Craig J. Mossman

The Internal Quaternary Ammonium Receptor Site of Shaker Potassium Channels

Quaternary ammonium (QA) compounds inhibit K+ conductance by entering and occluding the open pore of voltage-activated K+ channels. We characterized the effects of a series of alkyl-triethylammonium blockers on the Shaker K+ channel and tested them on a series of site-directed mutants of the channel protein in order to define the structural features of the binding sites. We found that mutations in two regions of the channel protein, the pore (P) region and the last transmembrane sequence (S6), appear to alter QA binding, not through their effects on gating but perhaps through direct effects on the binding site. Several mutations in the P region affect tetraethylammonium binding but have minimal effects on longer blockers, suggesting that the hydrophobic tail contributes to binding in a nonadditive fashion. Binding of the longer blockers can be affected by varying the hydrophobicity of 1 residue within S6 by site-specific substitution, in a manner consistent with a direct hydrophobic interaction between the side chain at this site and the alkyl chains of the blocker.

Intramolecular Schmidt reactions of alkyl azides with ketals and enol ethers

Abstract The ketals or enol ethers of 1,5-azidoketones were converted into lactams using a two-stage process. Treatment of the ketals and enol ethers with acid (trifluoroacetic acid, triflic acid, or trimethylsilyl triflate) afforded an oxonium ion which reacted with the tethered azide to give a 1,1-azido-alkoxy intermediate. Bond reorganization led to an iminium ether that was reacted with sodium iodide in acetone to expose the amide products. Seven intramolecular examples proceeding in yields of 68 to ≥95% are reported using dimethyl or diethyl ketals. Attempts using 1,3-dioxolanes and an intermolecular example are also described.

(2S, 3S, 5S)- and (2S, 3S, 5R)-5-carboxaldehyde-2,3-diphenyl-1,4-dioxane as surrogates for optically pure 2,3-O-isopropylideneglyceraldehyde in asymmetric synthesis

Abstract The title compounds were prepared from threo -hydrobenzoin, either enantiomer of which is readily available from trans -stilbene using the Sharpless asymmetric dihydroxylation reaction. Several organometallic reagents were added to the aldehydes and the resulting adducts treated with H 2 -Pd/C to give diastereomerically and enantiomerically enriched 1,2,3-triol-containing building blocks for asymmetric synthesis.

Short and efficient chiral pool and RCM approach towards the synthesis of the macrocyclic core of the salicylihalamides

The macrolactone core structure of the salicylihalamides was prepared from diacetone-D-glucose and via a ring-closing metathesis reaction.