RESUMO
This paper describes the fluorination of nitrogen heterocycles using anhydrous NBu4F. Quinoline derivatives as well as a number of 3- and 5-substituted pyridines undergo high-yielding fluorination at room temperature using this reagent. These results with anhydrous NBu4F compare favorably to traditional halex fluorinations using alkali metal fluorides, which generally require temperatures of ≥100 °C.
Assuntos
Fluoretos/química , Compostos Heterocíclicos/química , Piridinas/química , Compostos de Amônio Quaternário/química , Compostos de Amônio Quaternário/síntese química , Halogenação , Indicadores e Reagentes/química , Metais Alcalinos/químicaRESUMO
Multidrug-resistant (MDR) clinical isolate-769, human immunodeficiency virus type-1 (HIV-1) protease (PDB ID: 1TW7), was shown to exhibit wide-open flaps and an expanded active site cavity, causing loss of contacts with protease inhibitors. In the current study, the expanded active site cavity of MDR769 HIV-1 protease was screened with a series of peptide-inhibitors that were designed to mimic the natural substrate cleavage site, capsid/p2. Scanning Ala/Phe chemical mutagenesis approach was incorporated into the design of the peptide series to mimic the substrate co-evolution. Among the peptides synthesized and evaluated, a lead peptide (6a) with potent activity (IC50: 4.4nM) was identified against the MDR769 HIV-1 protease. Isothermal titration calorimetry data showed favorable binding profile for 6a against both wild type and MDR769 HIV-1 protease variants. Nuclear magnetic resonance spectrum of (15)N-labeled MDR769 HIV-1 protease in complex with 6a showed some major perturbations in chemical shift, supporting the peptide induced conformational changes in protease. Modeling analysis revealed multiple contacts between 6a and MDR769 HIV-1 protease. The lead peptide-inhibitor, 6a, with high potency and good binding profile can be used as the basis for developing potent small molecule inhibitors against MDR variants of HIV.
Assuntos
Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/química , Inibidores da Protease de HIV/farmacologia , Protease de HIV/metabolismo , HIV-1/enzimologia , Peptídeos/química , Peptídeos/farmacologia , Sequência de Aminoácidos , Desenho de Fármacos , Farmacorresistência Viral Múltipla , Infecções por HIV/virologia , Protease de HIV/genética , Inibidores da Protease de HIV/metabolismo , HIV-1/efeitos dos fármacos , HIV-1/genética , Humanos , Simulação de Acoplamento Molecular , Mutagênese , Biblioteca de Peptídeos , Peptídeos/genéticaRESUMO
Marine neuroexcitatory compounds isodomoic acids G and H were efficiently synthesized from a common intermediate using a silicon-based cross-coupling reaction. Dividing each target compound into the core fragment and the side-chain fragment enabled the synthesis to be convergent. The trans-2,3-disubstituted pyrrolidine core fragment was accessed through a diastereoselective rhodium-catalyzed carbonylative silylcarbocyclization reaction of a vinylglycine-derived 1,6-enyne. A stereochemically divergent desilylative iodination reaction was developed to convert the cyclization product to both E- and Z-alkenyl iodides, which would eventually lead to isodomoic acid G and isodomoic acid H, respectively. The late-stage alkenyl-alkenyl silicon-based cross-coupling reaction uniting the core alkenyl iodides and the side-chain alkenylsilanol was achieved under mild conditions. Finally, two mild deprotections afforded the target molecules.
Assuntos
Ácidos Heptanoicos/síntese química , Alcenos/química , Reagentes de Ligações Cruzadas , Ciclização , Ácidos Heptanoicos/química , Ácidos Heptanoicos/classificação , Estrutura Molecular , Silício/química , EstereoisomerismoRESUMO
A general strategy for the construction of macrocyclic lactones containing conjugated Z,Z-1,3-diene subunits is described. The centerpiece of the strategy is a sequential ring-closing metathesis (RCM) that forms an unsaturated siloxane ring, followed by an intramolecular cross-coupling reaction with a pendant alkenyl iodide. A highly modular assembly of the various precursors allowed the preparation of unsaturated macrolactones containing 11-, 12-, 13-, and 14-membered rings. Although the RCM process proceeded uneventfully, the intramolecular cross-coupling required extensive optimization of palladium source, solvent, fluoride source, and particularly fluoride hydration level. Under the optimal conditions (including syringe pump high dilution), the macrolactones were produced in 53-78% yield as single stereoisomers. A benzo-fused 12-membered-ring macrolactone containing an E,Z-1,3-diene unit was also prepared by the same general strategy. The E-2-styryl iodide was prepared by a novel Heck reaction of an aryl nonaflate with vinyltrimethylsilane followed by iododesilylation with ICl.
Assuntos
Macrolídeos/síntese química , Macrolídeos/química , Estrutura Molecular , EstereoisomerismoRESUMO
The total syntheses of marine natural products belonging to the kainoid family, isodomoic acids G and H, are described. The strategic connection involves a sequential silylcarbocyclization/silicon-based cross-coupling process. These total syntheses were achieved efficiently via a 12- and a 13-step, longest-linear sequence, respectively. The key transformations include a diastereoselective rhodium-catalyzed carbonylative silylcarbocyclization reaction of an (l)-vinylglycine-derived 1,6-enyne, a desilylative iodination reaction, as well as an alkenyl-alkenyl silicon-based cross-coupling reaction. The mechanistic insight garnered during the investigation of the iododesilylation reaction enabled stereocontrolled introduction of the iodine with either inversion or retention of double bond configuration. The invertive desilylative iodination leads to the total synthesis of isodomoic acid H, while its congener, isodomoic acid G, was obtained via a retentive iododesilylation.
Assuntos
Ácidos Heptanoicos/síntese química , Toxinas Marinhas/síntese química , Rodófitas/químicaRESUMO
The alkali-metal salts (potassium and sodium) of a large number of aryl- and heteroarylsilanols undergo efficient cross-coupling with a wide range of aromatic bromides and chlorides under mild conditions to form polysubstituted biaryls. The critical feature for the success of these coupling reactions and their considerable scope is the use of bis(tri-tert-butylphosphine)palladium. Under the optimized conditions, electron-rich, electron-poor, and sterically hindered arylsilanolates afford cross-coupling products in good yields. Many functional groups are compatible with the coupling conditions such as esters, ketones, acetals, ethers, silyl ethers, and dimethylamino groups. Two particularly challenging substrates, (2-benzofuranyl)dimethylsilanolate and (2,6-dichlorophenyl)dimethylsilanolate prepared as their sodium salts showed excellent activity in the coupling reactions, in the former case also with aromatic chlorides. General methods for the efficient synthesis of a wide range of aromatic silanols are also described.