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The development of a water-soluble iridium catalyst enables the trifluoromethylation of polar small molecules and peptides in DMSO solution or aqueous media. The reaction was optimized in a microtiter plate format under ambient air, using commercial Langlois reagent as a CF3 radical source, blue LEDs for excitation, and using DPBS as solvent to provide up to 60% CF3- peptide.

[Image: see text] Tau prions feature in the brains of patients suffering from Alzheimer’s disease and other tauopathies. For the development of therapeutics that target the replication of tau prions, a high-content, fluorescence-based cell assay was developed. Using this high-content phenotypic screen for nascent tau prion formation, a 4-piperazine isoquinoline compound (1) was identified as a hit with an EC(50) value of 390 nM and 0.04 K(p,uu). Analogs were synthesized using a hypothesis-based approach to improve potency and in vivo brain penetration resulting in compound 25 (EC(50) = 15 nM; K(p,uu) = 0.63). We investigated the mechanism of action of this series and found that a small set of active compounds were also CDK8 inhibitors.

The discovery and optimization of a novel series of aminoisoquinolines as potent, selective, and efficacious inhibitors of the mutant B-Raf pathway is presented. The N-linked pyridylpyrimidine benzamide 2 was identified as a potent, modestly selective inhibitor of the B-Raf enzyme. Replacement of the benzamide with an aminoisoquinoline core significantly improved kinase selectivity and imparted favorable pharmacokinetic properties, leading to the identification of 1 as a potent antitumor agent in xenograft models.

A range of N,N-dialkylanilines have been successfully converted to the parent substituted benzenes by a novel two-step pathway. The products are obtained in good yields and optical purity of adjacent stereocenters is maintained. This technology has been applied toward the synthesis of (R)-tolterodine.

A convenient synthesis of α-chiral sulfinates from readily available precursors has been accomplished via the corresponding heterocyclic thioethers and sulfones. Treatment of the sulfinates with hydroxylamine sulfonate in aqueous solution provides α-C-chiral primary sulfonamides in good yield (14 examples) with retention of stereochemical purity.

The first enantioselective organocatalytic alkylation of electron-rich benzene rings with alpha,beta-unsaturated aldehydes has been accomplished. The use of iminium catalysis has provided a new strategy for the enantioselective construction of benzylic stereogenicity, an important chiral synthon for natural product and medicinal agent synthesis. The (2S,5S)-5-benzyl-2-tert-butylimidazolidinone amine catalyst has been found to mediate the conjugate addition of a wide variety of substituted and unsubstituted anilines to unsaturated aldehydes. A diverse spectrum of aldehyde substrates can also be accommodated in this new organocatalytic transformation. While catalyst quantities of 10 mol % were generally employed in this study, successful alkylations conducted with catalyst loadings as low as 1 mol % are described.

Our laboratory has been engaged in the design of broadly useful new strategies for enantioselective catalysis that utilize organic chemicals as reaction catalysts. In our recent study, we reported that the LUMO-lowering activation of α,β-unsaturated aldehydes using the reversible formation of iminium ions with chiral imidazolidinones 1 (eq 1) is a valuable platform for the development of enantioselective organocatalytic Diels−Alder reactions (eq 2). In this work, we reveal that this catalytic strategy is also amenable to [3 + 2] cycloadditions between nitrones and α,β-unsaturated aldehydes to provide isoxazolidines (eq 3), useful synthons for the construction of biologically important amino acids, β-lactams, amino carbohydrates, and alkaloids. To our knowledge, this is the first example of an organocatalytic 1,3-dipolar cycloaddition.3 Moreover, this study further documents that chiral amines can be employed as asymmetric catalysts for a range of transformations that traditionally utilize metal salts.

The development of enantioselective Lewis acid catalyzed carbonyl addition reactions of π-nucleophiles such as enolsilanes and allylstannanes is a topic of current interest.1 The extension of this general process to include simple olefinic nucleophiles via the carbonyl-ene reaction2 has important practical implications. In this context, Mikami and Nakai have reported a catalytic enantioselective ene reaction with glyoxylate esters;3 however, due to the limiting reactivity of the catalyst-glyoxylate complex,4 only nucleophilic 1,1-disubstituted olefins may be employed. We have recently reported that bidentate bis(oxazolinyl) (box) Cu(II) complexes 1-3 are effective enantioselective catalysts in Diels-Alder5 and aldol reactions6 with substrates that can participate in catalyst chelation. In this study, we demonstrate that