RESUMO
A novel stereoselective electrocyclization developed for the total synthesis of reserpine has been explored by both experiment and theory. A stereocenter six atoms away from the newly forming chiral center is responsible for the diastereoselectivity of the ring closure. This stereogenic center, lying at the junction of two six-membered rings, defines the conformation of the substrates' fused ring skeleton that ultimately distinguishes between the two allowed, disrotatory triene geometries at the transition state. The presence of allylic strain in the disfavored transition state results in a torquoselective ring closure (dr up to 15.7:1).
Assuntos
Anti-Hipertensivos/síntese química , Reserpina/síntese química , Ciclização , Elétrons , Modelos Moleculares , EstereoisomerismoRESUMO
A catalytic, enantioselective synthesis of (+)-reserpine is reported. The route features a highly diastereoselective, chiral catalyst-controlled formal aza-Diels-Alder reaction between a 6-methoxytryptamine-derived dihydro-ß-carboline and an enantioenriched α-substituted enone to form a key tetracyclic intermediate. This approach addresses the challenge of setting the C3 stereogenic center by using catalyst control. Elaboration of the tetracycle to (+)-reserpine includes an intramolecular aldol cyclization and a highly diastereoselective hydrogenation of a sterically hindered enoate.
Assuntos
Reserpina/síntese química , Carbolinas , Catálise , Ciclização , Estrutura Molecular , Reserpina/química , EstereoisomerismoRESUMO
A highly torquoselective thermal triene 6π electrocyclization controls the relative stereochemistry between the C3 and C18 stereocenters of the dodecahydroindolo[2,3-a]benzo[g]quinolizine skeleton of reserpine-type alkaloids. Employing a tandem cross-coupling/electrocyclization protocol allowed us to form the requisite triene and ensure its subsequent cyclization. A novel low-temperature dibromoketene acetal Claisen rearrangement established the requisite exocyclic dienylbromide precursor for the palladium-catalyzed cross-coupling reaction.
Assuntos
Alcaloides/síntese química , Reserpina/síntese química , Acetais/química , Alcaloides/química , Catálise , Ciclização , Estrutura Molecular , Paládio , Reserpina/química , EstereoisomerismoRESUMO
Two iodophenylazide derivatives of reserpine and one iodophenylazide derivative of tetrabenazine have been synthesized and characterized as photoaffinity labels of the vesicle monoamine transporter (VMAT2). These compounds are 18-O-[3-(3'-iodo-4'-azidophenyl)-propionyl]methyl reserpate (AIPPMER), 18-O-[N-(3'-iodo-4'-azidophenethyl)glycyl]methyl reserpate (IAPEGlyMER), and 2-N-[(3'-iodo-4'-azidophenyl)-propionyl]tetrabenazine (TBZ-AIPP). Inhibition of [3H]dopamine uptake into purified chromaffin granule ghosts showed IC50 values of approximately 37 nM for reserpine, 83 nM for AIPPMER, 200 nM for IAPEGlyMER, and 2.1 microM for TBZ-AIPP. Carrier-free radioiodinated [125I]IAPEGlyMER and [125I]TBZ-AIPP were synthesized and used to photoaffinity label chromaffin granule membranes. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis showed specific [125I]IAPEGlyMER labeling of a polypeptide that migrated as a broad band (approximately 55-90 kDa), with the majority of the label located between 70 and 80 kDa. The labeling by [125I]IAPEGlyMER was blocked by 100 nM reserpine, 10 microM tetrabenazine, 1 mM serotonin, and 10 mM (-)-norepinephrine and dopamine. Analysis of [125I]TBZ-AIPP-labeled chromaffin granule membranes by SDS-PAGE and autoradiography demonstrated specific labeling of a similar polypeptide, which was blocked by 1 microM reserpine and 10 microM tetrabenazine. Incubation of [125I]TBZ-AIPP-photolabeled chromaffin granule membranes in the presence of the glycosidase N-glycanase shifted the apparent molecular weight of VMAT2 to approximately 51 kDa. These data indicate that [125I]IAPEGlyMER and [125I]TBZ-AIPP are effective photoaffinity labels for VMAT2.
Assuntos
Proteínas Vesiculares de Transporte de Monoamina/química , Marcadores de Afinidade/síntese química , Marcadores de Afinidade/química , Animais , Sítios de Ligação , Bovinos , Grânulos Cromafim/metabolismo , Técnicas In Vitro , Radioisótopos do Iodo , Reserpina/análogos & derivados , Reserpina/síntese química , Reserpina/química , Serotonina/metabolismo , Tetrabenazina/análogos & derivados , Tetrabenazina/síntese química , Tetrabenazina/química , Proteínas Vesiculares de Transporte de Monoamina/metabolismoRESUMO
Full details of three approaches to an entirely regio- and stereoselective synthesis of the well-known target reserpine are described, culminating in a total synthesis which efficiently meets these requirements.
Assuntos
Reserpina/química , Reserpina/síntese química , Ciclização , Estrutura Molecular , EstereoisomerismoRESUMO
The Rauwolfia alkaloids reserpine (1) and deserpidine (2), two alkaloids from Rauwolfia species, have been widely used for their antihypertensive action. Deserpidine (2) is a compound with limited availability from natural sources, and its synthesis from 1 in six steps (41% overall yield) is reported here.
Assuntos
Reserpina/análogos & derivados , Reserpina/química , Estrutura Molecular , Plantas Medicinais/química , Rauwolfia/química , Reserpina/análise , Reserpina/síntese química , EstereoisomerismoAssuntos
Reserpina/efeitos adversos , Animais , Anti-Hipertensivos/efeitos adversos , Anti-Hipertensivos/síntese química , Anti-Hipertensivos/química , Anti-Hipertensivos/toxicidade , Testes de Carcinogenicidade , Carcinógenos/síntese química , Carcinógenos/química , Carcinógenos/toxicidade , Feminino , Regulamentação Governamental , Guias como Assunto , Humanos , Hipnóticos e Sedativos/efeitos adversos , Hipnóticos e Sedativos/síntese química , Hipnóticos e Sedativos/química , Hipnóticos e Sedativos/toxicidade , Masculino , Camundongos , Modelos Biológicos , Exposição Ocupacional/efeitos adversos , Exposição Ocupacional/legislação & jurisprudência , Ratos , Reserpina/síntese química , Reserpina/química , Reserpina/toxicidade , Tranquilizantes/efeitos adversos , Tranquilizantes/síntese química , Tranquilizantes/química , Tranquilizantes/toxicidade , Estados UnidosRESUMO
The intramolecular Diels-Alder reaction of N-3,5-hexadienoyl ethyl acrylimidates provides an efficient method for the synthesis of cis-fused hexahydroisoquinolones. As a demonstration of the stereochemical control offered by this cycloaddition, two approaches to the construction of the DE rings of reserpine are reported. In the second entry, N-((4-(trimethylsilyl)ethoxymethoxy)methyl-6-benzyloxy-3Z,5E-hexadienoyl)-1-aza-2-ethoxy-1,3-butadiene (40) undergoes cycloaddition to produce as the major product (4aS,7R,8aS)-7-benzyloxy-5-((2-trimethylsilyl)ethoxymethoxy)methyl-3,4,4a,7,8,8a-hexahydroisoquinol-3-one (41). Cycloadduct 41 is then stereospecifically elaborated to (4aS,5S,6R,7R,8aR)-6-methoxy-5-methoxycarbonyl-7-(3,4,5-trimethoxy)benzoyldecahydroisoquinoline-2-carboxylic acid methyl ester (3), a key intermediate previously transformed to reserpine.
Assuntos
Técnicas de Química Combinatória , Isoquinolinas/síntese química , Reserpina/síntese química , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , EstereoisomerismoRESUMO
[reaction: see text] The intramolecular Diels-Alder reaction of N-acylvinylimidates provides an efficient entry into cis-fused perhydroisoquinoline ring systems. This is demonstrated by the preparation of isoquinoline 2, an intermediate, which has been previously transformed to reserpine.