piperidines and trifluoromethanesulfonic-acid

Topics: Acylation; Alkylation; Biological Products; Cyanides; Dihydropyridines; Indoles; Mesylates; Organometallic Compounds; Oxidation-Reduction; Piperidines; Pyridines; Stereoisomerism; Transition Elements

The identification of small molecule ligands is an important first step in drug development, especially drugs that target proteins with no intrinsic activity. Toward this goal, it is important to have access to technologies that are able to measure binding affinities for a large number of potential ligands in a fast and accurate way. Because ligand binding stabilizes the protein structure in a manner dependent on concentration and binding affinity, the magnitude of the protein stabilization effect elicited by binding can be used to identify and characterize ligands. For example, the shift in protein denaturation temperature (Tm shift) has become a popular approach to identify potential ligands. However, Tm shifts cannot be readily transformed into binding affinities, and the ligand rank order obtained at denaturation temperatures (≥60°C) does not necessarily coincide with the rank order at physiological temperature. An alternative approach is the use of chemical denaturation, which can be implemented at any temperature. Chemical denaturation shifts allow accurate determination of binding affinities with a surprisingly wide dynamic range (high micromolar to sub nanomolar) and in situations where binding changes the cooperativity of the unfolding transition. In this article, we develop the basic analytical equations and provide several experimental examples.

Topics: Acetazolamide; Calorimetry; Carbonic Anhydrase I; HIV Protease; Humans; Hydrogen-Ion Concentration; Kinetics; Ligands; Mesylates; Oxalates; Piperidines; Protein Binding; Protein Conformation; Protein Denaturation; Spectrometry, Fluorescence; Temperature; Thermodynamics; Urea

Alpha-mannopyranosyl phosphosugars are obtained in 61-90% yields from 4,6-O-benzylidene-protected mannosyl thioglycosides bearing ester functionality in the 3-O-position by coupling reactions with ammonium salts of phosphosugars on activation with 1-benzenesulfinyl piperidine, 2,4,6-tri-tert-butylpyrimidine, and trifluoromethanesulfonic anhydride. Due to the presence of the disarming ester group, only the formation of the alpha-isomer was observed.

Topics: Anhydrides; Benzylidene Compounds; Mannosephosphates; Mesylates; Molecular Structure; Piperidines; Pyrimidines; Quaternary Ammonium Compounds; Stereoisomerism; Thioglycosides

The synthesis of d- and l-glycero-alpha-manno-thioheptopyranosides, protected with 4,6-O-alkylidene-type acetals is described. In glycosylations carried out with preactivation with the 1-benzenesulfinylpiperidine/trifluoromethanesulfonic anhydride couple, both the D- and L-glycero series exhibit excellent beta-selectivity with a range of glycosyl acceptors. In contrast, a 4,7-O-alkylidene acetal was found not to afford beta-selectivity. With a 4,6-O-[1-cyano-2-(2-iodophenyl)ethylidene] acetal protected thioglycoside, excellent beta-selectivity was obtained in glycosylation reactions, and subsequent treatment with tributyltin hydride and azoisobutyronitrile brought about clean fragmentation to the 6-deoxy-glycero-beta-D-manno-heptopyranosides. This chemistry was applied to the stereocontrolled synthesis of methyl alpha-L-rhamno-pyranosyl-(1-->3)-D-glycero-beta-D-manno-heptopyranosyl-(1-->3)-6-deoxy-glycero-beta-D-manno-heptopyranosyl-(1-->4)-alpha-L-rhamno-pyranoside, a component of the lipopolysaccharide from Plesimonas shigelloides.

Topics: Acetals; Alkenes; Azo Compounds; Carbohydrate Conformation; Carbohydrate Sequence; Deoxy Sugars; Glycosylation; Heptoses; Lipopolysaccharides; Mesylates; Methylglycosides; Models, Chemical; Molecular Sequence Data; Nitriles; Oligosaccharides; Piperidines; Plesiomonas; Rhamnose; Stereoisomerism; Sulfinic Acids; Trialkyltin Compounds

The combination of 1-benzenesulfinyl piperidine (BSP) and trifluoromethanesulfonic anhydride (Tf(2)O) forms a new, powerful, metal-free thiophile that can readily activate both armed and disarmed thioglycosides, via glycosyl triflates, in a matter of minutes at -60 degrees C in dichloromethane, in the presence of 2,4,6-tri-tert-butylpyrimidine (TTBP). The glycosyl triflates are rapidly and cleanly converted to glycosides, upon treatment with alcohols, in good yield and selectivity.

Topics: Anhydrides; Carbohydrate Sequence; Cold Temperature; Drug Stability; Glycosides; Mesylates; Molecular Sequence Data; Piperidines; Sulfinic Acids; Thioglycosides