Identification of 2,3-disubstituted pyridines as potent, non-emetic PDE4 inhibitors.

A series of 2,3-disubstituted pyridines were synthesized as potential non-emetic PDE4 inhibitors. To decrease brain exposure and minimize emesis, we modified the lipophilic moiety of a series of emetic PDE4 inhibitors and found that introduction of a hydroxy group into the pyridine moiety of the side chain led to non-emetic compounds with preserved PDE4 inhibitory activity. Following optimization at the phenoxy group, we identified compound 1 as a potent non-emetic PDE4 inhibitor.

Carbonylation reactions of alkyl iodides through the interplay of carbon radicals and Pd catalysts.

Numerous methods for transition metal catalyzed carbonylation reactions have been established. Examples that start from aryl, vinyl, allyl, and benzyl halides to give the corresponding carboxylic acid derivatives have all been well documented. In contrast, the corresponding alkyl halides often encounter difficulty.

One-pot synthesis of cyanohydrin derivatives from alkyl bromides via incorporation of two one-carbon components by consecutive radical/ionic reactions.

The consecutive radical/ionic reaction consisting of radical formylation of alkyl bromides and nucleophilic addition of a cyanide ion was investigated, which gave moderate to good yields of cyanohydrin derivatives in one-pot.

Design and synthesis of an aminopiperidine series of γ-secretase modulators.

The design, synthesis, and SAR of cyclic diamines as novel γ secretase modulators (GSMs) are presented in this Letter. Starting from information in the literature and in-house cyclic diamines library, we have found a 3(S)-aminopiperidine as a potent structure for lowering Aβ42 production both in vitro and in vivo.

Identification of 2,3-disubstituted pyridines as potent, orally active PDE4 inhibitors.

A series of 2,3-disubstituted pyridines were synthesized and evaluated for their PDE4 inhibitory activity. We successfully modified undesirable cyano group of initial lead compound 2 to 4-pyridyl group with improvement of in vitro efficacy and optimized the position of nitrogen atoms in pyridine moiety and alkylene linker. The most potent compound showed significant efficacy in animal models of asthma and inflammation.

Reductive bromine atom-transfer reaction.

Atom-transfer radical (ATR) reactions of alkenes with R-X usually give products having new C-C and C-X bonds at the adjacent carbons. However, when the reaction was carried out under irradiation using a low-pressure Hg lamp, addition/reduction products were obtained in good yield. Hydrogen bromide, formed by H-abstraction of a bromine radical from alkenes, is likely to play a key role in the reductive ATR reaction.

Pd/light-accelerated atom-transfer carbonylation of alkyl iodides: applications in multicomponent coupling processes leading to functionalized carboxylic acid derivatives.

The atom-transfer carbonylation reaction of various alkyl iodides thereby leading to carboxylic acid esters was effectively accelerated by the addition of transition-metal catalysts under photoirradiation conditions. By using a combined Pd/hν reaction system, vicinal C-functionalization of alkenes was attained in which α-substituted iodoalkanes, alkenes, carbon monoxide, and alcohols were coupled to give functionalized esters. When alkenyl alcohols were used as acceptor alkenes, three-component coupling reactions, which were accompanied by intramolecular esterification, proceeded to give lactones.

Vicinal C-functionalization of alkenes. Pd/light-induced multicomponent coupling reactions leading to functionalized esters and lactones.

Under photoirradiation conditions using a xenon light, and in the presence of PdCl(2)(PPh(3))(2) as a catalyst, four-component coupling reactions comprising of α-substituted iodoalkanes, alkenes, carbon monoxide, and alcohols proceeded smoothly to give functionalized esters in good yields. When alkenyl alcohols were used as acceptor alkenes, three-component coupling reactions accompanied by intramolecular esterification proceeded to give lactones in good yields. The present reaction system represents the vicinal C-functionalization of alkenes.

Synthesis of alkyl alkynyl ketones by Pd/light-induced three-component coupling reactions of iodoalkanes, CO, and 1-alkynes.

Under photoirradiation conditions using xenon light, in the presence of a catalytic amount of PdCl(2)(PPh(3))(2) with triethylamine as a base, a three-component coupling reaction of iodoalkanes, carbon monoxide, and terminal alkynes proceeded to give alkyl alkynyl ketones in good yields.