RESUMO
A synthesis route to the pentacyclic alkaloid (-)-gilbertine, which features a cyclization cascade passing through a transient indolidene intermediate, was pursued. A key stereochemical relationship was set via a Nicholas-type enolate alkylation. Ultimately, undesired C-N cyclization thwarted the final projected C-C bond forming ring closure, and gilbertine could not be prepared by this route.
RESUMO
Tetracyclic products featuring predominantly a trans-hexahydroindane unit annelated onto the C(2)/C(3) positions of indole can be accessed by intramolecular cyclocondensation of tethered alkenyl sulfides with either indolidene or indolidenium cation intermediates. Studies with geometrically pure E- and Z-alkenyl sulfide isomers reveal a likely dichotomy of reaction paths that provide mixtures of both regioisomers and stereoisomers of the hexahydroindane adducts.
RESUMO
C(2)-C(3) cyclopentannelated indole constructs are prepared by either (a) a cyclization cascade of an alkenyl sulfide tethered to a 2-azido-1-allenylbenzene core or (b) cationic cyclization of a tethered alkenyl sulfide with a putative 2-indolidenium cation. In both cases, issues of C-C versus C-N bond formation emerge, and the results indicate that the former is favored.
RESUMO
The enantiomer of the bicyclic lomaiviticin aglycone A core was prepared via a two-directional, divergent approach featuring (1) a double Ireland Claisen rearrangement to establish key core bonds with correct relative stereochemistry and (2) a double olefin metathesis reaction to deliver both cyclohexene rings of the target.
Assuntos
Antineoplásicos/síntese química , Desenho de Fármacos , Fluorenos/síntese química , Antineoplásicos/química , Ciclização , Cicloexenos/química , Fluorenos/química , Modelos Moleculares , Conformação Molecular , EstereoisomerismoRESUMO
The pentacyclic Melodinus alkaloid (±)-meloscine was synthesized in 19 chemical steps from 2-bromobenzaldehyde through a route featuring an allenyl azide cyclization cascade to deliver the core azabicyclo[3.3.0]octane substructure. Peripheral functionalization of this core included a Tollens-type aldol condensation to set the quaternary center at C(20) and a diastereoselective ring closing metathesis to forge the tetrahydropyridine ring.
RESUMO
The bicyclic core of ent-lomaiviticin A was prepared in 11 operations from (S)-1-phenyl-2-propyn-1-ol in a two-directional route that features (1) a double Ireland Claisen rearrangement and (2) a double olefin metathesis reaction to form the key C-C bonds of the target.
Assuntos
Fluorenos/síntese química , Alcenos/química , Fluorenos/química , Estrutura Molecular , EstereoisomerismoRESUMO
We report herein that the oroidin-derived alkaloids palau'amine (1), dibromophakellin (2), and dibromophakellstatin (3) inhibit the proteolytic activity of the human 20S proteasome as well as the (i)20S immunoproteasome catalytic core. Palau'amine is found to prevent the degradation of ubiquitinylated proteins, including IκBα, in cell culture, which may be indicative of the potential mechanism by which these agents exhibit their exciting cytotoxic and immunosuppressive properties.
Assuntos
Alcaloides/farmacologia , Guanidinas/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Imidazóis/farmacologia , Inibidores de Proteassoma , Pirróis/farmacologia , Compostos de Espiro/farmacologia , Alcaloides/química , Guanidinas/química , Células HeLa , Compostos Heterocíclicos de 4 ou mais Anéis/química , Humanos , Imidazóis/química , Microscopia Confocal , NF-kappa B/metabolismo , Complexo de Endopeptidases do Proteassoma/química , Pirróis/química , Compostos de Espiro/química , EstereoisomerismoRESUMO
The pentacyclic alkaloid (±)-meloscine was prepared in 19 steps through a reaction sequence that features a putative azatrimethylenemethane intermediate, generated through cascade cyclization of an allenyl azide substrate, to deliver the core azabicyclo[3.3.0]octadiene substructure. Subsequent manipulation of the peripheral functionality then delivered (±)-meloscine.
Assuntos
Azidas/química , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Compostos Policíclicos/síntese química , Quinolinas/síntese química , Ciclização , Modelos Moleculares , Estrutura MolecularRESUMO
(±)-Dragmacidin E was synthesized in 25 steps from commercially available 7-(benzyloxy)indole. Key transformations in this sponge metabolite's preparation include (a) a Witkop cyclization to establish the bridging indole core, (b) cyclo-dehydrative pyrazinone formation to unite the two indole-bearing components, and (c) late-stage guanidine installation via chemoselective carbonyl activation.
RESUMO
The bis indole sponge alkaloid dragmacidin E was synthesized in racemic form over 25 steps starting from 7-benzhydroxyindole. Key steps include (a) a Witkop cyclization to facilitate construction of the indole-spanning seven-membered ring and (b) a cyclodehydrative pyrazinone synthesis that unites the two indole-containing sectors.
Assuntos
Alcaloides Indólicos/síntese química , Animais , Ciclização , Alcaloides Indólicos/química , Biologia Marinha , Estrutura Molecular , Poríferos/química , EstereoisomerismoRESUMO
Exploratory oxidative cyclization studies on cyclopentanelated and cyclohexenelated oroidin derivatives utilized Pummerer chemistry to generate pentacyclic structures related to the palau'amine family of sponge metabolites. Stereochemical issues were paramount, and appropriate choice of annelated ring size led to formation of the pentacyclic framework with complete diastereoselectivity for all of the core bonds.
Assuntos
Aminas/síntese química , Ciclização , Dimerização , Compostos Heterocíclicos , Modelos Moleculares , Estrutura Molecular , Oxirredução , EstereoisomerismoRESUMO
The conversion of a cycloheptannelated indole platform into the heptacyclic core structure of dragmacidin E proceeded over nine steps. Key sequences include a cyclocondensation to form an intermediate dihydropyrazinone ring and the conversion of a cyclic urea into the cyclic guanidine of the target.
Assuntos
Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Alcaloides Indólicos/síntese química , Azidas/química , Estrutura MolecularRESUMO
A pentacyclic model system featuring the trans azabicyclo[3.3.0]octane unit of dibromopalau'amine was prepared with complete diastereoselectivity in the polycyclic core from a tricyclic precursor. The key transformations of this sequence include (a) a Pummerer reaction-mediated oxidative bicyclization, and (b) a Wolff rearrangement-based ring contraction to deliver the strained azabicyclo[3.3.0]octane core.
Assuntos
Compostos de Bromo/química , Guanidinas/química , Compostos de Espiro/química , Cristalografia por Raios X , Ciclização , Modelos Moleculares , Estrutura Molecular , Oxirredução , EstereoisomerismoRESUMO
The base-mediated bicyclization of unsymmetrical bispropargyl sulfones furnishes varying yields of dihydroisobenzothiophene dioxides through a presumed diradical intermediate. Attempts to trap a putative thiophene dioxide intermediate via Diels-Alder reaction with a pendant alkyne were not successful.
RESUMO
Collaborative work between experimentalists and computational chemists have demonstrated a stong synergy which allowed the rationalization of allenyl azide chemistry and permited the development of an efficient synthetic tool aimed at the preparation of several alkaloids. Saturated allenyl azides undergo a reaction cascade involving key diradical intermediates that follow the Curtin-Hammett model whereas unsaturated allenyl azides form indolidene intermediates that furnish the final indole products via electrocyclic ring closure events taking place out of the Curtin-Hammett regime. The regiochemistry of the reaction cascade with the latter substrates can be manipulated by Cu(I) addition to the reaction mixture.
RESUMO
The thermal, photochemical, and photochemical/CuI-mediated cascade cyclizations of a range of substituted 1-(2-azidophenyl)-3-alkenylallenes are described. These reactions provide both 1,2- and 2,3-cyclopentennelated indole products in varying ratios. In most cases, high regioselectivity for the 2,3-annelated isomer can be achieved under the hnu/CuI conditions. Computational studies of this multistep reaction support the intermediacy of indolidene intermediates whose electrocyclizations (with or without copper present) define the regioselectivity branch point in the sequence.
Assuntos
Azidas/química , Indóis/síntese química , Simulação por Computador , Cobre/química , Ciclização , Indóis/química , Luz , Estrutura Molecular , Estereoisomerismo , TermodinâmicaRESUMO
The sponge-derived alkaloid dibromoagelaspongin was prepared from a dihydrooroidin derivative by exploiting the Pummerer reaction twice in succession. Oxidative cyclization of the substrate's pyrrole-2-carboxamide function into the imidazole moiety was achieved in a regiospecific manner to establish both C-N bonds to C(6) of the target.
Assuntos
Alcaloides/síntese química , Pirróis/síntese química , Alcaloides/química , Ciclização , Imidazolinas/química , Oxirredução , Pirróis/química , Estereoisomerismo , Especificidade por SubstratoRESUMO
The sponge metabolite dibromoagelaspongin was synthesized in 16 steps from imidazole. The route features two successive oxidative cyclizations with complete control of regiochemistry to deliver the unusual triaminomethane core of the target. These oxidative cyclizations likely resulted from Pummerer-like processes on the imidazole-2-sulfoxide (sulfide) precursors.
Assuntos
Pirróis/síntese química , Alcaloides/síntese química , Ciclização , Guanidinas/síntese química , Imidazóis/química , Oxirredução , Estereoisomerismo , Sulfetos/química , Sulfóxidos/químicaRESUMO
Detailed studies of the thermal conversion of 1-azidohepta-3,4,6-trienes into cyclopentennelated dihydropyrroles are presented. High levels of diastereoselectivity and regioselectivity are documented. A mechanistic proposal that accounts for all of the diverse results is developed through the use of density functional calculations. These calculations provide support for the intervention of unexpected mechanistic subtleties, such as the planarity of an azatrimethylenemethane diyl intermediate and an apparent Woodward-Hoffmann-type electrocyclization of a five-atom diyl array.
Assuntos
Compostos Aza/química , Azidas/química , Metano/análogos & derivados , Pirróis/química , Técnicas de Química Combinatória , Simulação por Computador , Metano/química , Estrutura MolecularRESUMO
Irradiation of 2-(3-alkenyl)allenylphenyl azides in the presence of excess CuI furnished functionalized 2,3-cyclopentenylindoles in good yield with only trace amounts of competitive C-N-bonded regioisomeric products. These results represent a significant departure from the modest-to-nonexistent regioselectivity that attended thermal cyclization of these allenyl azide substrates.