RESUMO
An efficient general methodology for the synthesis of 4-quinolinyl ethers is demonstrated via a highly reactive SNAr reaction of 4-quinolinyl sulfones with a range of structurally diversified 1°, 2°, and 3° alcohols with a wide substrate scope and high yields. By adapting this methodology, a convergent synthesis of a complex target of HCV NS3/4a protease inhibitor BI 201420 was accomplished.
Assuntos
Hepatite C , Proteínas não Estruturais Virais , Antivirais , Éteres , Hepacivirus , Humanos , Inibidores de Proteases/farmacologia , SulfonasRESUMO
Enantioenriched aldehydes are produced through asymmetric hydroformylation of styrene derivatives using BIBOP-type ligands. The featured example is enantioselective synthesis of 4-methyl-3,4-dihydroisocoumarin, which was prepared in a 95.1:4.9 enantiomeric ratio from asymmetric hydroformylation of ethyl 2-vinylbenzoate followed by in situ lactonization during the reduction process. The conditions are compatible with both electron-rich and electron-poor substituents.
Assuntos
Cumarínicos/síntese química , Estireno/química , Aldeídos/química , Cumarínicos/química , Ligantes , Estrutura Molecular , EstereoisomerismoRESUMO
A chromatography-free, asymmetric synthesis of the C2-symmetric P-chiral diphosphine t-Bu-SMS-Phos was developed using a chiral auxiliary-based approach in five steps from the chiral auxiliary in 36% overall yield. Separtion and recovery of the auxiliary were achieved with good yield (97%) to enable recycling of the chiral auxiliary. An air-stable crystalline form of the final ligand was identified to enable isolation of the final ligand by crystallization to avoid chromatography. This synthetic route was applied to prepare up to 4 kg of the final ligand. The utility of this material was demonstrated in the asymmetric hydrogenation of trifluoromethyl vinyl acetate at 0.1 mol % Rh loading to access a surrogate for the pharmaceutically relavent chiral trifluoroisopropanol fragment in excellent yield and enantiomeric excess (98.6%).
RESUMO
An efficient and practical synthesis of enantiomerically pure P-chiral dihydrobenzooxaphosphole (BOP) core 1 is developed that is amenable to large scale preparation of the related ligand series. The unique epimerization of the P-chiral center of the undesired (R,R)-diastereomeric phosphine oxide 19 through chlorination followed by crystallization makes this chemical resolution method achieve 65% yield of desired (R,S)-diastereomer 12.
RESUMO
An efficient Negishi cross-coupling was developed for the synthesis of the biaryl axes present in useful P-chiral dihydrobenzooxaphosphole ligands. This approach has allowed for the synthesis of new derivatives of these ligands that were not accessible by the previous route employing Suzuki-Miyaura cross-coupling. The use of Pd2(dba)3/BI-DIME as the catalyst system affords the desired biaryl compounds in good yields with excellent rates and with catalyst loadings as low as 0.25 mol %.
RESUMO
An efficient synthesis of the enantiomerically pure 3,3'-bis-arylated BINOL derivatives is accomplished through the palladium-catalyzed Suzuki-Miyaura coupling of the unprotected 3,3'-dibromo-BINOL with complete retention of enantiopurity. The active catalyst system Pd(OAc)2/BI-DIME has enabled mild reaction conditions at palladium loads as low as 500 ppm.
RESUMO
An efficient asymmetric synthesis of 11-ß-HSD inhibitor 1 has been accomplished in five linear steps and 53% overall yield, starting from the readily available 3-chloro-1-phenylpropan-1-one. The key feature of the synthesis includes an asymmetric methallylation of 3-chloro-1-phenylpropan-1-one catalyzed by the highly effective organocatalyst (S)-3,3'-F2-BINOL under solvent-free and metal-free conditions.
Assuntos
11-beta-Hidroxiesteroide Desidrogenases/antagonistas & inibidores , Naftóis/síntese química , Propano/análogos & derivados , 11-beta-Hidroxiesteroide Desidrogenases/química , Catálise , Cetonas/química , Naftóis/química , Propano/síntese química , Propano/química , EstereoisomerismoRESUMO
Hyosine butyl bromide, the active ingredient in Buscopan, is an anticholinergic and antimuscarinic drug used to treat pain and discomfort caused by abdominal cramps. A straightforward synthesis of carbon-14- and deuterium-labeled Buscopan was developed using scopolamine, n-butyl-1-14 C bromide, and n-butyl-2 H9 bromide, respectively. In a second carbon-14 synthesis, the radioactive carbon was incorporated in the tropic acid moiety to follow its metabolism. Herein, we describe the detailed preparations of carbon-14- and deuterium-labeled Buscopan.
Assuntos
Brometo de Butilescopolamônio/química , Radioisótopos de Carbono/química , Deutério/química , Brometo de Butilescopolamônio/síntese química , Marcação por IsótopoRESUMO
A nickel-catalyzed Heck cyclization for the construction of quaternary stereocenters is reported. This transformation is demonstrated in the synthesis of 3,3-disubstituted oxindoles, which are prevalent motifs seen in numerous biologically active molecules. The method shows broad scope, proceeds in synthetically useful yields, and provides a rare means to construct stereochemically complex frameworks by nonprecious-metal catalysis.
RESUMO
A practical sequence involving a noncryogenic stereospecific boronate rearrangement followed by a robust formylation with an in situ generated DCM anion has been developed for the asymmetric construction of an all-carbon quaternary stereogenic center of a FLAP inhibitor. The key boronate rearrangement was rendered noncryogenic and robust by using LDA as the base and instituting an in situ trapping of the unstable lithiated benzylic carbamate with the boronic ester. A similar strategy was implemented for the DCM formylation reaction. It was found that the 1,2-boronate rearrangement for the formylation reaction could be temperature-controlled, thus preventing overaddition of the DCM anion and rendering the process reproducible. The robust stereospecific boronate rearrangement and formylation were utilized for the practical asymmetric synthesis of a chiral quaternary FLAP inhibitor.
Assuntos
Inibidores da Proteína Ativadora de 5-Lipoxigenase/síntese química , Compostos de Boro/química , Carbamatos/química , Inibidores da Proteína Ativadora de 5-Lipoxigenase/química , Catálise , Estrutura Molecular , EstereoisomerismoRESUMO
The three-dimensional solution conformation of teicoplanin aglycone was determined using NMR spectroscopy. A combination of NOE and dihedral angle restraints in a DMSO solvation model was used to calculate an ensemble of structures having a root mean square deviation of 0.17 Å. The structures were generated using systematic searches of conformational space for optimal satisfaction of distance and dihedral angle restraints. Comparison of the NMR-derived structure of teicoplanin aglycone with the X-ray structure of a teicoplanin aglycone analog revealed a common backbone conformation with deviation of two aromatic side chain substituents. Experimentally determined backbone (13)C chemical shifts showed good agreement with those computed at the density functional level of theory, providing a cross validation of the backbone conformation. The flexible portion of the molecule was consistent with the region that changes conformation to accommodate protein binding. The results showed that a hydrogen-bonded DMSO molecule in combination with NMR-derived restraints together enabled calculation of structures that satisfied experimental data.
Assuntos
Simulação por Computador , Dimetil Sulfóxido/química , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Teicoplanina/análogos & derivados , Conformação Molecular , Soluções , Teicoplanina/químicaRESUMO
A practical and efficient synthesis of a complex chiral atropisomeric HIV integrase inhibitor has been accomplished. The combination of a copper-catalyzed acylation along with the implementation of the BI-DIME ligands for a ligand-controlled Suzuki cross-coupling and an unprecedented bis(trifluoromethane)sulfonamide-catalyzed tert-butylation renders the synthesis of this complex molecule robust, safe, and economical. Furthermore, the overall synthesis was conducted in an asymmetric and diastereoselective fashion with respect to the imbedded atropisomer.
Assuntos
Inibidores de Integrase de HIV/síntese química , Integrase de HIV/química , HIV/enzimologia , Acilação , Catálise , Cobre/química , Integrase de HIV/metabolismo , Inibidores de Integrase de HIV/química , Humanos , Ligantes , Estereoisomerismo , Sulfonamidas/químicaRESUMO
The use of chiral phosphinamides is relatively unexplored because of the lack of a general method for the synthesis. Reported herein is the development of a general, efficient, and highly enantioselective method for the synthesis of structurally diverse P-stereogenic phosphinamides. The method relies on nucleophilic substitution of a chiral phosphinate derived from the versatile chiral phosphinyl transfer agent 1,3,2-benzoxazaphosphinine-2-oxide. These chiral phosphinamides were utilized for the first synthesis of readily tunable P-stereogenic Lewis base organocatalysts, which were used successfully for highly enantioselective catalysis.
Assuntos
Amidas/síntese química , Bases de Lewis/química , Fosfinas/síntese química , Ácidos Fosfínicos/química , Amidas/química , Técnicas de Química Sintética , Estrutura Molecular , Fosfinas/química , EstereoisomerismoRESUMO
Air-stable P-chiral dihydrobenzooxaphosphole oxazoline ligands were designed and synthesized. When they were used in the iridium-catalyzed asymmetric hydrogenation of unfunctionalized 1-aryl-3,4-dihydronaphthalenes under one atmosphere pressure of H2 , up to 99:1 e.r. was obtained. High enantioselectivities were also observed in the reduction of the exocyclic imine derivatives of 1-tetralones.
Assuntos
Hidrogênio/química , Irídio/química , Oxazóis/química , Catálise , Hidrogenação , Iminas/química , Modelos Moleculares , EstereoisomerismoRESUMO
An enantioselective copper-catalyzed asymmetric conjugate addition of Me2Zn to (Z)-nitroalkenes led to the formation of all-carbon quaternary stereogenic centers with high stereoselectivity. The key features of the new method are the unprecedented use of [(MeCN)4Cu]PF6 in conjunction with the Hoveyda ligand L1 and the use of (Z)-nitroalkene substrates so that undesired nitroalkene isomerization is minimized and enantioselectivity is enhanced dramatically. We also describe a novel, practical, and highly (Z)-selective nitroalkene synthesis.
Assuntos
Alcenos/química , Cobre/química , Nitrogênio/química , Compostos Organometálicos/química , Catálise , Cromatografia Líquida de Alta Pressão , Isomerismo , Ligantes , EstereoisomerismoRESUMO
A general, efficient, and highly diastereoselective method for the synthesis of structurally and sterically diverse P-chiral phosphine oxides was developed. The method relies on sequential nucleophilic substitution on the versatile chiral phosphinyl transfer agent 1,3,2-benzoxazaphosphinine-2-oxide, which features enhanced and differentiated P-N and P-O bond reactivity toward nucleophiles. The reactivities of both bonds are fine-tuned to allow cleavage to occur even with sterically hindered nucleophiles under mild conditions.
Assuntos
Óxidos P-Cíclicos/síntese química , Fosfinas/síntese química , Óxidos P-Cíclicos/química , Ligantes , Estrutura Molecular , Fosfinas/química , EstereoisomerismoRESUMO
Carbamoyl anions, generated from N,N-disubstituted formamides and lithium diisopropylamide, add with high diastereoselectivity to chiral N-sulfinyl aldimines and ketimines to provide α-amino amides. The methodology enables the direct introduction of a carbonyl group without the requirement of unmasking steps as with other nucleophiles. The products may be converted to α-amino esters or 1,2-diamines. Iterative application of the reaction enabled the stereoselective synthesis of a dipeptide. Spectroscopic and computational studies support an anion structure with η(2) coordination of lithium by the carbonyl group.
Assuntos
Amidas/química , Amidas/síntese química , Iminas/química , Técnicas de Química Sintética , Dipeptídeos/síntese química , Dipeptídeos/química , Modelos Moleculares , Conformação Molecular , Estereoisomerismo , Especificidade por SubstratoRESUMO
The development of zinc-mediated and -catalyzed asymmetric propargylations of trifluoromethyl ketones with a propargyl borolane and the N-isopropyl-l-proline ligand is presented. The methodology provided moderate to high stereoselectivity and was successfully applied on a multikilogram scale for the synthesis of the Glucocorticoid agonist BI 653048. A mechanism for the boron-zinc exchange with a propargyl borolane is proposed and supported by modeling at the density functional level of theory. A water acceleration effect on the zinc-catalyzed propargylation was discovered, which enabled a catalytic process to be achieved. Reaction progress analysis supports a predominately rate limiting exchange for the zinc-catalyzed propargylation. A catalytic amount of water is proposed to generate an intermediate that catalyzes the exchange, thereby facilitating the reaction with trifluoromethyl ketones.
Assuntos
Ácidos Borônicos/química , Hidrocarbonetos Fluorados/química , Cetonas/química , Pargilina/análogos & derivados , Pargilina/química , Prolina/análogos & derivados , Prolina/química , Zinco/química , Catálise , Estrutura Molecular , EstereoisomerismoRESUMO
The development of a large scale synthesis of the glucocorticoid agonist BI 653048 BS H3PO4 (1·H3PO4) is presented. A key trifluoromethyl ketone intermediate 22 containing an N-(4-methoxyphenyl)ethyl amide was prepared by an enolization/bromine-magnesium exchange/electrophile trapping reaction. A nonselective propargylation of trifluoromethyl ketone 22 gave the desired diastereomer in 32% yield and with dr = 98:2 from a 1:1 diastereomeric mixture after crystallization. Subsequently, an asymmetric propargylation was developed which provided the desired diastereomer in 4:1 diastereoselectivity and 75% yield with dr = 99:1 after crystallization. The azaindole moiety was efficiently installed by a one-pot cross coupling/indolization reaction. An efficient deprotection of the 4-methoxyphenethyl group was developed using H3PO4/anisole to produce the anisole solvate of the API in high yield and purity. The final form, a phosphoric acid cocrystal, was produced in high yield and purity and with consistent control of particle size.
Assuntos
Amidas/química , Benzamidas/química , Glucocorticoides/agonistas , Glucocorticoides/química , Piridinas/química , Pirróis/química , Estrutura Molecular , EstereoisomerismoRESUMO
In this paper, we describe the enantiomeric separation of a chiral alcohol under subcritical fluid chromatography conditions using a 3 µm particle size bonded amylose carbamate stationary phase. Linear and branched alcohols were used as polar modifiers in CO2. The studies with linear alcohols showed a decrease in selectivity factor as the number of carbons in the linear chain increased. For branched alcohols, as the bulk of substituents at the α carbon atom increases the separation factor decreases. Thermodynamic studies showed that in the presence of the alcohols studies, except methanol and ethanol, a positive ΔΔS was observed. Molecular mechanics simulation brought more insights into the mechanism of enantiomeric separation on this stationary phase under subcritical fluid chromatography.