RESUMO
A formyl equivalent was generated in situ from Eschenmoser's salt in aqueous THF and was reacted with an allylindium species. Acylnitroso-derived hetero-Diels Alder adducts and related allyl acetates were shown to be substrates for Pd(0)/InI-mediated allylations of formaldehyde-related species to provide homoallylic alcohols. Hydroxymethyl groups were installed with regio- and diastereocontrol to provide relevant disubstituted carbocyclic scaffolds. Enantiopure anti-disubstituted cyclopentene products were prepared from a chiral allyl acetate.
RESUMO
Carbocyclic aminonucleosides and epi-4'-carbocyclic puromycin were prepared from an acylnitroso-derived hetero Diels-Alder cycloadduct. Pd(0)/InI-mediated allylations of a formyl species were used to install the 4'-hydroxymethyl group. A tethered aminohydroxylation strategy was employed to install the cis-2',3'-aminoalcohol moiety with complete regio- and diastereocontrol.
RESUMO
Carbocyclic uracil polyoxin C analogs are prepared from an acylnitroso-derived hetero Diels-Alder cycloadduct in fewer than nine steps. Pd(0)/InI-mediated allylation of 4-acetoxy-2-azetidinone is used to install the beta-amino acid side chain at the C-5' position of the carbocycle.
Assuntos
Azetidinas/química , Índio/química , Paládio/química , Nucleosídeos de Pirimidina/síntese química , Uracila/análogos & derivados , Estrutura Molecular , Nucleosídeos de Pirimidina/química , Estereoisomerismo , Uracila/síntese química , Uracila/químicaRESUMO
Titanocene(III) chloride (Cp(2)TiCl), generated in situ, reduces N-O bonds of various substrates in good to excellent yields (72-95%). Reactions may be performed with stoichiometric Cp(2)TiCl or with catalytic Cp(2)TiCl.
Assuntos
Carbamatos/química , Cloretos/química , Ácidos Hidroxâmicos/química , Compostos Organometálicos/química , Oxazinas/química , Catálise , Estrutura Molecular , Oxirredução , EstereoisomerismoRESUMO
Acylnitroso-derived hetero-Diels-Alder cycloadducts are susceptible to C-O bond cleavage with Pd(0) and InI to form allylic indium(III) species. The in situ prepared allylindium compounds readily react at room temperature with Eschenmoser's salt. Allylation of 4-acetoxy-2-azetidinone provides derivatized cyclopentenes in high regio- and diastereoselectivity.
Assuntos
Azetidinas/química , Ciclopentanos/síntese química , Índio/química , Paládio/química , Catálise , Cristalografia por Raios X , Ciclização , Ciclopentanos/química , Ácidos Hidroxâmicos/química , Conformação Molecular , EstereoisomerismoRESUMO
Homoallylic esters are obtained in a single transformation from allyl 2,2,2-trifluoroethyl malonates by using a Pd(0) catalyst. Facile decarboxylation of allyl 2,2,2-trifluoroethyl malonates is attributed to a decrease in pK(a) compared to allyl methyl malonates. Subsequent reduction of the homoallylic 2,2,2-trifluoroethyl ester provides a (hydroxyethyl)cyclopentenyl derivative that represents a key intermediate in the synthesis of carbocyclic nucleosides. A select allyl 2,2,2-trifluoroethyl malonate undergoes a decarboxylative Claisen rearrangement to provide a regioisomeric homoallylic ester.
Assuntos
Malonatos/química , Paládio/química , Catálise , Ciclização/efeitos da radiação , Descarboxilação/efeitos dos fármacos , Estrutura MolecularRESUMO
A series of novel 8-amino-1,3-disubstituted-imidazo[1,5-a]pyrazines was designed and synthesized as IGF-IR inhibitors.
Assuntos
Imidazóis/síntese química , Imidazóis/farmacologia , Pirazinas/síntese química , Pirazinas/farmacologia , Receptor IGF Tipo 1/antagonistas & inibidores , Trifosfato de Adenosina/metabolismo , Animais , Área Sob a Curva , Sítios de Ligação , Disponibilidade Biológica , Cristalografia por Raios X , Bases de Dados de Proteínas , Meia-Vida , Indicadores e Reagentes , Camundongos , Modelos Moleculares , Proteínas Tirosina Quinases/antagonistas & inibidores , Relação Estrutura-AtividadeRESUMO
3-[6-(2-Dimethylamino-1-imidazol-1-yl-butyl)-naphthalen-2-yloxy]-2,2-dimethyl-propionic acid and analogs were designed and synthesized as highly potent and selective CYP26 inhibitors, serving as retinoic acid metabolic blocking agents (RAMBAs), with demonstrated in vivo efficacy to increase the half-life of exogenous atRA.
Assuntos
Inibidores Enzimáticos/farmacologia , Naftalenos/farmacologia , Propionatos/farmacologia , Tretinoína/metabolismo , Cromatografia Líquida de Alta Pressão , Inibidores das Enzimas do Citocromo P-450 , Sistema Enzimático do Citocromo P-450 , Inibidores Enzimáticos/farmacocinética , Meia-Vida , Espectrometria de Massas , Naftalenos/farmacocinética , Propionatos/farmacocinética , Ácido Retinoico 4 Hidroxilase , Tretinoína/antagonistas & inibidoresRESUMO
A series of [2-imidazol-1-yl-2-(6-alkoxy-naphthalen-2-yl)-1-methyl-ethyl]-dimethyl-amines were designed and synthesized as CYP26 inhibitors, serving as retinoic acid metabolic blocking agents (RAMBA's).
Assuntos
Inibidores das Enzimas do Citocromo P-450 , Dimetilaminas/química , Dimetilaminas/farmacologia , Imidazóis/química , Imidazóis/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sistema Enzimático do Citocromo P-450 , Dimetilaminas/síntese química , Humanos , Imidazóis/síntese química , Masculino , Microssomos/enzimologia , Ratos , Ácido Retinoico 4 HidroxilaseRESUMO
The regio- and stereospecific conversion of syn- and anti-1,2-amino alcohols to their respective syn- and anti-1,2-imidazolylpropylamines via treatment with 1,1'-carbonyldiimidazole is described. The rationale behind the regio- and stereospecific nature as well as the generality of the reaction is discussed.