RESUMO
Deprotonating substituted cyclohexanecarbonitriles with TMPZnCl·LiCl affords zincated nitriles that diastereoselectively couple with aryl bromides in the presence of catalytic Pd(OAc)(2) and S-Phos. Steric and electronic effects influence the diastereoselectivity; 4-t-butyl-, 4-TBSO-, and 2-Me-cyclohexanecarbonitriles exert virtually complete diastereocontrol whereas modest diastereoselectivity is observed with 4-i-Pr-, 4-Me-, and 3-Me-cyclohexanecarbonitriles. The unusual diastereoselectivity trends should prove useful for synthesizing substituted cyclohexanecarbonitrile-containing pharmaceuticals.
Assuntos
Cicloexanos/química , Hidrocarbonetos Bromados/química , Cloreto de Lítio/química , Nitrilas/química , Nitrilas/síntese química , Compostos Organometálicos/química , Zinco/química , Estrutura Molecular , EstereoisomerismoRESUMO
A new general Pd-catalyzed arylation of various 2-methyl-5-membered heterocycles is reported. This novel method requires Li-, Mg-, or Zn-TMP bases and allows selective metalation of the benzylic position. Subsequent Negishi cross-coupling provides the corresponding arylated heterocycles.
Assuntos
Compostos Heterocíclicos/síntese química , Hidrocarbonetos Bromados/química , Paládio/química , Catálise , Compostos Heterocíclicos/química , Estrutura MolecularRESUMO
Protein farnesyltransferase (FTase) has recently appeared as a new target of parasitic diseases, a field poor in drugs in development. With the aim of creating new bisubstrate inhibitors of FTase, new farnesyl pyrophosphate analogues have been studied. Farnesyl analogues with a malonic acid function exhibited the best inhibitory activity on FTase. This group was introduced into our imidazole-containing model leading to new compounds with submicromolar activities. Kinetic experiments have been realized to determine their binding mode to the enzyme.
Assuntos
Farnesiltranstransferase/antagonistas & inibidores , Fosfatos de Poli-Isoprenil/síntese química , Fosfatos de Poli-Isoprenil/farmacologia , Sesquiterpenos/síntese química , Sesquiterpenos/farmacologia , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Cinética , Estrutura Molecular , Testes de Sensibilidade Parasitária , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/crescimento & desenvolvimento , Fosfatos de Poli-Isoprenil/química , Sesquiterpenos/química , Estereoisomerismo , Relação Estrutura-Atividade , Trypanosoma brucei brucei/efeitos dos fármacos , Trypanosoma brucei brucei/crescimento & desenvolvimentoRESUMO
With the aim of creating new bisubstrate inhibitors of protein farnesyltransferase (FTase), new carboxylic farnesyl pyrophosphate analogues have been designed and synthesized. The original structures are built around three elements: a prenyl moiety, a 1,4-diacid motif and an imidazole ring. All the compounds were evaluated for their ability to inhibit FTase and compared with the corresponding derivatives lacking the imidazole ring, synthesized for that purpose. These new compounds are not bisubstrate inhibitors probably because the imidazole ring is not in the right position to interact with the zinc atom. However these derivatives display FPP competitive inhibition with a good activity in the carboxylic farnesyl pyrophosphate analogues series.
