ABSTRACT
Fluazaindolizine is a new highly effective and selective product for the control of plant parasitic nematodes. Specificity for nematodes coupled with absence of activity against the target sites of commercial nematicides suggests that fluazaindolizine has a novel mode of action. The discovery, structure-activity development and biological properties for this new class of nematicides are presented.
Subject(s)
Heterocyclic Compounds, 2-Ring/pharmacology , Indolizines/pharmacology , Pesticides/pharmacology , Sulfonamides/pharmacology , Animals , Caenorhabditis elegans/drug effects , Crops, Agricultural/parasitology , Drosophila melanogaster/drug effects , Heterocyclic Compounds, 2-Ring/chemical synthesis , Heterocyclic Compounds, 2-Ring/toxicity , Indolizines/chemical synthesis , Indolizines/toxicity , Pesticides/chemical synthesis , Pesticides/toxicity , Plant Roots/parasitology , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/toxicity , Tylenchoidea/drug effectsABSTRACT
Bicyclic iminium ethers can be synthesized by the reactions of ketones with hydroxyalkyl azides. These cationic species react with a variety of nucleophiles via two possible pathways. The initially formed, kinetic product arises from direct addition to the iminium carbon in the substrate. In some cases, the initial adduct reverts to the starting iminium ether and the ultimate product arises from nucleophilic displacement at the O-alkyl group to afford the terminally functionalized N-substituted amide. The behavior of a range of nucleophiles was studied by using several iminium ethers. In general, the relevant pathway could be identified by characterization of the product formed. For hydroxide addition, which can afford only one product regardless of mechanism, the reaction was shown to arise by the kinetic pathway, using (18)O-labeled hydroxide. A one-pot synthesis of functionalized lactams entailing treatment of ketones first with hydroxyalkyl azides followed by nucleophilic addition was also developed.
Subject(s)
Ethers/chemistry , Heterocyclic Compounds/chemical synthesis , Imines/chemistry , Ketones/chemical synthesis , Heterocyclic Compounds/chemistry , Ketones/chemistry , Molecular Structure , StereoisomerismABSTRACT
Surface proteins in Gram-positive bacteria are anchored to the cell wall by the action of sortase enzymes. The Staphylococcus aureus sortase A (SrtA) protein anchors proteins by recognizing a cell wall sorting signal containing the amino acid sequence LPXTG. To understand how SrtA binds this sequence, we carried out NMR studies of new peptidyl-cyanoalkene and peptidyl-sulfhydryl inhibitors that contain the sorting signal sequence LPAT. These studies combined with amino acid mutagenesis identified a catalytically important and conserved binding surface formed by residues A118, T180, and I182. Compatible with its recently proposed role as a general base, R197 is also shown to be required for catalysis.
Subject(s)
Aminoacyltransferases/chemistry , Aminoacyltransferases/metabolism , Staphylococcus aureus/enzymology , Amino Acid Sequence , Aminoacyltransferases/genetics , Bacterial Proteins , Binding Sites , Cell Wall/enzymology , Cysteine Endopeptidases , Enzyme Inhibitors/pharmacology , Kinetics , Magnetic Resonance Spectroscopy , Models, Molecular , Protein Conformation , Signal Transduction , Staphylococcus aureus/geneticsABSTRACT
The reactions of 1,3- and 1,4-haloalkyl azides with enolates of 2-norbornanone (and a ring-expanded analog) afford polycyclic 1,2,3-triazolines in good yields. The reaction occurs by the initial azidation of the ketone enolate, followed in order by triazoline formation and O-alkylation. An interesting element of this process is the preferential reaction of the alkyl azide with an enolate anion as opposed to the more familiar reaction of the alkyl halide (including Cl and I derivatives). Reactions of acyclic or monocyclic enolates generally lead to 1,2,3-triazoles but none of the alternative C-alkylation product.
Subject(s)
Azides/chemistry , Bridged-Ring Compounds/chemistry , Hydrocarbons, Halogenated/chemistry , Ketones/chemistry , Alkylation , Molecular StructureABSTRACT
The rearrangement of nitrones to lactams can be carried out by photochemical activation or by treatment with Tf(2)O followed by KOH-promoted rearrangement (a modification of conditions originally introduced by Barton). Substrates in which the nitrone is part of a fused bicyclic ring system have traditionally proven problematic for this kind of reaction. In this study, a series of mono-, bi-, and tricyclic ring-fused nitrones were prepared to investigate the dependence of products on nitrone ring size and tether length. Results indicated that photochemical rearrangement of nitrones in benzene afforded reasonably good yields (30-68%) of lactams, while the two-step nonphotochemical process provided slightly better average yields (30-95%) of the same targets.
Subject(s)
Bridged Bicyclo Compounds/chemistry , Lactams/chemistry , Nitrogen Oxides/chemistry , Molecular Structure , PhotochemistryABSTRACT
An asymmetric equivalent of the Schmidt reaction permits stereocontrol in ring expansions of symmetrical cyclohexanones. The procedure involves the reaction of chiral 1,2- and 1,3-hydroxyalkyl azides with ketones under acid catalysis; the initial reaction affords an iminium ether that can be subsequently opened with base. A systematic study of this reaction is reported, in which ketone substrates, chiral hydroxyalkyl azides, and reaction conditions are varied. Selectivities as high as ca. 98:2 are possible for the synthesis of substituted caprolactams, with up to 1,7-stereoselection involved in the overall process. The fact that either possible migrating carbon is electronically identical provides an unusual opportunity to study a ring-expansion reaction controlled entirely by stereoelectronic factors. The mechanism of the reaction and the source of its stereoselectivity are also discussed.
Subject(s)
Azides/chemistry , Cyclohexanones/chemistry , Ketones/chemistry , Lactams/chemical synthesis , Azides/chemical synthesis , Lactams/chemistry , Models, Molecular , StereoisomerismABSTRACT
Many surface proteins are anchored to the cell wall by the action of sortase enzymes, a recently discovered family of cysteine transpeptidases. As the surface proteins of human pathogens are frequently required for virulence, the sortase-mediated anchoring reaction represents a potential target for new anti-infective agents. It has been suggested that the sortase from Staphylococcus aureus (SrtA), may use a similar catalytic strategy as the papain cysteine proteases, holding its Cys184 side chain in an active configuration through a thiolate-imidazolium ion interaction with residue His120. To investigate the mechanism of transpeptidation, we have synthesized a peptidyl-vinyl sulfone substrate mimic that irreversibly inhibits SrtA. Through the study of the pH dependence of SrtA inhibition and NMR, we have estimated the pKas of the active site thiol (Cys184) and imidazole (His120) to be approximately 9.4 and 7.0, respectively. These measurements are inconsistent with the existence of a thiolate-imidazolium ion pair and suggest a general base catalysis mechanism during transpeptidation.
Subject(s)
Aminoacyltransferases/chemistry , Aminoacyltransferases/physiology , Imidazoles/chemistry , Staphylococcus aureus/enzymology , Sulfhydryl Compounds/chemistry , Bacterial Proteins , Binding Sites , Catalysis , Chromatography, High Pressure Liquid , Cysteine/chemistry , Cysteine Endopeptidases , Histidine/chemistry , Hydrogen-Ion Concentration , Ions , Kinetics , Magnetic Resonance Spectroscopy , Models, Chemical , Peptides/chemistry , Peptidyl Transferases/chemistry , Sulfones/antagonists & inhibitors , Time FactorsABSTRACT
[reaction: see text] The total synthesis of (+)-sparteine was accomplished from 2,5-norbornadione in 15 steps and 15.7% overall yield. The key steps were two ring-expansion reactions, one involving an intramolecular Schmidt reaction and one using a novel variant of the photo-Beckmann rearrangement.
