Cyclic Products Research Articles

Quality Assurance Investigations and Impurity Characterization during Upscaling of [177Lu]Lu-PSMAI&T

[177Lu]Lu-PSMAI&T is widely used for the radioligand therapy of metastatic castration-resistant prostate cancer (mCRPC). Since this kind of therapy has gained a large momentum in recent years, an upscaled production process yielding multiple patient doses in one batch has been developed. During upscaling, the established production method as well as the HPLC quality control were challenged. A major finding was a correlation between the specific activity and the formation of a pre-peak, presumably caused by radiolysis. Hence, nonradioactive reference standards were irradiated with an X-ray source and the formed pre-peak was subsequently identified as a deiodination product by UPLC-MS. To confirm the occurrence of the same deiodinated side product in the routine batch, a customized deiodinated precursor was radiolabeled and analyzed with the same HPLC setup, revealing an identical retention time to the pre-peak in the formerly synthesized routine batches. Additionally, further cyclization products of [177Lu]Lu-PSMAI&T were identified as major contributors to radiochemical impurities. The comparison of two HPLC methods showed the likelihood of the overestimation of the radiochemical purity during the synthesis of [177Lu]Lu-PSMAI&T. Finally, a prospective cost reduction through an optimization of the production process was shown.

The Reactions of Alkenes with Phenyl-N-triflylimino-λ3-iodane: Solvent and Oxidant Impact.

The reactions of alkenes with phenyl-N-triflylimino-λ3-iodane PhI=NTf (1) have been studied in different conditions. In methylene chloride, in the presence of N-halosuccinimides, the products of mono and bis-triflamidation were obtained. In MeCN, the product of bromotriflamidation (with NBS) with solvent interception or of bis-triflamidation (with NIS) is formed. The reaction with trans-stilbene in acetonitrile with NBS gave rise to cyclization to 2-methyl-4,5-diphenyl-1-triflyl-4,5-dihydro-1H-imidazole. In contrast, with NIS as an oxidant, both in CH2Cl2 and MeCN, the major product was 2,3-diphenyl-1-triflylaziridine formed in good yield. With NBS, aziridine is also formed but as a minor product, the major one being a mixture of diastereomers of the product of bromotriflamidation. The reaction of compound 1 with vinylcyclohexane in methylene chloride affords the mixtures of regioisomers of the products of halotriflamidation, whereas in acetonitrile, the products of solvent interception and cyclization to the imidazoline are formed. A mechanism explaining the formation of all isolated products is proposed.

Multigram Synthesis of Dimethyl Stellane-1,5-Dicarboxylateas a Key Precursor for the ortho-Benzene Mimics.

Herein we present previously unavailable C(sp3)-rich polycyclic hydrocarbon scaffolds which have a potential to become valuable tools in medicinal chemistry and crop science as saturated bioisosteres of benzenoids. We have developed a scalable protocol (up to 50 g from a single synthetic run) for the synthesis of tricyclo[3.3.0.03,7]octane (bisnoradamantane or stellane) 1,5-dicarboxylic acid derivatives. X-ray crystallographic analysis of the stellane 1,5-dicarboxylic acid dimethyl ester has revealed that this scaffold is an optimal saturated isostere for ortho-disubstituted benzene where substituents exhibit the in-plane topology. The synthetic protocol is based on the oxidative cyclization of dimethyl octahydropentalene-2,5-dicarboxylate (DMOD) through lithiation followed by I2 oxidation. The reaction outcome is determined by the stereochemistry of the substrate. While the endo,endo cis-DMOD, exclusively gives the "unwanted" Claisen cyclization product the exo,endo cis- and exo,exo cis- stereoisomers afford the desired stellane 1,5-dicarboxylic acid dimethyl ester quantitatively. DFT computations have revealed that the reaction proceeds via the dianion of dimethyl octahydropentalene-2,5-dicarboxylate, which undergoes SET oxidation by I2 to form a radical anion. The subsequent cyclization followed by a second SET oxidation gives desired stellane derivative.

Synthesis of DNA-Encoded Macrocyclic Peptides via Nitrile-Aminothiol Click Reaction.

DNA-encoded library (DEL) technology holds exciting potential for discovering novel therapeutic macrocyclic peptides (MPs). Herein, we describe the development of a DEL-compatible peptide macrocyclization method that proceeds via intramolecular click-condensation between 3-(2-cyano-4-pyridyl)-l-alanine (Cpa) and an N-terminal cysteine. Cyclization takes place spontaneously in a buffered aqueous solution and affords the cyclized products in excellent yields. The reaction exhibits a broad substrate scope and can be employed to generate MPs of variable ring size and amino acid composition.

Carboxylative cyclization of propargyl alcohols with carbon dioxide for the synthesis of α-alkylidene cyclic carbonates in presence of Co(III) schiff base complex catalyst

A cobalt(III) complex, [Co(L)3](DMF) (1) of Schiff base ligand HL, 2-((E)-(benzylimino)methyl)-4-bromophenol is prepared and single crystal X-ray structural analysis have also been performed. The structures of complex 1 showed hexa-coordinated mononuclear systems that adopt octahedral geometry. The complex has also exhibited the supramolecular networks through non-covalent interactions like H-bonding, C–Hπ stacking. Moreover, the complex 1 is very effective in the catalytic fixation of carbon dioxide in propergyl alcohols to produce α-alkylidene cyclic carbonates. The catalytic production of α-alkylidene cyclic carbonates have been carried out through carboxylative cyclization of propargyl alcohols using CO2 balloon of 1 atm pressure at 80 °C. Solvent free condition (green synthesis) made this catalytic protocol eco-friendly towards the environment. Utilizing various substrates of propargyl alcohols moderate to high percentage yield (62–95%) of respective α-alkylidene cyclic carbonates product have been isolated over this catalytic reaction. Besides, the theoretical calculations (DFT) was performed for the prediction of probable mechanism of the catalytic reaction.

Three-Component Photochemical 1,2,5-Trifunctionalizations of Alkenes toward Densely Functionalized Lynchpins.

Radical remote 1,n-difunctionalization reactions (n > 2) of alkenes are powerful tools to efficiently introduce functional groups with selected distances into target molecules. Among these reactions, 1,5-difunctionalizations are an important subclass, leading to sought-after scaffolds, but typically suffer from tailored starting materials and strict limitations for the formed functional group in 2-position. Seeking to address these issues and to make radical 1,5-difunctionalizations of alkenes more applicable, we report a novel three-component 1,2,5-trifunctionalization reaction between imine-based bifunctional reagents and two distinct alkenes, driven by visible light energy transfer-catalysis. Key to achieving this selective one-step installation of three different functional groups via the choreographed formation of four bonds was the utilization of a 1,2-boron shift and the rigorous capitalization of radical polarities and stabilities. Thorough mechanistic studies were carried out, and the synthetic utility of the obtained products was demonstrated by various downstream modifications. Notably, in addition to the functionalization of individual functional groups, their interplay gave rise to a unique array of cyclic products.

The Utilization of N-Butanol to Olefins over Different Zeolite Structures

Bioalcohol is one of reliable renewable energy source in the future bioeconomy. Butanol is the next generation bioalcohol because of better quality comparing to lower-carbon alcohols. Its utilization to lower olefins opens the new route as chemical building blocks for polymer and value-added chemical production (instead of fossil fuel route). The n-butanol conversion to olefins was conducted over two different zeolite structures: ZSM-5 and SAPO-34. The small-pore 8-ring SAPO-34 produced exclusively C4 in the products (more than 97%) and showed high selectivity to butene. The large-pore 10-ring ZSM-5 gave lower yield of C4 and more classes toward larger hydrocarbon (C5-C12), which including aromatics and cyclic products. The SAPO-34 is suggested as promising shape-selective catalyst in the n-butanol conversion to butene product. The high purity butene can be used directly without further energy-consuming separation process.

Influence of Ring Strain on the Formation of Rearrangement vs Cyclization Isotwistane Products in the Acyl Radical Reaction of Bicyclo[2.2.2]octanone.

An acyl radical reaction of bicyclo[2.2.2]octenone to yield either rearranged or cyclized isotwistane products is described. The influence of ring strain on the reaction was demonstrated by alternating the sizes of the fused ring in the starting material. DFT calculations showed that the reaction is under thermodynamic control and proceeds via a 5-exo-trig cyclization intermediate, which undergoes either hydrogen-atom transfer (HAT) to give a cyclized product or rearrangement via a twistane intermediate to give a rearranged product.

6-Endo-dig cyclization: Flexible enforce to develop synthetic route in organic syntheses

The organic ring closure reaction of diverse acyclic compounds is governed mostly by the Baldwin rule. The ring closure compounds shows emergent application. In recent years, ring closure reactions that are favoured by the Baldwin rules have received a lot of attention. In particular, the Baldwin rule favours the usage of sp- geometrical (diagonal) molecules in the cyclization reaction. The endo-dig cyclization help for synthesis of bulky compound in simple manner via radical coupling. The radical coupling method help for synthesis of various cyclized compounds, also heterocyclic compounds like, three – eight memebered ring compounds. Also, the endo dig cyclization used for synthesis of C-C, C-N, C-O, C-S bond forming compounds. From the all ring closing reaction, 6-endo dig cyclization has great important for synthesis of highly active 6, 7, 8 membered ring compounds. The formed 6-endo dig cyclized product has selective activity against various field cosmetics, medicinal, dye, agrochemical. There are come list of organic compounds are synthesis via 6-endo-dig cyclization like, carbazole, fused benzimidazole, fused pyrimidine, oxazole, chromenos, pyridine, quinoline etc., analogues. The 6-endo-dig cyclization reaction proceed presence of transition metal catalyst and with out catalyst. The 6-endo-dig cyclization processes can be used to synthesise a wide range of 6 membered heterocycles and carbocycles. This review compiles the significant uses of 6-endo-dig cyclization in organic synthesis from a variety of perspectives.

Tetrachlorovancomycin: Total Synthesis of a Designed Glycopeptide Antibiotic of Reduced Synthetic Complexity.

A technically straightforward total synthesis of a new class of vancomycin analogues of reduced synthetic complexity was developed that provided tetrachlorovancomycin (1, LLS = 15 steps, 15% overall yield) and its precursor aglycon 29 (nearly 20% overall yield). The class retains all the intricate vancomycin structural features that contribute to its target binding affinity and selectivity, maintains the antimicrobial activity of vancomycin, and achieves the simplification by an unusual addition, not removal, of benign substituents to the core structure. The modification, accomplished by addition of two aryl chloride substituents to provide 1, permitted a streamlined total synthesis of the new glycopeptide antibiotic class by removing the challenges associated with CD and DE ring system atropisomer stereochemical control. This also enabled their simultaneous and further-activated SNAr macrocyclizations that establish the tricyclic skeleton of 1. Key elements of the approach include catalyst-controlled diastereoselective formation of the AB biaryl axis of chirality (>30:1 dr), an essentially instantaneous macrolactamization of the AB ring system free of competitive epimerization (>30:1 dr), racemization free coupling of the E ring tetrapeptide, room temperature simultaneous CD and DE ring system cyclizations, a highly refined 4-step conversion of the cyclization product to the aglycon, and a protecting-group-free one-pot enzymatic glycosylation for disaccharide introduction. In addition to the antimicrobial evaluation of tetrachlorovancomycin (1), the preparation of key peripherally modified derivatives, which introduce independent and synergistic mechanisms of action, revealed their exceptional antimicrobial potency and provide the foundation for future use of this new class of synthetic glycopeptide analogues.

Manganese/Cobalt Bimetallic Relay Catalysis for Divergent Dehydrogenative Difluoroalkylation of Alkenes

AbstractThe involvement of manganese radical for halogen atom transfer (XAT) reactions has been esteemed as one reliable method but encountered with limited catalytic models. In this paper, a novel bimetallic relay catalysis of Mn2(CO)10 and cobaloxime has been developed for divergent dehydrogenative difluoroalkylation of alkenes using commercially available difluoroalkyl bromides. A wide range of structurally diverse terminal, cyclic and internal alkenes as well as tetrasubstituted alkenes are found to be good coupling partners to deliver difluoroalkylated allylic products and difluoromethylated cyclic products, accompanied with the production of H2 as the by‐product. This bimetallic relay strategy features broad substrate scope, mild reaction conditions and excellent functional group compatibility. Its success represents an important step‐forward to expedite the construction of a rich library of difluoroalkylated products.

Formation of Novel Polycyclic Aromatic Compounds by Scholl Reactions of Di(1-anthryl) Ketones via Cyclization and Rearrangement

Abstract The Scholl reactions of di(1-anthryl) ketones were performed with chloranil under an acidic condition. The reaction of the parent ketone gave a cyclized product containing a seven-membered ring, which was enantiomerically separable. In contrast, the reaction of 4-(mesityloxy)-1-anthryl derivative mainly afforded an unexpected polycyclic aromatic ketone consisting of eight six-membered rings via skeletal rearrangement. The structure and properties of these products and the reaction mechanism are reported.

Configuration of super-fast Cu2+-responsive chemosensor by attaching diaminomaleonitrile to BODIPY scaffold for high-contrast fluorescence imaging of living cells

A highly fluorescent Cu2+-responsive sensor, 2-amino-3-(BODIPYmethyleneamino)maleonitrile (BD) was constructed by attaching diaminomaleonitrile to a BODIPY scaffold. Cu2+ can be selectively recognized on a 2-s time-scale by way of fluorescence emission. When Cu2+ and BD coexist in solution, typical BODIPY emission was observed and the emission intensity could be increased to 334 times that of the blank dye solution. The mechanism of fluorescence increase is based on the generation of highly fluorescent species by Cu2+-triggered oxidative cyclization of the attached diaminomaleonitrile. The absolute fluorescence quantum yield (AFQY) of the cyclization product is 98% determined by integrating sphere. The highly emissive character can be attributed to the imidazole ring and dicarbonitrile on the BODIPY scaffold. It surpasses the meso-phenyl substituted analogue in AFQY and detection limits (DL). The specific Cu2+ recognition behavior was also validated in Hela cells with high-contrast fluorescence images.

Flavones and Related Compounds: Synthesis and Biological Activity.

This review focuses on the synthesis and biological activity of flavones and their related flavonoidic compounds, namely flavonols and aurones. Among the biological activities of natural and synthetic flavones and aurones, their anticancer, antioxidant, and antimicrobial properties are highlighted and detailed in this review. Starting from the structures of natural flavones acting on multiple anticancer targets (myricetin, genkwanin, and other structurally related compounds), new flavone analogs were recently designed and evaluated for their anticancer activity. The most representative compounds and their anticancer activity are summarized in this review. Natural flavones recognized for their antimicrobial properties (baicalein, luteolin, quercetol, apigenin, kaempferol, tricin) have been recently derivatized or structurally modulated by chemical synthetic methods in order to obtain new effective antimicrobial flavonoidic derivatives with improved biological properties. The most promising antimicrobial agents are systematically highlighted in this review. The most applied method for the synthesis of flavones and aurones is based on the oxidative cyclization of o-hydroxychalcones. Depending on the reaction conditions and the structure of the precursor, in some cases, several cyclization products result simultaneously: flavones, flavanones, flavonols, and aurones. Based on the literature data and the results obtained by our research group, our aim is to highlight the most promising methods for the synthesis of flavones, as well as the synthetic routes for the other structurally related cyclization products, such as hydroxyflavones and aurones, while considering that, in practice, it is difficult to predict which is the main or exclusive cyclization product of o-hydroxychalcones under certain reaction conditions.

Formation of polyfluoro-1-ethylfluorenes in the reaction of perfluoropropylbenzene with tetrafluorobenzenes in an SbF5 medium

The interaction of perfluoropropylbenzene with 1,2,3,4-tetrafluorobenzene or 1,2,4,5-tetrafluorobenzene in an SbF5 medium at r.t. yields corresponding 1-(tetrafluorophenyl)perfluoro-1-phenylpropanes, which undergo cyclization into perfluoro-9-ethylfluorene or 1,2,3,4,5,7,8,9-octafluoro-9-(pentafluoroethyl)fluorene along with 1,2,3,4-tetrahydro-9H-fluorenes under the reaction conditions. The reaction of perfluoropropylbenzene with 1,2,3,5-tetrafluorobenzene under the same conditions leads to the formation of 1-(2,3,4,6-tetrafluorophenyl)perfluoro-1-phenylpropane, which does not give cyclization products at 50–55 °C.

Formation and characterization of polymetallic {CrxMy} rings in vacuo

Understanding the (dis)assembly mechanisms of large metallosupramolecules is critical in their design, stability and application. The inherent complexity of these structures leads to many potential pathways for combining (or separating) the constituent building blocks, which makes this task difficult. Here we use collision-induced dissociation mass spectrometry to study the disassembly of heterometallic complexes. Collisional activation leads to the formation of a series of previously unknown smaller ring products and we characterize their geometry using ion mobility. The disassembly of both {CrxCu2} hourglass structures (x = 10, 12) and of a {Cr12Gd4} cluster shows the formation of rare closed, heptametallic species {Cr6Cu}, {Cr5Cu2} and {Cr5Gd2} as dominant products, as well as other closed ions such as {Cr5Cu}, {Cr10Cu}, {Cr12Cu}, {Cr10}, {Cr12} and {Cr6Gd2}. The collision cross-section of cyclic products and precursors has a linear correlation with ion mass—a relationship that does not hold for acyclic systems. As these rings are non-trivial to synthesize individually in solution, we propose the presented workflow to identify and characterize feasible molecules for bulk phase synthesis.

DFT modeling of the carbon dioxide and alkene oxide reaction catalyzed by a CrIII complex

The mechanism of the carbon dioxide and alkene oxide reaction catalyzed by the pentagonal-bipyramidal CrIII complex, dichloro[2,6-diacetylpyridine bis(benzoylhydrazone)(1−)] chromium, includes the steps of sequential binding of the epoxide molecule, chloride ion and CO2 with the catalytic particle and subsequent cyclization, accompanied by dissociation of Cl−. The solvent effect is important for the formation of the cyclic carbonate product.

Investigation of Computational Reaction Mechanism for The Formation of The 6-endo Cyclization Product of 1- Vinyl 5-Hexenyl Radicals

1-Vinil 5-heksenil radikallerinin reaksiyon mekanizması için hesaplamalı bir çalışma, yoğunluk fonksiyonel teorisi kullanılarak gerçekleştirildi. Sonuçlarımız, termodinamik olarak kararlı 6-endo-trig halka kapanma ürününün oluşumuna yönelik reaksiyonun hem 5-ekso-trig hem de 6-endo-trig halka kapanma modları üzerinden ilerleyebileceğini gösterdi. Ayrıca, hesaplamalarımız, 5-ekso-trig halka kapanma ara ürününün kararlı olması durumunda, 6-endo-trig halka kapanma ürününün oluşumundan 5-ekso-trig modun sorumlu olacağını gösterdi.

Electrochemical C-N Coupling Reaction Mediated by π-Extended Haloarene Catalyst

Hypervalent iodine is a useful reagent in synthetic organic chemistry,[1] but because these reagents are synthesized by reaction with stoichiometric amounts of oxidants, their large-scale use is associated with safety and environmental impact concerns. Hypervalent iodine can also be synthesized by electrochemical oxidation of the corresponding iodoarenes, and the electrochemically generated hypervalent iodine can be immediately reacted and used catalytically, i.e., as an electrochemical mediator, to enable a reaction system that is safe and generates little waste.[2] The use of hypervalent iodine as an electrochemical mediator has been reported previously, [3,4] but the number is still limited. In addition, no quantitative kinetic analysis of catalytic reactions has ever been performed. The presenters hypothesized that the following two issues are responsible for this situation: (i) the high oxidation potential of iodoarenes makes their selective oxidation difficult, and (ii) the instability of the radical cation.In this study, we designed and synthesized a novel π-extended iodoarene 1, and developed it as an efficient electrochemical mediator (Figure 1). The extended π system realized stabilization of the radical cation intermediate, as well as lowering the oxidation potential. Electrochemical oxidations of various N-Boc-2-aminobiphenyl analogues (2) were performed, and successfully gave cyclized product 3 in high yield in the presence of a base. Kinetic analysis of the electrocatalytic process based on Foot-of-the-Wave analysis (FOWA)[5] was also investigated.[6] In addition, we have also investigated the electrocatalytic reaction and kintetics using mediators with bromo- and chloro-anthracene structures to uncover the structure-reactivity relationship of haloarene mediators.[1] A. Yoshimura, V. V. Zhdankin, Chem. Rev., 2016, 116, 3328–3435. [2] M. Elsherbini, T. Wirth, Chem. Eur. J. 2018, 24, 13399–13407. [3] T. Fuchigami, T. Fujita, J. Org. Chem. 1994 , 59, 7190-7192. [4] A. Maity, B. L. Frey, N. D. Hoskinson, D. C. Powers, J. Am. Chem. Soc. 2020, 142, 4990−4995. [5] C. Costentin, S. Drouet, M. Robert, J.-M. Savéant, J. Am. Chem. Soc. 2012, 134, 11235–11242. [6] S. Yoshinaga, M. Atobe, N. Shida, ChemRxiv, 2022, DOI: 10.26434/chemrxiv-2022-sggqd.

Synthesis of benzothienofuranones and dihydrobenzothienopyranones by palladium iodide-catalyzed carbonylative double cyclization

3-(2-(Methylthio)phenyl)prop-2-yn-1-ols have been successfully converted in one synthetic step into benzo[4,5]thieno[2,3-c]furan-1-ones by a PdI2/KI-catalyzed oxidative carbonylative double cyclization process, performed in MeCN under relative mild conditions (1–10 mol % PdI2, 7 equiv of KI, 80 °C, 60 atm of a 4:1 mixture CO–air). The process takes place through an ordered sequence of steps, involving 5-endo-dig S-cyclization, iodide-promoted demethylation of the ensuing sulfonium salt, CO insertion, a second cyclization (possibly, through the formation of a palladacycle intermediate followed by reductive elimination), and Pd(0) reoxidation by oxygen (from air) used as external benign oxidant. Under similar conditions, 4-(2-(methylthio)phenyl)but-3-yn-1-ols, bearing a butynol moiety ortho to the methylthio group, led to a mixture of double cyclization and dicarbonylation products, however, by slightly tuning the reaction conditions, dihydrobenzo[4,5]thieno[3,2-c]pyran-1-ones could be selectively obtained with no formation of the dicarbonylated byproduct. The structures of four representative products, including two tetracyclic derivatives, have been confirmed by XRD analysis.