RESUMEN
The first total synthesis of cadinane sesquiterpenoid alanense A, in which an intramolecular dehydrative Friedel-Crafts alkylation of 2,5-diaryl-2-pentanol is incorporated as a key step, has been achieved. The combinatorial use of p-TsOH·H2O as a catalyst and 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) as a solvent provides 1,1-disubstituted tetrahydronaphthalene in 97% yield. It was also found that the combination of p-TsOH and HFIP is effective for the removal of phenolic MOM ether.
RESUMEN
In order to elucidate the origins of the stable structures of dirhodium(II) tetrakis[N-phthaloyl-(S)-tert-leucinate] and the four derivatives with halogenated aromatic rings, the conformational stability and intramolecular interactions were investigated by DFT calculations. In all of these complexes, the conformation in which all ligands face in the same direction is the most stable. When adjacent ligands are in the same orientation, destabilization due to exchange repulsion is larger than that when they are in opposite orientations. However, this destabilizing effect is reversed by the sum of the stabilizing effects of the electronic and charge transfer interactions. The imide carbonyl group plays an important role in these stabilizing interactions. The negatively charged site and bond orbitals in the imide carbonyl group interact with the positively charged sites and bond orbitals in the aromatic ring, the carboxylate group, and the α-position of the carboxylate group in the adjacent ligands. In addition, the lone-pair orbitals of the halogen atoms contribute to conformational stabilization by interacting with the vacant orbitals in the adjacent ligands. However, the combinations of these charged sites or bond orbitals, which effectively contribute to the stabilization, are different for each complex.
RESUMEN
The new chalcogenylation of phosphines using nBu4Nâ§XCN (X = S, Se) is described. The reaction in 1,2-dichloroethane at 120 °C provided the corresponding phosphine sulfides in good to high yields. The protocol could be extended to the synthesis of phosphinic acid derivatives as well as sulfurization of poly(styrene-co-4-styryldiphenylphosphine).
Asunto(s)
Calcógenos , Fosfinas , Compuestos de Amonio Cuaternario , Fosfinas/química , Compuestos de Amonio Cuaternario/química , Compuestos de Amonio Cuaternario/síntesis química , Calcógenos/química , Calcógenos/síntesis química , Estructura MolecularRESUMEN
Before entering host cells, herpes simplex virus-1 uses its envelope glycoprotein B to bind paired immunoglobulin-like type 2 receptor α (PILRα) on immune cells. PILRα belongs to the Siglec (sialic acid (SA)-binding immunoglobulin-like lectin)-like family, members of which bind SA. PILRα is the only Siglec member to recognize not only the sialylated O-linked sugar T antigen (sTn) but also its attached peptide region. We previously determined the crystal structure of PILRα complexed with the sTn-linked glycopeptide of glycoprotein B, revealing the simultaneous recognition of sTn and peptide by the receptor. However, the contribution of each glycopeptide component to PILRα binding was largely unclear. Here, we chemically synthesized glycopeptide derivatives and determined the thermodynamic parameters of their interaction with PILRα. We show that glycopeptides with different sugar units linking SA and peptides (i.e. "GlcNAc-type" and "deoxy-GlcNAc-type" glycopeptides) have lower affinity and more enthalpy-driven binding than the wild type (i.e. GalNAc-type glycopeptide). The crystal structures of PILRα complexed with these glycopeptides highlighted the importance of stereochemical positioning of the O4 atom of the sugar moiety. These results provide insights both for understanding the unique O-glycosylated peptide recognition by the PILRα and for the rational design of herpes simplex virus-1 entry inhibitors.
Asunto(s)
Glicoproteínas de Membrana/metabolismo , Modelos Moleculares , Fragmentos de Péptidos/metabolismo , Receptores Inmunológicos/metabolismo , Proteínas del Envoltorio Viral/metabolismo , Acetilgalactosamina/análogos & derivados , Acetilgalactosamina/química , Acetilgalactosamina/metabolismo , Sitios de Unión , Calorimetría , Cristalografía por Rayos X , Escherichia coli/metabolismo , Humanos , Cinética , Ligandos , Glicoproteínas de Membrana/química , Glicoproteínas de Membrana/genética , Fragmentos de Péptidos/síntesis química , Fragmentos de Péptidos/química , Fragmentos de Péptidos/genética , Polisacáridos/síntesis química , Polisacáridos/química , Polisacáridos/metabolismo , Conformación Proteica , Dominios y Motivos de Interacción de Proteínas , Receptores Inmunológicos/química , Receptores Inmunológicos/genética , Proteínas Recombinantes , Estereoisomerismo , Termodinámica , Proteínas del Envoltorio Viral/síntesis química , Proteínas del Envoltorio Viral/químicaRESUMEN
Herpes simplex virus type 1 (HSV-1) is a causative agent for a variety of diseases. Although antiherpetic drugs such as acyclovir have been developed to inhibit virus replication through interaction with DNA kinases, their continuous administration leads to an increase in the frequency of drug-resistant HSV-1, which is an important clinical issue that requires urgent solution. Recently, we reported that the sialylated O-linked sugar T antigen (sTn) and its attached peptide region (O-glycosylated sTn peptide) derived from the HSV-1 glycoprotein B (gB) protein inhibited HSV-1 infection by specifically targeting paired immunoglobulin-like type 2 receptor alpha (PILRα) in vitro. In this study, to further identify novel inhibitors of gB-mediated HSV-1 infection in vitro, we established a cell-based fusion assay for rapid drug screening. Chinese hamster ovary (CHO) cells were transfected with expression plasmids for HSV-1 gB, gD, gH, and gL, and T7 RNA polymerase, and were designated as the effector cells. The CHO-K1 cells stably expressing PILRα were transfected with the expression plasmid for firefly luciferase under the T7 promoter, and were designated as the target cells. The effector and target cells were co-cultured, and luminescence was measured when both cells were successfully fused. Importantly, we found that cell-to-cell fusion was specifically inhibited by O-glycosylated sTn peptide in a dose dependent manner. Our results suggested that this virus-free cell-based fusion assay system could be a useful and promising approach to identify novel inhibitors of gB-mediated HSV-1 infection, and will aid in the development of antiviral therapeutic strategies for HSV-1-associated diseases.
Asunto(s)
Antígenos Virales de Tumores/química , Antivirales/farmacología , Herpesvirus Humano 1 , Péptidos/farmacología , Proteínas del Envoltorio Viral/genética , Animales , Bioensayo , Células CHO , Fusión Celular , Técnicas de Cocultivo , Cricetinae , Cricetulus , ARN Polimerasas Dirigidas por ADN/genética , Herpes Simple/tratamiento farmacológico , Herpesvirus Humano 1/inmunología , Herpesvirus Humano 1/patogenicidad , Luciferasas de Luciérnaga/genética , Glicoproteínas de Membrana/genética , Receptores Inmunológicos/genética , Proteínas Virales/genéticaRESUMEN
An asymmetric total synthesis of the guaiane sesquiterpene (-)-englerin A, a potent and selective inhibitor of the growth of renal cancer cell lines, was accomplished. The basis of the approach is a highly diastereo- and enantioselective carbonyl ylide cycloaddition with an ethyl vinyl ether dipolarophile under catalysis by dirhodium(II) tetrakis[N-tetrachlorophthaloyl-(S)-tert-leucinate], [Rh2 (S-TCPTTL)4 ], to construct the oxabicyclo[3.2.1]octane framework with concomitant introduction of the oxygen substituent at C9 on the exo-face. Another notable feature of the synthesis is ruthenium tetraoxide-catalyzed chemoselective oxidative conversion of C9 ethyl ether to C9 acetate.
Asunto(s)
Antineoplásicos/síntesis química , Complejos de Coordinación/química , Éteres de Etila/química , Neoplasias Renales/química , Sesquiterpenos de Guayano/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Factores Biológicos/química , Catálisis , Línea Celular Tumoral , Reacción de Cicloadición , Humanos , Neoplasias Renales/patología , Estructura Molecular , Rodio/química , Sesquiterpenos de Guayano/química , EstereoisomerismoRESUMEN
We report an effective synthetic route to multi-substituted phenanthrenes via an internal redox reaction/ring expansion sequence. The interesting feature of the present system is that it allows for the divergent synthesis of the target skeleton depending on the selected Lewis acid catalyst. When benzylidene malonates with a cyclic structure at the ortho-position were treated with BF3·OEt2, three sequential processes (internal redox reaction/elimination of the alkoxy group/ring expansion) proceeded to give phenanthrene derivatives in which the alkoxycarbonyl (CO2R) group and the alkyl (R) group were in close proximity to each other, in good chemical yields. In sharp contrast, treatment with Bi(OTf)3 exclusively led to the formation of another type of phenanthrene, whose R group was positioned distal to the CO2R group.
RESUMEN
The first catalytic asymmetric carbonyl ylide cycloaddition with arylallenes is described. With dirhodium(II) tetrakis[N-tetrachlorophthaloyl-(S)-tert-leucinate], Rh2(S-TCPTTL)4, the cycloaddition of carbonyl ylides derived from diazoketoesters with arylallenes proceeded in a fully chemo- and regioselective manner to give highly functionalized 8-oxabicyclo[3.2.1]octanes with up to 99% ee and perfect exo diastereoselectivity.
Asunto(s)
Alcadienos/química , Compuestos Bicíclicos con Puentes/síntesis química , Leucina/análogos & derivados , Octanos/síntesis química , Rodio/química , Catálisis , Reacción de Cicloadición , EstereoisomerismoRESUMEN
The reaction of a six-membered cyclic formyl-carbonyl ylide derived from alpha-diazo-beta-ketoester with phenylacetylene derivatives under the catalysis of dirhodium(II) tetrakis[N-tetrachlorophthaloyl-(S)-tert-leucinate], Rh(2)(S-TCPTTL)(4), provides cycloadducts containing an 8-oxabicyclo[3.2.1]octane ring system in up to 97% ee. This represents the first example of an enantioselective 1,3-dipolar cycloaddition of a cyclic formyl-carbonyl ylide. Using this catalytic process, an asymmetric synthesis of endo-6-aryl-8-oxabicyclo[3.2.1]oct-3-en-2-one natural product 1 from Ligusticum chuanxing Hort. has been achieved.
Asunto(s)
Factores Biológicos/síntesis química , Compuestos Bicíclicos con Puentes/química , Cetonas/química , Ligusticum/química , Compuestos Organometálicos/química , Rodio/química , Factores Biológicos/química , Catálisis , Ciclización , Estructura Molecular , EstereoisomerismoRESUMEN
A novel direct C4 benzylation of indoles utilizing 2-benzyloxyindoles has been developed to access 4-benzyl-2-oxindoles. This strategy involves the in situ formation of isotoluene intermediates via benzyl Claisen rearrangements, which undergoes Cope rearrangement and aromatization. The method provides the desired products in moderate to high yields and shows good functional group tolerance.
RESUMEN
Dirhodium(II) tetrakis[N-tetrafluorophthaloyl-(S)-tert-leucinate], Rh2(S-TFPTTL)4, is an exceptionally efficient catalyst for enantioselective aminations of silyl enol ethers derived from acyclic ketones or alpha,beta-enones with [N-(2-nitrophenylsulfonyl)imino]phenyliodinane (NsN=IPh), providing N-(2-nitrophenylsulfonyl)-alpha-amino ketones in high yields and with enantioselectivities of up to 95% ee. The effectiveness of the present catalytic protocol has been demonstrated by an asymmetric formal synthesis of (-)-metazocine.
Asunto(s)
Éteres/química , Morfinanos/síntesis química , Compuestos Organometálicos/química , Rodio/química , Aminación , Catálisis , Estructura MolecularRESUMEN
A novel indole-2,3-epoxide equivalent, 2-hydroxyindoline-3-triethylammonium bromide, was found to be a convenient reagent for formal C3-electrophilic reactions of indoles with various nucleophiles. By taking advantage of the nucleophilic character of the oxygen of the 2-hydroxyindoline, the interrupted retro-Claisen and interrupted Feist-Bénary reactions with 1,3-dicarbonyl compounds were efficiently achieved.
RESUMEN
The first total synthesis of brasilicardins A and C, novel diterpenoid-saccharide-amino acid hybrid metabolites with unique immunosuppressive activity, is described. The key step is a Diels-Alder/reductive angular methylation sequence capitalizing on a trans-fused bicyclic α-cyano-α,ß-enone as its precursor to construct the 8,10-dimethyl-trans/syn/trans-perhydrophenanthrene skeleton. Other notable features include an anti-selective aldol reaction, a stereocontrolled glycosylation of a C2 alcohol, and a one-pot, two-step global deprotection sequence that did not damage these sensitive molecules.
Asunto(s)
Aminoglicósidos/síntesis química , Aminoácidos , Carbohidratos , Glicosilación , Estructura Molecular , EstereoisomerismoRESUMEN
[formula: see text] The enantioselective intramolecular C-H insertion reaction of aryldiazoacetates has been explored with use of dirhodium(II) carboxylate catalysts, which incorporate N-phthaloyl- or N-benzene-fused-phthaloyl-(S)-amino acids as chiral bridging ligands. Dirhodium tetrakis[N-phthaloyl-(S)-tert-leucinate], Rh2(S-PTTL)4, has proven to be the catalyst of choice for this process, providing exclusively cis-2-aryl-3-methoxycarbonyl-2,3-dihydobenzofurans in up to 94% ee.
RESUMEN
The first catalytic asymmetric hetero-Diels-Alder reaction between 2-aza-3-silyloxy-1,3-butadienes and aldehydes is described. With dirhodium(II) tetrakis[N-benzene-fused-phthaloyl-(S)-piperidinonate], Rh(2)(S-BPTPI)(4), the cycloaddition reaction proceeded exclusively in an endo mode to give all-cis-substituted 1,3-oxazinan-4-ones in high yields with up to 98% ee.
Asunto(s)
Aldehídos/química , Butadienos/química , Complejos de Coordinación/química , Rodio/química , Catálisis , Oxazinas/síntesis química , Oxazinas/química , EstereoisomerismoAsunto(s)
Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Inhibidores Enzimáticos/síntesis química , Farnesil Difosfato Farnesil Transferasa/antagonistas & inhibidores , Compuestos Azo/química , Ciclización , Estructura Molecular , Estereoisomerismo , Ácidos Tricarboxílicos/síntesis químicaRESUMEN
The first example of a chiral Lewis acid-catalyzed enantioselective hetero-Diels-Alder (HDA) reaction between 1-dimethylamino-3-silyloxy-1,3-butadiene (Rawal's diene) and aldehydes is described. The cycloaddition reaction under the influence of 1 mol% of dirhodium(II) tetrakis[N-benzene-fused-phthaloyl-(S)-piperidinonate], Rh(2)(S-BPTPI)(4), proceeded cleanly and gave, after treatment with acetyl chloride, the corresponding dihydropyranones in up to 99% ee.