied to the analysis of a structure of the natural product migrastatin. They lay the groundwork for the development of models to understand macrocycle‐biomolecule interactions and for the preparation of macrocycles with designed properties and activities.