Synthesis Of Macrocycles Research Articles

Cyclic natural product oligomers: diversity and (bio)synthesis of macrocycles.

Cyclic compounds are generally preferred over linear compounds for functional studies due to their enhanced bioavailability, stability towards metabolic degradation, and selective receptor binding. This has led to a need for effective cyclization strategies for compound synthesis and hence increased interest in macrocyclization mediated by thioesterase (TE) domains, which naturally boost the chemical diversity and bioactivities of cyclic natural products. Many non-ribosomal peptide synthetase (NRPS) and polyketide synthase (PKS) derived natural products are assembled to form cyclodimeric compounds, with these molecules possessing diverse structures and biological activities. There is significant interest in identifying the biosynthetic pathways that produce such molecules given the challenge that cyclodimerization represents from a biosynthetic perspective. In the last decade, many groups have pursued the characterization of TE domains and have provided new insights into this biocatalytic machinery: however, the enzymes involved in formation of cyclodimeric compounds have proven far more elusive. In this review we focus on natural products that involve macrocyclization in their biosynthesis and chemical synthesis, with an emphasis on the function and biosynthetic investigation on the special family of TE domains responsible for forming cyclodimeric natural products. We also introduce additional macrocyclization catalysts, including butelase and the CT-mediated cyclization of peptides, alongside the formation of cyclodipeptides mediated by cyclodipeptide synthases (CDPS) and single-module NRPSs. Due to the interdisciplinary nature of biosynthetic research, we anticipate that this review will prove valuable to synthetic chemists, drug discovery groups, enzymologists, and the biosynthetic community in general, and inspire further efforts to identify and exploit these biocatalysts for the formation of novel bioactive molecules.

Efficient synthesis of porous triazine-based macrocycles with 22-carbon and 6-nitrogen ring atoms and their adsorption/desorption of non-volatile organic compounds.

Porous triazine-based macrocycles with 22-carbon and 6-nitrogen ring atoms were efficiently synthesized and used for adsorbing bisphenol A, sulfamethoxazole, sodium dodecyl sulfate, and polyoxyethylene laural ether from aqueous media; after adsorption, simple extraction to desorb the guests from these porous macrocycles demonstrates a facile and efficient approach for porous materials to adsorb and desorb non-volatile organic compounds, thus being potentially applied to other surfactants or antibiotics.

Synthesis of the Fluorine-Edged Macrocycle for Promoting High-Resolution Gas Chromatographic Separation

Synthesis of the Fluorine-Edged Macrocycle for Promoting High-Resolution Gas Chromatographic Separation

Design, Synthesis, and Biological Evaluation of Novel Diaminopyrimidine Macrocycles as Fourth Generation Reversible EGFR Inhibitors That Overcome Clinical Resistance to Osimertinib Mediated by C797S Mutation.

Overcoming clinical resistance to osimertinib mediated by the tertiary C797S mutation remains an unmet medical need. To date, there are no effective drugs that have been approved for patients who harbor EGFRT790M/C797S mutations. Herein, we applied a structure-based drug design strategy to discover a series of potent and selective diaminopyrimidine macrocycles as novel EGFRT790M/C797S inhibitors. The representative compound 21v potently inhibited EGFR19del/T790M/C797S and EGFRL858R/T790M/C797S mutants with IC50 values of 2.3 nM and 12.5 nM, respectively, and exhibited antiproliferative activity against Ba/F3-EGFR19del/T790M/C797S and Ba/F3-EGFRL858R/T790M/C797S cells with IC50 values of 41 and 52 nM, respectively. Further, 21v inhibited proliferation of the EGFR19del/T790M/C797S mutant PC-9-OR NSCLC cell line with an IC50 value of 56 nM and displayed selectivity over parental Ba/F3 and A431 cells. Moreover, 21v exhibited antitumor efficacy in a Ba/F3-EGFR19del/T790M/C797S xenograft model. This study provides a promising macrocyclic lead for anticancer drug discovery overcoming EGFRC797S mutation mediated resistance in NSCLC patients.

Ring Expansion Reactions via C-N Bond Cleavage in the Synthesis of Medium-sized Cycles and Macrocycles

The literature review discusses and systematizes synthetic approaches to medium-sized cycles and macrocycles based on ring expansion reactions of bi- or polycyclic systems via C-N bond cleavage. Ring expansion reactions of bicyclic ammonium salts proceed via thermal decomposition or the action of strong bases. Bi- or polycyclic systems containing a common amine group can be reduced with strong reducing reagents, e.g. lithium aluminum hydride. Ammonium derivatives are much more prone to nucleophilic attack and quite often are used as starting materials for the synthesis of medium-sized cycles. Bicyclic systems containing a common aminal or amidine group are used for the synthesis of medium-sized rings and macrocycles via cleavage of the endocyclic C-N bond. Various methods of their activation and reduction are discussed in the review.

Recent Advances on Catalytic Atroposelective Synthesis of Planar-Chiral Macrocycles.

Planar-chiral skeletons widely exist in natural products, bioactive compounds, and other functional molecules. Although significant progress has been made in the field of asymmetric synthesis of centrally or axially chiral molecules over the past years, enantioselective constructing of planar chirality is still a big obstacle and numerous efforts have been made in this field. Previous works have mainly focused on the assembly of planar-chiral [2,2]-paracyclophanes and metallocenes. This Minireview describes recent advancements in asymmetric catalytic synthesis of planar-chiral macrocycles, including ansa chain construction, plane formation and asymmetric transformation strategies. It is anticipated that this Minireview will sever as a source of inspiration for developing new unconventional procedures for access to planar-chiral skeletons.

Recent Advances on Catalytic Atroposelective Synthesis of Planar‐Chiral Macrocycles

AbstractPlanar‐chiral skeletons widely exist in natural products, bioactive compounds, and other functional molecules. Although significant progress has been made in the field of asymmetric synthesis of centrally or axially chiral molecules over the past years, enantioselective constructing of planar chirality is still a big obstacle and numerous efforts have been made in this field. Previous works have mainly focused on the assembly of planar‐chiral [2,2]‐paracyclophanes and metallocenes. This Minireview describes recent advancements in asymmetric catalytic synthesis of planar‐chiral macrocycles, including ansa chain construction, plane formation and asymmetric transformation strategies. It is anticipated that this Minireview will sever as a source of inspiration for developing new unconventional procedures for access to planar‐chiral skeletons.

Chiral Macrocycles for Enantioselective Recognition.

The efficient synthesis of chiral macrocycles with highly enantioselective recognition remains a challenge. We have addressed this issue by synthesizing a pair of chiral macrocycles, namely, R/S-BINOL[2], achieving total isolated yields of up to 62% through a two-step reaction sequence. These macrocycles are readily purified by column chromatography over silica gel without the need for chiral separation, thus streamlining the overall synthesis. R/S-BINOL[2] demonstrated enantioselective recognition toward chiral ammonium salts, with enantioselectivity (KS/KR) values reaching up to 13.2, although less favorable separations were seen for other substrates. R/S-BINOL[2] also displays blue circularly polarized luminescence with a |glum| value of up to 2.2 × 10-3. The R/S-BINOL[2] macrocycles of this study are attractive as chiral hosts in that they both display enantioselective guest recognition and benefit from a concise, high-yielding synthesis. As such, they may have a role to play in chiral separations.

Self‐Assembly of an Unlikely Occurring Quadrangular Tube by Modulating Intramolecular Forces

AbstractOne of the central focuses in self‐assembly is precisely controlling the self‐assembly pathway so that the target molecules can be produced exclusively. Trans‐1,2‐cyclohexanediamine contains two amino units that form a 60° angle when projected on a plane. This angle naturally favors the formation of triangular products in most cases when trans‐1,2‐cyclohexanediamine is used as a bisamino building block in the synthesis of macrocycles and tubes. Here, we synthesized a slightly bent tetraformyl precursor bearing a central dibenzothiophene moiety, whose 3,7‐positions are functionalized with two m‐phthalaldehyde units. We observed that combining this tetraformyl building block with trans‐1,2‐cyclohexanediamine yielded a quadrangular tube when the concentrations of the precursors were relatively high. Both experimental measurements and theoretical calculations indicate that the formation of this unlikely occurring quadrangular product was driven by the intramolecular C−H⋅⋅⋅π interactions between the dibenzothiophene building blocks within the tube framework. This driving force, however, was disturbed in the triangular tube, a smaller counterpart whose formation was considered previously much more thermodynamically favored. These results improved our fundamental understanding on how to create those products whose syntheses are considered difficult or impossible, by modulating the intramolecular driving forces.

Self-Assembly of an Unlikely Occurring Quadrangular Tube by Modulating Intramolecular Forces.

One of the central focuses in self-assembly is precisely controlling the self-assembly pathway so that the target molecules can be produced exclusively. Trans-1,2-cyclohexanediamine contains two amino units that form a 60° angle when projected on a plane. This angle naturally favors the formation of triangular products in most cases when trans-1,2-cyclohexanediamine is used as a bisamino building block in the synthesis of macrocycles and tubes. Here, we synthesized a slightly bent tetraformyl precursor bearing a central dibenzothiophene moiety, whose 3,7-positions are functionalized with two m-phthalaldehyde units. We observed that combining this tetraformyl building block with trans-1,2-cyclohexanediamine yielded a quadrangular tube when the concentrations of the precursors were relatively high. Both experimental measurements and theoretical calculations indicate that the formation of this unlikely occurring quadrangular product was driven by the intramolecular C-H⋅⋅⋅π interactions between the dibenzothiophene building blocks within the tube framework. This driving force, however, was disturbed in the triangular tube, a smaller counterpart whose formation was considered previously much more thermodynamically favored. These results improved our fundamental understanding on how to create those products whose syntheses are considered difficult or impossible, by modulating the intramolecular driving forces.

Hydrogen Bond‐Assisted Macrocyclic Synthesis: An Extended Application For 4‐Hydroxybenzylamine Derivatives

AbstractThis work involved synthesizing three N‐benzyl‐4‐hydroxybenzylamines using indirect reductive amination of aromatic aldehydes and 4‐hydroxybenzylamine. Such benzylamines’ reaction with formaldehyde produced tricyclic azacyclophanes formed by two benzylamine units joined by methylene bridges. Computational calculations established that macrocyclization was promoted by template formation stabilized by hydrogen bonds and π‐stacking.

Facile synthesis of a new chiral polyimine macrocycle and its application for enantioseparation in high-performance liquid chromatography

Macrocyclic compounds such as crown ethers and cyclodextrins play an important role in the field of chromatography and show excellent separation performance. The design of simple and convenient methods for the efficient synthesis of novel chiral macrocycles for chromatographic separation is of great significance. In this work, a novel chiral polyimine macrocycle (PIMC) was designed and synthesized by the simply one-step reaction of 2,6-diformyl-4-tert-butylphenol with (S)-(-)-1,2-propanediamine. Then, it was bonded onto silica by the thiol-ene click reaction to construct a new chiral stationary phase (CSP) for high-performance liquid chromatography (HPLC). The chiral separation performance of the proposed CSP was examined by separating various racemates in the normal-phase (NP) and reversed-phase (RP) HPLC. In total, twelve and nine racemates, including ethers, esters, amines, alcohols, organic acids, ketones, and epoxides, were separated to varying degrees via NP-HPLC and RP-HPLC, respectively, Moreover, the CSP offered good chiral separation complementarity to Chiralcel OD-H and Chiralpak AD-H columns for resolution of these test racemates, and it can separate several racemic compounds that either cannot be separated or cannot be separated well be separated by the two commercially available columns. After the column was used for hundreds of injections, the relative standard deviations of the retention time and resolution were below 0.56 % and 0.45 %, respectively, showing the good reproducibility and stability of the CSP. This study provides a simple and convenient approach to synthesize a novel chiral macrocycle and CSP and also indicates the broad application prospects of such chiral PIMCs in HPLC chiral separation.

Solid-Phase Synthesis of Diverse Macrocycles by Regiospecific 2-Pyridone Formation: Scope and Applications.

This study introduces a novel solid-phase macrocyclization method generating 2-pyridone rings. This method relies on the intramolecular condensation between secondary and tertiary dimethoxy-propionic amide units. This selective reaction leads to the formation of a single well-defined regioisomer. The method demonstrates remarkable efficiency in producing diverse peptidic and nonpeptidic bioactive targets, paving the way for the development of innovative macrocycle libraries featuring the 2-pyridone unit.

On-Surface Synthesis of Macrocycles, Non-Planar Carbon Ribbons and Heteroatom-Doped Nanographenes

On-surface synthesis via covalent coupling of adsorbed molecules on metal surfaces has attracted significant attention recently due to its potential to fabricate low-dimensional carbon materials with atomic precision. The bottom-up, atomically precise synthesis of carbon nanostructures enables the tailoring of their electronic properties at a molecular level. To understand and control the surface-chemistry-driven synthesis, many efforts have been made to design innovative precursors, explore novel reaction schemes, and utilize templating effects from the substrate.My presentation focuses on high-resolution scanning probe microscopy experiments combined with density functional theory to demonstrate recent highlights on the assembly of surface-supported low-dimensional carbon structures on metal surfaces. First, the assembly and electronic structure of planar π-extended cycloparaphenylene macrocycles, representing the first nanographene with an all-armchair edge topology, will be presented [1]. The second part will discuss the bottom-up synthesis of covalently-linked non-planar carbon ribbons and their electronic properties depending on their adsorption geometry. Finally, I will conclude with the on-surface cyclomerization of oxygen heterocycles to understand the on-surface synthesis of furan and pyran derivatives from ketone-functionalized precursors on metal surfaces.[1] Xiang, et al. Nature Chem., 2022 14, 871–876.

Record Quantum Tunneling Time in an Air-Stable Exchange-Bias Dysprosium Macrocycle.

In recent years, dysprosium macrocycle single-molecule magnets (SMMs) have received increasing attention due to their excellent air/thermal stability, strong magnetic anisotropy, and rigid molecular skeleton. However, they usually display fast zero-field quantum tunneling of the magnetization (QTM) rate, severely hindering their data storage applications. Herein, we report the design, synthesis, and characterization of an air-stable monodecker didysprosium macrocycle integrating strong single-ion anisotropy, near-perfect local crystal field (CF) symmetry, and efficient exchange bias. These indispensable features enable clear-cut elucidation of the crucial role of very weak antiferromagnetic coupling on magnetization dynamics, creating a prominent SMM with a large effective energy barrier (Ueff) of 670 cm-1, open hysteresis loops at zero field up to 14.9 K, and a record relaxation time of QTM (τQTM), 24281 s, for all known nonradical-bridged lanthanide SMMs.

Chemoenzymatic synthesis of macrocycles via dynamic kinetic resolution of secondary alcohols

Chemoenzymatic synthesis of macrocycles via dynamic kinetic resolution of secondary alcohols

Benzothiadiazole-based water-soluble macrocycle: Synthesis, aggregation-induced emission and selective detection of spermine

Reported here is the synthesis of a new macrocycle bearing anionic carboxylate groups with water-soluble aggregation-induced emission (AIE). The water-soluble macrocycle without typical AIE luminogens is constructed based on the building block of benzothiadiazole. It exhibits a remarkable AIE effect. This water-soluble macrocycle can selectively bind different types of biogenic amines in aqueous media with the tightest binding towards spermine. The fluorescence enhancement induced by supramolecular encapsulation is used to detect spermine.

Pd‐Catalyzed [3+6+3+6] Macrocyclizations of Aryl α‐Diazo‐β‐Ketoesters

AbstractThanks to Pd(II)‐catalysis, an efficient synthesis of unsaturated macrocycles is achieved by [3+6+3+6] condensation of cyclic ethers with aryl α‐diazo‐β‐ketoesters. The presence of the electron‐rich aryl ester moieties forbids the use of dirhodium complexes as these diazo decomposition catalysts provoke unforeseen intermolecular Csp2−H insertion reactions that derail the targeted reactivity. However, with Pd(acac)2, using high concentration conditions (1 M), a variety of 18‐membered macrocycles (16 examples) is afforded with both aryl and alkyl diazo reagents. Catalyst selection for either electrophilic aromatic substitution (Rh) or ylide (Pd) pathways are explained by computational approaches.

One-Step Catalyst-Transfer Macrocyclization: Expanding the Chemical Space of Azaparacyclophanes.

In this paper, we report on a one-step catalyst-transfer macrocyclization (CTM) reaction, based on the Pd-catalyzed Buchwald-Hartwig cross-coupling reaction, selectively affording only cyclic structures. This route offers a versatile and efficient approach to synthesize aza[1n]paracyclophanes (APCs) featuring diverse functionalities and lumens. The method operates at mild reaction temperatures (40 °C) and short reaction times (∼2 h), delivering excellent isolated yields (>75% macrocycles) and up to 30% of a 6-membered cyclophane, all under nonhigh-dilution concentrations (35-350 mM). Structural insights into APCs reveal variations in product distribution based on different endocyclic substituents, with steric properties of exocyclic substituents having minimal influence on the macrocyclization. Aryl-type endocyclic substituents predominantly yield 6-membered macrocycles, while polycyclic aromatic units such as fluorene and carbazole favor 4-membered species. Experimental and computational studies support a proposed mechanism of ring-walking catalyst transfer that promotes the macrocycle formation. It has been found that the macrocyclization is driven by the formation of cyclic conformers during the oligomerization step favoring an intramolecular C-N bond formation that, depending on the cycle size, hinges on either preorganization effect or kinetic increase of the reductive elimination step or a combination of the two. The CTM process exhibits a "living" behavior, facilitating sequential synthesis of other macrocycles by introducing relevant monomers, thus providing a practical synthetic platform for chemical libraries. Notably, CTM operates both under diluted and concentrated regimes, offering scalability potential, unlike typical macrocyclization reactions usually operating in the 0.1-1 mM range.

Polycationic Open-Shell Cyclophanes: Synthesis of Electron-Rich Chiral Macrocycles, and Redox-Dependent Electronic States.

π-Conjugated chiral nanorings with intriguing electronic structures and chiroptical properties have attracted considerable interests in synthetic chemistry and materials science. We present the design principles to access new chiral macrocycles (1 and 2) that are essentially built on the key components of main-group electron-donating carbazolyl moieties or the π-expanded aza[7]helicenes. Both macrocycles show the unique molecular conformations with a (quasi) figure-of-eight topology as a result of the conjugation patterns of 2,2',7,7'-spirobifluorenyl in 1 and triarylamine-coupled aza[7]helicene-based building blocks in 2. This electronic nature of redox-active, carbazole-rich backbones enabled these macrocycles to be readily oxidized chemically and electrochemically, leading to the sequential production of a series of positively charged polycationic open-shell cyclophanes. Their redox-dependent electronic states of the resulting multispin polyradicals have been characterized by VT-ESR, UV/Vis-NIR absorption and spectroelectrochemical measurements. The singlet (ΔES-T=-1.29 kcal mol-1) and a nearly degenerate singlet-triplet ground state (ΔES-T(calcd)=-0.15 kcal mol-1 and ΔES-T(exp)=0.01 kcal mol-1) were proved for diradical dications 12+2⋅ and 22+2⋅, respectively. Our work provides an experimental proof for the construction of electron-donating new chiral nanorings, and more importantly for highly charged polyradicals with potential applications in chirospintronics and organic conductors.