RESUMO
An efficient synthesis of S-allyl thioimidate hydrobromide salts via coupling of thioamides with allyl bromide derivatives is described. A range of mono-, di-, and trisubstituted olefins as well as alkyl- and arylthioamides with variations in electronics are tolerated. A rapid anti-diastereoselective halocyclization of these salts provides a variety of substituted alkyl- and arylthiazolines. Initial development of an efficient enantioselective synthesis of quaternary-substituted thiazolines through the organo-catalyzed halocyclization of sulfonate thioimidate salts is also described.
RESUMO
An improved and expanded preparation of thiohydroxamic acids is reported along with a one-pot conversion of these compounds to novel thiohydroximic acid derivatives. A variety of aryl, heteroaryl, and alkyl substituents are well tolerated to provide a rapid approach to alkene-functionalized thiohydroximic acids that serve as potentially useful building blocks for organic synthesis.
RESUMO
A diversity-oriented synthesis (DOS) strategy was developed for the synthesis of stereochemically diverse fused-ring systems containing a pyran moiety. Each scaffold contains an amine and methyl ester for further diversification via amine capping and amide coupling. Scaffold diversity was evaluated in comparison to previously prepared scaffolds by a shape-based principal moments of inertia (PMI) analysis.
Assuntos
Glicosídeos/síntese química , Glicosídeos/química , Conformação Molecular , Piranos/química , EstereoisomerismoRESUMO
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 , EstereoisomerismoRESUMO
An oxidative formation of 1,4,2-oxathiazoles from readily available thiohydroximic acids is reported. A variety of alkyl, aryl, and heteroaryl substituents are well tolerated for both the thiohydroximic acid and activating fragments, and the reaction has been demonstrated on gram-scale. This reaction represents the only method currently available to prepare a diverse set of oxathiazoles and expands the chemistry of C-H oxidation via appended N-OH functional groups. Finally, we also demonstrate the rapid preparation of a 1,4,2-oxathiazole analog of an anticancer lead molecule.
Assuntos
Antineoplásicos/síntese química , Oximas/química , Tiazóis/síntese química , Antineoplásicos/química , Catálise , Cobre/química , Ciclização , Estrutura Molecular , Oxirredução , Tiazóis/químicaRESUMO
A copper catalyzed aminobromination of alkene tethered thiohydroximic acids is described, providing a rapid approach to unnatural thiazoline scaffolds not readily available via existing methods. Moderate to high yields of bromothiazolines are obtained with alkyl- and aryl-substituted thiohydroximic acid building blocks containing mono-, di-, and trisubstituted alkenes. The reaction provides high levels of 5-exo selectivity, and terminally monosubstituted alkenes result in predominant syn-diastereoselectivity.
Assuntos
Cobre/química , Hidrocarbonetos Bromados/síntese química , Oximas/química , Tiazolidinas/síntese química , Alcenos/síntese química , Aminas/síntese química , Catálise , Técnicas de Química Combinatória , Hidrocarbonetos Bromados/química , Estrutura Molecular , Estereoisomerismo , Tiazolidinas/químicaRESUMO
Hydroxamic acids were designed, synthesized, and evaluated for their ability to selectively inhibit human histone deacetylase 6 (HDAC6). Several inhibitors, including compound 14 (BRD9757), exhibited excellent potency and selectivity despite the absence of a surface-binding motif. The binding of these highly efficient ligands for HDAC6 is rationalized via structure-activity relationships. These results demonstrate that high selectivity and potent inhibition of HDAC6 can be achieved through careful choice of linker element only.