Polar-Radical Cyclization Cascades with Magnesiated Nitriles.

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.

The discovery and characterization of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor potentiator N-{(3S,4S)-4-[4-(5-cyano-2-thienyl)phenoxy]tetrahydrofuran-3-yl}propane-2-sulfonamide (PF-04958242).

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.

Metalated Nitriles: Stereodivergent Cation-Controlled Cyclizations1.

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.

Metalated nitriles: cation-controlled cyclizations.

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.