RESUMO
A concise asymmetric total synthesis of (-)-quinocarcin has been accomplished with high step economy from commercially available starting materials. A catalytic enantioselective reductive 1,3-dipolar cycloaddition reaction of N-heteroaryl secondary amides with reactive dipolarophiles using iridium/copper relay catalysis was developed to prepare the key chiral pyrrolidine intermediate with three stereocenters. This protocol features excellent regio-, exo- and enantioselectivities, broad substrate scope, and good functional group tolerance. The high efficiency was also ensured by a RhIII -catalyzed C-H activation/cyclization and a tandem diastereoselective hydrogenation/cyclization to construct the tetrahydroisoquinoline-pyrrolidine tetracyclic core unit of quinocarcin.
Assuntos
Amidas , Pirrolidinas , Reação de Cicloadição , Estereoisomerismo , CatáliseRESUMO
A versatile synthesis of α-amino bisphosphonates has been achieved through one-pot interrupted Ritter-type reaction under mild conditions. The reactive Ritter intermediate nitrilium is in situ generated by treatment of nitrile with readily accessible Tf2O/HC(OR1)3, which is trapped by phosphite ester to deliver the desired product. This protocol is efficient, scalable, and well compatible with a broad scope of substrates. In addition, plentiful characteristic JP-C couplings including unusual five-bond long-range 5JP-C and 3JP-C across quaternary carbon and hetero (N) atoms were observed in 13C NMR spectra.
Assuntos
Difosfonatos , Nitrilas , Carbono/química , Nitrilas/químicaRESUMO
The first organocatalytic asymmetric synthesis of an advanced intermediate of (+)-sarain A was achieved. This approach featured the employment of an organocatalytic asymmetric Michael addition reaction and a nitrogen-to-carbon chirality transfer to forge three chiral centers, as well as a catalytic hydrosilylation for the chemoselective reduction of a key lactam intermediate. The tricyclic intermediate contained all the required functionalities for elaborating into (+)-sarain A.
RESUMO
In this paper, we document the construction of functionalized and fused eight-membered carbocycles by the triflic anhydride-mediated cyclization of 7-enamides. Taking advantage of the high electrophilicity of the nitrilium ion intermediates, generated in situ from secondary N-(2,6-dimethyl)anilides, the nonactivated, trisubstituted alkene-nitrilium cyclization reactions proceeded smoothly to afford nonconjugated ß,γ-enimines (for fused 6/6/8 ring systems), conjugated α,ß-enimines (for 6/5/8), or fused 5/8 ring systems in good yields. When the cyclization reactions were followed by one-pot acidic hydrolysis, the reaction led directly to the corresponding α,ß-enones. For some substrates, the reaction afford an efficient access to pendent cyclic ß,γ-enimines/enones.
Assuntos
Alcenos , CiclizaçãoRESUMO
We report a two-step approach to bicyclic and monocyclic 5-(1-alkoxyalkylidene)tetronates starting from lactones/esters. The method features the use of thionolactones and thionoesters as activated forms of lactones/esters that allows the direct condensation with tetronates via one-pot enolate formation, nucleophilic addition, S-methylation, and DBU-promoted elimination. The value of the method was demonstrated by the stereoselective syntheses of two natural products: 5,6-Z-fadyenolide (Z/E ratio = 6:1) and 9,10-methylenedioxy-5,6-Z-fadyenolide (Z/E ratio = 9:1).
Assuntos
Produtos Biológicos , Ésteres , Lactonas , EstereoisomerismoRESUMO
This article describes the full details of our synthetic efforts toward the enantioselective total synthesis of the complex alkaloid methoxystemofoline. The enantioselective construction of the tetracyclic core features: (1) the Keck allylation at the N-α bridgehead carbon to forge the tetrasubstituted stereocenter; (2) an olefin cross-metathesis reaction for the side-chain elongation that is amenable for the synthesis of congeners and analogues; and (3) a regioselective aldol addition reaction with methyl pyruvate that ensured the subsequent regioselective cyclization reaction to construct the fourth ring. Overman's method was employed to install the 5-(alkoxyalky1idene)-3-methyl-tetronate moiety. In the last step, a nonstereoselective reaction resulted in the formation of both the proposed structure of methoxystemofoline and its E-stereoisomer, the natural product (revised structure), in a 1:1 ratio. We suggest to rename the natural product as isomethoxystemofoline, and report for the first time the complete 1H NMR data for this natural product.
Assuntos
Alcaloides , Compostos Heterocíclicos de 4 ou mais Anéis , Ciclização , EstereoisomerismoRESUMO
Ten types of Tf2O/TTBP-mediated amide transformation reactions were investigated. The results showed that compared with pyridine derivatives 2,6-di-tert-butyl-4-methylpyridine (DTBMP) and 2-fluoropyridine (2-F-Pyr.), TTBP can serve as an alternative amide activation system for the direct transformation of both secondary and tertiary amides. For most surveyed examples, higher or comparable yields were generally obtained. In addition, Tf2O/TTBP combination was used to promote the condensation reactions of 2-(tert-butyldimethylsilyloxy)furan (TBSOF) with both tertiary and secondary amides, the one-pot reductive Bischler-Napieralski-type reaction of tertiary lactams, and Movassaghi and Hill's modern version of the Bischler-Napieralski reaction. The value of the Tf2O/TTBP-based methodology was further demonstrated by the concise and high-yielding syntheses of several natural products.
Assuntos
Amidas , Lactamas , Estrutura MolecularRESUMO
A facile method for the preparation of 2,3-dialkyl-substituted quinazolinones from readily available N-arylamides and commercial isocyanates was developed. This one-pot procedure involves the chemoselective activation of the secondary amide with Tf2O/2-Br-Pyr, the sequential addition of isocyanate, and cyclization. The mild reaction is general for a wide range of substrates and can be run on a gram scale.
Assuntos
Amidas , Isocianatos , Ciclização , Estrutura Molecular , QuinazolinonasRESUMO
A variety of inert tertiary amides have been successfully transformed into synthetically important chiral propargylamines in high yields with good to excellent enantioselectivities via a relayed sequence of Ir catalyzed partial reduction and Cu/GARPHOS catalyzed asymmetric alkynylation with terminal alkynes. The reaction was readily extended to some drug molecules and the transformations of representative products have been demonstrated, thus attesting the practical utilities and the robust nature of the protocol.
RESUMO
The combination of transition-metal catalysis and organocatalysis increasingly offers chemists opportunities to realize diverse unprecedented chemical transformations. By combining iridium with chiral thiourea catalysis, direct enantioselective reductive cyanation and phosphonylation of secondary amides have been accomplished for the first time for the synthesis of enantioenriched chiral α-aminonitriles and α-aminophosphonates. The protocol is highly efficient and enantioselective, providing a novel route to the synthesis of optically active α-functionalized amines from the simple, readily available feedstocks. In addition, the reactions are scalable and the thiourea catalyst can be recycled and reused.
RESUMO
The efficiency becomes a key issue in today's natural product total synthesis. While biomimetic synthesis is one of the most elegant strategies to achieve synthetic efficiency and thus to approach the ideal synthesis, most biogenetic pathways are unknown or unconfirmed. In this account, we demonstrate, through the shortest and also the most efficient asymmetric total syntheses of the hexacyclic alkaloid (-)-chaetominine to date, that on the basis of biogenetic thinking, one can develop quite efficient bio-inspired total synthesis, which in turn serves to suggest and chemically validate plausible biosynthetic routes for the natural product. The synthetic strategy thus developed is also inspiring for the development of other synthetic methods and efficient total synthesis of other natural products.
Assuntos
Produtos Biológicos/síntese química , Alcaloides Indólicos/síntese química , Quinazolinonas/síntese química , Biomimética/métodos , Ciclização , EstereoisomerismoRESUMO
We report a step-economical, enantioselective total synthesis of (-)-robustanoid B and (-)-robustanoid A and four novel natural product-like compounds. Our strategy relied on our biosynthetic hypothesis and on a novel complexity generation methodology, namely, the one-pot hydroxylative double cyclization reaction. The latter consists of a modified 3,3-dimethyldioxirane-triggered epoxidation-epoxide-ring-opening cyclization reaction cascade and Trost's regioselectivity umpolung methodology ("anti-Michael addition").
Assuntos
Biomimética , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Catálise , Técnicas de Química Sintética , Compostos Heterocíclicos de 4 ou mais Anéis/química , EstereoisomerismoRESUMO
An efficient and mild protocol for the direct and flexible synthesis of 3-amino-1,4-diynes bearing an aza-quaternary carbon from tertiary amides and lactams has been established. The one-pot method consists of in situ activation of amides with trifluoromethanesulfonic anhydride, followed by double addition of alkynyllithium reagents at a concentration of 0.5 mol·L-1 in dichloromethane. This constitutes an extension of the method of direct reductive bisalkylation of amides that allows both employing alkynyllithium reagents as the first-addition nucleophiles and incorporating an alkynyl group as the first-introduced group.
RESUMO
Reported herein is the first direct, metal-catalyzed reductive functionalization of secondary amides to give functionalized amines and heterocycles. The method is shown to have exceptionally broad scope with respect to suitable nucleophiles, which cover both hard and soft Câ nucleophiles as well as a Pâ nucleophile. The reaction exhibits good chemoselectivity and tolerates several sensitive functional groups.
RESUMO
The imino-Nazarov cyclization of the polysubstituted pentan-1,4-diene-3-imines was realized. To this aim, a one-pot procedure involving reductive alkenyliminylation of α,ß-unsaturated secondary amides with potassium organotrifluoroborates, followed by acid-catalyzed imino-Nazarov cyclization of the polysubstituted pentan-1,4-diene-3-imine intermediates, was studied systematically. This mild, operationally simple, flexible, and high-yielding protocol efficiently affords polysubstituted pentan-1,4-diene-3-imines, cyclopentenimines, and α-amino cyclopentenones, which are useful scaffolds in organic synthesis. The substituent effect at the C2 position of the polysubstituted pentan-1,4-diene-3-imines was studied by means of density-functional theory calculations. Results suggested that the electron-donating group facilitates the imino-Nazarov cyclization process.
RESUMO
Sepsis, a hyperinflammatory response that can result in multiple organ dysfunctions, is a leading cause of mortality from infection. Here, we show that orphan nuclear receptor Nur77 (also known as TR3) can enhance resistance to lipopolysaccharide (LPS)-induced sepsis in mice by inhibiting NF-κB activity and suppressing aberrant cytokine production. Nur77 directly associates with p65 to block its binding to the κB element. However, this function of Nur77 is countered by the LPS-activated p38α phosphorylation of Nur77. Dampening the interaction between Nur77 and p38α would favor Nur77 suppression of the hyperinflammatory response. A compound, n-pentyl 2-[3,5-dihydroxy-2-(1-nonanoyl) phenyl]acetate, screened from a Nur77-biased library, blocked the Nur77-p38α interaction by targeting the ligand-binding domain of Nur77 and restored the suppression of the hyperinflammatory response through Nur77 inhibition of NF-κB. This study associates the nuclear receptor with immune homeostasis and implicates a new therapeutic strategy to treat hyperinflammatory responses by targeting a p38α substrate to modulate p38α-regulated functions.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Inflamação/prevenção & controle , Lipopolissacarídeos/toxicidade , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/efeitos dos fármacos , Fenilacetatos/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/efeitos dos fármacos , Animais , Diabetes Mellitus Tipo 2/complicações , Avaliação Pré-Clínica de Medicamentos , Homeostase/efeitos dos fármacos , Inflamação/induzido quimicamente , Ligantes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Moleculares , Conformação Molecular , Sepse/tratamento farmacológico , Sepse/genética , Fator de Transcrição RelA/antagonistas & inibidoresRESUMO
Versatile and chemoselective C-C bond forming methods for the one-pot transformation of amides into other classes of compounds are highly demanding. In this report, we demonstrate the reductive addition of isocyanoacetates to common amides and lactams to produce 5-methoxyoxazoles or bicyclic imidazolines. This one-pot procedure involves partial reduction of amides with Schwartz reagent and chemoselective addition of the carbon of isocyanide group or α-carbon in isocyanoacetates. The quite different reactivity of the isocyanoacetate is due to the different steric hindrance of the amides and lactams.
RESUMO
Autophagy is linked to cell death, yet the associated mechanisms are largely undercharacterized. We discovered that melanoma, which is generally resistant to drug-induced apoptosis, can undergo autophagic cell death with the participation of orphan nuclear receptor TR3. A sequence of molecular events leading to cellular demise is launched by a specific chemical compound, 1-(3,4,5-trihydroxyphenyl)nonan-1-one, newly acquired from screening a library of TR3-targeting compounds. The autophagic cascade comprises TR3 translocation to mitochondria through interaction with the mitochondrial outer membrane protein Nix, crossing into the mitochondrial inner membrane through Tom40 and Tom70 channel proteins, dissipation of mitochondrial membrane potential by the permeability transition pore complex ANT1-VDAC1 and induction of autophagy. This process leads to excessive mitochondria clearance and irreversible cell death. It implicates a new approach to melanoma therapy through activation of a mitochondrial signaling pathway that integrates a nuclear receptor with autophagy for cell death.
Assuntos
Autofagia , Cetonas/química , Mitocôndrias/fisiologia , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Pirogalol/análogos & derivados , Transdução de Sinais , Animais , Linhagem Celular Tumoral , Cristalografia por Raios X , Modelos Animais de Doenças , Humanos , Cetonas/farmacologia , Melanoma/tratamento farmacológico , Proteínas de Membrana/metabolismo , Camundongos , Conformação Proteica , Proteínas Proto-Oncogênicas/metabolismo , Pirogalol/química , Pirogalol/farmacologia , Proteínas Supressoras de Tumor/metabolismoRESUMO
The combination of amide activation by Tf2O with B(C6F5)3-catalyzed hydrosilylation with TMDS constitutes a method for the one-pot reduction of secondary amides to amines under mild conditions. The method displays a broad applicability for the reduction of many types of substrates, and shows good compatibility and excellent chemoselectivity for many sensitive functional groups. Reductions of a multifunctionalized α,ß-unsaturated amide obtained from another synthetic methodology, and a C-H functionalization product produced the corresponding amines in good to excellent yield. Chemoselective reduction of enantiomeric pure (ee >99%) tetrahydro-5-oxo-2-furaneamides yielded 5-(aminomethyl)dihydrofuran-2(3H)-ones in a racemization-free manner. The latter were converted in one pot to N-protected 5-hydroxypiperidin-2-ones, which are building blocks for the synthesis of many natural products. Further elaboration of an intermediate led to a concise four-step synthesis of (-)-epi-pseudoconhydrine.
RESUMO
The direct transformation of common secondary amides into aromatic ketimines and aromatic ketones with C-C bond formation is described. The reaction can also be used for N-deacylation of secondary amides to release amines. This method consists of in situ amide activation with triflic anhydride and intermolecular capture of the resulting highly electrophilic nitrilium intermediate with an arene. The reaction is applicable to various kinds of secondary amides (electrophiles), but only electron-rich and moderately electron-rich arenes can be used as nucleophiles. Thanks to the use of bench stable arenes instead of reactive and basic organometallics as nucleophiles, the reaction proceeded with high chemoselectivity at the secondary amido group in the presence of a series of sensitive functional groups such as aldehyde, ketone, ester, cyano, nitro, and tertiary amido groups. The reaction can be viewed as a Friedel-Crafts-type reaction using secondary amides as acylating agents or as an intermolecular version of the Bischler-Napieralski reaction.