Synthesis of α‑Substituted Vinylsulfonium Salts and Their Application as Annulation Reagents in the Formation of Epoxide- and Cyclopropane-Fused Heterocycles

The discovery of new methods for the synthesis of classes of potentially bioactive molecules remains an important goal for synthetic chemists. Vinylsulfonium salts have been used for the synthesis of a wide variety of small heterocyclic motifs; however, further developments to this important class of reagents has been focused on reaction with new substrates rather than development of new vinylsulfonium salts. We herein report the synthesis of a range of α-substituted vinylsulfonium tetraphenylborates (10 examples) in a 3 step procedure from commercially available styrenes. The important role of the tetraphenylborate counterion on the stability and accessibility of the vinylsulfonium salts is also detailed. The α-substituted vinylsulfonium tetraphenylborates gave good to excellent yields in the epoxyannulation of β-amino ketones (15 examples) and the cyclopropanation of allylic amines (4 examples). Hydrogenation of an epoxyannulation product proceeded with good diastereoselectivity

Stereoselective Glycosylation of 2‑Nitrogalactals Catalyzed by a Bifunctional Organocatalyst

The use of a bifunctional cinchona/thiourea organocatalyst for the direct and α-stereoselective glycosylation of 2-nitrogalactals is demonstrated for the first time. The conditions are mild, practical, and applicable to a wide range of glycoside acceptors with products being isolated in good to excellent yields. The method is exemplified in the synthesis of mucin type Core 6 and 7 glycopeptides

Discovery of 6‑Amino-2-{[(1<i>S</i>)‑1-methylbutyl]oxy}-9-[5-(1-piperidinyl)pentyl]-7,9-dihydro‑8<i>H</i>‑purin-8-one (GSK2245035), a Highly Potent and Selective Intranasal Toll-Like Receptor 7 Agonist for the Treatment of Asthma

Induction of IFNα in the upper airways via activation of TLR7 represents a novel immunomodulatory approach to the treatment of allergic asthma. Exploration of 8-oxoadenine derivatives bearing saturated oxygen or nitrogen heterocycles in the <i>N</i>-9 substituent has revealed a remarkable selective enhancement in IFNα inducing potency in the nitrogen series. Further potency enhancement was achieved with the novel (<i>S</i>)-pentyloxy substitution at <i>C</i>-2 leading to the selection of GSK2245035 (<b>32</b>) as an intranasal development candidate. In human cell cultures, compound <b>32</b> resulted in suppression of Th2 cytokine responses to allergens, while <i>in vivo</i> intranasal administration at very low doses led to local upregulation of TLR7-mediated cytokines (IP-10). Target engagement was confirmed in humans following single intranasal doses of <b>32</b> of ≥20 ng, and reproducible pharmacological response was demonstrated following repeat intranasal dosing at weekly intervals