Synthesis Of Macrocycles Research Articles

Synthesis of Large Macrocycles with Chiral Sulfur Centers via Enantiospecific SuFEx and SuPhenEx Click Reactions.

Here we report the first asymmetric synthesis of large chiral macrocycles with chiral sulfur atoms. Building on stereospecific SuFEx and SuPhenEx click chemistries, this approach utilizes disulfonimidoyl fluorides and disulfonimidoyl p-nitrophenolates─which are efficient building blocks with two chiral sulfur centers, and diphenols to efficiently form novel S-O bonds. Characteristic results include the enantiospecific one-step synthesis of rings consisting of 21-58 members and characterization of both enantiomers (R,R and S,S) by e.g. X-ray crystallography.

β-Bracelets: Macrocyclic Cross-β Epitope Mimics Based on a Tau Conformational Strain.

The aggregation of misfolded tau into neurotoxic fibrils is linked to the progression of Alzheimer's disease (AD) and related tauopathies. Disease-associated conformations of filamentous tau are characterized by hydrophobic interactions between side chains on unique and distant β-strand modules within each protomer. Here, we report the design and diversity-oriented synthesis of β-arch peptide macrocycles composed of the aggregation-prone PHF6 hexapeptide of tau and the cross-β module specific to the AD tau fold. Termed "β-bracelets", these proteomimetics assemble in a sequence- and macrocycle-dependent fashion, resulting in amyloid-like fibrils that feature in-register parallel β-sheet structure. Backbone N-amination of a selected β-bracelet affords soluble inhibitors of tau aggregation. We further demonstrate that the N-aminated macrocycles block the prion-like cellular seeding activity of recombinant tau as well as mature fibrils from AD patient extracts. These studies establish β-bracelets as a new class of cross-β epitope mimics and demonstrate their utility in the rational design of molecules targeting amyloid propagation and seeding.

Synthesis and characterization of a new Cu(II)-ionic macrocycle Schiff base complex and its use as an efficient catalyst in one pot-multicomponent Click Synthesis of 1,2,3-Triazoles in water

The new ionic dialdehyde (DA) was synthesized by the reaction of 1,2-bis((1H-imidazol-1-yl)methyl)benzene and 5-(chloromethyl)-2-hydroxybenzaldehyde in acetonitrile at reflux conditions. The reaction of DA and ethylenediamine in methanol at reflux conditions resulted to synthesis of new ionic Schiff base macrocycle (L). The new ionic Schiff base macrocycle Cu(II) complex(LCu) was synthesized by the reaction of L and CuCl2 in methanol in reflux conditions. All the synthesized compounds were characterized via different analytical and spectral methods. The catalytic activity of the LCu complex was investigated in the click reaction and different reaction parameters such as solvent effect, reaction temperature and the catalyst amount were optimized. The results revealed that the high reaction yield was obtained in water as green solvent at 70 °C in the presence of catalytic amount of LCu. Then the reaction of different alkynes, alkyl halides and NaN3 in the presence of catalytic amount of LCu in optimal conditions were efficiently converted to the related 1,2,3-Triazoles.

Design and Synthesis of New Type of Macrocyclic Architectures Used for Optoelectronic Materials and Supramolecular Chemistry.

Supramolecular chemistry has received much attention for decades. Macrocyclic architectures as representative receptors play a vital role in supramolecular chemistry and are applied in many fields such as supramolecular assembly and host-guest recognition. However, the classical macrocycles generally lack functional groups in the scaffolds, which limit their further applications, especially in optoelectronic materials. Therefore, developing a new design principle is not only essential to better understand macrocyclic chemistry and the supramolecular behaviors, but also further expand their applications in many research fields. In recent years, the doping compounds with main-group heteroatoms (B, N, S, O, P) into the carbon-based π-conjugated macrocycles offered a new strategy to build macrocyclic architectures with unique optoelectronic properties. In particular, the energy gaps and redox behavior can be effectively tuned by incorporating heteroatoms into the macrocyclic scaffolds. In this Minireview, we briefly summarize the design and synthesis of new macrocycles, and further discuss the related applications in optoelectronic materials and supramolecular chemistry.

Tetraurea Macrocycles: Template-Directed One-Pot Synthesis and Anion Binding Properties

Given the significance of anion in life, study of anion recognition attracted great attentions in the past decades. Macrocyclic receptors display intriguing anion binding properties; however, the synthesis of macrocycles is challenging. Here, we reported a new strategy of making tetraurea in one-step. By using 1-butyl-3-methylimidazolium ([hmim][X], X = anion) as the solvent and template reagent, tetraurea macrocycle comprised of bis(urea) binding moiety and hexyl chain spacers is selectively formed with high yield. The obtained macrocycles displayed interesting anion binding properties as indicated by single crystal X-ray diffraction structures and computational modelling.

Quintuply orthogonal pyrrolysyl-tRNA synthetase/tRNAPyl pairs.

Mutually orthogonal aminoacyl transfer RNA synthetase/transfer RNA pairs provide a foundation for encoding non-canonical amino acids into proteins, and encoded non-canonical polymer and macrocycle synthesis. Here we discover quintuply orthogonal pyrrolysyl-tRNA synthetase (PylRS)/pyrrolysyl-tRNA (tRNAPyl) pairs. We discover empirical sequence identity thresholds for mutual orthogonality and use these for agglomerative clustering of PylRS and tRNAPyl sequences; this defines numerous sequence clusters, spanning five classes of PylRS/tRNAPyl pairs (the existing classes +N, A and B, and newly defined classes C and S). Most of the PylRS clusters belong to classes that were unexplored for orthogonal pair generation. By testing pairs from distinct clusters and classes, and pyrrolysyl-tRNAs with unusual structures, we resolve 80% of the pairwise specificities required to make quintuply orthogonal PylRS/tRNAPyl pairs; we control the remaining specificities by engineering and directed evolution. Overall, we create 924 mutually orthogonal PylRS/tRNAPyl pairs, 1,324 triply orthogonal pairs, 128 quadruply orthogonal pairs and 8 quintuply orthogonal pairs. These advances may provide a key foundation for encoded polymer synthesis.

3次元に共役する大環状分子の芳香族性

Aromaticity is an important concept that controls the stability, electronic property and reactivity of π-conjugated compounds. The conventional understanding of aromaticity, however, often fails to explain the behavior of compounds with highly complicated networks. This review highlights the recent development of syntheses of 3D π-conjugated macrocycles and discussions about aromaticity in 3D π-conjugated systems.

Biphenarenes, Versatile Synthetic Macrocycles for Supramolecular Chemistry.

The development of supramolecular chemistry has always been accompanied by the innovation of macrocyclic hosts. The synthesis of novel macrocycles with unique structures and functions will bring new development opportunities for supramolecular chemistry. As a new generation of macrocyclic hosts, biphenarenes have customizable cavity sizes and diverse backbones, overcoming the limitation that the cavities of traditionally popular macrocyclic hosts are generally smaller than 10 Å. These features undoubtedly endow biphenarenes with distinguished host-guest properties, which have attracted more and more attention. In this review, the structural characteristics and molecular recognition properties of biphenarenes are summarized. In addition, the applications of biphenarenes in adsorption and separation, drug delivery, fluorescence sensing and other fields are introduced. Hopefully, this review will provide a reference for the study of macrocyclic arenes, especially biphenarenes.

Post-Ugi Cyclizations Towards Polycyclic N-Heterocycles.

The Ugi reaction has become one of the highly explored reactions for the formation of multifunctional adducts, due to the mild reaction conditions, wide scope and high variability. By carefully selecting the starting four components, Ugi-adducts could undergo different kinds of post-transformations for the synthesis of bioactive heterocycles, natural products and macrocycles. Considering the significance of polycycles, diverse post-Ugi transformations have been developed over the years for constructing structurally novel polycycles. In this account, we summarize important efforts for the synthesis of polycyclic N-heterocycles via post-Ugi cyclizations from the Van der Eycken laboratory onwards 2016. With the aid of transition metal catalysis from gold, rhodium, silver and palladium, as well as metal-free strategies, versatile polyheterocycles are prepared with high efficiency and step-economy.

Synthesis of Bioactive Macrocycles Involving Ring-Closing Metathesis Strategy

AbstractThis review reports the synthesis of various bioactive macrocycles, involving ring-closing metathesis as a key step, developed since ca. 2000. These macrocycles exhibited biological activities such as antiviral, antifungal, antibacterial, and anticancer activities, and more. Thus, their syntheses and utilization are essential for both synthetic organic and medicinal chemists.

Synthesis of π-Conjugated Chiral Organoborane Macrocycles with Blue to Near-Infrared Emissions and the Diradical Character of Cations

Highly emissive π-conjugated macrocycles with tunable circularly polarized luminescence (CPL) have sparked theoretical and synthetic interests in recent years. Herein, we report a synthetic approach to obtain new chiral organoborane macrocycles (CMC1, CMC2, and CMC3) that are built on the structurally chiral [5]helicenes and highly luminescent triarylborane/amine moieties embedded into the cyclic systems. These rarely accessible B/N-doped main-group chiral macrocycles show a unique topology dependence of the optoelectronic and chiroptical properties. CMC1 and CMC2 show a higher luminescence dissymmetry factor (glum) together with an enhanced CPL brightness (BCPL) as compared with CMC3. Electronic effects were also tuned and resulted in bathochromic shifts of their emission and CPL responses from blue for CMC1 to the near-infrared (NIR) region for CMC3. Furthermore, chemical oxidations of the N donor sites in CMC1 gave rise to a highly stable radical cation (CMC1·+SbF6-) and diradical dication species (CMC12·2+2SbF6-) that serve as a rare example of a positively charged open-shell chiral macrocycle.

Cyclocondensation Reaction for the Synthesis of N-Containing Macrocycles

Cyclocondensation reaction between amine and ketone is a robust, efficient and green method widely adopted for the synthesis of nitrogen-containing planar π-conjugated molecules. Recently, it has also been utilized to construct macrocycles with donor-acceptor structures. This highlight review summarizes recent examples that cyclocondensation is used for the synthesis of nanohoops, nanohoop dimers and nanobelts.

Synthesis, X-ray Crystal Structure, Anticancer, Hirshfeld Surface Analysis, DFT, TD-DFT, ADMET, and Molecular Docking of 3-Phenyl-1,2,4-triazolo[3,4-h]-13,4-thiaza-11-crown-4

In this work, we describe the synthesis of new macrocycles derived from 3-phenyl-1,2,4-triazole-5-thione 1 in a heterogeneous medium using liquid-solid phase transfer catalysis (PTC) conditions. The structures of the two compounds (3 and 4) isolated were elucidated based on spectral data (1H-NMR, 13C-NMR) and confirmed in the case of 3-phenyl-1,2,4-triazolo [3,4-h]-13,4--thiaza-11-crown-4 (3) by a single-crystal X-ray diffraction analysis. Furthermore, the experimental spectral and the X-ray geometrical parameters were compared with their corresponding predicted ones obtained at the B3LYP/6-311++G(d,p) level of theory. The intercontacts between crystal units were investigated through Hirshfeld surface analysis. The drug-like macrocycles were predicted using ADMET and drug-likeness properties, which showed that 3 may act as an inhibitor of DNA-dependent protein kinase (DNA-PK). This assumption was confirmed by the well-binding fitting of 3 into the binding site of DNA-PK and the formation of a stable 3-DNA-PK complex with a binding energy of -7 kcal-mol-1. Finally, the anticancer activity of 3 was assessed by an MTT assay against A549 cells, which showed that 3 has moderate anticancer activity compared to that of the doxorubicin reference drug.

Synthesis of chiral bispidine-based macrocycles

The first representatives of chiral ferrocenophanes based on bispidines have been synthesized. It is shown that their structure in solution is similar to the previously described achiral ferrocenophane.

Synthesis of Chiral Macrocycles Based on Bispidine

Synthesis of Chiral Macrocycles Based on Bispidine

Transition-Metal-Catalyzed C–C Bond Macrocyclization via Intramolecular C–H Bond Activation

Macrocycles are commonly synthesized via late-stage macrolactamization and macrolactonization. Strategies involving C–C bond macrocyclization have been reported, and examples include the transition-metal-catalyzed ring-closing metathesis and coupling reactions. In this mini-review, we summarize the recent progress in the direct synthesis of polyketide and polypeptide macrocycles using a transition-metal-catalyzed C–H bond activation strategy. In the first part, rhodium-catalyzed alkene–alkene ring-closing coupling for polyketide synthesis is described. The second part summarizes the synthesis of polypeptide macrocycles. The activation of indolyl and aryl C(sp2)–H bonds followed by coupling with various coupling partners such as aryl halides, arylates, and alkynyl bromide is then documented. Moreover, transition-metal-catalyzed C–C bond macrocyclization reactions via alkyl C(sp3)–H bond activation are also included. We hope that this mini-review will inspire more researchers to explore new and broadly applicable strategies for C–C bond macrocyclization via intramolecular C–H activation.

Modular Biomimetic Strategy Enabled Discovery of Simplified Pseudo-Natural Macrocyclic P-Glycoprotein Inhibitors Capable of Overcoming Multidrug Resistance.

Natural macrocycles have shown impressive activity to overcome P-glycoprotein (P-gp)-mediated multidrug resistance (MDR). However, the total synthesis and structural modification of natural macrocycles are challenging, which would hamper the deeper investigations of their structure-activity relationship (SAR) and drug likeness. Herein, we describe a modular biomimetic strategy to expeditiously achieve a new class of macrocycles featuring polysubstituted 1,3-diene, which efficiently inhibited P-gp and reversed MDR in cancer cells. The SAR analysis revealed that the size and linker of the macrocycles are important structural characteristics to restore activity. Particularly, 32 containing a naphthyl group and (d)-Phe moiety has higher potency with an excellent reversal fold than verapamil at a concentration of 5 μM, which induces conformational change of P-gp and inhibits its function instead of altering P-gp expression. Furthermore, 23 and 32 were identified to be attractive leads, which possess a good pharmacokinetic profile and antitumor activity in a KBV200 xenograft mouse model.

Synthesis of a water-soluble naphthalene-based macrocycle and its host-guest properties.

Reported here is the synthesis of a naphthalene-based macrocycle bearing anionic carboxylato groups on the rims along with its complexation with cationic guests in aqueous media. The macrocycle could strongly bind guests in a molecular clip model with association constants of 106-107 M-1.

Synthesis and spontaneous self-assembly of non-planar aromatic amide macrocycles

We report here the self-assembly behavior of a series of nonplanar phenanthroline-based macrocycles bearing polyaromatic bridges. Even without any directional noncovalent interaction, they undergo spontaneous self-assembly and produce well-defined nanostructures....

Synthesis of maleimide-braced peptide macrocycles and their potential anti-SARS-CoV-2 mechanisms.

Macrocycles often exhibit good biological properties and potential druggability, which lead to versatile applications in the pharmaceutical industry. Herein, we report a highly efficient and practical methodology for the functionalization and macrocyclization of Trp and Trp-containing peptides via Pd(II)-catalyzed C-H alkenylation at the Trp C4 position. This method provides direct access to C4 maleimide-decorated Trp-containing peptidomimetics and maleimide-braced 17- to 30-membered peptide macrocycles. In particular, these unique macrocycles revealed low micro- to sub-micromolar EC50 values with promising anti-SARS-CoV-2 activities. Further explorations with computational methodologies and experimental validations indicated that these macrocycles exert antiviral effects through binding with the N protein of SARS-CoV-2.