Matthias Breuning

Atroposelective total synthesis of axially chiral biaryl natural products.

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

The directed synthesis of axially chiral ligands, reagents, catalysts, and natural products through the ‘lactone methodology’ ☆

Abstract Axially chiral biaryls have become increasingly important during the past years—as structurally, biosynthetically, and pharmacologically remarkable natural products, but also as useful tools in asymmetric synthesis: as chiral reagents, ligands, and catalysts. Nevertheless, only few generally applicable synthetic protocols for the atropo-enantio- or -diastereoselective construction of biaryl bonds have been developed. The ‘lactone methodology’ as described in detail in the preceeding article, provides directed, atropo-divergent access to any of the two respective atropisomers starting from the identical immediate precursor, a (usually) configurationally unstable, since lactone-bridged biaryl. In this article the efficiency of the ‘lactone method’ in the total synthesis of natural products and in the preparation of axially chiral ligands is demonstrated for selected examples.

The lactone concept—a novel approach to the metal-assisted atroposelective construction of axially chiral biaryl systems

The atroposelective synthesis of axially chiral biaryls via configurationally unstable, lactone-bridged biaryls is reviewed. These key molecules are easily accessible by regioselective intramolecular cross-coupling of ester-linked, even sterically hindered aromatic portions and can be cleaved highly atropo-enantio- or -diastereoselectively by three principal options, either (a) by using a wide range of chiral metalated nucleophiles (usually with external asymmetric induction), (b) after Lewis acid activation of the lactone CO function using uncharged chiral or achiral nucleophiles, or (c) with internal asymmetric induction, using the stereoelement of planar chirality originating from η6-coordination (typically involving Cr or Ru complexes). The resulting ring-opened configurationally stable biaryls are obtained in mostly excellent chemical and optical yields. By the choice of the respective enantiomer of the nucleophile, the method allows the atropo-divergent synthesis of both atropisomers from the same immediate biaryl precursor and, if required, a recycling of the undesired minor atropisomer is possible, too. Such advantages are otherwise well-known for the stereoselective preparation of centrochiral compounds.

Chiral 2‐endo‐Substituted 9‐Oxabispidines: Novel Ligands for Enantioselective Copper(II)‐Catalyzed Henry Reactions

A flexible approach, applicable on a gram scale, to chiral 2-endo-substituted 9-oxabispidines was developed. The key intermediate, a cis-configured 6-aminomethylmorpholine-2-carbonitrile, was prepared from (R)-3-aminopropane-1,2-diol and 2-chloroacrylonitrile. The 2-endo substituent was introduced by Grignard addition, cyclization, and exo-selective reduction, thus furnishing the enantiomerically pure bi- and tricyclic 9-oxabispidines in 19-59 % yield. The CuCl(2) complex of the tricyclic 9-oxabispidine, which carries an 2-endo,N-anellated piperidine ring, is an excellent catalyst for enantioselective Henry reactions giving the S-configured beta-nitro alcohols in 91-98 % ee (13 examples). Surprisingly, the analogous copper complexes of the bicyclic 9-oxabispidines delivered the enantiocomplementary R-configured products in 33-57 % ee. The respective transition states were discussed.

Atropo-enantioselective synthesis of an axially chiral C1-symmetric phosphine ligand and its application in the asymmetric hydrosilylation of styrenes

Abstract The axially chiral monodentate phosphine P - 8 was synthesized in enantiomerically pure form, starting from the readily available, configurationally unstable lactone 1 . Furthermore, its application as a ligand in the Pd-catalyzed stereoselective hydrosilylation of styrenes was investigated.

A Flexible Route to Chiral 2-endo-Substituted 9-Oxabispidines and Their Application in the Enantioselective Oxidation of Secondary Alcohols

A new and flexible route to enantiomerically pure bi- and tricyclic 9-oxabispidines has been developed with use of (1R,5S)-7-methyl-2-oxo-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester as the common late-stage intermediate. The 9-oxabispidines synthesized were evaluated as the chiral ligands in the Pd(II)-catalyzed oxidative kinetic resolution of secondary alcohols giving good to excellent selectivity factors of up to 19.

ATROPO-DIASTEREOSELECTIVE CLEAVAGE OF CONFIGURATIONALLY UNSTABLE BIARYL LACTONES WITH ALKALI METAL ACTIVATED PRIMARY 1-ARYLETHYLAMINES

Axially chiral biaryls with diastereomeric ratios of up to 95:5 are synthesized by highly atropo-selective cleavage of configurationally unstable, lactone-bridged biaryls with chiral metalated 1-arylethlamines (see scheme). This methodology permits optional preparation of each of the two atropisomers from the same lactone precursor just by the use of the appropiate amine reagent or its enantiomer for the ring-opening (atropo-divergence), and offers the possibility of recycling the minor isomer back to the lactone. The chiral 1-arylethyl(amine) group can subsequently split off without any loss of stereoinformation at the axis.

Atropo-enantioselective synthesis of a C3-symmetric tripodal ligand with three axially chiral biaryl subunits ☆

Abstract In contrast to the numerous successful applications of C 2 -symmetric biaryls as powerful tools for asymmetric synthesis, there have so far been only few reports on combinations of C 3 -symmetry with axial chirality. We present here the first enantioselective synthesis of a novel family of tripodal ligands containing three axially chiral biaryl subunits in an ( M , M , M )- or, optionally, ( P , P , P )-configured form. The incorporation of a PCl 2 - and a TiCl-fragment into the central cavity was achieved.

Atropo-enantioselective reduction of configurationally unstable biaryl lactones with BINAL-H

Abstract The atropo-enantioselective reduction of configurationally unstable biaryl lactones with BINAL-H yields axially chiral biaryl alcohols in high enantiomeric ratios of up to 94:6 (er >99.5:0.5 after one crystallization step). Within this two-step reduction process the stereochemically deciding step is the first attack on the lactones and not the reduction of the likewise configurationally unstable biaryl lactol/hydroxy aldehyde intermediates, as evident from the non-stereoselective reduction of the latter under the same conditions.

The ortho-hydroxy-ortho′-formyl biaryl/lactol equilibrium: Quantumchemical studies on structure and dynamics☆

Abstract The equilibrium between the lactol-bridged biaryls 3 and the ring opened hydroxy aldehyde isomers 4 as well as their atropisomerization are investigated by quantumchemical calculations. The suitability of semiempirical and different modern ab initio methods is validated by comparison with experimentally observed equilibria and crystallographic data. It is shown that for the description of the equilibrium between 3 and 4 Hartree-Fock ab initio methods lead to a significant improvement compared with semiempirical methods. Furthermore, the consideration of solvent effects by using AM1-SM4, PM3-SM4 and PM3-SM3 gives satisfying results in the description of the equilibrium investigated.