RESUMO
A novel series of benzo[6,7]indolo[3,4-c]isoquinolines 3a-3f was designed by scaffold hopping of topoisomerase I inhibitor benzo[g][1]benzopyrano[4,3-b]indol-6(13H)-ones (BBPIs), which were developed by structural modification of the natural marine product lamellarin. The unconventional pentacycle was constructed by Bischler-Napieralski-type condensation of amide 11 and subsequent intramolecular Heck reaction. In vitro anticancer activity of the synthesized benzo[6,7]indolo[3,4-c]isoquinolines was evaluated on a panel of 39 human cancer cell lines (JFCR39). Among the compounds tested, N-(3-morpholinopropyl) derivative 3e showed the most potent antiproliferative activity, with a mean GI50 value of 39 nM. This compound inhibited topoisomerase I activity by stabilizing the enzyme-DNA complex.
Assuntos
Antineoplásicos , Cumarínicos , Compostos Heterocíclicos de 4 ou mais Anéis , Isoquinolinas , Inibidores da Topoisomerase I , Humanos , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , DNA Topoisomerases Tipo I/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Isoquinolinas/síntese química , Isoquinolinas/química , Isoquinolinas/farmacologia , Relação Estrutura-Atividade , Inibidores da Topoisomerase I/síntese química , Inibidores da Topoisomerase I/química , Inibidores da Topoisomerase I/farmacologia , Desenho de Fármacos , Cumarínicos/síntese química , Cumarínicos/química , Cumarínicos/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/química , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologiaRESUMO
This short review aims at highlighting recent design strategies hinged on using seven-membered rings. Analyses of the different selected examples coupled with torsion profiles derived from the CCDC suggest some of these strategies could have broad applications.
Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/química , Estrutura MolecularRESUMO
A series of histamine (HST)-related compounds were synthesized and tested for their activating properties on five physiologically relevant human Carbonic Anhydrase (hCA) isoforms (I, II, Va, VII and XIII). The imidazole ring of HST was replaced with different 5-membered heterocycles and the length of the aliphatic chain was varied. For the most interesting compounds some modifications on the terminal amino group were also performed. The most sensitive isoform to activation was hCA I (KA values in the low micromolar range), but surprisingly none of the new compounds displayed activity on hCA II. Some derivatives (1, 3a and 22) displayed an interesting selectivity for activating hCA I over hCA II, Va, VII and XIII.
Assuntos
Anidrase Carbônica I/metabolismo , Compostos Heterocíclicos de 4 ou mais Anéis/química , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Histamina/química , Histamina/farmacologia , Anidrase Carbônica I/efeitos dos fármacos , Anidrase Carbônica II/efeitos dos fármacos , Anidrase Carbônica II/metabolismo , Anidrase Carbônica V/efeitos dos fármacos , Anidrase Carbônica V/metabolismo , Anidrases Carbônicas/efeitos dos fármacos , Anidrases Carbônicas/metabolismo , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Histamina/análogos & derivados , Histamina/síntese química , Humanos , Imidazóis/química , Isoformas de Proteínas/efeitos dos fármacos , Isoformas de Proteínas/metabolismoRESUMO
The design of novel nucleoside triphosphate (NTP) analogues bearing an all-carbon quaternary center at C2' or C3' is described. The construction of this all-carbon stereogenic center involves the use of an intramoleculer photoredox-catalyzed reaction. The nucleoside analogues (NA) hydroxyl functional group at C2' was generated by diastereoselective epoxidation. In addition, highly enantioselective and diastereoselective Mukaiyama aldol reactions, diastereoselective N-glycosylations and regioselective triphosphorylation reactions were employed to synthesize the novel NTPs. Two of these compounds are inhibitors of the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2, the causal virus of COVID-19.
Assuntos
Antivirais/farmacologia , Carbono/química , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Nucleotídeos/farmacologia , RNA Polimerase Dependente de RNA/antagonistas & inibidores , SARS-CoV-2/enzimologia , Antivirais/síntese química , Antivirais/química , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/química , Nucleotídeos/síntese química , Nucleotídeos/química , SARS-CoV-2/efeitos dos fármacos , EstereoisomerismoRESUMO
Although computational simulation-based natural product syntheses are in their initial stages of development, this concept can potentially become an indispensable resource in the field of organic synthesis. Herein we report the asymmetric total syntheses of several resveratrol dimers based on a comprehensive computational simulation of their biosynthetic pathways. Density functional theory (DFT) calculations suggested inconsistencies in the biosynthesis of vaticahainol A and B that predicted the requirement of structural corrections of these natural products. According to the computational predictions, total syntheses were examined and the correct structures of vaticahainol A and B were confirmed. The established synthetic route was applied to the asymmetric total synthesis of (-)-malibatol A, (-)-vaticahainol B, (+)-vaticahainol A, (+)-vaticahainol C, and (-)-albiraminol B, which provided new insight into the biosynthetic pathway of resveratrol dimers. This study demonstrated that computation-guided organic synthesis can be a powerful strategy to advance the chemical research of natural products.
Assuntos
Produtos Biológicos/química , Desenho de Fármacos/métodos , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Resveratrol/síntese química , Estilbenos/síntese química , Técnicas de Química Sintética , Teoria da Densidade Funcional , Dimerização , Humanos , Resveratrol/análogos & derivados , EstereoisomerismoRESUMO
The bioactive natural product perophoramidine has proved a challenging synthetic target. An alternative route to its indolo[2,3-b]quinolone core structure involving a N-chlorosuccinimde-mediated intramolecular cyclization reaction is reported. Attempts to progress towards the natural product are also discussed with an unexpected deep-seated rearrangement of the core structure occurring during an attempted iodoetherification reaction. X-ray crystallographic analysis provides important analytical confirmation of assigned structures.
Assuntos
Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Hidrocarbonetos Halogenados/síntese química , Quinolinas/síntese química , Produtos Biológicos/química , Cristalografia por Raios X , Ciclização , Estrutura Molecular , EstereoisomerismoRESUMO
Rational manipulation of nonradiative decay channels is of crucial significance to improve photothermal conversion efficiency (PCE) and design photothermal agents. We first used the "internal and external combined" nonradiative decay strategy to enhance PCE. Specifically, organic IR-Y6 NPs with strong NIR absorption and high molar extinction coefficient were prepared and characterized. By means of TD-DFT calculations and fs-TA spectroscopy, the dual nonradiative decay channels composed of the free rotor (external strategy) and ultrafast dark excited states (DESs) between S0 and S1 states (internal strategy) were proved, which significantly enhanced PCE, up to 66%. IR-Y6 NPs were applied to a mice tumor model for photoacoustic image-guided photothermal therapy, showing complete tumor ablation ability and good biocompatibility for the normal organs. This work is of significance to deeply understand the nonradiation decay mechanism and rational design of high-performance PTT agents.
Assuntos
Antineoplásicos/uso terapêutico , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Indanos/uso terapêutico , Nanopartículas/uso terapêutico , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/síntese química , Antineoplásicos/efeitos da radiação , Linhagem Celular Tumoral , Terapia Combinada , Teoria da Densidade Funcional , Feminino , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/efeitos da radiação , Humanos , Indanos/síntese química , Indanos/efeitos da radiação , Raios Infravermelhos , Camundongos Endogâmicos BALB C , Modelos Químicos , Nanopartículas/química , Nanopartículas/efeitos da radiação , Técnicas Fotoacústicas , Terapia Fototérmica , Nanomedicina Teranóstica/métodosRESUMO
A new reaction mode of palladium/norbornene (Pd/NBE) cooperative catalysis is reported involving the selective coupling of two different carbon-based electrophiles for vicinal double C-H functionalization of five-membered heteroarenes in a site-selective and redox-neutral manner. The key is to use alkynyl bromides as the second electrophile, which allows vicinal difunctionalization of a wide range of heteroarenes including pyrroles, thiophenes and furans at their C4 and C5 positions. One- or two-step tetrafunctionalizations of simple pyrrole and thiophene have also been realized. The C2-substituted NBEs prove most effective in these reactions, and the mechanistic exploration discloses the origin of the high selectivity of this transformation. Synthetic utility of this method has been exemplified in the concise preparations of thiophene-containing organic materials and a protein kinase inhibitor analogue. Preliminary success has also been achieved in a direct annulation event, using a tethered ketone as the second electrophile.
Assuntos
Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Tiofenos/síntese química , Catálise , Compostos Heterocíclicos de 4 ou mais Anéis/química , Estrutura Molecular , Norbornanos/química , Oxirredução , Paládio/química , Tiofenos/químicaRESUMO
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease, and its incidence rate is rapidly rising. However, effective therapies for the treatment of IPF are still lacking. Phosphodiesterase 4 (PDE4) inhibitors were reported to be potential anti-fibrotic agents, but their clinical use was hampered by side effects like emesis and nausea. Herein, structure-based hit-to-lead optimizations of natural mangostanin resulted in the novel and orally active PDE4 inhibitor 18a with potent inhibitory affinity (IC50 = 4.2 nM), favorable physico-chemical properties, and a different binding pattern from roflumilast. Emetic activity tests on dogs demonstrated that 18a cannot cause emesis even at an oral dose of 10 mg/kg, whereas rolipram had severe emetic effects at an oral dose of 1 mg/kg. Finally, the oral administration of 18a (10 mg/kg) exhibited comparable anti-pulmonary fibrosis effects with pirfenidone (150 mg/kg) in a bleomycin-induced IPF rat model, indicating its potential as a novel anti-IPF agent with improved safety.
Assuntos
Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Fibrose Pulmonar Idiopática/tratamento farmacológico , Inibidores da Fosfodiesterase 4/uso terapêutico , Células A549 , Animais , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Cães , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/metabolismo , Humanos , Fibrose Pulmonar Idiopática/patologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Masculino , Estrutura Molecular , Inibidores da Fosfodiesterase 4/síntese química , Inibidores da Fosfodiesterase 4/metabolismo , Ligação Proteica , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
Starting from six potential hits identified in a virtual screening campaign directed to a cryptic pocket of BACE-1, at the edge of the catalytic cleft, we have synthesized and evaluated six hybrid compounds, designed to simultaneously reach BACE-1 secondary and catalytic sites and to exert additional activities of interest for Alzheimer's disease (AD). We have identified a lead compound with potent in vitro activity towards human BACE-1 and cholinesterases, moderate Aß42 and tau antiaggregating activity, and brain permeability, which is nontoxic in neuronal cells and zebrafish embryos at concentrations above those required for the in vitro activities. This compound completely restored short- and long-term memory in a mouse model of AD (SAMP8) relative to healthy control strain SAMR1, shifted APP processing towards the non-amyloidogenic pathway, reduced tau phosphorylation, and increased the levels of synaptic proteins PSD95 and synaptophysin, thereby emerging as a promising disease-modifying, cognition-enhancing anti-AD lead.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Aminoquinolinas/farmacologia , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Fármacos Neuroprotetores/farmacologia , Doença de Alzheimer/metabolismo , Aminoquinolinas/síntese química , Aminoquinolinas/química , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Encéfalo/metabolismo , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/química , Humanos , Simulação de Dinâmica Molecular , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade , Proteínas tau/antagonistas & inibidores , Proteínas tau/metabolismoRESUMO
The divergent total synthesis strategy can be successfully applied to the preparation of families of natural products using a common late-stage pluripotent intermediate. This approach is a powerful tool in organic synthesis as it offers opportunities for the efficient preparation of structurally related compounds. This article reviews the synthesis of the marine natural product aureol, as well as its use as a common intermediate in the divergent synthesis of other marine natural and non-natural tetracyclic meroterpenoids.
Assuntos
Organismos Aquáticos/química , Produtos Biológicos/química , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Sesquiterpenos/síntese química , Terpenos/síntese química , Animais , Produtos Biológicos/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/química , Sesquiterpenos/química , Terpenos/químicaRESUMO
The sesquiterpene-tropolones belong to a distinctive structural class of meroterpene natural products with impressive biological activities, including anticancer, antifungal, antimalarial, and antibacterial. In this article, we describe a concise, modular, and cycloaddition-based approach to a series of sesquiterpene mono- and bistropolones, including (-)-epolone B, (+)-isoepolone B, (±)-dehydroxypycnidione, and (-)-10-epi-pycnidione. Alongside the development of a general strategy to access this unique family of metabolites were computational modeling studies that justified the diastereoselectivity observed during key cycloadditions. Ultimately, these studies prompted stereochemical reassignments of the pycnidione subclass and shed additional light on the biosynthesis of these remarkable natural products.
Assuntos
Sesquiterpenos/química , Tropolona/química , Produtos Biológicos/síntese química , Produtos Biológicos/química , Reação de Cicloadição , Teoria da Densidade Funcional , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/química , Conformação Molecular , Sesquiterpenos Monocíclicos/síntese química , Sesquiterpenos Monocíclicos/química , Sesquiterpenos/síntese química , Estereoisomerismo , Tropolona/análogos & derivados , Tropolona/síntese químicaRESUMO
Covering: 2010 to 2020Benzocycloheptane is a fundamental and unique structural motif found in pharmaceuticals and natural products. The total syntheses of natural products bearing the benzocycloheptane subunit are challenging and there are only a few efficient approaches to access benzocycloheptane. Thus, new methods and innovative strategies for preparing such natural products need to be developed. In this review, recent progress in the total syntheses of natural products bearing the benzocycloheptane motif is presented, and key transformations for the construction of benzocycloheptane are highlighted. This review provides a useful guide for those engaged in the syntheses of natural products containing the benzocycloheptane motif.
Assuntos
Benzocicloeptenos/síntese química , Produtos Biológicos/síntese química , Reação de Cicloadição , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Hidrocarbonetos Policíclicos Aromáticos/síntese química , Estilbenos/síntese químicaRESUMO
Nitrogen heterocycles (azacycles) are common structural motifs in numerous pharmaceuticals, agrochemicals, and natural products. Many powerful methods have been developed and continue to be advanced for the selective installation and modification of nitrogen heterocycles through C-H functionalization and C-C cleavage approaches, revealing new strategies for the synthesis of targets containing these structural entities. Here, we report the first total syntheses of the lycodine-type Lycopodium alkaloids casuarinine H, lycoplatyrine B, lycoplatyrine A, and lycopladine F as well as the total synthesis of 8,15-dihydrohuperzine A through bioinspired late-stage diversification of a readily accessible common precursor, N-desmethyl-ß-obscurine. Key steps in the syntheses include oxidative C-C bond cleavage of a piperidine ring in the core structure of the obscurine intermediate and site-selective C-H borylation of a pyridine nucleus to enable cross-coupling reactions.
Assuntos
Alcaloides/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Alcaloides/química , Compostos Heterocíclicos de 4 ou mais Anéis/química , Lycopodium/química , Estrutura Molecular , EstereoisomerismoRESUMO
Lamellarin D, a marine natural product, acts as a potent inhibitor of DNA topoisomerase I (Topo I). To modify its physicochemical property and biological activity, a series of mono- and di-glycosylated derivatives were designed and synthesized through 22-26 multi-steps. Their inhibition of human Topo I was evaluated, and most of the glycosylated derivatives exhibited high potency in inhibiting Topo I activity as well as lamellarin D. All the 15 target compounds were evaluated for their cytotoxic activities against five human cancer cell lines. The typical lamellarin derivative ZL-3 exhibited the best activity with IC50 values of 3 nM, 10 nM, and 15 nM against human lung cancer A549 cells, human colon cancer HCT116 cells and human hepatocellular carcinoma HepG2 cells. Compound ZL-1 exhibited anti-cancer activity with IC50 of 14 nM and 24 nM against human colon cancer HCT116 cells and human hepatocellular carcinoma HepG2 cells, respectively. Cell cycle analysis in MDA-MB-231 suggested ZL-3 inhibited cell growth through arresting cells at the G2/M phase of the cell cycle. Further tests showed a significant improvement in aqueous solubility of ZL-1 and ZL-7. This study suggested that glycosylation could be utilized as a useful strategy to optimize lamellarin D derivatives as Topo I inhibitors and anticancer agents.
Assuntos
Antineoplásicos/farmacologia , Produtos Biológicos/farmacologia , Cumarínicos/farmacologia , Desenho de Fármacos , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Isoquinolinas/farmacologia , Inibidores da Topoisomerase I/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Produtos Biológicos/síntese química , Produtos Biológicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cumarínicos/síntese química , Cumarínicos/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Glicosilação , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/química , Humanos , Isoquinolinas/síntese química , Isoquinolinas/química , Estrutura Molecular , Relação Estrutura-Atividade , Inibidores da Topoisomerase I/síntese química , Inibidores da Topoisomerase I/química , Células Tumorais CultivadasRESUMO
Azalamellarin N, a synthetic lactam congener of the marine natural product lamellarin N, and its A-ring-modified analogues were synthesized and evaluated as potent and non-covalent inhibitors of the drug-resistant epidermal growth factor receptor T790M/L858R mutant. An in vitro tyrosine kinase assay indicated that the inhibitory activities of the synthetic azalamellarin analogues were higher than those of the corresponding lamellarins. The azalamellarin analogue bearing two 3-(dimethylamino)propoxy groups at C20- and C21-positions exhibited the highest activity and selectivity against the mutant kinase [IC50 (T790M/L858R) = 1.7 nM; IC50 (WT) = 4.6 nM]. The inhibitory activity was attributed to the hydrogen bonding interaction between the lactam NH group of the B-ring and carbonyl group of a methionine residue.
Assuntos
Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Afatinib/farmacologia , Linhagem Celular Tumoral , Gefitinibe/farmacologia , Humanos , Modelos Moleculares , Estrutura Molecular , Mutação , Conformação ProteicaRESUMO
Alzheimer's disease (AD) is one of the most common types of dementia, especially in elderly, with an increasing number of people suffering from this disease worldwide. There are no available disease-modifying therapies and only four drugs are approved for the relief of symptoms. Currently, the therapeutic approach used for AD treatment is based on single target drugs, which are not capable to stop its progression. To address this issue, multi-target compounds, combining two or more pharmacophores in a single molecular entity, have gained increasing interest to deal with the multiple factors related to AD. The exact cause of AD is not yet completely disclosed, and several hallmarks have been associated to this neurodegenerative disease. Even though, the accumulation of both amyloid-ß plaques (Aß) and neurofibrillary tangles (NFTs) are fully accepted as the main AD hallmarks, being object of lots of research for early-stage diagnosis and pharmacological therapy. In this context, this review summarizes the state-of-the-art in the field of dual-target inhibitors of both Aß and tau aggregation simultaneously, including the design and synthetic strategy of the dual-target compounds, as well as a brief structure-activity relationships (SAR) analysis.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Aminoquinolinas/farmacologia , Peptídeos beta-Amiloides/antagonistas & inibidores , Curcumina/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Tacrina/farmacologia , Proteínas tau/antagonistas & inibidores , Doença de Alzheimer/metabolismo , Aminoquinolinas/síntese química , Aminoquinolinas/química , Peptídeos beta-Amiloides/metabolismo , Curcumina/síntese química , Curcumina/química , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/química , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Tacrina/síntese química , Tacrina/química , Proteínas tau/metabolismoRESUMO
Polycyclic natural products are an inexhaustible source of medicinal agents, and their complex molecular architecture renders challenging synthetic targets where innovative and effective approaches for their rapid construction are urgently required. The total synthesis of polycyclic natural products has witnessed exponential progression along with the emergence of new synthetic strategies and concepts, such as sequential C-H functionalizations, radical-based transformations, and functional group pairing strategies. Our group exerts continued interest in the construction of bioactive and structurally complex natural products as well as evaluation of the mode of action of these molecules. In this Account, we will showcase how these new synthetic strategies are employed and guide our total synthesis endeavors.During the last two decades, a series of remarkable advances in C-H functionalization have led to the emergence of many new approaches to directly functionalize C-H bonds into useful functional groups. These selective transformations have provided a great opportunity for the step- and atom-economical construction of key fragments in complex molecule synthesis. We recently furnished the total syntheses for polycyclic natural products: incarviatone A, chrysomycin A, polycarcin V, and gilvocarcin V by employing a multiple C-H bond functionalization strategy. The polysubstituted benzene or naphthalene skeleton was constructed through sequential and site-selective C-H functionalizations from readily available simple starting materials, which reduced the number of steps and streamlined synthesis.Recently, we have also completed the total syntheses for a number of skeletally diverse tetracyclic Isodon diterpenoids inspired by their biogenesis and radical-based retrosynthetic disconnections. Radical transformations are strategically and tactically utilized in our syntheses, and radical-based reactions, including organo-SOMO catalysis, Birch reduction, regioselective 1,6-dienyne reductive cyclization, visible-light-mediated Schenck ene reaction, and photoradical-mediated late-stage skeletal rearrangement, play significant roles in our synthetic endeavors. Protecting-group-free and scalable syntheses are also built into our work to achieve the "ideal" synthesis. Furthermore, our synthetic work reveals that late-stage skeletal rearrangement through a photo radical process is possible in a biological setting in complement with nature's carbocation chemistry in complex natural product biosynthesis.Lycopodium alkaloids are a large family of structurally unique polycyclic natural products with impressive biological activities. Owing to their fascinating polycyclic architectures and diverse biological activities, these alkaloids have continued to serve as targets as well as inspirations for the synthetic community for decades. To access these bioactive natural products or natural product-like molecules for biological exploration and drug discovery, we applied a novel functional group pairing strategy to furnish the total syntheses for several Lycopodium alkaloids and obtained numerous skeletally diverse compounds with structural complexity comparable to natural products.
Assuntos
Produtos Biológicos/síntese química , Alcaloides/síntese química , Alcaloides/química , Aminoglicosídeos/síntese química , Aminoglicosídeos/química , Produtos Biológicos/química , Carbono/química , Catálise , Ciclização , Diterpenos/síntese química , Diterpenos/química , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/química , Hidrogênio/química , Luz , Oxirredução , EstereoisomerismoRESUMO
The powerful insecticidal and multi-drug-resistance-reversing activities displayed by the stemofoline group of alkaloids render them promising lead structures for further development as commercial agents in agriculture and medicine. However, concise, enantioselective total syntheses of stemofoline alkaloids remain a formidable challenge due to their structural complexity. We disclose herein the enantioselective total syntheses of four stemofoline alkaloids, including (+)-stemofoline, (+)-isostemofoline, (+)-stemoburkilline, and (+)-(11S,12R)-dihydrostemofoline, in just 19 steps. Our strategy relies on a biogenetic hypothesis, which postulates that stemoburkilline and dihydrostemofolines are biogenetic precursors of stemofoline and isostemofoline. Other highlights of our approach are the use of Horner-Wadsworth-Emmons reaction to connect the two segments of the molecule, an improved protocol allowing gram-scale access to the tetracyclic cage-type core, and a Cu-catalyzed direct and versatile nucleophilic alkylation reaction on an anti-Bredt iminium ion. The synthetic techniques that we developed could also be extended to the preparation of other Stemona alkaloids.
Assuntos
Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Inseticidas/síntese química , Stemonaceae/química , Alcaloides/síntese química , Alcaloides/química , Compostos Heterocíclicos de 4 ou mais Anéis/química , Inseticidas/química , Estrutura Molecular , Extratos Vegetais/síntese química , Extratos Vegetais/química , EstereoisomerismoRESUMO
The rearrangement of carbon-carbon (C-C) single bonds in readily available carbocyclic scaffolds can yield uniquely substituted carbocycles that would be challenging to construct otherwise. This is a powerful and often non-intuitive approach for complex molecule synthesis. The transition-metal-mediated cleavage of C-C bonds has the potential to broaden the scope of this type of skeletal remodeling by providing orthogonal selectivities compared to more traditional pericyclic and carbocation-based rearrangements. To highlight this emerging technology, a unified, asymmetric, total synthesis of the phomactin terpenoids was developed, enabled by the selective C-C bond cleavage of hydroxylated pinene derivatives obtained from carvone. In this full account, the challenges, solutions, and intricacies of Rh(I)-catalyzed cyclobutanol C-C cleavage in a complex molecule setting are described. In addition, details of the evolution of strategies that ultimately led to the total synthesis of phomactins A, K, P, R, and T, as well as the synthesis and structural reassignment of Sch 49027, are given.