Discovery of (1R,2S)-2-{[(2,4-Dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide (E2006): A Potent and Efficacious Oral Orexin Receptor Antagonist.

The orexin/hypocretin receptors are a family of G protein-coupled receptors and consist of orexin-1 (OX1) and orexin-2 (OX2) receptor subtypes. Orexin receptors are expressed throughout the central nervous system and are involved in the regulation of the sleep/wake cycle. Because modulation of these receptors constitutes a promising target for novel treatments of disorders associated with the control of sleep and wakefulness, such as insomnia, the development of orexin receptor antagonists has emerged as an important focus in drug discovery research. Here, we report the design, synthesis, characterization, and structure-activity relationships (SARs) of novel orexin receptor antagonists. Various modifications made to the core structure of a previously developed compound (-)-5, the lead molecule, resulted in compounds with improved chemical and pharmacological profiles. The investigation afforded a potential therapeutic agent, (1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide (E2006), an orally active, potent orexin antagonist. The efficacy was demonstrated in mice in an in vivo study by using sleep parameter measurements.

Chiral Brønsted acid catalyzed stereoselective addition of azlactones to 3-vinylindoles for facile access to enantioenriched tryptophan derivatives.

Syn-gled out: The syn diastereo- and enantioselective addition of azlactones to 3-vinylindoles was accomplished by using a chiral, binapthol-derived, Brønsted acid catalyst (see scheme). This method enables facile access to tryptophan derivatives with adjacent quaternary and tertiary stereogenic centers, which are potentially useful for the synthesis of peptidomimetics.

Activation of hemiaminal ethers by chiral Brønsted acids for facile access to enantioselective two-carbon homologation using enecarbamates.

An enriching experience: Chiral phosphoric acids have been used to catalyze the title transformation for aromatic and aliphatic hemiaminal ethers. The process affords the corresponding products in good to high enantioselectivity (see scheme; Boc = tert-butoxycarbonyl, G = aromatic group). The method enables facile access to highly enantioenriched 1,3-diamine derivatives.

Enantioselective direct aldol-type reaction of azlactone via protonation of vinyl ethers by a chiral Brønsted acid catalyst.

Highly enantio- and diastereoselective direct aldol-type reaction of azlactones with oxocarbenium ions generated by protonation of vinyl ethers using a chiral phosphoric acid catalyst is presented. The method provides efficient access to biologically and pharmaceutically intriguing beta-hydroxy-alpha-amino acid derivatives having a quaternary stereogenic center at the alpha-carbon atom.

Relay catalysis by a metal-complex/Brønsted acid binary system in a tandem isomerization/carbon-carbon bond forming sequence.

A one-pot tandem isomerization/carbon-carbon bond forming sequence catalyzed by a ruthenium complex/Brønsted acid binary system is demonstrated. The method enables the use of readily available allylamides to deliver reactive imines under relay catalysis using a binary catalytic system. Subsequent Brønsted acid catalyzed carbon-carbon bond forming reactions of the generated imines with nucleophilic components afforded Friedel-Crafts and Mannich products in good yields.

Organocatalytic asymmetric direct alkylation of alpha-diazoester via C-H bond cleavage.

A new variant of phosphoric acid-catalyzed C-C bond forming reaction, direct alkylation of alpha-diazoester, via C-H bond cleavage is presented. The resulting products, beta-amino-alpha-diazoesters, are highly functionalized and useful synthetic precursors for various types of beta-amino acids.

Organocatalytic asymmetric aza-Friedel-Crafts alkylation of furan.

A new asymmetric entry of the 1,2-aza-Friedel-Crafts reaction catalyzed by a chiral phosphoric acid is described. The present reaction has provided an atom-economical route to furan-2-ylamine derivatives in a highly enantioselective fashion. The synthetic utility of these products was displayed by oxidative cleavage of the furan ring (aza-Achmatowicz reaction) to form a 1,4-dicarbonyl compound that could be further derivatized to a chiral gamma-butenolid.