RESUMO
An asymmetric synthesis of HCV NS5B nucleoside polymerase inhibitor (1) is described. This novel route features several remarkably diastereoselective and high-yielding transformations, including construction of the all-carbon quaternary stereogenic center at C-2 via a thermodynamic aldol reaction. A subsequent glycosylation reaction with activated uracil via C-1 phosphate and installation of the cyclic phosphate group using an achiral phosphorus(III) reagent followed by oxidation provides 1.
Assuntos
Antivirais/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/síntese química , Antivirais/química , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Humanos , Estrutura Molecular , Estereoisomerismo , Proteínas não Estruturais Virais/metabolismoRESUMO
The first example of an intramolecular asymmetric reductive amination of a dialkyl ketone with an aliphatic amine has been developed for the synthesis of Suvorexant (MK-4305), a potent dual Orexin antagonist under development for the treatment of sleep disorders. This challenging transformation is mediated by a novel Ru-based transfer hydrogenation catalyst that provides the desired diazepane ring in 97% yield and 94.5% ee. Mechanistic studies have revealed that CO(2), produced as a necessary byproduct of this transfer hydrogenation reaction, has pronounced effects on the efficiency of the Ru catalyst, the form of the amine product, and the kinetics of the transformation. A simple kinetic model explains how product inhibition by CO(2) leads to overall first-order kinetics, but yields an apparent zero-order dependence on initial substrate concentration. The deleterious effects of CO(2) on reaction rates and product isolation can be overcome by purging CO(2) from the system. Moreover, the rate of ketone hydrogenation can be greatly accelerated by purging of CO(2) or trapping with nucleophilic secondary amines.
Assuntos
Azepinas/síntese química , Rutênio/química , Triazóis/síntese química , Aminação , Catálise , Hidrogenação , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Cinética , Neuropeptídeos/antagonistas & inibidores , Orexinas , EstereoisomerismoRESUMO
Previous syntheses of the biologically active 2-aminated benzoxazoles have relied on forcing thermal conditions to generate the products directly from the corresponding thiols. The resulting yields have ranged from moderate to poor. A mild and high-yielding alternative one-pot chlorination-amination procedure is described. Compounds with a variety of substitution patterns are reported and the methodology has been successfully extended to benzothiazoles. Palladium catalysis on suitably activated examples has been employed to generate the desired compounds of interest.
Assuntos
Benzotiazóis/síntese química , Benzoxazóis/síntese química , Hidrocarbonetos Halogenados/química , Aminação , Benzotiazóis/química , Benzoxazóis/química , Catálise , Espectroscopia de Ressonância Magnética/métodos , Estrutura Molecular , Relação Estrutura-Atividade , Compostos de Sulfidrila/química , TemperaturaRESUMO
We describe in full the first synthesis of the potent insect antifeedant azadirachtin through a highly convergent approach. An O-alkylation reaction is used to unite decalin ketone and propargylic mesylate fragments, after which a Claisen rearrangement constructs the central C8-C14 bond in a stereoselective fashion. The allene which results from this sequence then enables a second critical carbon-carbon bond forming event whereby the [3.2.1] bicyclic system, present in the natural product, is generated via a 5-exo-radical cyclisation process. Finally, using knowledge gained through our early studies into the reactivity of the natural product, a series of carefully designed steps completes the synthesis of this challenging molecule.
Assuntos
Inseticidas/síntese química , Limoninas/síntese química , Inseticidas/química , Limoninas/química , Conformação Molecular , EstereoisomerismoRESUMO
The enantioselective total synthesis of thapsigargin, a potent, selective inhibitor of the Ca2+ pump SERCA, is described. Starting from ketoalcohol 8, key steps involve regioselective introduction of the internal olefin at C4-C5, judicious protecting group choice to allow chelation-controlled reduction at C3, and chemoselective introduction of the angelate ester function at C3-O. A selective esterification approach completes the total synthesis in a total of 42 steps and 0.61% overall yield (88.6% average yield per step). [reaction: see text].
Assuntos
Inibidores Enzimáticos/síntese química , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/antagonistas & inibidores , Tapsigargina/síntese química , Álcoois/química , Alcenos/química , Quelantes/química , Indicadores e Reagentes , Oxirredução , EstereoisomerismoRESUMO
The development of a convergent and highly stereoselective synthesis of an HCV NS3/4a protease inhibitor possessing a unique spirocyclic and macrocyclic architecture is described. A late-stage spirocyclization strategy both enabled rapid structure-activity relationship studies in the drug discovery phase and simultaneously served as the basis for the large scale drug candidate preparation for clinical use. Also reported is the discovery of a novel InCl3-catalyzed carbonyl reduction with household aluminum foil or zinc powder as the terminal reductant.
Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/farmacologia , Compostos de Espiro/síntese química , Compostos de Espiro/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/química , Descoberta de Drogas , Compostos Heterocíclicos de 4 ou mais Anéis/química , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Compostos Macrocíclicos/química , Estrutura Molecular , Compostos de Espiro/química , Relação Estrutura-AtividadeRESUMO
A practical, enantioselective synthesis of cis-2,5-disubstituted pyrrolidine is described. Application of an enzymatic DKR reduction of a keto ester, which is easily accessed through a novel intramolecular NâC benzoyl migration, yields syn-1,2-amino alcohol in >99% ee and >99:1 dr. Subsequent hydrogenation of cyclic imine affords the cis-pyrrolidine in high diastereoselectivity. By integrating biotechnology into organic synthesis and isolating only three intermediates over 11 steps, the core scaffold of ß3-AR agonists is synthesized in 38% overall yield.
Assuntos
Agonistas de Receptores Adrenérgicos beta 3/síntese química , Pirrolidinas/síntese química , Agonistas de Receptores Adrenérgicos beta 3/química , Agonistas de Receptores Adrenérgicos beta 3/farmacologia , Amino Álcoois/química , Catálise , Hidrogenação , Iminas/química , Estrutura Molecular , Oxirredução , Pirrolidinas/química , Pirrolidinas/farmacologia , EstereoisomerismoRESUMO
A highly diastereoselective bifunctional organocatalyst controlled Michael addition, a nitro-Mannich/lactamization cascade, a furan N-acyliminium cyclisation, a sequential alkyne RCM/syn-reduction and an alkene RCM has allowed a 19 step, highly stereoselective synthesis of (-)-nakadomarin A.
Assuntos
Carbolinas/síntese química , Alcenos/química , Alcinos/química , Carbolinas/química , Oxirredução , EstereoisomerismoRESUMO
A novel synthesis of 3-methylindoles from chlorotriflates through a Heck reaction, carbamate/aryl chloride coupling, and isomerization sequence is presented. The three-step sequence is highly efficient and general, enabling the regiocontrolled synthesis of substituted indoles in short order.
Assuntos
Hidrocarbonetos Clorados/química , Mesilatos/química , Escatol/análogos & derivados , Escatol/síntese química , Catálise , Técnicas de Química Combinatória , Ciclização , Estrutura Molecular , Escatol/químicaRESUMO
Lithium 2,2,6,6-tetramethylpiperidide (LTMP)-induced intramolecular cyclopropanation of unsaturated terminal epoxides provides an efficient and completely stereoselective entry to bicyclo[3.1.0]hexan-2-ols and bicyclo[4.1.0]heptan-2-ols. Further elaboration of C-5 and C-6 stannyl-substituted bicyclo[3.1.0]hexan-2-ols via Sn-Li exchange/electrophile trapping or Stille coupling generates a range of substituted bicyclic cyclopropanes. An alternative straightforward cyclopropanation protocol using a catalytic amount of 2,2,6,6-tetramethylpiperidine (TMP) allows for a convenient (1 g-7.5 kg) synthesis of bicyclo[3.1.0]hexan-2-ol and other bicyclic adducts. The synthetic utility of this chemistry has been demonstrated in a concise asymmetric synthesis of (+)-beta-cuparenone. The related unsaturated chlorohydrins also undergo intramolecular cyclopropanation via in situ epoxide formation.
Assuntos
Cloridrinas/química , Ciclopropanos/química , Compostos de Epóxi/química , Aldeídos/química , Compostos Bicíclicos com Pontes/química , Catálise , Heptanos/química , Hexanos/química , Isomerismo , Estrutura Molecular , Sesquiterpenos/síntese química , Sesquiterpenos/químicaRESUMO
Herein we describe the total synthesis of five guaianolide natural products: thapsigargin, thapsivillosin C, thapsivillosin F, trilobolide and nortrilobolide. Prodrug derivatives of thapsigargin have shown selective in vivo cytotoxicity against prostate tumours and the need for further investigation of this phenomenon highlights the importance of these total syntheses. The first absolute stereochemical assignment of thapsivillosin C is also delineated.
Assuntos
Inibidores Enzimáticos/síntese química , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/antagonistas & inibidores , Sesquiterpenos de Guaiano/síntese química , Tapsigargina/síntese química , Alcenos/química , Fatores Biológicos/síntese química , Fatores Biológicos/química , Fatores Biológicos/farmacologia , Ciclização , Relação Dose-Resposta a Droga , Retículo Endoplasmático/enzimologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Estrutura Molecular , Nanotecnologia , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/química , Sesquiterpenos de Guaiano/química , Sesquiterpenos de Guaiano/farmacologia , Estereoisomerismo , Tapsigargina/análogos & derivados , Tapsigargina/farmacologiaRESUMO
A two-step selenocyclisation-oxidative deselenaton sequence was used to establish the 3a-hydroxy-pyrrolo[2,3-b]indole core; these tricycles were used as effective precursors to 10b-hydroxy-pyrazino[1',2':1,5]pyrrolo[2,3-b]indole-1,4-diones.
RESUMO
The first total synthesis of (+)-okaramine C is described. Our previously described selenocyclisation-oxidative deselenation sequence was used to establish a 3a-hydroxy-pyrrolo[2,3-b]indole core, which was modified by selective epimerisation to the common pyrrolo[2,3-b]indole of the okaramines.
Assuntos
Alcaloides Indólicos/síntese química , Alcaloides Indólicos/química , Conformação MolecularRESUMO
The synthesis of the germination self-inhibitor (-)-Gloeosporone is reported. The embedded 1,7-diol motif in the product is constructed by an ironcarbonyl tether controlled Mukaiyama aldol reaction. The key step in the synthesis is the reductive removal of the ligating iron species by treatment of an acetoxycomplex 6 with lithium naphthalenide.
Assuntos
Antifúngicos/síntese química , Antifúngicos/farmacologia , Lactonas/química , Lactonas/síntese química , Lactonas/farmacologia , Esporos Fúngicos/efeitos dos fármacos , Antifúngicos/química , Colletotrichum/química , Estrutura Molecular , Esporos Fúngicos/fisiologiaRESUMO
The thapsigargins are a family of complex guaianolides with potent and selective Ca(2+)-modulating properties. This article documents the evolution of a synthetic route through several iterations to a final practical and scaleable synthetic route capable of generating both unnatural and natural products based around the guaianolide skeleton.