RESUMO
Bioorthogonal reactions have revolutionized chemical biology by enabling selective chemical transformations within living organisms and cells. This review comprehensively explores bioorthogonal chemistry, emphasizing inverse-electron-demand Diels-Alder (IEDDA) reactions between tetrazines and strained dienophiles and their crucial role in chemical biology and various applications within the human body. This highly reactive and selective reaction finds diverse applications, including cleaving antibody-drug conjugates, prodrugs, proteins, peptide antigens, and enzyme substrates. The versatility extends to hydrogel chemistry, which is crucial for biomedical applications, yet it faces challenges in achieving precise cellularization. In situ activation of cytotoxic compounds from injectable biopolymer belongs to the click-activated protodrugs against cancer (CAPAC) platform, an innovative approach to tumor-targeted prodrug delivery and activation. The CAPAC platform, relying on click chemistry between trans-cyclooctene (TCO) and tetrazine-modified biopolymers, exhibits modularity across diverse tumor characteristics, presenting a promising approach in anticancer therapeutics. The review highlights the importance of bioorthogonal reactions in developing radiopharmaceuticals for positron emission tomography (PET) imaging and theranostics, offering a promising avenue for diverse therapeutic applications.
Assuntos
Reação de Cicloadição , Ciclo-Octanos , Humanos , Ciclo-Octanos/química , Ciclo-Octanos/síntese química , Química Click , Compostos Heterocíclicos com 1 Anel/química , Compostos Heterocíclicos com 1 Anel/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Neoplasias/tratamento farmacológico , Neoplasias/diagnóstico por imagem , Estrutura MolecularRESUMO
Polymer gels have recently attracted attention for their application in flexible devices, where mechanically robust gels are required. While there are many strategies to produce tough gels by suppressing nanoscale stress concentration on specific polymer chains, it is still challenging to directly verify the toughening mechanism at the molecular level. To solve this problem, the use of the flapping molecular force probe (FLAP) is promising because it can evaluate the nanoscale forces transmitted in the polymer chain network by ratiometric analysis of a stress-dependent dual fluorescence. A flexible conformational change of FLAP enables real-time and reversible responses to the nanoscale forces at the low force threshold, which is suitable for quantifying the percentage of the stressed polymer chains before structural damage. However, the previously reported FLAP only showed a negligible response in solvated environments because undesirable spontaneous planarization occurs in the excited state, even without mechanical force. Here, we have developed a new ratiometric force probe that functions in common organogels. Replacement of the anthraceneimide units in the flapping wings with pyreneimide units largely suppresses the excited-state planarization, leading to the force probe function under wet conditions. The FLAP-doped polyurethane organogel reversibly shows a dual-fluorescence response under sub-MPa compression. Moreover, the structurally modified FLAP is also advantageous in the wide dynamic range of its fluorescence response in solvent-free elastomers, enabling clearer ratiometric fluorescence imaging of the molecular-level stress concentration during crack growth in a stretched polyurethane film.
Assuntos
Ciclo-Octanos/química , Corantes Fluorescentes/química , Géis/química , Fenazinas/química , Poliuretanos/química , Ciclo-Octanos/síntese química , Fluorescência , Corantes Fluorescentes/síntese química , Conformação Molecular , Fenazinas/síntese química , Estresse MecânicoRESUMO
Amyloid aggregates of proteins are known to be involved in various diseases such as Alzheimer's disease (AD). It is therefore speculated that the inhibition of amyloid formation can play an important role in the prevention of various diseases involving amyloids. Recently, we have found that acrolein reacts with polyamines, such as spermine, and produces 1,5-diazacyclooctane, such as cyclic spermine (cSPM). cSPM could suppress the aggregation of amyloid ß 1-40 (Aß40), one of the causative proteins of AD. This result suggests the potential inhibitory effect of cSPM against Aß 1-42 (Aß42) and other amyloid protein aggregation which are the main pathological features of AD and other diseases. However, the effect on the aggregation of such proteins remains unclear. In this study, the effect of cSPM on the amyloid formation of Aß42, amylin, and insulin was investigated. These three amyloidogenic proteins forming amyloids under physiological conditions (pH 7.4 and 37â) served as model and are thought to be the causative proteins of AD, type 2 diabetes, and insulin-derived amyloidosis, respectively. Our results indicate that cSPM can suppress the amyloid aggregation of these proteins and reduce cytotoxicity. This study contributes to a better understanding of means to potentially counteract diseases by the means of polyamine and acrolein.
Assuntos
Acroleína/farmacologia , Compostos Aza/farmacologia , Ciclo-Octanos/farmacologia , Espermina/farmacologia , Acroleína/química , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Compostos Aza/síntese química , Compostos Aza/química , Ciclo-Octanos/síntese química , Ciclo-Octanos/química , Relação Dose-Resposta a Droga , Humanos , Insulina/metabolismo , Polipeptídeo Amiloide das Ilhotas Pancreáticas/antagonistas & inibidores , Polipeptídeo Amiloide das Ilhotas Pancreáticas/metabolismo , Estrutura Molecular , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/metabolismo , Agregados Proteicos/efeitos dos fármacos , Espermina/química , Relação Estrutura-AtividadeRESUMO
Phytochemical investigation on the roots of Kadsura coccinea led to the isolation five previously unknown dibenzocyclooctadiene lignans, named heilaohusuins A-E (1-5). Their structures determined by NMR spectroscopy, HR-ESI-MS, and ECD spectra. Hepatoprotection effects of a series of dibenzocyclooctadiene derivatives (1-68) were investigated against acetaminophen (APAP) induced HepG2 cells. Compounds 2, 10, 13, 21, 32, 41, 46, and 49 showed remarkable protective effects, increasing the viabilities to > 52.2% (bicyclol, 52.1 ± 1.3%) at 10 µM. The structure-activity relationships (SAR) for hepatoprotective activity were summarized, according to the activity results of dibenzocyclooctadiene derivatives. Furthermore, we found that one new dibenzocyclooctadiene lignan heilaohusuin B attenuates hepatotoxicity, the mechanism might be closely correlated with oxidative stress inhibition via activating the Nrf2 pathway.
Assuntos
Acetaminofen/antagonistas & inibidores , Ciclo-Octanos/farmacologia , Kadsura/química , Lignanas/farmacologia , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Substâncias Protetoras/farmacologia , Acetaminofen/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Ciclo-Octanos/síntese química , Ciclo-Octanos/química , Relação Dose-Resposta a Droga , Células Hep G2 , Humanos , Lignanas/síntese química , Lignanas/química , Estrutura Molecular , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/síntese química , Substâncias Protetoras/química , Relação Estrutura-AtividadeRESUMO
trans-Cyclooctenes (TCOs) are essential partners in the fastest known bioorthogonal reactions, but current synthetic methods are limited by poor diastereoselectivity. Especially hard to access are hydrophilic TCOs with favorable physicochemical properties for live cell or inâ vivo experiments. Described is a new class of TCOs, "a-TCOs", prepared in high yield by stereocontrolled 1,2-additions of nucleophiles to trans-cyclooct-4-enone, which itself was prepared on a large scale in two steps from 1,5-cyclooctadiene. Computational transition-state models rationalize the diastereoselectivity of 1,2-additions to deliver a-TCO products, which were also shown to be more reactive than standard TCOs and less hydrophobic than even a trans-oxocene analogue. Illustrating the favorable physicochemical properties of a-TCOs, a fluorescent TAMRA derivative in live HeLa cells was shown to be cell-permeable through intracellular Diels-Alder chemistry and to wash out more rapidly than other TCOs.
Assuntos
Ciclo-Octanos/síntese química , Físico-Química , Reação de Cicloadição , Ciclo-Octanos/química , Células HeLa , Humanos , Estrutura Molecular , EstereoisomerismoRESUMO
The tetrazine/trans-cyclooctene (TCO) inverse electron-demand Diels-Alder (IEDDA) reaction is the fastest bioorthogonal "click" ligation process reported to date. In this context, TCO reagents have found widespread applications; however, their availability and structural diversity is still somewhat limited due to challenges connected with their synthesis and structural modification. To address this issue, we developed a novel strategy for the conjugation of TCO derivatives to a biomolecule, which allows for the creation of greater structural diversity from a single precursor molecule, i.e., trans,trans-1,5-cyclooctadiene [(E,E)-COD] 1, whose preparation requires standard laboratory equipment and readily available reagents. This two-step strategy relies on the use of new bifunctional TCO linkers (5a-11a) for IEDDA reactions, which can be synthesized via 1,3-dipolar cycloaddition of (E,E)-COD 1 with different azido spacers (5-11) carrying an electrophilic function (NHS-ester, N-succinimidyl carbonate, p-nitrophenyl-carbonate, maleimide) in the ω-position. Following bioconjugation of these electrophilic linkers to the nucleophilic residue (cysteine or lysine) of a protein (step 1), the resulting TCO-decorated constructs can be subjected to a IEDDA reaction with tetrazines functionalized with fluorescent or near-infrared (NIR) tags (step 2). We successfully used this strategy to label bovine serum albumin with the TCO linker 8a and subsequently reacted it in a cell lysate with the fluorescein-isothiocyanate (FITC)-derived tetrazine 12. The same strategy was then used to label the bacterial wall of Gram-positive Staphylococcus aureus, showing the potential of these linkers for live-cell imaging. Finally, we determined the impact of structural differences of the linkers upon the stability of the bioorthogonal constructs. The compounds for stability studies were prepared by conjugation of TCO linkers 6a, 8a, and 10a to mAbs, such as Rituximab and Obinutuzumab, and subsequent labeling with a reactive Cy3-functionalized tetrazine.
Assuntos
Alcadienos/química , Corantes Fluorescentes/química , Alcadienos/síntese química , Animais , Bovinos , Química Click , Reação de Cicloadição , Ciclo-Octanos/síntese química , Ciclo-Octanos/química , Corantes Fluorescentes/síntese química , Soroalbumina Bovina/química , Staphylococcus aureus/citologia , Staphylococcus aureus/isolamento & purificaçãoRESUMO
A series of oxime ester-derivatives were prepared by utilizing the schizandrin (1), a major compound isolated from Schisandra grandiflora, which is deployed in different traditional system of medicine. The in vitro antiproliferative activities of the synthesized compounds were assessed against a selected panel of human cancer cell lines (A549, RKO P3, DU145 and Hela) and normal cell (HEK293). Several of these derivatives were found more potent in comparison to parent compound, schizandrin (1). Particularly, 4a and 4b demonstrated potent activity against DU-145 and RKOP3 cell lines with IC50 values of 3.42 µM and 3.35 µM respectively. To characterize the molecular mechanisms involved in antitumoral activity, these two compounds, 4a and 4b were selected for further studies. Cell cycle analysis revealed that both the compounds were able to induce apoptosis and cell cycle arrest at G0/G1 phase. To know the extent of apoptosis in DU145 and RKOP3 cell lines, Annexin V-FITC were performed. Moreover, the tubulin polymerization assay indicated that 4a and 4b exhibits potent inhibitory effect on the tubulin assembly. Molecular docking studies and competitive binding assay also indicated that 4a and 4b effectively bind at the colchicine binding site of the tubulin.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Ciclo-Octanos/farmacologia , Lignanas/farmacologia , Compostos Policíclicos/farmacologia , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Antineoplásicos Fitogênicos/síntese química , Antineoplásicos Fitogênicos/química , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ciclo-Octanos/síntese química , Ciclo-Octanos/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HEK293 , Humanos , Lignanas/síntese química , Lignanas/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Compostos Policíclicos/síntese química , Compostos Policíclicos/química , Polimerização/efeitos dos fármacos , Schisandra/química , Relação Estrutura-Atividade , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/químicaRESUMO
Avibactam is a non ß-lactam ß-lactamase inhibitor that has recently been approved in association with a ß-lactam antibiotic for the treatment of severe infections caused by otherwise resistant bacteria. Its therapeutic success encouraged the development of many congeners based on its particular diazabicyclooctane scaffold. This review presents a detailed overview of the synthetic strategies that have been implemented to acces these complex bicyclic compounds with a particular focus on those that are currently on the market or in clinical trials.
Assuntos
Compostos Aza/síntese química , Compostos Azabicíclicos/síntese química , Ciclo-Octanos/síntese química , Inibidores de beta-Lactamases/síntese química , Compostos Aza/química , Compostos Aza/farmacologia , Compostos Azabicíclicos/química , Compostos Azabicíclicos/farmacologia , Ciclo-Octanos/química , Ciclo-Octanos/farmacologia , Ciclopropanos/química , Inibidores de beta-Lactamases/química , Inibidores de beta-Lactamases/farmacologiaRESUMO
The rapid surface immobilization of protein on monodispersed polyester microcarriers is reported. A model protein, functionalized with a dibenzocyclooctyne core, immobilizes on the surface of azide-terminal polycaprolactone microcarriers within 10 min compared to 12 h for other conjugation techniques, and it is conducted in physiological conditions and in the absence of coupling reagents.
Assuntos
Azidas/química , Química Click/métodos , Proteínas Imobilizadas/química , Poliésteres/química , Albumina Sérica Humana/química , Alcinos/síntese química , Alcinos/química , Azidas/síntese química , Ciclo-Octanos/síntese química , Ciclo-Octanos/química , Emulsões/síntese química , Emulsões/química , Proteínas Imobilizadas/síntese química , Poliésteres/síntese química , Albumina Sérica Humana/síntese químicaRESUMO
Herein, we report the 1JCH analyses, natural bond orbital analyses, and X-ray crystal structures of a number of C, O, and N constrained tricyclic cycles. These experiments provide access into the nature of the apparent Perlin effect previously reported in constrained tricyclic cycles, as well as evidence suggesting both steric contraction and long-range hyperconjugation account for the observed 1JCH perturbations. We report a true Perlin effect of 10.9 Hz in an azocane and large steric effect resulting in Δ1JC-H = 10.9 Hz in a cyclooctane.
Assuntos
Ciclo-Octanos/química , Cristalografia por Raios X , Reação de Cicloadição , Ciclo-Octanos/síntese química , Eletrônica , Modelos Moleculares , Estrutura Molecular , Teoria QuânticaRESUMO
The use of radiolabelled antibodies and antibody-derived recombinant constructs has shown promise for both imaging and therapeutic use. In this context, the biotin-avidin/streptavidin pairing, along with the inverse-electron-demand Diels-Alder (iEDDA) reaction, have found application in pretargeting approaches for positron emission tomography (PET). This study reports the fluorinase-mediated transhalogenation [5'-chloro-5'-deoxyadenosine (ClDA) substrates to 5'-fluoro-5'-deoxyadenosine (FDA) products] of two antibody pretargeting tools, a FDA-PEG-tetrazine and a [18 F]FDA-PEG-biotin, and each is assessed either for its compatibility towards iEDDA ligation to trans-cyclooctene or for its affinity to avidin. A protocol to avoid radiolytically promoted oxidation of biotin during the synthesis of [18 F]FDA-PEG-biotin was developed. The study adds to the repertoire of conjugates for use in fluorinase-catalysed radiosynthesis for PET and shows that the fluorinase will accept a wide range of ClDA substrates tethered at C-2 of the adenine ring with a PEGylated cargo. The method is exceptional because the nucleophilic reaction with [18 F]fluoride takes place in water at neutral pH and at ambient temperature.
Assuntos
Biotina/química , Desoxiadenosinas/química , Radioisótopos de Flúor/química , Imunoconjugados/química , Polietilenoglicóis/química , Tomografia por Emissão de Pósitrons/métodos , Proteínas de Bactérias/química , Biotina/síntese química , Reação de Cicloadição , Ciclo-Octanos/síntese química , Ciclo-Octanos/química , Desoxiadenosinas/síntese química , Halogenação , Oxirredutases/química , Polietilenoglicóis/síntese química , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/química , Estreptavidina/químicaRESUMO
The cyclooctyne BCN and the trans-cyclooctene s-TCO are widely used in bioorthogonal chemistry. A bottleneck for their synthesis had been a poorly selective cyclopropanation with ethyl diazoacetate. Here, we describe that low catalyst loadings (0.27 mol %) of Rh2( S-BHTL)4 provide the BCN precursor with 79:21 syn/ anti selectivity. The synthesis of the s-TCO precursor was best achieved through a sequence of Rh2(OAc)4 (0.33 mol %)-catalyzed cyclopropanation, followed by ester hydrolysis under epimerizing conditions. Both sequences could be carried out on multigram scale.
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Ciclo-Octanos/síntese química , Catálise , Estrutura MolecularRESUMO
Organocatalysis constitutes one of the main research areas in organic chemistry from the last two decades. This chemistry has been applied to the synthesis of many natural products and structures in a manner that reduces the residues and so the ecological impact. In this review, we consider the work that has been done for the synthesis of bicyclo[3.2.1]octane framework. This structure is present in many natural products with very important biological activities.
Assuntos
Produtos Biológicos/química , Ciclo-Octanos/síntese química , Catálise , Ciclo-Octanos/química , Estrutura Molecular , Fenômenos de Química Orgânica , EstereoisomerismoRESUMO
α-Hydroxy-γ-pyrone-based oxidopyrylium cycloaddition reactions are useful methods for accessing a highly diverse range of oxabicyclo[3.2.1]octane products. Intermolecular variants of the reaction require the formation of a methyl triflate-based pre-ylide salt that upon treatment with base in the presence of alkenes or alkynes leads to α-methoxyenone-containing bicyclic products. Herein, we describe our discovery that the use of ethanol-stabilized chloroform as solvent leads to the generation of α-ethoxyenone-containing bicyclic byproducts. This three-component process was further optimized by gently heating a mixture of a purified version of the oxidopyrylium dimer in the presence of an alcohol prior to addition of a dipolarophile. Using this convenient procedure, several new oxidopyrylium cycloaddition products can be generated in moderate yields. We also highlight the method in a tandem ring-opening/debenzylation method for the generation of α-hydroxytropolones.
Assuntos
Compostos Bicíclicos com Pontes/química , Reação de Cicloadição , Ciclo-Octanos/química , Pironas/química , Tropolona/química , Compostos Bicíclicos com Pontes/síntese química , Ciclo-Octanos/síntese química , EstereoisomerismoRESUMO
The marasmane sesquiterpenoid structure can be found in the skeleton of a variety of natural products bearing interesting bioactivity. The unique fused-5,6,3-tricyclic ring structure, in which the rings are cis-fused and the five- and three-membered rings are mutually trans, provides a synthetic challenge for organic chemists. In this work, we took advantage of the photoinduced decarbonylative rearrangement of bicyclo[2.2.2]octenone to develop a new methodology for construction of the highly functionalized fused-5,6,3-tricyclic ring structure in a concise reaction sequence.
Assuntos
Compostos Bicíclicos com Pontes/química , Ciclo-Octanos/síntese química , Sesquiterpenos/síntese química , Fenômenos Bioquímicos , Ciclo-Octanos/química , Estrutura Molecular , Sesquiterpenos Policíclicos , Sesquiterpenos/químicaRESUMO
Novel bacterial topoisomerase inhibitors (NBTIs) represent a new class of broad-spectrum antibacterial agents targeting bacterial Gyrase A and ParC and have potential utility in combating antibiotic resistance. A series of novel oxabicyclooctane-linked NBTIs with new tricyclic-1,5-naphthyridinone left hand side moieties have been described. Compounds with a (R)-hydroxy-1,5-naphthyridinone moiety (7) showed potent antibacterial activity (e.g., Staphylococcus aureus MIC 0.25 µg/mL), acceptable Gram-positive and Gram-negative spectrum with rapidly bactericidal activity. The compound 7 showed intravenous and oral efficacy (ED50) at 3.2 and 27 mg/kg doses, respectively, in a murine model of bacteremia. Most importantly they showed significant attenuation of functional hERG activity (IC50 >170 µM). In general, lower logD attenuated hERG activity but also reduced Gram-negative activity. The co-crystal structure of a hydroxy-tricyclic NBTI bound to a DNA-gyrase complex exhibited a binding mode that show enantiomeric preference for R isomer and explains the activity and SAR. The discovery, synthesis, SAR and X-ray crystal structure of the left-hand-side tricyclic 1,5-naphthyridinone based oxabicyclooctane linked NBTIs are described.
Assuntos
Antibacterianos/farmacologia , Ciclo-Octanos/farmacologia , DNA Topoisomerases Tipo II/metabolismo , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Naftiridinas/farmacologia , Inibidores da Topoisomerase II/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Ciclo-Octanos/síntese química , Ciclo-Octanos/química , Relação Dose-Resposta a Droga , Bactérias Gram-Negativas/enzimologia , Bactérias Gram-Positivas/enzimologia , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Naftiridinas/síntese química , Naftiridinas/química , Relação Estrutura-Atividade , Inibidores da Topoisomerase II/síntese química , Inibidores da Topoisomerase II/químicaRESUMO
The gas-phase enthalpy of formation of cubane (603.4 ± 4 kJâ¯mol(-1)) was calculated using an explicitly correlated composite method (W1-F12). The result obtained for cubane, together with the experimental value for the enthalpy of sublimation, 54.8 ± 2.0 kJâ¯mol(-1), led to 548.6 ± 4.5 kJâ¯mol(-1) for the solid-phase enthalpy of formation. This value is only 6.8 kJâ¯mol(-1) higher than the 50-year-old original calorimetric result. The carbon-hydrogen bond dissociation enthalpy (C-H BDE) of cubane (438.4 ± 4 kJâ¯mol(-1)), together with properties relevant for its experimental determination using gas-phase ion thermochemistry, namely the cubane gas-phase acidity (1704.6 ± 4 kJâ¯mol(-1)), cubyl radical electron affinity (45.8 ± 4 kJâ¯mol(-1)), cubane ionization energy (1435.1 ± 4 kJâ¯mol(-1)), cubyl radical cation proton affinity (918.8 ± 4 kJâ¯mol(-1)), cubane cation appearance energy (1099.6 ± 4 kJâ¯mol(-1)), and cubyl ionization energy (661.2 ± 4 kJâ¯mol(-1)), were also determined. These values were compared with those calculated for unstrained hydrocarbons (viz., methane, ethane, and isobutane). The strain energy of cubane (667.2 kJâ¯mol(-1)) and cubyl radical (689.4 kJâ¯mol(-1)) were independently estimated via quasihomodesmotic reactions. These values were related via a simple model to the C-H BDE in cubane. Taking into account the accuracy of the computational method, the comparison with high-precision experimental results, and the data consistency afforded by the relevant thermodynamic cycles, we claim an uncertainty better than ±4 kJâ¯mol(-1) for the new enthalpy of formation values presented.
Assuntos
Ciclo-Octanos/análogos & derivados , Ciclo-Octanos/química , Ciclo-Octanos/síntese química , Teoria Quântica , TermodinâmicaRESUMO
A transient protection method of cyclooctynes from a click reaction with an azide through 1:1 complexation with a cationic copper(I) salt is reported. The application of the method to a cyclooctyne bearing a terminal alkyne enabled the selective copper-catalyzed click conjugation with an azide at the terminal alkyne moiety, which made cyclooctyne derivatives readily accessible.
Assuntos
Alcinos/química , Cobre/química , Ciclo-Octanos/síntese química , Compostos Organometálicos/química , Azidas/química , Química Click , Ciclo-Octanos/química , Estrutura MolecularRESUMO
Highly strained cyclic acetylenes 5,6,11,12-tetradehydrodibenzo[a,e]cyclooctenes (Sondheimer-Wong diynes) having various substituents on their benzene rings were synthesized successfully by one-pot treatment of the corresponding formyl sulfones with diethyl chlorophosphate/lithium hexamethyldisilazide (LiHMDS) and then lithium diisopropylamide (LDA). When mixtures of two types of formyl sulfones bearing different substituents were subjected to this protocol, the unsymmetrically substituted Sondheimer-Wong diynes could be synthesized in a stepwise manner by isolation of the heterocoupled vinyl sulfone intermediates followed by their treatment with LDA. The UV-vis absorption spectra and cyclic voltammograms of the substituted Sondheimer-Wong diynes were recorded. The electronic effect of substituents on the diynes was investigated in their click reactions and nucleophilic and electrophilic additions.
Assuntos
Ciclo-Octanos/química , Ciclo-Octanos/síntese química , Di-Inos/química , Compostos de Lítio/química , Propilaminas/química , Silanos/química , Catálise , Estrutura Molecular , EstereoisomerismoRESUMO
A straightforward gram-scale synthesis of 1,3,5,7-tetrakis(methylidene)cyclooctane (TMCO) from commercial adamantane-1,3-dicarboxylic acid has been developed. TMCO exhibits high reactivity toward a number of carbenes and epoxidizing reagents, undergoing multiple cyclopropanations, dihalocyclopropanations, or epoxidations of four double bonds to yield polyspirocyclic products. Stereochemical features of polyspirocyclopropanated compounds have been thoroughly examined in experimental (NMR) and theoretical (DFT) studies. Comprehensive stereochemical assignment of TMCO adducts with dihalocarbenes and spiroepoxy products was achieved. The conditions of the formation of 1-methyl-3,7-bis(methylidene)bicyclo[3.3.1]nonane from the adamantane derivative were optimized, and diadducts of this diene with dihalocarbenes were isolated and characterized.