The majority of medications can be coadministered with the 3D regimen of OBV, PTV/r, and DSV without dose adjustment, or with clinical monitoring or dose adjustment. Although no dose adjustment is necessary for the 3D regimen when coadministered with 17 of the 20 medications, coadministration with gemfibrozil, carbamazepine, or ethinyl estradiol-containing contraceptives is contraindicated.

Asymmetric hydrogenation of quinolines catalyzed by chiral cationic η(6)-arene-N-tosylethylenediamine-Ru(II) complexes have been investigated. A wide range of quinoline derivatives, including 2-alkylquinolines, 2-arylquinolines, and 2-functionalized and 2,3-disubstituted quinoline derivatives, were efficiently hydrogenated to give 1,2,3,4-tetrahydroquinolines with up to >99% ee and full conversions. This catalytic protocol is applicable to the gram-scale synthesis of some biologically active tetrahydroquinolines, such as (-)-angustureine, and 6-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline, a key intermediate for the preparation of the antibacterial agent (S)-flumequine. The catalytic pathway of this reaction has been investigated in detail using a combination of stoichiometric reaction, intermediate characterization, and isotope labeling patterns. The evidence obtained from these experiments revealed that quinoline is reduced via an ionic and cascade reaction pathway, including 1,4-hydride addition, isomerization, and 1,2-hydride addition, and hydrogen addition undergoes a stepwise H(+)/H(-) transfer process outside the coordination sphere rather than a concerted mechanism. In addition, DFT calculations indicate that the enantioselectivity originates from the CH/π attraction between the η(6)-arene ligand in the Ru-complex and the fused phenyl ring of dihydroquinoline via a 10-membered ring transition state with the participation of TfO(-) anion.

Even though seminal reports on phosphine catalysis appeared in the 1960s, in the last few decades of the past century trivalent phosphines were viewed primarily as useful ligands for transition-metal-mediated processes. The 1990s saw revived interest in using phosphines in organic catalysis, but the key advances in asymmetric phosphine catalysis have all come within the past decade. The uniqueness of phosphine catalysis can be attributed to the high nucleophilicity of the phosphorus atom. In typical phosphine-catalyzed reactions, nucleophilic attacks of the phosphorus atom on electron-deficient multiple bonds create different reactive ylide-type intermediates. When such structurally diverse zwitterionic species react with a variety of suitable substrates, new reaction patterns are often discovered and a diverse array of reactions can be developed. In recent years, substantial progress has been made in the field of asymmetric phosphine catalysis; many new reactions have been discovered, and numerous enantioselective processes have been reported. However, we felt that powerful and versatile phosphine catalysts that can work for a wide range of asymmetric reactions are still lacking. We therefore set our goal to develop a family of easily derived phosphine catalysts that are efficient in asymmetric induction for a broad range of phosphine-mediated transformations. This Account describes our efforts in the past few years on the development of amino acid-based bifunctional phosphines and their applications to enantioselective processes. Building upon our previous success in primary-amine-mediated enamine catalysis, we first established that bifunctional phosphines could be readily prepared from amino acids. In most of our studies, we chose threonine as the key backbone for catalyst development, and threonine-based monoamino acid or dipeptide bifunctional phosphines have displayed remarkable stereochemical control. We began our investigations by demonstrating the usefulness of our phosphine catalysts in aza-Morita-Baylis-Hillman (aza-MBH) and MBH reactions. We then showed the great power of amino acid/dipeptide phosphines in a wide range of [3 + 2] annulation processes, including [3 + 2] cycloaddition of allenoates to acrylates/acrylamides, [3 + 2] annulation of imines with allenoates, and [3 + 2] cyclization employing MBH carbonates and activated alkenes. By utilizing α-substituted allenoates and activated alkenes, we developed an enantioselective [4 + 2] annulation to access functionalized cyclohexenes. We also devised a novel enantioselective [4 + 2] annulation process by using α-substituted allenones for the construction of 3,4-dihydropyrans. With the use of β'-acetate allenoate, a [4 + 1] annulation process has been designed to access chiral spiropyrazolones. Another array of reactions that make use of the basicity of zwitterionic phosphonium enolate intermediates have been successfully attained, including the first phosphine-catalyzed asymmetric Michael addition, enantioselective allylic substitution of MBH carbo...

Room-temperature ionic liquids (RTILs) have recently received a great deal of attention as alternative reaction media.[1] Numerous catalytic reactions have proven feasible in a variety of ionic liquids, with many reactions displaying enhanced reactivities and selectivities, and some of which were not possible in common organic solvents.[2] Furthermore, RTILs have served as a promising means to immobilize a catalyst, therefore facilitating product isolation and offering an opportunity to reuse the catalyst. However, the use of RTILs in asymmetric catalytic reactions is still limited. [1f,g, 2f, 3] The recycling and reuse of chiral catalysts in ionic liquids have often been problematic because of the instability and/or leaching of the catalysts. From a practical standpoint, development of highly effective and recyclable catalysts in ionic liquids for use in asymmetric hydrogenation remains a challenge: in particular for heteroaromatic substrates which are difficult to hydrogenate.Although a variety of chiral Rh, Ru, and Ir complexes have been efficient and enantioselective reagents for the hydrogenation of prochiral olefins, ketones, and imines, [4] most of these catalysts failed to give satisfactory results in the asymmetric hydrogenation of heteroaromatic compounds.[5] A few successful examples for the asymmetric hydrogenation of quinolines have recently been reported. [6] However, all catalysts for such reactions have at least one phosphine ligand around the metal center and are often air sensitive.[7] From the viewpoints of both scientific interest and practical application, it is highly desirable to develop recyclable and phosphine-free chiral catalysts for the highly enantioselective hydrogenation of quinolines. Few examples of phosphine-free homogeneous catalysts capable of activating molecular hydrogen have been reported. [8] Recently, Noyori and co-workers reported that chiral h 6 -arene/Ntosylethylenediamine-Ru II complexes (which are known as excellent catalysts for asymmetric transfer hydrogenation, for example Ru/Ts-dpen) can be used for the asymmetric hydrogenation of prochiral ketones under slightly acidic conditions.[9] Inspired by this important breakthrough and following our continued pursuit of developing effective and environmentally benign catalyst systems for asymmetric hydrogenations, [10] herein we report a practical and efficient catalyst system of Ru/Ts-dpen in [BMIM]PF 6 (BMIM = 1-nbutyl-3-methylimidazolium) for the enantioselective hydrogenation of quinolines (Scheme 1).We have found that quinoline substrates could be efficiently hydrogenated to give 1,2,3,4-tetrahydroquinolines with excellent enantioselectivities (up to 99 % ee) in neat ionic liquid without the need for additives. Furthermore, the catalyst, which was highly stable in ionic liquid and maintained the same activity even after exposure to air for 30 days, could be easily recycled.Considering that methanol has been successfully used in the asymmetric hydrogenation of ketones by Noyori and coworkers, [9] we first examined ...

An enantioselective synthesis of spiropyrazolones from allenoate-derived MBH acetates and pyrazolones through a phosphine-mediated [4+1] annulation process has been developed. Spiropyrazolones were readily prepared in good chemical yields and good to high enantioselectivities. This is the first asymmetric example in which α-substituted allenoates were utilized as a C4 synthon for phosphine-catalyzed [4+1] annulation.

No abstract

A new method for facile access to enantioenriched tertiary thioethers/alcohols.

Phosphine-catalyzed regiodivergent enantioselective C-2- and C-4-selective γ-additions of oxazolones to 2,3-butadienoates have been developed. The C-4-selective γ-addition of oxazolones occurred in a highly enantioselective manner when 2-aryl-4-alkyloxazol-5-(4H)-ones were employed as pronucleophiles. With the employment of 2-alkyl-4-aryloxazol-5-(4H)-ones as the donor, C-2-selective γ-addition of oxazolones took place in a highly enantioselective manner. The C-4-selective adducts provided rapid access to optically enriched α,α-disubstituted α-amino acid derivatives, and the C-2-selective products led to facile synthesis of chiral N,O-acetals and γ-lactols. Theoretical studies via DFT calculations suggested that the origin of the observed regioselectivity was due to the distortion energy that resulted from the interaction between the nucleophilic oxazolide and the electrophilic phosphonium intermediate.