The biaryl structural motif is a predominant feature in many pharmaceutically relevant and biologically active compounds. As a result, for over a century 1 organic chemists have sought to develop new and more efficient aryl -aryl bond-forming methods. Although there exist a variety of routes for the construction of aryl -aryl bonds, arguably the most common method is through the use of transition-metalmediated reactions. 2-4 While earlier reports focused on the use of stoichiometric quantities of a transition metal to carry out the desired transformation, modern methods of transitionmetal-catalyzed aryl -aryl coupling have focused on the development of high-yielding reactions achieved with excellent selectivity and high functional group tolerance under mild reaction conditions. Typically, these reactions involve either the coupling of an aryl halide or pseudohalide with an organometallic reagent (Scheme 1), or the homocoupling of two aryl halides or two organometallic reagents. Although a number of improvements have developed the former process into an industrially very useful and attractive method for the construction of aryl -aryl bonds, the need still exists for more efficient routes whereby the same outcome is accomplished, but with reduced waste and in fewer steps. In particular, the obligation to use coupling partners that are both activated is wasteful since it necessitates the installation and then subsequent disposal of stoichiometric activating agents. Furthermore, preparation of preactivated aryl substrates often requires several steps, which in itself can be a time-consuming and economically inefficient process.

http://aether.cmi.ua.ac.be/artikels/Artikels%20Gitte/Artikels/Reviews/Heck-Type-lautens.pdf

Aryl-aryl bond formation by transition-metal-catalyzed direct arylation.

The area of transition-metal-catalyzed direct arylation through cleavage of CH bonds has undergone rapid development in recent years, and is becoming an increasingly viable alternative to traditional cross-coupling reactions with organometallic reagents In particular, palladium and ruthenium catalysts have been described that enable the direct arylation of (hetero)arenes with challenging coupling partners—including electrophilic aryl chlorides and tosylates as well as simple arenes in cross-dehydrogenative arylations Furthermore, less expensive copper, iron, and nickel complexes were recently shown to be effective for economically attractive direct arylations

Transition-metal-catalyzed direct arylation of (hetero)arenes by C-H bond cleavage.

Intellectual curiosity has always been one of the major driving forces leading to new advances in chemistry. At the onset of the 20th century, the fact that biaryls could be optically active even if lacking asymmetrically substituted carbon atoms arose interest, hinting at a novel type of stereomerism. It took quite a while (and some bizarre explanations)1 until in 1922 Christie and Kenner2 first correctly recognized that the phenomenon was the consequence of a hindered rotation about the aryl-aryl single bondshence termed atropisomerism by Kuhn. Still, no particular attention was initially paid to this class of stereoisomers until enantiomerically pure biaryls, such as BINAP (1),3 were found to be excellent ligands in asymmetric catalysis and until the chiral biaryl unit was recognized as the decisive structural element of many natural products (Figure 1).4,5 With the modern screening techniques and the bioassayguided search for novel compounds, the number of isolated axially chiral natural biaryls is steadily increasing.4 This class of secondary metabolites is characterized by a broad structural diversity, reaching from relatively simple molecules like the C2-symmetric biphenyl 2, which solely contains the element of axial chirality,6 to more complex compounds, like, e.g., the dimeric naphthylisoquinoline alkaloids michellamine A [(P,P)-3] and its axial epimer (i.e., its atropodiastereomer), michellamine B [(P,M)-3],7,8 which possess even three biaryl axes, of which the two outer ones are stereogenic, while * To whom correspondence should be addressed. E-mail: bringmann@ chemie.uni-wuerzburg.de; breuning@chemie.uni-wuerzburg.de. † These authors contributed equally to this work. ‡ Present address: Institute of Organic Chemistry, RWTH Aachen, Landoltweg 1, 52074 Aachen, Germany. § Present address: Kekulé Institute of Chemistry and Biochemistry, University of Bonn, Gerhard-Domagk Str. 1, 53121 Bonn, Germany. Gerhard Bringmann was born in 1951 and studied chemistry in Gie en and Münster, Germany. After his Ph.D. with Prof. B. Franck in 1978 and postdoctoral studies with Prof. Sir D. H. R. Barton in Gif-sur-Yvette (France), he passed his habilitation at the University of Münster in 1984. In 1986, he received offers for full professorships of Organic Chemistry at the Universities of Vienna and Würzburg, of which he accepted the latter in 1987. In 1998, he was offered the position of director at the Leibniz Institute of Plant Biochemistry in Halle, which he declined. His research interests focus on the field of analytical, synthetic, and computational natural product chemistry, i.e., on axially chiral biaryls. He received several prizes and awards, among them the Otto-Klung Award in chemistry (1988), the Prize for Good Teaching of the Free State of Bavaria (1999), the Adolf-Windaus Medal (2006), the Honorary Doctorate of the University of Kinshasa (2006), the Paul-J.-Scheuer Award (2007), and the Honorary Guest Professorship of Peking University (2008). Chem. Rev. 2011, 111, 563–639 563

Atroposelective total synthesis of axially chiral biaryl natural products.

Transition metal-mediated C–H bond activation and functionalization represent one of the most straightforward and powerful tools in modern organic synthetic chemistry. Bi(hetero)aryls are privileged π-conjugated structural cores in biologically active molecules, organic functional materials, ligands, and organic synthetic intermediates. The oxidative C–H/C–H coupling reactions between two (hetero)arenes through 2-fold C–H activation offer a valuable opportunity for rapid assembly of diverse bi(hetero)aryls and further exploitation of their applications in pharmaceutical and material sciences. This review provides a comprehensive overview of the fundamentals and applications of transition metal-mediated/catalyzed oxidative C–H/C–H coupling reactions between two (hetero)arenes. The substrate scope, limitation, reaction mechanism, regioselectivity, and chemoselectivity, as well as related control strategies of these reactions are discussed. Additionally, the applications of these established methods in the s...

Oxidative C-H/C-H Coupling Reactions between Two (Hetero)arenes.

Despite the impressive progress achieved in asymmetric catalysis during the last decade, an increasing number of new catalysts, ligands, and applications are reported every year to satisfy the need to embrace a wider range of reactions and to improve the efficiency of existing processes. Because of their availability, unique stereochemical aspects, and wide variety of coordination modes and possibilities for the fine-tuning of the steric and electronic properties, ferrocene-based ligands constitute one of the most versatile ligand architectures in the current scenario of asymmetric catalysis. Over the last few years ferrocene catalysts have been successfully applied in an amazing variety of enantioselective processes. This Review documents these recent advances, with special emphasis on the most innovative asymmetric processes and the development of novel, efficient types of ferrocene ligands.

Recent applications of chiral ferrocene ligands in asymmetric catalysis.

A rotationally hindered and thus stereogenic biaryl axis is the structurally and stereochemically decisive element of a steadily growing number of natural products, chiral auxiliaries, and catalysts. Thus, it is not surprising that significant advances have been made in the asymmetric synthesis of axially chiral biaryl compounds over the past decade. In addition to the classic approach (direct stereoselective aryl-aryl coupling), innovative concepts have been developed in which the asymmetric information is introduced into a preformed, but achiral-that is, symmetric or configurationally labile-biaryl compound, or in which an aryl--C single bond is stereoselectively transformed into an axis. This Review classifies these strategies according to their underlying concepts and critically evaluates their scope and limitations with reference to selected model reactions and applications. Furthermore, the preconditions required for the existence of axial chirality in biaryl compounds are discussed.

Atroposelective Synthesis of Axially Chiral Biaryl Compounds

Eine rotationsgehinderte und dadurch stereogene Biarylachse ist das strukturell und stereochemisch entscheidende Element einer standig wachsenden Zahl von Naturstoffen, chiralen Auxiliaren und Katalysatoren. Daher ist es nicht uberraschend, dass im letzten Jahrzehnt bedeutende Fortschritte in der asymmetrischen Synthese axial-chiraler Biaryle erzielt worden sind. Neben dem klassischen Zugangsweg, der direkten Aryl-Aryl-Kupplung, sind innovative Konzepte entwickelt worden, in denen die asymmetrische Information in ein schon vorhandenes, aber nicht optisch aktives – symmetrisches oder konfigurativ labiles – Biaryl eingefuhrt oder eine Aryl-C-Einfachbindung stereoselektiv in eine Achse umgewandelt wird. In diesem Aufsatz werden die Strategien nach den zugrunde liegenden Konzepten klassifiziert, und ihre Anwendungsbreite und ihre Beschrankungen werden anhand ausgewahlter Beispiele kritisch beurteilt. Ferner werden die Voraussetzungen fur das Auftreten von Axialchiralitat diskutiert.

Atropselektive Synthese axial‐chiraler Biaryle

The utilization pathway for the uptake of NAD and nicotinamide riboside was previously characterized for Haemophilus influenzae . We now report on the cellular location, topology, and substrate specificity of PnuC. pnuC of H. influenzae is only distantly related to pnuC of Escherichia coli and Salmonella enterica serovar Typhimurium. When E. coli PnuC was expressed in an H. influenzae pnuC mutant, it was able to take up only nicotinamide riboside and not nicotinamide mononucleotide. Therefore, we postulated that PnuC transporters in general possess specificity for nicotinamide riboside. Earlier studies showed that 3-aminopyridine derivatives (e.g., 3-aminopyridine adenine dinucleotide) are inhibitory for H. influenzae growth. By testing characterized strains with mutations in the NAD utilization pathway, we show that 3-aminopyridine riboside is inhibitory to H. influenzae and is taken up by the NAD-processing and nicotinamide riboside route. 3-Aminopyridine riboside is utilized effectively in a pnuC + background. In addition, we demonstrate that 3-aminopyridine adenine dinucleotide resynthesis is produced by NadR. 3-Aminopyridine riboside-resistant H. influenzae isolates were characterized, and mutations in nadR could be detected. We also tested other species of the family Pasteurellaceae , Pasteurella multocida and Actinobacillus actinomycetemcomitans , and found that 3-aminopyridine riboside does not act as a growth inhibitor; hence, 3-aminopyridine riboside represents an anti-infective agent with a very narrow host range.

Anne J. Price Mortimer

Papers

Atroposelective Synthesis of Axially Chiral Biaryl Compounds

Atropselektive Synthese axial‐chiraler Biaryle

Atroposelective Synthesis of Axially Chiral Biaryl Compounds

PnuC and the Utilization of the Nicotinamide Riboside Analog 3-Aminopyridine in Haemophilus influenzae