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1.
Angew Chem Int Ed Engl ; 55(6): 2113-7, 2016 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-26732047

RESUMO

This study describes, for the first time, the generation of a SF5 -substituted ester enolate from benzyl SF5 -acetate under soft enolization conditions, which in turn participates in aldol addition reactions in high yield. The reaction was applied in the synthesis of 3-SF5 -quinolin-2-ones, 3-SF5 -quinolines, and 3-SF5 -pyridin-2-ones, none of which have previously been reported. To provide guidelines for their use in drug discovery, the physicochemical properties of these building blocks were determined and compared with those of their CF3 - and t-Bu-analogues.


Assuntos
Cetonas/química , Piridonas/síntese química , Quinolinas/síntese química , Quinolonas/síntese química , Físico-Química , Dissulfetos/química , Fluoretos/química , Estrutura Molecular , Piridonas/química , Quinolinas/química , Quinolonas/química , Compostos de Prata/química
2.
Proc Natl Acad Sci U S A ; 108(17): 6751-6, 2011 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-21383141

RESUMO

Complexity and the presence of stereogenic centers have been correlated with success as compounds transition from discovery through the clinic. Here we describe the synthesis of a library of pyran-containing macrocycles with a high degree of structural complexity and up to five stereogenic centers. A key feature of the design strategy was to use a modular synthetic route with three fragments that can be readily interchanged or "shuffled" to produce subtly different variants with distinct molecular shapes. A total of 352 macrocycles were synthesized ranging in size from 14- to 16-membered rings. In order to facilitate the generation of stereostructure-activity relationships, the complete matrix of stereoisomers was prepared for each macrocycle. Solid-phase assisted parallel solution-phase techniques were employed to allow for rapid analogue generation. An intramolecular nitrile-activated nucleophilic aromatic substitution reaction was used for the key macrocyclization step.


Assuntos
Compostos Macrocíclicos/química , Compostos Macrocíclicos/síntese química , Piranos/química , Estrutura Molecular
3.
Pure Appl Chem ; 85(9): 1789-1801, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26180266

RESUMO

The use of thioglycosides and other glycan derivatives with anomeric sulfur linkages is gaining increasing interest, both in synthesis and in various biological contexts. Herein, we demonstrate the occurrence and circumvention of anomerization during 1-S-glycosylation reactions, and present highly efficient and stereocontrolled syntheses of a series of photoprobe-thiosaccharide conjugates. Mutarotation of glycosyl thiols proved to be the origin of the anomeric mixtures formed, and kinetic effects could be used to circumvent anomerization. The synthesized carbohydrate conjugates were then evaluated by both solution- and solid-phase-based techniques. Both binding results showed that the S-linked glyco-sides interact with their cognate lectins comparably to the corresponding O-analogs in the present cases, thus demonstrating the reliability of the solid-support platform built upon our photo-initiated carbohydrate immobilization method for probing protein bindings, and showing the potential of combining these two means for studying carbohydrate-protein interactions.

4.
J Org Chem ; 77(17): 7187-211, 2012 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-22853001

RESUMO

The synthesis and diversification of a densely functionalized azetidine ring system to gain access to a wide variety of fused, bridged, and spirocyclic ring systems is described. The in vitro physicochemical and pharmacokinetic properties of representative library members are measured in order to evaluate the use of these scaffolds for the generation of lead-like molecules to be used in targeting the central nervous system. The solid-phase synthesis of a 1976-membered library of spirocyclic azetidines is also described.


Assuntos
Azetidinas/farmacocinética , Sistema Nervoso Central/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/farmacocinética , Compostos de Espiro/síntese química , Compostos de Espiro/farmacocinética , Animais , Azetidinas/sangue , Azetidinas/síntese química , Células CACO-2 , Permeabilidade da Membrana Celular/efeitos dos fármacos , Sistema Nervoso Central/citologia , Células Endoteliais/efeitos dos fármacos , Humanos , Camundongos , Estrutura Molecular , Solubilidade , Compostos de Espiro/sangue , Estereoisomerismo
5.
Org Lett ; 15(20): 5147-9, 2013 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-24090251

RESUMO

The preparation of new pentafluorosulfanyl-substituted potassium aryltrifluoroborates via Ir-catalyzed C-H borylation is reported. The utility of these novel building blocks was demonstrated in the Suzuki-Miyaura cross-coupling reaction, giving access to 3,5-disubstituted pentafluorosulfanylbenzenes.


Assuntos
Boratos/química , Fluoretos/química , Irídio/química , Compostos Organometálicos/síntese química , Potássio/química , Compostos de Enxofre/química , Catálise , Estrutura Molecular , Compostos Organometálicos/química , Paládio/química
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