RESUMO
Indolizidine alkaloids such as anticancer drugs vinblastine and vincristine are exceptionally attractive due to their widespread occurrence, prominent bioactivity, complex structure, and sophisticated involvement in the chemical defense for the producing organisms. However, the versatility of the indolizidine alkaloid biosynthesis remains incompletely addressed since the knowledge about such biosynthetic machineries is only limited to several representatives. Herein, we describe the biosynthetic gene cluster (BGC) for the biosynthesis of curvulamine, a skeletally unprecedented antibacterial indolizidine alkaloid from Curvularia sp. IFB-Z10. The molecular architecture of curvulamine results from the functional collaboration of a highly reducing polyketide synthase (CuaA), a pyridoxal-5'-phosphate (PLP)-dependent aminotransferase (CuaB), an NADPH-dependent dehydrogenase (CuaC), and a FAD-dependent monooxygenase (CuaD), with its transportation and abundance regulated by a major facilitator superfamily permease (CuaE) and a Zn(II)Cys6 transcription factor (CuaF), respectively. In contrast to expectations, CuaB is bifunctional and capable of catalyzing the Claisen condensation to form a new C-C bond and the α-hydroxylation of the alanine moiety in exposure to dioxygen. Inspired and guided by the distinct function of CuaB, our genome mining effort discovers bipolamines A-I (bipolamine G is more antibacterial than curvulamine), which represent a collection of previously undescribed polyketide alkaloids from a silent BGC in Bipolaris maydis ATCC48331. The work provides insight into nature's arsenal for the indolizidine-coined skeletal formation and adds evidence in support of the functional versatility of PLP-dependent enzymes in fungi.
Assuntos
Alcaloides/biossíntese , Ascomicetos/enzimologia , Ascomicetos/metabolismo , Indolizidinas/metabolismo , Policetídeo Sintases/metabolismo , Fosfato de Piridoxal/metabolismo , Alcaloides/genética , Alcaloides/isolamento & purificação , Antibacterianos/metabolismo , Ascomicetos/genética , Aspergillus oryzae/genética , Aspergillus oryzae/metabolismo , Catálise , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Genes Fúngicos/genética , Hidroxilação , Alcaloides Indólicos , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Oxigenases de Função Mista/genética , Oxigenases de Função Mista/metabolismo , Família Multigênica , Filogenia , Policetídeo Sintases/classificação , Policetídeo Sintases/genética , Policetídeos , Fosfato de Piridoxal/genética , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Transaminases/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
Indolizidine alkaloids, which have versatile bioactivities, are produced by various organisms. Although the biosynthesis of some indolizidine alkaloids has been studied, the enzymatic machinery for their biosynthesis in Streptomyces remains elusive. Here, we report the identification and analysis of the biosynthetic gene cluster for iminimycin, an indolizidine alkaloid with a 6-5-3 tricyclic system containing an iminium cation from Streptomyces griseus. The gene cluster has 22 genes, including four genes encoding polyketide synthases (PKSs), which consist of eight modules in total. Inâ vitro analysis of the first module revealed that its acyltransferase domain selects malonyl-CoA, although predicted to select methylmalonyl-CoA. Inactivation of seven tailoring enzyme-encoding genes and structural elucidation of four compounds accumulated in mutants provided important insights into iminimycin biosynthesis, although some of these compounds appeared to be shunt products. This study expands our knowledge of the biosynthetic machinery of indolizidine alkaloids and the enzymatic chemistry of PKS.
Assuntos
Alcaloides/biossíntese , Família Multigênica , Streptomyces griseus/química , Streptomyces griseus/genética , Alcaloides/química , Indolizidinas/química , Conformação Molecular , Streptomyces griseus/metabolismoRESUMO
A Ni-catalyzed (4 + 2) cycloaddition of bicyclic 3-azetidinones and alkynes was developed to access indolizidine and quinolizidine alkaloids. A key element was the development of a diazomethylation procedure that allows the efficient synthesis of bicyclic azetidinones from pyroglutamic and 6-oxopiperidine-2-carboxylic acid. A ligand screening led to improved regioselectivity and enantiopurity during the Ni-catalyzed (4 + 2) cycloaddition. This straightforward methodology was leveraged to synthesize (+)-ipalbidine, (+)-septicine, (+)-seco-antofine, and (+)-7-methoxy-julandine.
Assuntos
Alcaloides , Indolizidinas , Quinolizidinas , Catálise , Reação de Cicloadição , NíquelRESUMO
Indolizidine alkaloids are chemical constituents isolated from various marine and terrestrial plants and animals, including but not limited to trees, fungi, ants, and frogs, with a myriad of important biological activities. In this review, we discuss the biological activity and pharmacological effects of indolizidine alkaloids and offer new avenues toward the discovery of new and better drugs based on these naturally occurring compounds.
Assuntos
Alcaloides , Indolizidinas , Alcaloides/farmacologia , Animais , Fungos , Indolizidinas/farmacologia , PlantasRESUMO
Structurally unprecedented antibacterial alkaloids containing multiple electron-rich pyrrole units have recently been isolated from Curvularia sp. and Bipolaris maydis fungi. This article documents the evolution of a synthetic program aimed at accessing the flagship metabolites curvulamine and curindolizine which are presumably a dimer and trimer of a C10N biosynthetic building block, respectively. Starting with curvulamine, we detail several strategies to merge two simple, bioinspired fragments, which while ultimately unsuccessful, led us toward a pyrroloazepinone building block-based strategy and an improved synthesis of this 10π-aromatic heterocycle. A two-step annulation process was then designed to forge a conserved tetracyclic bis-pyrrole architecture and advanced into a variety of late-stage intermediates; unfortunately, however, a failed decarboxylation thwarted the total synthesis of curvulamine. By tailoring our annulation precursors, success was ultimately found through the use of a cyanohydrin nucleophile which enabled a 10-step total synthesis of curvulamine. Attempts were then made to realize a biomimetic coupling of curvulamine with an additional C10N fragment to arrive at curindolizine, the most complex family member. Although unproductive, we developed a 14-step total synthesis of this alkaloid through an abiotic coupling approach. Throughout this work, effort was made to harness and exploit the innate reactivity of the pyrrole nucleus, an objective which has uncovered many interesting findings in the chemistry of this reactive heterocycle.
Assuntos
Alcaloides/síntese química , Alcaloides Indólicos/síntese química , Alcaloides/química , Azepinas/química , Bipolaris/química , Bipolaris/metabolismo , Cristalografia por Raios X , Curvularia/química , Curvularia/metabolismo , Ciclização , Alcaloides Indólicos/química , Indolizidinas/química , Conformação Molecular , Pirróis/química , EstereoisomerismoRESUMO
The Ir-catalyzed asymmetric hydrogenation of cyclic pyridinium salts is presented as a new strategy for the convenient and efficient synthesis of chiral indolizidines. The asymmetric hydrogenation of cyclic pyridinium salts derived from 2-(2-acylphenyl)pyridines proceeded smoothly in the presence of [Ir(cod)Cl]2 and (R)-DM-SegPhos to provide the desired chiral 7,8-benzoindolizidines 6 in high to excellent yields with moderate enantioselectivity (up to 86:14 er) and excellent diastereoselectivity (>20:1 dr). The enantiomeric purity of 6j was increased to 92:8 through recrystallization.
Assuntos
Indolizidinas , Sais , Catálise , Hidrogenação , EstereoisomerismoRESUMO
Smoking-cessation drugs bind many off-target nicotinic acetylcholine receptors (nAChRs) and cause severe side effects if they are based on nicotine. New drugs that bind only those receptors, such as α6ß2* nAChR, implicated in nicotine addiction would avoid the off-target binding. Indolizidine (-)-237D (IND (-)-237D), a bicyclic alkaloid, has been shown to block α6ß2* containing nAChRs and functionally inhibit the nicotine-evoked dopamine release. To improve the affinity of indolizidine (-)-237D for α6ß2*, we built a library of 2226 analogs. We screened virtually the library against a homology model of α6ß2 nAChR that we derived from the recent crystal structure of α4ß2 nAChR. We also screened the crystal structure of α4ß2 nAChR as a control on specificity. We ranked the compounds based on their predicted free energy of binding. We selected the top eight compounds bound in their best pose and subjected the complexes to 100 ns molecular dynamics simulations to assess the stability of the complexes. All eight analogs formed stable complexes for the duration of the simulations. The results from this work highlight nine distinct analogs of IND (-)-237D with high affinity towards α6ß2* nAChR. These leads can be synthesized and tested in in vitro and in vivo studies as lead candidates for drugs to treat nicotine addiction.
Assuntos
Descoberta de Drogas , Indolizidinas/química , Simulação de Dinâmica Molecular , Receptores Nicotínicos/química , Humanos , Antagonistas Nicotínicos/química , Ligação Proteica , Receptores Nicotínicos/metabolismo , Abandono do Hábito de FumarRESUMO
13a-(S)-3-pivaloyloxyl-6,7-dimethoxyphenanthro(9,10-b)-indolizidine (CAT3) is a novel oral anti-glioma pro-drug with a potent anti-tumor effect against temozolomide-resistant glioma. 13a(S)-3-hydroxyl-6,7-dimethoxyphenanthro(9,10-b)-indolizidine (PF403) is the active in vivo lipase degradation metabolite of CAT3. Both CAT3 and PF403 can penetrate the blood-brain barrier to cause an anti-glioma effect. However, PF403, which is produced in the gastrointestinal tract and plasma, causes significant gastrointestinal side effects, limiting the clinical application of CAT3. The objective of this paper was to propose a metabolism modification for CAT3 using a self-microemulsifying drug delivery system (SMEDDS), in order to reduce the generation of PF403 in the gastrointestinal tract and plasma, as well as increase the bioavailability of CAT3 in vivo and the amount of anti-tumor substances in the brain. Thus, a CAT3-loaded self-microemulsifying drug delivery system (CAT3-SMEDDS) was prepared, and its physicochemical characterization was systematically carried out. Next, the pharmacokinetic parameters of CAT3 and its metabolite in the rats' plasma and brain were measured. Furthermore, the in vivo anti-glioma effects and safety of CAT3-SMEDDS were evaluated. Finally, Caco-2 cell uptake, MDCK monolayer cellular transfer, and the intestinal lymphatic transport mechanisms of SMEDDS were investigated in vitro and in vivo. Results show that CAT3-SMEDDS was able to form nanoemulsion droplets in artificial gastrointestinal fluid within 1 min, displaying an ideal particle size (15-30 nm), positive charge (5-9 mV), and controlled release behavior. CAT3-SMEDDS increased the membrane permeability of CAT3 by 3.9-fold and promoted intestinal lymphatic transport. Hence, the bioavailability of CAT3 was increased 79% and the level of its metabolite, PF403, was decreased to 49%. Moreover, the concentrations of CAT3 and PF403 were increased 2-6-fold and 1.3-7.2-fold, respectively, in the brain. Therefore, the anti-glioma effect in the orthotopic models was improved with CAT3-SMEDDS compared with CAT3 in 21 days. Additionally, CAT3-SMEDDS reduced the gastrointestinal side effects of CAT3, such as severe diarrhea, necrosis, and edema, and observed less inflammatory cell infiltration in the gastrointestinal tract, compared with the bare CAT3. Our work reveals that, through the metabolism modification effect, SMEDDS can improve the bioavailability of CAT3 and reduce the generation of PF403 in the gastrointestinal tract and plasma. Therefore, it has the potential to increase the anti-glioma effect and reduce the gastrointestinal side effects of CAT3 simultaneously.
Assuntos
Antineoplásicos/farmacologia , Sistemas de Liberação de Medicamentos , Glioblastoma/tratamento farmacológico , Indolizidinas/farmacologia , Fenantrenos/farmacologia , Animais , Disponibilidade Biológica , Cães , Liberação Controlada de Fármacos , Emulsões , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Células Madin Darby de Rim Canino , Masculino , Camundongos , Camundongos Endogâmicos ICR , Ratos , Ratos Sprague-DawleyRESUMO
Herein we report the synthesis of substituted indolizidines and related N-fused bicycles from simple saturated cyclic amines through sequential C-H and C-C bond functionalizations. Inspired by the Norrish-Yang Type II reaction, C-H functionalization of azacycles is achieved by forming α-hydroxy-ß-lactams from precursor α-ketoamide derivatives under mild, visible light conditions. Selective cleavage of the distal C(sp2)-C(sp3) bond in α-hydroxy-ß-lactams using a Rh-complex leads to α-acyl intermediates which undergo sequential Rh-catalyzed decarbonylation, 1,4-addition to an electrophile, and aldol cyclization, to afford N-fused bicycles including indolizidines. Computational studies provide mechanistic insight into the observed positional selectivity of C-C cleavage, which depends strongly on the groups bound to Rh trans to the phosphine ligand.
Assuntos
Compostos Aza/química , Compostos Heterocíclicos/síntese química , Indolizidinas/síntese química , Ciclização , Compostos Heterocíclicos/química , Indolizidinas/química , Estrutura Molecular , EstereoisomerismoRESUMO
Many natural products that contain basic nitrogen atoms--for example alkaloids like morphine and quinine-have the potential to treat a broad range of human diseases. However, the presence of a nitrogen atom in a target molecule can complicate its chemical synthesis because of the basicity of nitrogen atoms and their susceptibility to oxidation. Obtaining such compounds by chemical synthesis can be further complicated by the presence of multiple nitrogen atoms, but it can be done by the selective introduction and removal of functional groups that mitigate basicity. Here we use such a strategy to complete the chemical syntheses of citrinalin B and cyclopiamine B. The chemical connections that have been realized as a result of these syntheses, in addition to the isolation of both 17-hydroxycitrinalin B and citrinalin C (which contains a bicyclo[2.2.2]diazaoctane structural unit) through carbon-13 feeding studies, support the existence of a common bicyclo[2.2.2]diazaoctane-containing biogenetic precursor to these compounds, as has been proposed previously.
Assuntos
Alcaloides/síntese química , Alcaloides/isolamento & purificação , Produtos Biológicos/síntese química , Alcaloides Indólicos/síntese química , Alcaloides Indólicos/isolamento & purificação , Indolizidinas/síntese química , Indolizidinas/isolamento & purificação , Alcaloides/biossíntese , Alcaloides/química , Produtos Biológicos/química , Técnicas de Química Sintética , Alcaloides Indólicos/química , Alcaloides Indólicos/metabolismo , Indolizidinas/química , Indolizidinas/metabolismo , Estrutura Molecular , Nitrogênio/química , Oxirredução , Oxigênio/metabolismo , EstereoisomerismoRESUMO
Two new indolizidine alkaloids, crepidatumines C (1) and D (2), together with crepidine (3), isocrepidamine (4), and crepidamine (5) were isolated from the Dendrobium crepidatum Lindl. ex Paxt. X-ray diffraction experiments established the absolute configurations of known compounds 3 and 4. The planar structures and relative configurations of new compounds 1 and 2 were elucidated by extensive spectra analysis including HR-ESI-MS, NMR (1H, 13C, 1H-1H COSY, HSQC, HMBC, and NOESY spectra), and the absolute configurations of 1 and 2 were suggested on the basis of possible biosynthetic pathways. The biological results confirmed that isocrepidamine (4) displayed a potent hypoglycemic effect in vitro without cytotoxicity.
Assuntos
Alcaloides/química , Alcaloides/farmacologia , Dendrobium/química , Indolizidinas/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Difração de Raios XRESUMO
Eight new cyclizidine-type alkaloids (1-8) and one known alkaloid (9) were identified from the chemical investigations of a marine-derived actinomycete, Streptomyces sp. HNA39. Among these alkaloids, compounds 3, 7, and 8 contain a chlorine atom, and the known alkaloid, (+)-ent-cyclizidine (9), is now first reported as a natural product. Their structures were elucidated by extensive NMR-spectroscopic analysis and HRESIMS data. The absolute configurations of all of the compounds were established by ECD calculations. Cytotoxicity evaluations of all of the compounds showed that compound 2 exhibited significant activity against the PC3 and HCT116 human-cancer-cell lines with IC50 values of 0.52 ± 0.03 and 8.3 ± 0.1 µM, respectively. Interestingly, compounds 2, 5, 7, and 8 exhibited moderate inhibition against the ROCK2 protein kinase with IC50 values from 7.0 ± 0.8 to 42 ± 3 µM.
Assuntos
Alcaloides/química , Indolizidinas/química , Streptomyces/química , Alcaloides/farmacologia , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Linhagem Celular Tumoral , Cloro/química , Cloro/farmacologia , Citotoxinas/química , Citotoxinas/farmacologia , Células HCT116 , Humanos , Indolizidinas/farmacologia , Espectroscopia de Ressonância Magnética/métodos , Células PC-3 , Quinases Associadas a rho/antagonistas & inibidoresRESUMO
In this study, 2,3-dihydro-1H-indolizinium alkaloid-prosopilosidine (PPD), that was isolated from Prosopis glandulosa, was evaluated against C. neoformans in a murine model of cryptococcosis. In vitro and in vivo toxicity of indolizidines were also evaluated. Mice were infected via the tail vein with live C. neoformans. Twenty-four hours post-infection, the mice were treated with PPD once a day (i.p.) or twice a day (bid) orally, or with amphotericin B (Amp B) intraperitoneally (IP), or with fluconazole (Flu) orally for 5 days. The brains of all of the animals were aseptically removed and the numbers of live C. neoformans were recovered. In vitro toxicity of indolizidine alkaloids was determined in HepG2 cells. PPD showed to be potent in vivo activity against C. neoformans at a dose of 0.0625 mg/kg by eliminating ~76% of the organisms compared to ~83% with Amp B (1.5 mg/kg). In addition, PPD was found to be equally efficacious, but less toxic, at either 0.125 or 0.0625 mg/kg compared to Amp B (1.5 mg/kg) when it was administered bid (twice a day) by an i.p. route. When tested by an oral route, PPD (10 mg/kg) showed potent activity in this murine model of cryptococcosis with ~82% of organisms eliminated from the brain tissue, whereas Flu (15 mg/kg) reduced ~90% of the infection. In vitro results suggest that quaternary indolizidines were less toxic as compared to those of tertiary bases. PPD (20 mg/kg) did not cause any alteration in the plasma chemistry profiles. These results indicated that PPD was active in eliminating cryptococcal infection by oral and i.p. routes at lower doses compared to Amp B. or Flu.
Assuntos
Criptococose/tratamento farmacológico , Criptococose/microbiologia , Cryptococcus neoformans/fisiologia , Indolizidinas/uso terapêutico , Prosopis/química , Administração Oral , Alcaloides/administração & dosagem , Alcaloides/química , Alcaloides/farmacologia , Alcaloides/uso terapêutico , Animais , Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/metabolismo , Peso Corporal/efeitos dos fármacos , Criptococose/sangue , Cryptococcus neoformans/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Células Hep G2 , Humanos , Indolizidinas/administração & dosagem , Indolizidinas/sangue , Indolizidinas/química , Camundongos , Resultado do TratamentoRESUMO
A facile and convergent approach has been developed for the stereoselective construction of biologically important polyhydroxylated 2-acyl indolizidine framework using aza-Cope rearrangement-Mannich cyclization as a key step. The generality of this methodology is demonstrated with various lactol-tosylates derived from carbohydrates. The presented method provides an easy access to indolizidine- and tetrahydroindolizine-based iminosugar derivatives in good yields.
Assuntos
Indolizidinas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Compostos Aza/química , Carboidratos/química , Cristalografia por Raios X , Ciclização , Indolizidinas/síntese química , Conformação Molecular , EstereoisomerismoRESUMO
A homo-chiral synthesis of (7R,8aS)-octahydro-5,5-dimethylindolizin-7-amine 8 and (7S, 8aS)-octahydro-5,5-dimethylindolizin-7-ol 9, amine building blocks which have found applications within the pharmaceutical industry, is presented. The approach uses a Novozym 435-mediated kinetic resolution of racemic octahydroindolizine (indolizidine) alcohol 13 as a key step (up to 100 g scale).
Assuntos
Álcoois/química , Indolizidinas/química , Indolizidinas/síntese química , Lipase/metabolismo , Biocatálise , Técnicas de Química Sintética , Enzimas Imobilizadas , Proteínas Fúngicas , Cinética , Modelos Moleculares , Conformação Molecular , EstereoisomerismoRESUMO
Samarium(II) iodide enables a wide range of highly chemoselective umpolung radical transformations proceeding by electron transfer to carbonyl groups; however, cyclizations of important nitrogen-containing precursors have proven limited due to their prohibitive redox potential. Herein, we report the first reductive cyclizations of unactivated cyclic imides onto N-tethered olefins using SmI2 /H2 O. This new umpolung protocol leads to the rapid synthesis of nitrogen-containing heterocycles that are of particular significance as precursors to pharmaceutical pharmacophores and numerous classes of alkaloids. The reaction conditions tolerate a wide range of functional groups. Excellent chemoselectivity is observed in the cyclization over amide and ester functional groups. Such unconventional reactivity has important implications for the design and optimization of new bond-forming reactions by umpolung radical processes. The reaction advances the SmI2 cyclization platform to the challenging unactivated N-tethered acyl-type radical precursors to access nitrogen-containing architectures.
Assuntos
Alcaloides/síntese química , Alcenos/química , Amidas/química , Indolizidinas/síntese química , Iodetos/química , Lactamas/síntese química , Nitrogênio/química , Samário/química , Água/química , Alcaloides/química , Ciclização , Transporte de Elétrons , Ésteres , Indolizidinas/química , Lactamas/química , Estrutura MolecularRESUMO
3,5-Dialkyl indolizidines have been prepared in four linear steps from commercially available starting materials. The sequence involves two direct α-functionalization steps and a subsequent reductive amination and provides diastereoselective access to both C-3 epimers of the 5,9-trans-substituted indolizines. The naturally occurring indolizidines 195B and 223AB have been synthesized using this methodology.
Assuntos
Alcaloides/síntese química , Indolizidinas/síntese química , Alcaloides/química , Indolizidinas/química , Estrutura MolecularRESUMO
A pair of racemic indolizidine enantiomers, (±)-homocrepidine A (1), and a piperidine derivative, homocrepidine B (2), were isolated from Dendrobium crepidatum along with the known alkaloid crepidine (3). The racemic mixture of 1 was separated into a pair of enantiomers, (+)-1 and (-)-1, by HPLC using a chiral chromatographic substrate, which represents the first successful example of resolving indolizidine racemic mixtures. The absolute configurations of (+)-1 and (-)-1 were assigned from single-crystal X-ray diffraction data. The evaluation of anti-inflammatory activity with LPS-induced RAW 264.7 macrophages revealed that (+)-1 strongly inhibited the production of nitric oxide (IC50, 3.6 µM) and significantly decreased the expression of inducible nitric oxide synthase, while (-)-1 and (±)-1 only had moderate inhibitory effects (IC50, 22.8 and 14.7 µM). Compound 2 showed moderate anti-inflammatory activity (IC50, 27.6 µM).
Assuntos
Alcaloides/isolamento & purificação , Alcaloides/farmacologia , Anti-Inflamatórios não Esteroides/isolamento & purificação , Anti-Inflamatórios não Esteroides/farmacologia , Dendrobium/química , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Indolizidinas/isolamento & purificação , Indolizidinas/farmacologia , Alcaloides/química , Animais , Anti-Inflamatórios não Esteroides/química , Cristalografia por Raios X , Medicamentos de Ervas Chinesas/isolamento & purificação , Indolizidinas/química , Concentração Inibidora 50 , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Camundongos , Conformação Molecular , Estrutura Molecular , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Piperidinas , Caules de Planta/química , EstereoisomerismoRESUMO
A highly adaptable method targeting the ubiquitous and very important pyrrolizidine and indolizidine scaffolds is presented. The general synthetic utility of the method is underscored by its application to the rapid and easy synthesis of five natural products starting from readily accessible alkylfuran precursors. These unprotected primary furylalkylamines are subjected to photooxygenation conditions, which initiate a complex cascade reaction sequence concluding with the production of high value motifs. This sequence can be tailored to need by varying the choice of both photosensitizer and base additive.
Assuntos
Aminas/química , Indolizidinas/química , Oxigênio/química , Processos Fotoquímicos , Alcaloides de Pirrolizidina/químicaRESUMO
The first detailed studies of intramolecular aza-Prins and aza-silyl-Prins reactions, starting from acyclic materials, are reported. The methods allow rapid and flexible access toward an array of [6,5] and [6,6] aza-bicycles, which form the core skeletons of various alkaloids. On the basis of our findings on the aza-Prins and aza-silyl-Prins cyclizations, herein we present simple protocols for the intramolecular preparation of the azabicyclic cores of the indolizidines and quinolizidines using a one-pot cascade process of N-acyliminium ion formation followed by aza-Prins cyclization and either elimination or carbocation trapping. It is possible to introduce a range of different substituents into the heterocycles through a judicial choice of Lewis acid and solvent(s), with halo-, phenyl-, and amido-substituted azabicyclic products all being accessed through these highly diastereoselective processes.