RESUMO
A mild and nonreversible tert-butylation of alcohols and phenols can be achieved in high yields using the noncoordinating acid-base catalyst [bis(trifluoromethane)sulfonimide and 2,6-lutidine] with a tert-butylation reagent, tert-butyl 2,2,2-trichloroacetimidate. This method allows the use of substrates containing acid sensitive groups such as ketal, Boc, and boronate esters.
Assuntos
Álcoois , Fenóis , Ácidos , Catálise , ÉteresRESUMO
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
A concise asymmetric synthesis of an 11ß-HSD-1 inhibitor has been achieved using inexpensive starting materials with excellent step-economy at low catalyst loadings. The catalytic enantioselective total synthesis of 1 was accomplished in 7 steps and 38% overall yield aided by the development of an innovative, sequential strategy involving Pd-catalyzed pyridinium C-H arylation and Ir-catalyzed asymmetric hydrogenation of the resulting fused tricyclic indenopyridinium salt highlighted by the use of a unique P,N-ligand (MeO-BoQPhos) with 1000 ppm of [Ir(COD)Cl]2.
Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Piperidinas/síntese química , Piperidinas/farmacologia , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Catálise , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Hidrogenação , Irídio/química , Conformação Molecular , Paládio/química , Piperidinas/química , EstereoisomerismoRESUMO
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
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
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
A practical, one-step process for the synthesis of 2,5-disubstituted pyrimidines is presented. The protocol proved to be general for the synthesis of a variety of pyrimidine-containing compounds bearing an assortment of functional groups.
Assuntos
Nitrilas/química , Pirimidinas/síntese química , Estrutura Molecular , Pirimidinas/químicaRESUMO
The epidermal growth factor receptor (EGFR), when carrying an activating mutation like del19 or L858R, acts as an oncogenic driver in a subset of lung tumors. While tumor responses to tyrosine kinase inhibitors (TKIs) are accompanied by marked tumor shrinkage, the response is usually not durable. Most patients relapse within two years of therapy often due to acquisition of an additional mutation in EGFR kinase domain that confers resistance to TKIs. Crucially, oncogenic EGFR harboring both resistance mutations, T790M and C797S, can no longer be inhibited by currently approved EGFR TKIs. Here, we describe the discovery of BI-4020, which is a noncovalent, wild-type EGFR sparing, macrocyclic TKI. BI-4020 potently inhibits the above-described EGFR variants and induces tumor regressions in a cross-resistant EGFRdel19â¯T790Mâ¯C797S xenograft model. Key was the identification of a highly selective but moderately potent benzimidazole followed by complete rigidification of the molecule through macrocyclization.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Animais , Antineoplásicos/farmacocinética , Benzimidazóis/química , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Cristalografia por Raios X , Ciclização , Entropia , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/química , Receptores ErbB/genética , Feminino , Hepatócitos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Transgênicos , Mutação , Conformação Proteica , Inibidores de Proteínas Quinases/farmacocinética , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A copper-catalyzed site-selective propargylation/allenylation reaction toward carbonyl compounds has been mechanistically investigated using a computational approach. Different reaction pathways and catalytic cycles were investigated. Control of the site selectivity arises from a destabilizing interaction introduced by the phenyl-substituted ligand.
Assuntos
Alcadienos/química , Catálise , Cobre , Cetonas , Ligantes , Estrutura MolecularRESUMO
A practical noncryogenic process for the Aggarwal stereospecific boronate rearrangement with chiral secondary benzylic carbamates has been developed. The use of LDA instead of sec-BuLi combined with an in situ trapping of the unstable lithiated carbamate was critical to success. Furthermore, this new process increased the substrate scope to include the versatile aryl iodide and bromide substrates. The methodology was applied to a diverse array of substrates and was demonstrated on multikilogram scale.
Assuntos
Compostos de Benzil/química , Ácidos Borônicos/síntese química , Carbamatos/química , Ácidos Borônicos/química , Ésteres , Estrutura Molecular , EstereoisomerismoRESUMO
A practical and highly site-selective copper-PhBPE-catalyst-controlled allenylation with propargyl boronates has been developed. The methodology has shown to be tolerant of diverse ketones and aldehydes providing the allenyl adducts in high selectivity. The BPE ligand and boronate substituents were shown to direct the site selectivity for which either propargyl or allenyl adducts can be acquired in high selectivity. A model is proposed that explains the origin of the site selectivity.
Assuntos
Aldeídos/química , Alcadienos/síntese química , Compostos de Boro/química , Cobre/química , Cetonas/química , Alcadienos/química , Catálise , Ligantes , Modelos Moleculares , Estrutura MolecularRESUMO
A highly convergent large scale synthesis of a 15-membered macrocyclic hepatitis C virus (HCV) protease inhibitor BI 201302 was achieved, in which the key features are the practical macrocyclization by Ru-catalyzed ring-closing metathesis (0.1 mol % Grela catalyst, 0.1-0.2 M concentration) and the efficient sulfone-mediated SNAr reaction.
Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Peptídeos Cíclicos/síntese química , Peptídeos Cíclicos/farmacologia , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Antivirais/química , Catálise , Ciclização , Estrutura Molecular , Peptídeos Cíclicos/química , Inibidores de Proteases/químicaRESUMO
A series of novel P-chiral monophosphorus ligands exhibit efficiency in asymmetric Suzuki-Miyaura coupling reactions, enabling the construction of an array of chiral biaryl products in high yields and excellent enantioselectivities (up to 96% ee) under mild conditions. The carbonyl-benzooxazolidinone moiety in these chiral biaryl products allows facile derivatization for further synthetic applications. A computational study has revealed that a π-π interaction between the two coupling partners can enhance the enantioselectivity of the coupling reaction.
Assuntos
Benzoxazóis/química , Compostos Organofosforados/química , Paládio/química , Catálise , Técnicas de Química Combinatória , Ligantes , Estrutura Molecular , Compostos Organofosforados/síntese química , EstereoisomerismoRESUMO
In combination with the Bedford Pd precursor, the new biaryl monophosphorus ligand 5 was efficient for palladium-catalyzed Miyaura borylation of sterically hindered aryl bromides at low catalyst loadings.
Assuntos
Compostos de Boro/química , Compostos de Boro/síntese química , Hidrocarbonetos Bromados/química , Compostos Organofosforados/química , Paládio/química , Catálise , Ligantes , Estrutura Molecular , Compostos Organofosforados/síntese químicaRESUMO
A series of structurally novel, operationally convenient, and efficient chiral 2-phosphino-2,3-dihydrobenzo[d][1,3]oxaphosphole ligands was developed. Applications of ligands 3a and 3b in rhodium-catalyzed asymmetric hydrogenation of alpha-(acylamino)acrylates and beta-(acylamino)acrylates provided excellent enantioselectivities (up to >99% ee) and reactivities (up to 10,000 TON).