RESUMEN
This paper reports the halocyclization of alkynoic thioesters, as S-nucleophiles, with N-halosuccinimide, followed by oxidative aromatization with the same reagent for the one-pot synthesis of thiophenes, important heterocycles exhibiting remarkable applications in different disciplines. Brief mechanistic studies were also performed to elucidate the halocyclization process. The potential diverse applications of the product, dihydrothiophene, were also assessed.
RESUMEN
Using sulfur-containing nucleophiles in halocyclization has been underexplored notwithstanding their potential to generate novel S-heterocycles and despite the extensive exploration of oxygen, nitrogen, and carbon nucleophiles. In this study, we focused on the bromocyclization of alkenoic thioesters with N-bromoacetamide, which leads to the formation of cyclic bromosulfides. Investigation into the mechanistic pathways of these reactions revealed that the sulfur atom behaves as a nucleophile, leading to S-acetylsulfonium intermediates. HBr and Br2 played significant roles in these transformations.
RESUMEN
Although oxygen, nitrogen, and carbon have been extensively studied as nucleophilic elements in the halocyclization of alkenes, sulfur-based nucleophiles are relatively unexplored. Herein, we investigated bromocyclization chemistry involving unsaturated thioesters, with a focus on their use as potential S-nucleophiles. We developed a bromocyclization method that uses alkenoic thioesters and N-bromoacetamide (NBA) to form cyclic bromosulfides. The resulting 5-exo products are labile and can be used in various nucleophilic substitution reactions.
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Guided by the transition-metal hydrogen atom transfer and radical-polar crossover concepts, we developed a functional-group-tolerant and scalable method for the synthesis of cyclic carbamates and ureas, which are found in the structures of bioactive compounds. This method provides not only a common five-membered ring but also six-to-eight-membered ring products. The reaction proceeds through the intramolecular displacement of an alkylcobalt(IV) intermediate and dealkylation by 2,4,6-collidine; the activation energies of these steps were calculated by DFT.
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The catalytic enantioselective synthesis of tetrahydrofurans, which are found in the structures of many biologically active natural products, via a transition-metal-catalyzed hydrogen atom transfer (TM-HAT) and radical-polar crossover (RPC) mechanism is described herein. Hydroalkoxylation of nonconjugated alkenes proceeded efficiently with excellent enantioselectivity (up to 94% ee) using a suitable chiral cobalt catalyst, N-fluoro-2,4,6-collidinium tetrafluoroborate, and diethylsilane. Surprisingly, the absolute configuration of the product was highly dependent on the steric hindrance of the silane. Slow addition of the silane, the dioxygen effect on the solvent, thermal dependence, and DFT calculation results supported the unprecedented scenario of two competing selective mechanisms. For the less-hindered diethylsilane, a high concentration of diffused carbon-centered radicals invoked diastereoenrichment of an alkylcobalt(III) intermediate by a radical chain reaction, which eventually determined the absolute configuration of the product. On the other hand, a more hindered silane resulted in less opportunity for a radical chain reaction, instead facilitating enantioselective kinetic resolution during the late-stage nucleophilic displacement of the alkylcobalt(IV) intermediate.
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In this review, I tell the story of the cobalt chemistry that has been developed in my group since 2011. First, we achieved the total synthesis of polyketide natural product trichodermatide A, which involved a late-stage Isayama-Mukaiyama hydration of an enol ether using cobalt(II) acetylacetonate (Co(acac)2) that gave the desired product chemo-, regio-, and diastereoselectively. After our report of this total synthesis in 2013, we were required to revise the originally reported structure of trichodermatide A following the accurate and important report from the Trauner group. Second, we found unique cobalt-catalyzed hydroelementation reactions of olefins involving a cobalt-salen complex, N-fluoro-2,4,6-trimethylpyridinium salt, and a silane reagent. Under these reaction conditions, a carbocationic or carbon radical species is generated from an olefin, and then C-X (X=O, N, C, F) bond formation occurs with good functional group tolerance for a broad substrate scope. This review also covers recent examples of switching chemistry and natural product synthesis involving my cobalt chemistry reported by several groups.
Asunto(s)
Alquenos/química , Productos Biológicos/síntesis química , Cobalto/química , Complejos de Coordinación/química , Productos Biológicos/química , Catálisis , Estructura Molecular , EstereoisomerismoRESUMEN
A mild, general, scalable, and functional group tolerant intramolecular hydroarylation of unactivated olefins using a Co(salen) complex, a N-fluoropyridinium salt, and a disiloxane reagent was reported. This method, which was carried out at room temperature, afforded six-membered benzocyclic compounds from mono-, 1,1- or trans-1,2-di, and trisubstituted olefins.
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A mild, general, and functional group tolerant intramolecular hydroalkoxylation and hydroacyloxylation of unactivated olefins using a Co(salen) complex, an N-fluoropyridinium salt, and a disiloxane reagent is described. This reaction was carried out at room temperature and afforded five- and six-membered oxygen heterocyclic compounds, such as cyclic ethers and lactones. The Co complex was optimized for previously rare medium ring formation by hydrofunctionalization of unactivated olefins. The powerful Co catalyst system also enables the deprotective hydroalkoxylation of O-protected alkenyl alcohol and hydroacyloxylation of alkenyl ester to afford cyclic ethers and lactones directly. The substrate scope and mechanistic proof of deprotection were investigated. The experimental evidence supports the concerted transition state of the bond-forming step involving a cationic Co complex.
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We developed an addition reaction of fluorous solvents to olefins using salen-cobalt (Co) complex, N-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate, and 1,1,3,3-tetramethyldisiloxane. This reaction condition was found to activate olefins, which enabled them to be attacked by 2,2,2-trifluoroethanol (TFE) and 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP), both of which are electronically weak nucleophiles.
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Alquenos/química , Cobalto/química , Flúor/química , Solventes/química , Catálisis , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Espectrofotometría InfrarrojaRESUMEN
Functional group tolerance is one of the important requirements for chemical reactions, especially for the synthesis of complex molecules. Herein, we report a mild, general, and functional group tolerant intramolecular hydroamination of unactivated olefins using a Co(salen) complex, an N-fluoropyridinium salt, and a disiloxane reagent. This method, which was carried out at room temperature (or 0 °C), afforded three-, five-, six-, and seven-membered ring nitrogen-containing heterocyclic compounds and was compatible with diverse functional groups.
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Alquenos/química , Aminas/síntesis química , Cobalto/química , Compuestos Heterocíclicos/química , Compuestos Organometálicos/química , Aminación , Aminas/química , Catálisis , Estructura MolecularRESUMEN
Catalytic hydrofluorination of olefins using a cobalt catalyst was developed. The exclusive Markovnikov selectivity, functional group tolerance, and scalability of this reaction make it an attractive protocol for the hydrofluorination of olefins. A preliminary mechanistic experiment showed the involvement of a radical intermediate.
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Alquenos/química , Cobalto/química , Flúor/química , Hidrocarburos Fluorados/síntesis química , Compuestos Organometálicos/química , Catálisis , Radicales Libres/química , Hidrocarburos Fluorados/química , Estructura MolecularRESUMEN
A unique Markovnikov hydroalkoxylation of unactivated olefins with a cobalt complex, silane, and N-fluoropyridinium salt is reported. Further optimization of reaction conditions yielded high functional group tolerance and versatility of alcoholic solvent employed, including methanol, i-propanol, and t-butanol. Use of trifluorotoluene as a solvent made the use of alcohol in stoichiometric amount possible. Mechanistic insight into this novel catalytic system is also discussed. Experimental results suggest that catalysis involves both carbon radical and carbocation intermediates.
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Alcoholes/síntesis química , Alquenos/química , Carbono/química , Alcoholes/química , Catálisis , Cobalto/química , Radicales Libres/química , Estructura Molecular , Compuestos Organometálicos/química , Compuestos de Piridinio/química , Silanos/químicaRESUMEN
Full details are provided for an improved synthesis of cortistatin A and related structures as well as the underlying logic and evolution of strategy. The highly functionalized cortistatin A-ring embedded with a key heteroadamantane was synthesized by a simple and scalable five-step sequence. A chemoselective, tandem geminal dihalogenation of an unactivated methyl group, a reductive fragmentation/trapping/elimination of a bromocyclopropane, and a facile chemoselective etherification reaction afforded the cortistatin A core, dubbed "cortistatinone". A selective Δ(16)-alkene reduction with Raney Ni provided cortistatin A. With this scalable and practical route, copious quantities of cortistatinone, Δ(16)-cortistatin A (the equipotent direct precursor to cortistatin A), and its related analogues were prepared for further biological studies.
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Compuestos Policíclicos/síntesis química , Células Cultivadas , Humanos , Compuestos Policíclicos/químicaRESUMEN
One stereocenter makes all the difference: The synthesis and biological evaluation of 17-epi-cortistatin A is reported from a common intermediate used to procure natural cortistatin A. The synthesis features a unique stereocontrolled Raney-Ni reduction process that can be employed to reliably produce both alpha- and beta-configured D-ring aryl steroids. Biological evaluations of these "cortalogs" are reported for the first time.
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Inhibidores de la Angiogénesis/química , Isoquinolinas/química , Isoquinolinas/síntesis química , Compuestos Policíclicos/química , Compuestos Policíclicos/síntesis química , Esteroides/química , Inhibidores de la Angiogénesis/síntesis química , Inhibidores de la Angiogénesis/farmacología , Línea Celular , Humanos , Isoquinolinas/farmacología , Compuestos Policíclicos/farmacología , Estereoisomerismo , Esteroides/síntesis química , Esteroides/farmacología , Relación Estructura-ActividadRESUMEN
Optically pure N-Boc-norpandamarilactonine-B was diastereoselectively synthesized starting from L-serine by employing a double ring closing metathesis (RCM) of a tetraene derivative as a key reaction. N-Boc-norpandamarilactonine-B obtained was further converted to pandamarilactonine-A.
Asunto(s)
Alcaloides de Amaryllidaceae/síntesis química , Lactonas/síntesis química , Pandanaceae/química , Pirrolidinas/síntesis química , Indicadores y Reactivos , Espectroscopía de Resonancia Magnética , Conformación Molecular , Espectrofotometría Infrarroja , EstereoisomerismoRESUMEN
[reaction: see text] A novel synthetic path to proaporphine alkaloids was established by employing aromatic oxidation with a hypervalent iodine reagent, where an unprecedented carbon-carbon bond forming reaction between the para-position of a phenol group and an enamide-carbon took place smoothly to give the desired spiro-cyclohexadienone.