Isolation and synthesis of biologically active carbazole alkaloids

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

Occurrence, Biogenesis, and Synthesis of Biologically Active Carbazole Alkaloids

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.

Quality control of herbal medicines

The first total synthesis of the Murraya alkaloid murrastifoline-F (3), an unsymmetric, N,C-bonded heterobiarylic biscarbazole, is described. Starting from the likewise naturally occurring-but here synthetically prepared-"monomer" murrayafoline-A (6), lead tetraacetate-mediated oxidative non-phenolic biaryl coupling gives 3 as the main regioisomer. The existence of this natural product as a pair of stable atropo-enantiomers was demonstrated analytically through LC-CD investigations. Preparatively, the racemate resolution succeeded by O-demethylation, derivatization with Mosher's reagent, and chromatographic separation of the resulting diastereomers. The absolute configurations of the atropisomers were assigned by CD spectroscopy in combination with quantum chemical CD calculations at the stage of the alkaloid 3 and by ROESY experiments of the diastereomeric Mosher derivatives. In the root extract of the curry leaf plant Murraya koenigii (Rutaceae), murrastifoline-F (3) was found to exist as a 56:44 mixture in favor of the M-enantiomer, by LC-CD coupling.

Murrastifoline-F: first total synthesis, atropo-enantiomer resolution, and stereoanalysis of an axially chiral N,C-coupled biaryl alkaloid.

The applicability of on-line coupling of gradient eluted nonchiral reversed-phase high-pressure liquid chromatography (HPLC) to circular dichroism (CD) spectroscopy for the stereochemical analysis of crude plant extracts was investigated. A detector measuring simultaneously UV absorbances and CD effects at constant wavelengths in the same detection cell was used. The solvent system water/acetonitrile was found to be suited to give high-quality CD chromatograms as a function of the elution time and even complete characteristic CD spectra in the stop-flow mode. The method was applied to the tropical liana Habropetalum dawei (Dioncophyllaceae). First, the extract solution was investigated by the combined application of HPLC−NMR and HPLC−ESI-MS/MS techniques. The constitution and relative configuration of two as yet unknown natural products thus detected, the isoquinoline phylline (5) and the naphthylisoquinoline alkaloid 5‘-O-methyldioncopeltine A (6), were characterized. Subsequent HPLC−CD experiments permi...

HPLC−CD On-Line Coupling in Combination with HPLC−NMR and HPLC−MS/MS for the Determination of the Full Absolute Stereostructure of New Metabolites in Plant Extracts

Kim Messer

Papers

Murrastifoline-F: first total synthesis, atropo-enantiomer resolution, and stereoanalysis of an axially chiral N,C-coupled biaryl alkaloid.

HPLC−CD On-Line Coupling in Combination with HPLC−NMR and HPLC−MS/MS for the Determination of the Full Absolute Stereostructure of New Metabolites in Plant Extracts

Dioncophylline E from Dioncophyllum thollonii, the first 7,3'-coupled dioncophyllaceous naphthylisoquinoline alkaloid.

Habropetaline A, an antimalarial naphthylisoquinoline alkaloid from Triphyophyllum peltatum.

The absolute configuration of (+)-isoshinanolone and in situ LC-CD analysis of its stereoisomers from crude extracts.