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

The Walden memorial at the Technical University in Riga is pictured in the frontispiece to mark the recent centennial of the Walden inversion. This is a rare public monument to key events from the first era of exploration in stereocontrolled synthesis, and may be the only such monument to use the language of organic chemistry expressed at the molecular level. The reaction of racemic substrates with chiral nucleophiles is one of many methods currently known to achieve kinetic resolution, a phenomenon that ranks as the oldest and most general approach for the synthesis of highly enantioenriched substances. The first nonenzymatic kinetic resolutions as well as the original forms of the Walden inversion were studied in the 1890s. All of these investigations were conducted within the first generation following the demonstration that carbon is tetrahedral, and provided abundant evidence that the principles and importance of enantiocontrolled syntheses were understood. However, a reliable, rapid technique to quantify results and guide the optimization process was still lacking. Many decades passed before this problem was solved by the advent of HPLC and GLPC assays on chiral supports, which stimulated explosive growth in the synthesis of nonracemic substances by kinetic resolution. The Walden monument is accessible to passers-by for hands-on inspection as well as for contemplation and learning. In a similar way, kinetic resolution is experimentally accessible and can be thought-provoking at several levels. We follow the story of kinetic resolution from the early discoveries through fascinating historical milestones and conceptual developments, and close with a focus on modern techniques that maximize efficiency.

Efficiency in nonenzymatic kinetic resolution.

Readily available biphenyl derivatives containing an alkyne unit at one of their ortho-positions are converted into substituted phenanthrenes on exposure to catalytic amounts of either PtCl2, AuCl, AuCl3, GaCl3 or InCl3 in toluene. This 6-endo-dig cyclization likely proceeds through initial pi-complexation of the alkyne unit followed by interception of the resulting eta2-metal species by the adjacent arene ring. The reaction is inherently modular, allowing for substantial structural variations and for the incorporation of substituents at any site of the phenanthrene product. Moreover, it is readily extended to the heterocyclic series as exemplified by the preparation of benzoindoles, benzocarbazoles, naphthothiophenes, as well as bridgehead nitrogen heterocycles such as pyrrolo[1,2-a]quinolines. Depending on the chosen catalyst, biaryls bearing halo-alkyne units can either be converted into the corresponding 10-halo-phenanthrenes or into the isomeric 9-halo-phenanthrenes; in the latter case, the concomitant 1,2-halide shift is best explained by assuming a metal vinylidene species as the reactive intermediate. The scope of this novel method for the preparation of polycyclic arenes is illustrated by the total synthesis of a series of polyoxygenated phenanthrenes that are close relatives of the anticancer agent combretastatin A-4, as well as by the total synthesis of the aporphine alkaloid O-methyl-dehydroisopiline and its naturally occurring symmetrical dimer.

Synthesis of Phenanthrenes and Polycyclic Heteroarenes by Transition‐Metal Catalyzed Cycloisomerization Reactions

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

Das im Vortitel gezeigte Walden-Denkmal auf dem Campus der Technischen Universitat Riga ist sicher eines der wenigen offentlichen Monumente, die Schlusselereignisse aus der Anfangszeit der stereokontrollierten Synthese thematisieren und vielleicht das einzige, das die “molekulare Sprache” der organischen Chemie gebraucht. Die ersten nichtenzymatischen kinetischen Racematspaltungen wurden, ebenso wie die ursprunglichen Varianten der Walden-Umkehr, in den 1890er Jahren untersucht – also noch in der ersten Forschergeneration nach Entdeckung der tetraedrischen Natur des Kohlenstoffs. Aus diesen fruhen Arbeiten ist abzulesen, dass die Prinzipien und die Bedeutung enantiokontrollierter Synthesen bereits gut verstanden waren. Was noch fehlte war eine verlassliche und schnelle Methode zur Quantifizierung der Ergebnisse und zur Optimierung der Experimente. Viele Jahrzehnte sollten vergehen, bis das Problem mit Einfuhrung von HPLC- und GPLC-Testreihen auf chiralen Tragern gelost wurde. Das Walden-Denkmal ladt den Vorubergehenden zur spielerischen Betrachtung ein – auf ahnliche Weise, wie auch die kinetische Racematspaltung zum Experimentieren einladt. Dieser Aufsatz verfolgt den Verlauf der Geschichte angefangen von den ersten Entdeckungen uber die faszinierenden historischen Meilensteine und konzeptionellen Entwicklungen und schliest mit einem Blick auf moderne Techniken zur Effizienzmaximierung.

Effizienz in der nichtenzymatischen kinetischen Racematspaltung

A naturally occurring 1,1‘-biphenanthrene, blestriarene C (1), was prepared in 13 steps and 30% overall yield. The key steps are the ester-mediated nucleophilic aromatic substitution on 2,6-di-tert-butyl-4-methoxyphenyl 5-isopropoxy-2-methoxybenzoate (4) by 2-methoxy-4-methoxymethoxy-6-methylphenylmagnesium bromide (5) and a novel intramolecular cyclization of the resulting 4-isopropoxy-2‘-methoxy-4‘-methoxymethoxy-6‘-methylbiphenyl-2-carboxylic ester 14 to 7-isopropoxy-4-methoxy-2-(methoxymethoxy)phenanthren-9-ol (15). The racemic blestriarene C was optically resolved by chiral HPLC on a preparative scale to give several 10-mg yields of both the enantiomers in up to 95% ee. The absolute stereochemistry was determined to be Sa-(−) by the axial chirality recognition method, which was based on the stereospecific formation of a 12-membered cyclic diester containing two biaryl-o,o‘-diyl unites joined by ester −CO2− linkages. The validity of the method was confirmed by an X-ray crystallographic analysis and ab...

Synthesis, resolution, and absolute stereochemistry of (-)-blestriarene C.

First determination of the absolute stereochemistry of a naturally occurring 1,1′-biphenanthrene, (−)-blestriarene C, and its unexpected photoracemization

/pdf/synthesis-resolution-and-absolute-stereochemistry-of-40jtd52c1d.pdf

Synthesis, Resolution, and Absolute Stereochemistry of (‐)‐Blestriarene C.

A naturally occurring 1,1′-biphenanthrene, blestriarene C, was prepared and its absolute stereochemistry was determined to be Sa-(−) by an empirical method, during which the compound was found to undergo rapid photoracemization even under ambient light exposure.

First Determination of the Absolute Stereochemistry of a Naturally Occurring 1,1′-Biphenanthrene, (-)-Blestriarene C, and Its Unexpected Photoracemization.

Yuhi Shimazumi

Papers

Synthesis, resolution, and absolute stereochemistry of (-)-blestriarene C.

First determination of the absolute stereochemistry of a naturally occurring 1,1′-biphenanthrene, (−)-blestriarene C, and its unexpected photoracemization

Synthesis, Resolution, and Absolute Stereochemistry of (‐)‐Blestriarene C.

First Determination of the Absolute Stereochemistry of a Naturally Occurring 1,1′-Biphenanthrene, (-)-Blestriarene C, and Its Unexpected Photoracemization.