ABSTRACT
Adenosine-derived ketone 5 was subjected to Noyori asymmetric transfer hydrogenation (ATH) using aqueous sodium formate as a stoichiometric reductant. Despite the well-known sensitivity of ATH to stereoelectronic effects from a contiguous stereogenic center, the 5' stereochemistry was overwhelmingly controlled by the chirality of the catalyst. Both the (5'S,4'R) and the (5'R,4'R) diastereomers could be prepared selectively in good yields. An efficient three-step route that provides ketone 5 in 75% overall yield was developed.
Subject(s)
Adenosine/analogs & derivatives , Adenosine/chemistry , Deoxyguanosine/chemistry , Indicators and Reagents/chemistry , Ketones/chemical synthesis , Catalysis , Ketones/chemistry , StereoisomerismABSTRACT
Telaprevir 2 (VX-950), an inhibitor of the hepatitis C virus (HCV(a)) NS3-4A protease, is in phase 3 clinical trials. One of the major metabolites of 2 is its P1-(R)-diastereoisomer, 3 (VRT-394), containing an inversion at the chiral center next to the alpha-ketoamide on exchange of a proton with solvent. Compound 3 is approximately 30-fold less active against HCV protease. In an attempt to suppress the epimerization of 2 without losing activity against the HCV protease, the proton at that chiral site was replaced with deuterium (d). The compound 1 (d-telaprevir) is as efficacious as 2 in in vitro inhibition of protease activity and viral replication (replicon) assays. The kinetics of in vitro stability of 1 and 2 in buffered pH solutions and plasma samples, including human plasma, suggest that 1 is significantly more stable than 2. Oral administration (10 mg/kg) in rats resulted in a approximately 13% increase of AUC for 1.
Subject(s)
Antiviral Agents/blood , Oligopeptides/blood , Serine Proteinase Inhibitors/blood , Viral Nonstructural Proteins/antagonists & inhibitors , Administration, Oral , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Buffers , Deuterium/chemistry , Dogs , Drug Stability , Hepacivirus/enzymology , Humans , Hydrogen-Ion Concentration , Injections, Intravenous , Isotope Labeling , Oligopeptides/chemical synthesis , Oligopeptides/chemistry , Oligopeptides/pharmacokinetics , Rats , Serine Proteinase Inhibitors/chemical synthesis , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/pharmacokinetics , StereoisomerismABSTRACT
Reported herein is a novel approach to the total syntheses of (-)-alpha-kainic acid and (+)-alpha-allokainic acid, where the stereochemistries on C(2), C(3), and C(4) of the pyrrolidine core were introduced efficiently and selectively. A regio- and stereoselective C-H insertion reaction was utilized to prepare the gamma-lactam as an intermediate. A Michael-type cyclization of phenylsulfone with a conjugated acetylenic ketone was developed to prepare the tricyclic ketone as a key intermediate for (-)-alpha-kainic acid. Subsequently, a stereoselective dephenylsulfonylation was carried out successfully to secure the cis relationship at C(3) and C(4) centers. An unprecedented acetylation on the phenylsulfone, followed by a stereoselective dephenylsulfonylation, secured the trans relationship at C(3) and C(4) centers in (+)-alpha-allokainic acid.
Subject(s)
Kainic Acid/analogs & derivatives , Kainic Acid/chemical synthesis , Cyclization , Kainic Acid/chemistry , Molecular Conformation , StereoisomerismABSTRACT
We report herein the development of a general and mild protocol of oxygen-promoted Pd(II) catalysis resulting in the selective cross-couplings of alkenyl- and arylboron compounds with various olefins. Unlike most cross-coupling reactions, this new methodology works well even in the absence of bases, consequently averting undesired homo-couplings. Nitrogen-based ligands including dimethyl-phenanathroline enhance reactivities and offer a highly efficient and stereoselective methodology to overcome challenging substrate limitations. For instance, oxidative palladium(II) catalysis is effective with highly substituted alkenes and cyclic alkenes, which are known to be incompatible with other known catalytic conditions. Most examined reactions progressed smoothly to completion at low temperatures and in short times. These interesting results provide mechanistic insights and utilities for a new paradigm of palladium catalytic cycles without bases.
Subject(s)
Carbon/chemistry , Cross-Linking Reagents/chemistry , Nitrogen/chemistry , Palladium/chemistry , Alkenes/chemistry , Boron/chemistry , Boronic Acids/chemistry , Catalysis , Cyclohexanones/chemistry , Esterification , Ligands , Molecular Structure , Oxidation-Reduction , Solvents , TemperatureABSTRACT
Reported herein is a mild and efficient Pd(II) catalysis, leading to the formation of carbon-carbon bonds between a broad spectrum of organoboron compounds and alkenes. Molecular oxygen was employed to reoxidize the resultant Pd(0) species back to Pd(II) during catalytic cycles. This oxygen protocol promoted the desired Pd(II) catalysis, whereas it retarded competing Pd(0) catalytic pathways such as Heck or Suzuki couplings. [reaction: see text]
Subject(s)
Alkenes/chemistry , Boron Compounds/chemistry , Oxygen/chemistry , Palladium/chemistry , Benzene Derivatives/chemistry , CatalysisABSTRACT
We report herein a mild and efficient method for carbon-carbon bond formation between aryl stannanes and olefins via Pd(II) catalysis in the presence of oxygen or Cu(II) oxidants as a reoxidant. The process allows reactions between various olefins and aryl stannanes of varying electron density. Coupling methods under these oxidation conditions are comparatively described, and the benefits and limitations are also discussed.
