- Pd- And Ni-Based Systems for the Catalytic Borylation of Aryl (Pseudo)halides with B2(OH)4
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Despite recent advancements in metal-catalyzed borylations of aryl (pseudo)halides, there is a continuing need to develop robust methods to access both early-stage and late-stage organoboron intermediates amendable for further functionalization. In particular, the development of general catalytic systems that operate under mild reaction conditions across a broad range of electrophilic partners remains elusive. Herein, we report the development and application of three catalytic systems (two Pd-based and one Ni-based) for the direct borylation of aryl (pseudo)halides using tetrahydroxydiboron (B2(OH)4). For the Pd-based catalyst systems, we have identified general reaction conditions that allow for the sequestration of halide ions through simple precipitation that results in catalyst loadings as low as 0.01 mol % (100 ppm) and reaction temperatures as low as room temperature. We also describe a complementary Ni-based catalyst system that employs simple unligated Ni(II) salts as an inexpensive alternative to the Pd-based systems for the borylation of aryl (pseudo)halides. Extrapolation of all three systems to a one-pot tandem borylation/Suzuki-Miyaura cross-coupling is also demonstrated on advanced intermediates and drug substances.
- Munteanu, Charissa,Spiller, Taylor E.,Qiu, Jun,Delmonte, Albert J.,Wisniewski, Steven R.,Simmons, Eric M.,Frantz, Doug E.
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p. 10334 - 10349
(2020/09/18)
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- Discovery and gram-scale synthesis of BMS-593214, a potent, selective FVIIa inhibitor
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A 6-amidinotetrahydroquinoline screening hit was driven to a structurally novel, potent, and selective FVIIa inhibitor through a combination of library synthesis and rational design. An efficient gram-scale synthesis of the active enantiomer BMS-593214 was developed, which required significant optimization of the key Povarov annulation. Importantly, BMS-593214 showed antithrombotic efficacy in a rabbit arterial thrombosis model. A crystal structure of BMS-593214 bound to FVIIa highlights key contacts with Asp 189, Lys 192, and the S2 pocket.
- Priestley, E. Scott,De Lucca, Indawati,Zhou, Jinglan,Zhou, Jiacheng,Saiah, Eddine,Stanton, Robert,Robinson, Leslie,Luettgen, Joseph M.,Wei, Anzhi,Wen, Xiao,Knabb, Robert M.,Wong, Pancras C.,Wexler, Ruth R.
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supporting information
p. 2432 - 2435
(2013/05/09)
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- Selective monosaccharide transport through lipid bilayers using boronic acid carriers
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Twenty-one boronic acids were studied for their ability to transport saccharides in and out of liposomes. The rates of liposome efflux were determined using an enzymatic assay, whereas the influx studies used a radiotracer method. All boronic acids examined, except those that were highly hydrophilic, facilitated monosaccharide transport. The order of transport selectivity was sorbitol > fructose > glucose. The disaccharides maltose and sucrose were not transported to any significant degree. Facilitated transport was demonstrated with a variety of liposome types, including multilamellar and unilamellar vesicles with anionic or cationic polar lipid additives. Transport mechanism studies included the accumulation of structure-activity data, as well as systematic investigations of various environmental changes such as pH, added salt, membrane potential, and temperature. Overall, the evidence is strongly in favor of a membrane carrier mechanism. The boronic acid combines reversibly with a diol group on the monosaccharide to produce a tetrahedral, anionic boronate, which is the major complexed structure in bulk, aqueous solution. At the bilayer surface, the tetrahedral boronate is in equilibrium with its neutral, trigonal form, which is the actual transported species. At low carrier concentrations, a first-order dependence on carrier was observed indicating that the transported species was a 1:1 sugar-boronate. At higher carrier concentrations the kinetic order approached 2, suggesting the increased participation of a 1:2 sugar-bisboronate transport pathway. The effect of boronic acids on liposomal bilayer fluidity was probed by fluorescence spectroscopy using appropriate reporter molecules. Adding cholesterol to the liposome membranes reduced translational fluidity by 'packing and ordering' the bilayer. Addition of lipophilic arylboronic acids (either free or complexed with monosaccharides) induced a similar but smaller effect.
- Westmark, Pamela R.,Gardiner, Stephen J.,Smith, Bradley D.
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p. 11093 - 11100
(2007/10/03)
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