ABSTRACT
Cross-coupling chemistry is widely applied to carbon-carbon bond formation in the synthesis of medicines, agrochemicals, and other functional materials. Recently, single-electron-induced variants of this reaction class have proven particularly useful in the formation of C(sp2)-C(sp3) linkages, although certain compound classes have remained a challenge. Here, we report the use of sulfones to activate the alkyl coupling partner in nickel-catalyzed radical cross-coupling with aryl zinc reagents. This method's tolerance of fluoroalkyl substituents proved particularly advantageous for the streamlined preparation of pharmaceutically oriented fluorinated scaffolds that previously required multiple steps, toxic reagents, and nonmodular retrosynthetic blueprints. Five specific sulfone reagents facilitate the rapid assembly of a vast set of compounds, many of which contain challenging fluorination patterns.
ABSTRACT
A practical electrochemical oxidation of unactivated C-H bonds is presented. This reaction utilizes a simple redox mediator, quinuclidine, with inexpensive carbon and nickel electrodes to selectively functionalize "deep-seated" methylene and methine moieties. The process exhibits a broad scope and good functional group compatibility. The scalability, as illustrated by a 50 g scale oxidation of sclareolide, bodes well for immediate and widespread adoption.
Subject(s)
Carbon/chemistry , Hydrogen/chemistry , Electrochemical Techniques , Molecular Structure , Oxidation-ReductionABSTRACT
Olefin chemistry, through pericyclic reactions, polymerizations, oxidations, or reductions, has an essential role in the manipulation of organic matter. Despite its importance, olefin synthesis still relies largely on chemistry introduced more than three decades ago, with metathesis being the most recent addition. Here we describe a simple method of accessing olefins with any substitution pattern or geometry from one of the most ubiquitous and variegated building blocks of chemistry: alkyl carboxylic acids. The activating principles used in amide-bond synthesis can therefore be used, with nickel- or iron-based catalysis, to extract carbon dioxide from a carboxylic acid and economically replace it with an organozinc-derived olefin on a molar scale. We prepare more than 60 olefins across a range of substrate classes, and the ability to simplify retrosynthetic analysis is exemplified with the preparation of 16 different natural products across 10 different families.
Subject(s)
Alkenes/chemistry , Alkenes/chemical synthesis , Biological Products/chemistry , Biological Products/chemical synthesis , Carboxylic Acids/chemistry , Alkenes/classification , Amides/chemistry , Biological Products/classification , Carbon Dioxide/chemistry , Carbon Dioxide/isolation & purification , Catalysis , Iron/chemistry , Nickel/chemistry , Oxidation-Reduction , Polyketides/chemical synthesis , Polyketides/chemistry , Substrate Specificity , Tartrates/chemical synthesis , Tartrates/chemistry , Zinc/chemistryABSTRACT
A highly efficient Ir-catalyzed asymmetric hydrogenation of racemic ß-keto lactams via dynamic kinetic resolution (DKR) for the synthesis of optically active ß-hydroxyl lactams has been described. With the Ir-SpiroSAP catalyst, a series of racemic ß-keto lactams including ß-keto γ-, δ-, and ε-lactams were hydrogenated to chiral ß-hydroxy lactams in high yields (87-99%) with excellent enantio- and diastereoselectivity (83-99.9% ee, syn/anti: 97:3->99:1) at low catalyst loading under mild reaction conditions. This efficient method has been successfully applied in the synthesis of the chiral intermediate of fluoroquinolone antibiotic premafloxacine.
Subject(s)
Iridium/chemistry , beta-Lactams/chemistry , Anti-Bacterial Agents/chemical synthesis , Catalysis , Drug Design , Fluoroquinolones/chemical synthesis , Hydrogenation , Kinetics , Molecular Structure , Pyrroles/chemical synthesis , StereoisomerismABSTRACT
The chiral tridentate spiro P-N-S ligands (SpiroSAP) were developed, and their iridium complexes were prepared. Introduction of a 1,3-dithiane moiety into the ligand resulted in a highly efficient chiral iridium catalyst for asymmetric hydrogenation of ß-alkyl-ß-ketoesters, producing chiral ß-alkyl-ß-hydroxyesters with excellent enantioselectivities (95-99.9% ee) and turnover numbers of up to 355,000.
ABSTRACT
A synthetic strategy featuring efficient ruthenium-catalyzed asymmetric hydrogenation of racemic α-aryloxy cyclic ketone via dynamic kinetic resolution and palladium-catalyzed intramolecular reductive Heck cyclization has been developed for the asymmetric total synthesis of (-)-galanthamine (20.1%, 12 steps) and (-)-lycoramine (40.2%, 10 steps).
