A novel inhaled Syk inhibitor blocks mast cell degranulation and early asthmatic response.

Spleen tyrosine kinase (Syk) is essential for signal transduction of immunoreceptors. Inhibition of Syk abrogates mast cell degranulation and B cell responses. We hypothesized that Syk inhibition in the lung by inhaled route could block airway mast cells degranulation and the early asthmatic response without the need of systemic exposure.

A nonacid degradable linker for solid-phase synthesis.

Synthesis and applications of two new nonacid degradable linkers as an alternative to the Wang linker for solid-phase synthesis are described. Resin from linker 2 looks superior to linker 1 in terms of yields for both anchoring of the first building block and cleavage and in terms of higher purity of the final product. Use of linker 2 avoids side reactions associated with the use of Wang resin due to an undesired cleavage during final acid treatment.

Synthesis of the ABC ring system of manzamine A.

A synthesis of the core ABC ring system of the manzamine alkaloids is described, starting from arecoline. The key steps involve a Claisen rearrangement to set up a 4-substituted-3-methylenepiperidine and a stereoselective azomethine ylide dipolar cycloaddition reaction. Condensation of the aldehyde 6 and sarcosine ethyl ester hydrochloride salt gives an intermediate azomethine ylide, which undergoes an intramolecular cycloaddition reaction to set up two new rings and three new chiral centers stereoselectively.

Total Syntheses of (+/-)-Deethylibophyllidine Using a Crisscross Annulation: Ring Cleavage of Octahydroindolo[2,3-a]quinolizines Followed by Tandem Cyclizations of Octahydroazecino[5,4-b]indoles.

The total synthesis of (+/-)-deethylibophyllidine (1) is described. Three different sequences provide this pentacyclic alkaloid using a common strategy involving a crisscross annulation. Key steps include (i) C/D ring cleavage of a 2-formyloctahydroindolo[2,3-a]quinolizine to obtain octahydroazecino[5,4-b]indoles, via either a chloroformate induced process or a quaternary ammonium salt formation followed by treatment with lithium, and (ii) a tandem process consisting of an intramolecular Pictet-Spengler double cyclization upon a beta-indole position of a 2,3-disubstituted indole to generate the quaternary spiro center of the pentacyclic skeleton of ibophyllidine alkaloids.