The muscle nicotinic acetylcholine receptor is a large, allosteric, ligand-gated ion channel with the subunit composition ␣ 2 ␤␥␦. Although much is now known about the structure of the binding site, relatively little is understood about how the binding event is communicated to the channel gate, causing the pore to open. Here we identify a key hydrogen bond near the binding site that is involved in the gating pathway. Using mutant cycle analysis with the novel unnatural residue ␣-hydroxyserine, we find that the backbone N-H of ␣Ser-191 in loop C makes a hydrogen bond to an anionic side chain of the complementary subunit upon agonist binding. However, the anionic partner is not the glutamate predicted by the crystal structures of the homologous acetylcholine-binding protein. Instead, the hydrogen-bonding partner is the extensively researched aspartate ␥Asp-174/␦Asp-180, which had originally been identified as a key binding residue for cationic agonists.

The reductive deoxygenation of acyl phosphonates using a Wolff-Kishner-like sequence is described. This transformation allows direct access to alkyl phosphonates from acyl phosphonates at room temperature. The method can be combined with acyl phosphonate synthesis into a one pot, four-step procedure for the conversion of carboxylic acids into alkyl phosphonates. The methodology works well for a variety of aliphatic acids, and shows a functional group tolerance similar to that of other hydrazone-forming reactions.Phosphonates are a key functional group in both organic synthesis and biological chemistry. 1 In synthesis, they are a direct precursor of olefins through the Horner-WadsworthEmmons reaction.2 In biological chemistry, their unique structure and charge distribution give them an important role in pharmaceuticals3 and phosphoester mimicry.4 Phosphonates have traditionally been accessed through the Arbuzov reaction:5 , 6 a double S N 2 process between an alkyl halide and a trialkylphosphite (Scheme 1), and this remains the most commonly employed route today. Notable exceptions include aryl/vinyl phosphonates,7 whose corresponding halides cannot readily participate in S N 2 reactions, and α-hydroxyl/α-amino phosphonates,8 whose corresponding halides are unstable.Despite its prevalence, the Arbuzov reaction has two key drawbacks. First, the elevated temperatures typically required limit the scope of substrates suitable for the reaction. Second, the reaction generates one equivalent of alkyl halide, which can react with the phosphite under the reaction conditions to reduce yield and reaction efficiency. A modification using dialkylphosphite salts instead of trialkylphosphites eliminates the problem of new alkyl halide generation, but the yields are typically poorer, and this strategy is much less used.9 A number of other strategies for alkyl phosphonate synthesis have been developed,10 , 11 most notably the transition metal-mediated hydrophosphonylation of olefins with cyclic five-membered hydrogen phosphonates.12 Yet even this reaction is limited by the phosphite component scope and prolonged heating. Here we present a roomtemperature alternative to the Arbuzov reaction that allows for the synthesis of phosphonates from carboxylic acids.We began with the observation that the Arbuzov reaction of acyl halides is strikingly mild in comparison to the alkyl variant, often going to completion in several minutes at room dadougherty@caltech.edu .

A novel synthetic route to 1-oxo-5-hydroxytryptamine, the benzofuran analogue of serotonin, has been developed. The new synthesis proceeds via the [3+2] cycloaddition of p-benzoquinone and 2,3-dihydrofuran, followed by a Lewis acid-catalyzed isomerization. This molecule proves to be a competent agonist (equipotent to serotonin) of the 5-HT3 receptor, demonstrating that the indolic proton of serotonin is not essential to its activation of the receptor.

A one‐pot multistep procedure to prepare alkyl phosphonates from the commercially available acid chlorides or from acid chlorides, generated in situ from the corresponding carboxylic acids with oxalyl chloride.