Simple and efficient synthesis of 3,4-dihydro-2-pyridones via novel solid-supported aza-annulation

A diverse array of 3,4-dihydro-2-pyridones 13 were produced utilizing the unique properties of solid-supported reactions to both drive the reactions to completion and isolate the desired products. The pyridones were synthesized in high purity by a simple sequence of novel steps commencing from an acetophenone-functionalized resin. The para-substituted acetophenone 9 could be anchored to the resin through either a sulfonamide or a carboxamide linkage. The sulfonamide resin 9a, which gave the best results, was treated with several aryl aldehydes and ethoxide to give a variety of chalcones 10a-k in excellent yield (82-99%) upon TFA cleavage. Addition of either methyl or allyl malonate and DBU to 10a-k afforded smoothly the Michael adducts 11a-j (70-99%) which were subsequently cyclized in one step employing acetic acid as a catalyst and several diverse amines to give pure 3,4-dihydro-2-pyridones 13a-p in moderate to excellent yields (30-98%).     

A long-wavelength biolabeling reagent based on the oxonol fluorophore

A red fluorescent dye of the oxonol class, bis-[1-(carboxymethyl)barbituric acid-(5)]-pentamethinoxonol, has been synthesized and, in the form of the succinimidyl active ester, has been applied to antibody labeling for application to flow cytometry and to imaging of tissue sections. The new dye, named CMOX (for carboxymethyloxonol), shows maximum excitation at 583 nm and emission at 611 nm, with a quantum yield of 0.2 in aqueous buffer and methanol. Antibodies labeled with the new dye show favorable brightness, photostability, and low levels of nonspecific binding.     

On the strength of no normal precipitous filter

We consider a question of T. Jech and K. Prikry that asks if the existence of a precipitous filter implies the existence of a normal precipitous filter. The aim of this paper is to improve a result of Gitik (Israel J Math, 175:191?C219, 2010) and to show that measurable cardinals of a higher order rather than just measurable cardinals are necessary in order to have a model with a precipitous filter but without a normal one.     

Choosing fair lotteries to defeat the competition

We study the following game: each agent i chooses a lottery over nonnegative numbers whose expectation is equal to his budget b _i . The agent with the highest realized outcome wins (and agents only care about winning). This game is motivated by various real-world settings where agents each choose a gamble and the primary goal is to come out ahead. Such settings include patent races, stock market competitions, and R&D tournaments. We show that there is a unique symmetric equilibrium when budgets are equal. We proceed to study and solve extensions, including settings where agents choose their budgets (at a cost) and where budgets are private information.     

Synthesis and Kinetic Evaluation of Inhibitors of the Phosphatidylinositol-Specific Phospholipase C from Bacillus cereus

Substrate analogues of phosphatidylinositol (1) were synthesized and evaluated as potential inhibitors of the bacterial phosphatidylinositol-specific phospholipase C (PI-PLC) from Bacillus cereus. The chiral analogues of the water-soluble phospholipid substrate 5 were designed to probe the effects of varying the inositol C-2 hydroxyl group, which is generally believed to serve as the nucleophile in the first step of the hydrolysis of phosphatidylinositols by PI-PLC. In the analogues 6-9, the C-2 hydroxyl group on the inositol ring of the phosphatidylinositol derivatives was rationally altered in several ways. Inversion of the stereochemistry at C-2 of the inositol ring led to the scyllo derivative 6. The inositol C-2 hydroxy group was replaced with inversion by a fluorine to produce the scyllo-fluoro inositol 7 and with a hydrogen atom to furnish the 2-deoxy compound 8. The C-2 hydroxyl group was O-methylated to prepare the methoxy derivative 9. The natural inositol configuration at C-2 was retained in the nonhydrolyzable phosphorodithioate analogue 10. The inhibition of PI-PLC by each of these analogues was then analyzed in a continuous assay using D-myo-inositol 1-(4-nitrophenyl phosphate) (25) as a chromogenic substrate. The kinetic parameters for each of these phosphatidylinositol derivatives were determined, and each was found to be a competitive inhibitor with K(i)'s as follows: 6, 0.2 mM; 10, 0.6 mM; 8, 2.6 mM; 9, 6.6 mM; and 7, 8.8 mM. This study further establishes that the hydrolysis of phosphatidylinositol analogues by bacterial PI-PLC requires not only the presence of a C-2 hydroxyl group on the inositol ring, but the stereochemistry at this position must also correspond to the natural myo-configuration. For future inhibitor design, it is perhaps noteworthy that the best inhibitors 6 and 10 each possess a hydroxyl group at the C-2 position. Several of the inhibitors identified in this study are now being used to obtain crystallographic information for an enzyme-inhibitor complex to gain further insights regarding the mechanism of hydrolysis of phosphatidylinositides by this PI-PLC.