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[reaction: see text] Diisobutylaluminum hydride (DIBAL-H) and triisobutylaluminum have been found to be outstanding reductants for secondary phosphine oxides (SPOs). All classes of SPOs can be readily reduced, including diaryl, arylalkyl, and dialkyl members. Many SPOs can now be reduced at cryogenic temperatures, and conditions for preservation of(More)
A sequential allyl vinyl ether formation-Claisen rearrangement process catalyzed by a palladium(II)-phenanthroline complex is reported. The effects of allylic alcohol structure, type of vinylating agent, and palladium catalysts are discussed. This method provides a convenient approach to gamma,delta-unsaturated aldehydes under mild conditions that avoid the(More)
A potent reversible inhibitor of the cysteine protease cathepsin-S was prepared on large scale using a convergent synthetic route, free of chromatography and cryogenics. Late-stage peptide coupling of a chiral urea acid fragment with a functionalized aminonitrile was employed to prepare the target, using 2-hydroxypyridine as a robust, nonexplosive(More)
The ability of the macrocyclic HCV protease inhibitor BILN 2061 to bind different classes of cations has been studied by (15)N, (13)C, and (1)H NMR. (15)N NMR experiments were performed at natural abundance or with isotopically labeled materials. Three classes of cations: alkali metals, alkaline earth metals, and transition metals, were examined, using two(More)
A large-scale synthesis of the hepatitis C virus drug Faldaprevir revealed precipitation of an unknown insoluble solid from methanol solutions of the drug substance. The unknown impurity was determined to be a polymer of Faldaprevir based on analytical methods that included size exclusion chromatography in combination with electrospray ionization mass(More)
Asymmetric hydrogenation of unsaturated urea esters with the BIPI Ligands has been examined. Optimization of the P-N ligand structure has led to the development of chiral rhodium catalysts capable of producing the targets with >99% ee. The critical phosphine borane SNAr reaction needed for ligand synthesis has been optimized to give the adducts in high(More)
Racemization of chiral imidazolines with base has been studied for the first time following an unexpected finding in the synthesis of chiral imidazoline ligands. Amine bases do not cause racemization. Strong inorganic bases can induce racemization, yet this occurs only when the nitrogen is unsubstituted, in agreement with a symmetry-allowed thermal(More)
The reduction of tertiary phosphine oxides (TPOs) and sulfides with diisobutylaluminum hydride (DIBAL-H) has been studied in detail. An extensive solvent screen has revealed that hindered aliphatic ethers, such as MTBE, are optimum for this reaction at ambient temperature. Many TPOs undergo considerable reduction at ambient temperature and then stall due to(More)
The direct addition of anionic secondary phosphine boranes to carbodiimides yields both chiral and achiral phosphaguanidine boranes under ambient temperature conditions. An analogous preparation of menthol-derived phosphinite boranes is also described. These products can be deborinated to give the corresponding phosphines, and subsequently oxidized to give(More)
Four unknown trace impurities (7-10) were observed in the capsule formulation of the HIV drug Tipranavir after prolonged storage at 30 degrees C/70% RH. Extensive NMR and LC/MS analyses revealed the compounds to be covalent adducts between TRIS, an excipient of the formulation, and diastereomeric Tipranavir alcohols formed via slow air oxidation of the drug(More)