Hybrid Macrocycles Research Articles

Semi-synthesis of a DNA-Tagged Polyketide-Peptide Hybrid Macrocycle Using a Biosynthetically Prepared Fungal Macrolide as a Synthetic Component.

Presented herein is a synthetic biological method using genome mining and heterologous expression systems that provides access to natural products with desirable structural features as building blocks. In this investigation, we synthesized polyketide-peptide hybrid macrocycles with DNA tags, which have the potential to access a DNA-encoded library containing over one million compounds. This study demonstrates that synthetic biology offers a tool for expanding the diversity of building blocks, facilitating the exploration of unexplored chemical space.

Synthesis, X-ray structures, and anion binding properties of 1,8-disulfonamidocarbazole-di(thio)amide hybrid macrocycles

An easy-to-prepare 1,8-disulfonamidocarbazole-diamide hybrid macrocycle 1 and its thioamide analogue 2 were reported, along with their anion recognition properties as determined by UV-vis and 1H NMR spectroscopic titrations as well as single crystal X-ray diffraction analyses. The conversion of amides into thioamides in the macrocyclic structures generated notable effects on the anion-binding affinity and selectivity. For example, amide-bearing macrocycle 1 was found to bind H2PO4- over one order of magnitude more strongly than thioamide-containing macrocycle 2, despite having more acidic NH groups for the latter. Additionally, macrocycle 1 displayed the highest affinity for PhCOO- in DMSO (Ka >105 M-1 for the formed 1:1 complex) followed by H2PO4- and AcO- ions, whereas a different binding order AcO- > PhCOO- >> H2PO4- was observed for macrocycle 2. More importantly, the single crystal X-ray diffraction analysis clearly revealed that macrocycle 1 indeed formed a 1:1 complex with PhCOO- ion in the solid state.

Synthesis, Structure and Properties of Core‐Modified Calixporphyrinoids

AbstractCalix[n]porphyrinoids containing both sp2 and sp3 meso‐carbons can bind metals like porphyrinoids and anions like calix[n]pyrroles. Thus, calix[n]porphyrinoids are hybrid macrocycles of porphyrinoids and calix[n]pyrroles. The core‐modified calix[n]porphyrinoids resulted by replacing one or more pyrroles of calix[n]porphyrinoids with different heterocycles or carbacycles that possesses very attractive structural, spectral, and coordination properties. For the past two decades, several different types of core‐modified calix[n]porphyrinoids in which one or more pyrroles were replaced with other heterocycles such as thiophene, selenophene, tellurophene, silole, phosphole, pyridine, etc and carbacycles such as m/p‐phenylene have been synthesized and explored their structure, metal coordination and anion sensing properties. This review describes different synthetic strategies used for the synthesis of various types of core‐modified calix[4]phyrins and expanded calix[n]phyrins and discusses their key structural aspects, properties, coordination chemistry and applications.

Deep-Cavity Calix[4]naphth[4]arene Macrocycles: Synthesis, Conformational Features, and Solid-State Structures.

We recently introduced calix[n]naphth[m]arenes as a novel class of deep-cavity hybrid macrocycles constituted by phenol (n) and naphthalene (m) units. In this study, we report the synthesis, conformational analysis, spectroscopic properties, and solid-state structures of calix[4]naphth[4]arene (C4N4) and its permethylated analog (C4N4-Me), thereby expanding the calix[n]naphth[m]arene family. C4N4 was synthesized through a 2 + 2 fragment coupling macrocyclization under acidic conditions, where the solvent played a crucial role in selectively forming the C4N4 derivative. The X-ray structure of C4N4 reveals a chair-like 1,2,3,4-alternate conformation characterized by two opposing 3/4-cone moieties stabilized by intramolecular hydrogen bonds. In contrast, the X-ray structure of C4N4-Me exhibits a 1,3,5,7-alternate conformation.

Bulking Up the Bay-Position Substituents Enables Enhanced Selectivity of Cs-Symmetric Boron Subphthalocyanine-Subnaphthalocyanine Hybrids.

The precise synthesis of subporphyrinoid hybrids with π-expanded topologies and unique material properties plays a promising role in the design of functional macrocycles. Easy, selective, and controllable routes to boron subphthalocyanine-subnaphthalocyanine hybrids, Bsub(Pc3-p-Ncp)s, are desirable for this purpose yet synthetically challenging due to random mixtures of Cs-, C3v-, and, in some cases, C1-symmetric compounds that form during traditional statistical mixed cyclotrimerizations. Herein, we addressed this issue by developing a sterically driven mixed cyclotrimerization with enhanced selectivity for the targeted Cs-symmetric hybrid and complete suppression of sterically crowded macrocyclic byproducts. This process, coupled with a rationally designed precursor bearing bulky phenyl substituents, enabled the synthesis and characterization of bay-position phenylated Ph2-(Rp)8Bsub(Pc2-Nc1) hybrids with halogens (Rp = Cl or F) in their peripheral isoindole rings. Reaction selectivity ranged between 59 and 72% with remarkable yields, significantly higher than that of conventional mixed cyclotrimerizations. These findings were augmented by theoretical calculations on precursor Lewis basicity as guiding principles into hybrid macrocycle formation. Additionally, the incorporation of unfused phenyl groups and halogen atoms into the hybrid framework resulted in fine-tuned optical, structural, electronic, and electrochemical properties. This straightforward approach achieved improved selectivity and controlled narrowing of the product distribution, affording the efficient synthesis of structurally sophisticated Bsub(Pc2-Nc1) hybrids. This then expands the library of 3-dimensional π-extended macrocycles for use in a range of applications, such as in optoelectronic devices with precisely tailored optical properties.

Merging Bambus[6]uril and Biotin[6]uril into an Enantiomerically Pure Monofunctionalized Hybrid Macrocycle.

Bambus[6]urils and biotin[6]urils are macrocycles with an exceptional affinity for inorganic anions. Here, we investigated statistical condensation of 2,4-dibenzylglycoluril and d-biotin, monomers of the corresponding macrocycles, to prepare the enantiomerically pure macrocycle 1 containing a single d-biotin and five glycoluril units. Host-guest properties of 1 in chloroform solution and solid state were investigated. The macrocycle 1 bearing a single functional group was employed in the formation of [1]rotaxane utilizing reversible covalent bonds.

Absorption spectra of calix[3]pyrrole analogs as probes for contracted macrocycles

Calix[3]pyrrole and its furan derivatives exhibited bathochromically shifted lowest-energy electronic transition bands in their absorption spectra compared with their calix[4]- and calix[6]-pyrrole analogues, despite the repeating units being the same. We also observed fluorescence emission for calix[3]-type macrocycles. The Stokes shift of the furan/pyrrole hybrid macrocycles, calix[2]furan[1]-pyrrole, and calix[1]furan[2]pyrrole, substantially varied depending on the solvent polarity. Non-covalent interaction (NCI) analyses indicated enhanced interactions between neighboring aromatic rings in the calix[3]pyrrole macrocycle, whereas such interactions were weak in calix[4]pyrrole, in which the interchromophore distance is remarkably longer than in calix[3]pyrrole. Theoretical analyses indicated that the red-shifted, lowest-energy bands of calix[3]pyrrole correspond to HOMO–LUMO transitions, the energy gap of which was narrow compared with calix[4]pyrroles. The characteristic absorption bands for calix[3]pyrrole and its related macrocycles are useful as probes for distinguishing such macrocycles from higher calix[[Formula: see text]]pyrrole ([Formula: see text] 4) analogues that exhibit almost identical absorption spectra.

Crownphyrins: Metal‐Mediated Transformations of the Porphyrin‐Crown Ether Hybrids

AbstractCrownphyrins are hybrid macrocycles combining structural features of porphyrin and crown ethers. The molecular architecture renders them an intriguing class of hosts capable of binding neutral, and ionic guests. The presence of dynamic covalent imine linkages connecting the dipyrrin segment with the ether chain enables unusual coordination behavior of crownphyrins, as demonstrated by the formation of two classes of strikingly different complexes. The remarkable metal‐mediated expansion to the helical [2+2] macrocyclic complex is reversible. The reaction of the figure‐eight mercury(II) assembly with [2.2.2]cryptand results in ring contraction providing the metal‐free crownphyrin macrocycle.

Crownphyrins: Metal-Mediated Transformations of the Porphyrin-Crown Ether Hybrids.

Crownphyrins are hybrid macrocycles combining structural features of porphyrin and crown ethers. The molecular architecture renders them an intriguing class of hosts capable of binding neutral, and ionic guests. The presence of dynamic covalent imine linkages connecting the dipyrrin segment with the ether chain enables unusual coordination behavior of crownphyrins, as demonstrated by the formation of two classes of strikingly different complexes. The remarkable metal-mediated expansion to the helical [2+2] macrocyclic complex is reversible. The reaction of the figure-eight mercury(II) assembly with [2.2.2]cryptand results in ring contraction providing the metal-free crownphyrin macrocycle.

Artificial Water Channels—Progress Innovations and Prospects

Artificial Water Channels—Progress Innovations and Prospects

Hybrid Macrocyclic Polymers: Self-Assembly Containing Cucurbit[m]uril-pillar[n]arene.

Supramolecular self-assembly by hybrid macrocycles containing both cucurbit[m]uril (CB[m]) and pillar[n]arene was discussed and summarized in this review. Due to different solubility, diverse-sized cavities, and various driving forces in recognizing guests, the role of CB[m] and pillar[n]arene in such hybrid macrocyclic systems could switch between competitor in capturing specialized guests, and cooperator for building advanced hybridized macrocycles, by controlling their characteristics in host–guest inclusions. Furthermore, both CB[m] and pillar[n]arene were employed for fabricating advanced supramolecular self-assemblies such as mechanically interlocked molecules and supramolecular polymers. In those self-assemblies, CB[m] and pillar[n]arene played significant roles in, e.g., microreactor for catalyzing particular reactions to bridge different small pieces together, molecular “joint” to connect different monomers into larger assemblies, and “stabilizer” in accommodating the guest molecules to adopt a favorite structure geometry ready for assembling.

Single-metal site-embedded conjugated macrocyclic hybrid catalysts enable boosted CO2 reduction and evolution kinetics in Li-CO2 batteries

Rechargeable Li-CO2 batteries, an emerging battery technology to confront the environmental and energy crises, hold promise for CO2 fixation and energy storage. However, state-of-the-art Li-CO2 systems generally suffer from sluggish CO2 reduction/evolution reaction kinetics, and powerful catalysts that can simultaneously facilitate both processes are much desired but largely unrealized. Here, we report a series of Ru, metal-chelated conjugated N4-macrocyclic metal complex (M-CPY) and carbon nanotube (CNT)-based hybrid materials (Ru/[email protected]) with the advantages of highly dispersed Ru and M-CPY, high-conductivity, and tunable loadings that can be applied as multi-functional cathode catalysts. Ru/[email protected] cells deliver an ultra-low overpotential (0.84 V) and enable fully reversible discharge/charge with a high specific capacity of 24,740 mAh/g within 2.0–4.5 V at 200 mA/g. It can rapidly discharge/charge for 180 cycles at 500 mA/g, and the CO2 activation process is intensively investigated by density functional theory (DFT) calculations.

Nisin- and Ripcin-Derived Hybrid Lanthipeptides Display Selective Antimicrobial Activity against Staphylococcus aureus.

Lanthipeptides are (methyl)lanthionine ring-containing ribosomally synthesized and post-translationally modified peptides (RiPPs). Many lanthipeptides show strong antimicrobial activity against bacterial pathogens, including antibiotic-resistant bacterial pathogens. The group of disulfide-bond-containing antimicrobial peptides (AMPs) is well-known in nature and forms a rich source of templates for the production of novel peptides with corresponding (methyl)lanthionine analogues instead of disulfides. Here, we show that novel macrocyclic lanthipeptides (termed thanacin and ripcin) can be synthesized using the known antimicrobials thanatin and rip-thanatin as templates. Notably, the synthesized nisin(1–20)–ripcin hybrid lanthipeptides (ripcin B–G) showed selective antimicrobial activity against S. aureus, including an antibiotic-resistant MRSA strain. Interestingly, ripcin B–G, which are hybrid peptides of nisin(1–20) and ripcin that are each inactive against Gram-negative pathogens, showed substantial antimicrobial activity against the tested Gram-negative pathogens. Moreover, ripcin B–G was highly resistant against the nisin resistance protein (NSR; a peptidase that removes the C-terminal 6 amino acids of nisin and strongly reduces its antimicrobial activity), opposed to nisin itself. This study provides an example of converting disulfide-bond-based AMPs into (methyl)lanthionine-based macrocyclic hybrid lanthipeptides and can yield antimicrobial peptides with selective antimicrobial activity against S. aureus.

Optical Characteristics of Hybrid Macrocycles with Dithienogermole and Tricoordinate Boron Units.

The introduction of unconventional elements into π-conjugated systems has been studied to manipulate the electronic states and properties of compounds. Herein, boron- and germanium-containing hybrid macrocycles, as a new class of element-hybrid conjugated systems, have been synthesized. The palladium-catalyzed Stille cross coupling of bis(bromothienyl)borane and bis(trimethylstannylthienyl)- or bis(trimethylstannylphenyl)-substituted dithienogermoles as the boron- and germanium-containing building blocks, respectively, produced a mixture of several macrocyclic compounds. Single-crystal X-ray analysis of the 2:2 coupling product revealed a planar structure with a cavity inside the macrocycle. The optical properties of the macrocyclic products indicated rather small electronic interactions between the building units. However, intramolecular photoenergy transfer from the dithienogermole unit to the boron unit was clearly observed with respect to the fluorescence spectra.

Theoretical study of chloride complexes with hybrid macrocycles

Macrocycle receptors are investigated from DFT calculations to simultaneously recognize two Cl− anions, which show several applications in the environment.

Influence of stereochemistry on the activity of rapadocin, an isoform-specific inhibitor of the nucleoside transporter ENT1.

Rapadocin is a novel rapamycin-inspired polyketide–tetrapeptide hybrid macrocycle that possesses highly potent and isoform-specific inhibitory activity against the human equilibrative nucleoside transporter 1 (hENT1). Rapadocin contains an epimerizable chiral center in phenylglycine and an olefin group, and can thus exist as a mixture of four stereoisomers. Herein, we report the first total synthesis of the four stereoisomers of rapadocin using two different synthetic strategies and the assignment of their structures. The inhibitory activity of each of the four synthetic isomers on both hENT1 and hENT2 was determined. It was found that the stereochemistry of phenylglycine played a more dominant role than the configuration of the olefin in the activity of rapadocin. These findings will guide the future design and development of rapadocin analogs as new modulators of adenosine signaling.

Divergent synthesis of pyrrolidine and glutamic acid derivatives using a macrocyclic phase-transfer catalyst under high-pressure conditions

The reactivity of the glycine ketimine ester with α,β-unsaturated ketones in the presence of macrocyclic hybrid phase-transfer catalysts under high pressure conditions has been investigated.

Calix[2]naphth[2]arene: A Class of Naphthalene-Phenol Hybrid Macrocyclic Hosts.

Calix[2]naphth[2]arenes make up a new class of phenol–naphthalene hybrid macrocycles. X-ray studies show that calix[2]naphth[2]arene 1 adopts a 1,2-alternate conformation. Alkali metal cations are complexed by the calixnaphtharenes in a 1,2-alternate conformation, by cation···π interactions with the naphthalene walls, and by RO···M+ ion–dipole interactions. In the presence of Cs+, chiral complexes of calixnaphtharenes 5 and 6 were observed in which the cation is nested on one of the two faces of the macrocycle.

Asymmetric Synthesis of a Bacteriochlorophyll Model Compound Containing trans-Dialkyl Substituents in Ring D

Challenges to the de novo synthesis of bacteriochlorophyll a (BChl a), the chief pigment for anoxygenic bacterial photosynthesis, include creating the macrocycle along with the trans-dialkyl substituents in both pyrroline rings (B and D). A known route to a model bacteriochlorophyll with a gem-dimethyl group in each pyrroline ring has been probed for utility in the synthesis of BChl a by preparation of a hybrid macrocycle (BC-1), which contains a trans-dialkyl group in ring D and a gem-dimethyl group in ring B. Stereochemical definition began with the synthesis of (2S,3S)-2-ethyl-3-methylpent-4-ynoic acid, a precursor to the trans-dialkyl-substituted AD dihydrodipyrrin. Knoevenagel condensation of the latter and a gem-dimethyl, β-ketoester-substituted BC dihydrodipyrrin afforded the enone (E, 70%; Z, 3%); subsequent double-ring cyclization of the E-enone (via Nazarov, electrophilic aromatic substitution, and elimination reactions) gave BC-1 (53% yield) along with a trace of chlorin byproduct (1.4% relative to BC-1 upon fluorescence assay). BC-1 exhibited the desired trans-dialkyl stereochemistry in ring D and was obtained as a 7:1 mixture of (expected) epimers owing to the configuration of the 132-carbomethoxy substituent. The strategy wherein trans-dialkyl substituents are installed very early and carried through to completion, as validated herein, potentially opens a synthetic path to native photosynthetic pigments.

Supramolecular control over LCST behavior of hybrid macrocyclic system based on pillar[5]arene and crown ether

A hybrid system containing a pillar[5]arene unit and ten crown ether moieties was developed. The LCST behavior and thermo-responsiveness were successfully introduced into this pillar[5]arene-crown ether system. Both host–guest interactions and salting-out effect displayed great effects in realizing the supramolecular control over LCST properties and thermo-responsiveness. Compared with the individual macrocycles, this hybrid macrocycle system dramatically amplified the supramolecular control effect over LCST behavior.