Tricyclic Triazoles as σ Receptor Antagonists for Treating Pain.

The synthesis and pharmacological activity of a new series of 5a,7,8,8a-tetrahydro-4,6-pyrrolo[3,4-][1,2,3]triazolo[1,5-][1,4]oxazine derivatives as potent sigma-1 receptor (σR) ligands are reported. A lead optimization program aimed at improving the aqueous solubility of parent racemic nonpolar derivatives led to the identification of several σR antagonists with a good absorption, distribution, metabolism, and excretion in vitro profile, no off-target affinities, and characterized by a low basic p (around 5) that correlates with high exposure levels in rodents. Two compounds displaying a differential brain-to-plasma ratio distribution profile, and , exhibited a good analgesic profile and were selected as preclinical candidates for the treatment of pain.

Bicyclic Diazepinones as Dual Ligands of the α2δ-1 Subunit of Voltage-Gated Calcium Channels and the Norepinephrine Transporter.

The synthesis and pharmacological activity of a new series of bicyclic diazepinones with dual activity toward the α2δ-1 subunit of voltage-gated calcium channels (Caα2δ-1) and the norepinephrine transporter (NET) are reported. Exploration of the positions amenable for substitution on a nonaminoacidic Caα2δ-1 scaffold allowed the identification of favorable positions for the attachment of NET pharmacophores. Among the patterns explored, attachment of the 2-ethylamino-9-methyl-6-phenyl-6,7,8,9-tetrahydro-5-pyrimido[4,5-][1,4]diazepin-5-one framework to the meta-position of the phenyl ring of the 3-methylamino-1-phenylpropoxy and 3-methylamino-1-thiophenylpropoxy moieties provided dual compounds with excellent NET functionality.

Ni-catalyzed reduction of inert C-O bonds: a new strategy for using aryl ethers as easily removable directing groups.

An efficient Ni-catalyzed protocol for the reductive cleavage of inert C-O bonds has been developed. The method is characterized by its simplicity and wide scope, thereby allowing the use of aryl ethers as easily removable directing groups in organic synthesis.

Pd-catalyzed intramolecular acylation of aryl bromides via C-H functionalization: a highly efficient synthesis of benzocyclobutenones.

A new catalyst system for the intramolecular acylation of aldehydes with aryl bromides via C-H functionalization is described. The transformation is distinguished by a remarkable functional group tolerance and hence allows for the synthesis of a wide variety of highly functionalized benzocyclobutenones with a diverse set of substitution patterns from simple and easily accessible precursors.

Stereoselective synthesis of the published structure of feigrisolide A. Structural revision of feigrisolides A and B.

The total synthesis of the proposed structure of feigrisolide A is reported. Ethyl (S)-3-hydroxybutyrate was the chiral starting material. A Brown asymmetric allylation and an Evans aldol reaction were key steps of the synthesis.

Synthesis and structure of [(Sn(mu-PCy))3(Na x PMDETA)2], containing an electron-deficient [(Sn(mu-PCy))3]2- dianion.

The reaction of CyPHNa with Sn(NMe2)2 in the presence of PMDETA (= (Me2NCH2CH2)2NMe) gives the title compound [(Sn(mu-PCy))3(Na x PMDETA)2] (1), containing an electron-deficient [(Sn(mu-PCy))]3(2-) dianion with a novel two-electron, three centre (2e-3c) bonding arrangement.