RESUMO
Naphthalene converts magnesiated ω-alkenylnitriles into bi- and tricyclic ketones via a polar-radical addition-cyclization cascade. One-electron oxidation of magnesiated nitriles generates nitrile-stabilized radicals that cyclize onto a pendant olefin and then rebound onto the nitrile through a reduction-cyclization sequence; subsequent hydrolysis affords a diverse array of bicyclo[3.2.0]heptan-6-ones. Combining the polar-radical cascade with a 1,2:1,4-carbonyl-conjugate addition generates complex cyclobutanones containing four new carbon-carbon bonds and four chiral centers in one synthetic operation.
RESUMO
A unique tetrahydrofuran ether class of highly potent α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor potentiators has been identified using rational and structure-based drug design. An acyclic lead compound, containing an ether-linked isopropylsulfonamide and biphenyl group, was pharmacologically augmented by converting it to a conformationally constrained tetrahydrofuran to improve key interactions with the human GluA2 ligand-binding domain. Subsequent replacement of the distal phenyl motif with 2-cyanothiophene to enhance its potency, selectivity, and metabolic stability afforded N-{(3S,4S)-4-[4-(5-cyano-2-thienyl)phenoxy]tetrahydrofuran-3-yl}propane-2-sulfonamide (PF-04958242, 3), whose preclinical characterization suggests an adequate therapeutic index, aided by low projected human oral pharmacokinetic variability, for clinical studies exploring its ability to attenuate cognitive deficits in patients with schizophrenia.
Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Receptores de AMPA/metabolismo , Sulfonamidas/farmacologia , Tiofenos/farmacologia , Administração Oral , Adolescente , Adulto , Idoso , Animais , Sítios de Ligação , Modelos Animais de Doenças , Cães , Relação Dose-Resposta a Droga , Descoberta de Drogas , Estabilidade de Medicamentos , Feminino , Humanos , Masculino , Memória de Curto Prazo/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Conformação Proteica , Ratos Sprague-Dawley , Esquizofrenia/tratamento farmacológico , Relação Estrutura-Atividade , Sulfonamidas/química , Tiofenos/química , Adulto JovemRESUMO
Stereodivergent cyclizations of gamma-hydroxy cyclohexanecarbonitriles are controlled simply through judicious choice of cation in the alkylmetal base. Deprotonating a series of cyclic gamma-hydroxy nitriles with i-PrMgBr generates C-magnesiated nitriles that cyclize under stereoelectronic control to cis-fused hydrindanes, decalins, and bicyclo [5.4.0] undecanes. An analogous deprotonation with BuLi triggers cyclization to trans-fused hydrindanes, decalins, and bicyclo [5.4.0] undecanes consistent with a sterically controlled electrophilic attack on an equatorial nitrile anion. Using cations to control the geometry of metalated nitriles provides a versatile, stereodivergent cyclization to cis- and trans-hydrindanes, decalins, and [5. 4. 0] undecanes, and reveals the key geometric requirements for intramolecular S(N)2 and S(N)2' displacements.
RESUMO
Judicious choice of cation allows the selective cyclization of substituted gamma-hydroxynitriles to trans- or cis-decalins and trans- or cis-bicyclo[5.4.0]undecanes. The stereoselectivities are consistent with deprotonations generating two distinctly different metalated nitriles: an internally coordinated nitrile anion with BuLi, and a C-magnesiated nitrile with i-PrMgCl. Employing cations to control the geometry of metalated nitriles permits stereodivergent cyclizations with complete control over the stereochemistry of the quaternary, nitrile-bearing carbon.
