RESUMO
Carbocyclic nucleosides (-)-5'-homocarbovir and (+)-epi-4'-homocarbovir were prepared from an acylnitroso-derived hetero Diels-Alder cycloadduct. A kinetic enzymatic resolution generated an enantiopure aminocyclopentenol and Pd(0)-mediated decarboxylative allylations of allyl 2,2,2-trifluoroethyl malonates were used to install the 4'-hydroxyethyl groups. Late stage derivatization gave access to the cyclopropylamine congenors, (-)-5'-homoabacavir and (+)-epi-4'-homoabacavir. All carbonucleoside target molecules were evaluated for antiviral activity.
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
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
By employing an intramolecular Pd(0)-mediated ring opening of an acylnitroso-derived cycloadduct, new hydroxamic acid containing benzodiazepines have been synthesized and have demonstrated biological activity in MCF-7 and PC-3 tumor cell lines. Subsequent N-O bond reduction of the hydroxamate has provided access to amide analogues for SAR studies. During the course of our syntheses, an intermediate oxazoline N-oxide was isolated and gave insight into the mechanism of the key Pd(0)-mediated reaction.
Assuntos
Antineoplásicos/síntese química , Benzodiazepinas/síntese química , Ácidos Hidroxâmicos/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Benzodiazepinas/química , Benzodiazepinas/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
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.