A one-pot tandem Pd-catalyzed hydrostannylation/Stille coupling protocol for the stereoselective generation of vinyltins and their subsequent union, employing only catalytic amounts of tin, is described. By recycling the organotin halide Stille byproduct back to organotin hydride, a hydrostannylation/cross-coupling sequence can be carried out with catalytic amounts of tin. Such a process is most effective with Me(3)SnCl serving as the tin source. This protocol allows a 94% reduction of the tin requirement, while maintaining good yields (up to 90%) for a variety of Stille products. Furthermore, since one cycle requires the tin to undergo at least four transformations, each moiety of trialkyltin is experiencing a minimum of 60 reactions over the course of the hydrostannylation/Stille sequence.

No abstract

We have found that either Bu 3 SnCl/PMHS/KF (aq) or the combination of tributyltin fluoride, PMHS, and catalytic quantities of tetrabutylammonium fluoride can serve as in situ sources of tributyltin hydride for both free radical and palladium-catalyzed hydrostannylation reactions. These methods are tolerant of a variety of functional groups, including silyl ethers. Furthermore, Me 3 SnCl is also reduced under these conditions, providing a relatively convenient and safe manner by which Me 3 -SnH can be formed and reacted. We have also observed that the Bu 3 SnCl/siloxane/fluoride combination offers improvements over the existing protocols for transforming 1-bromoalkynes into trans-1-(tributylstannyl)-1-alkenes. Specifically, the KF/PMHS methodology allows the 1-bromoalkyne to be formed and reacted in a single pot and with substoichiometric amounts of tin. Finally, alternative reductants such as Red-Sil are also amenable to the method.

No abstract

PI3Kδ is a lipid kinase that is believed to be important in the migration and activation of cells of the immune system. Inhibition is hypothesized to provide a powerful yet selective immunomodulatory effect that may be beneficial for the treatment of conditions such as asthma or rheumatoid arthritis. In this work, we describe the identification of inhibitors based on a thiazolopyridone core structure and their subsequent optimization for inhalation. The initially identified compound (13) had good potency and isoform selectivity but was not suitable for inhalation. Addition of basic substituents to a region of the molecule pointing to solvent was tolerated (enzyme inhibition pIC > 9), and by careful manipulation of the pK and lipophilicity, we were able to discover compounds (20b, 20f) with good lung retention and cell potency that could be taken forward to in vivo studies where significant target engagement could be demonstrated.