Biaryl Axis Research Articles

Parvistemins A–D, a new type of dimeric phenylethyl benzoquinones from Stemona parviflora Wright

Four naturally occurring dimeric phenylethyl benzoquinones, parvistemins A–D, were isolated from the aerial parts of Stemona parviflora Wright. Their constitutions were established by spectroscopic methods. Due to restricted rotation about the central biaryl axis, the compounds are chiral, although racemic. Their two respective atropo-enantiomers were resolved by HPLC on a chiral phase and were stereochemically characterized online, in hyphenation with circular dichroism (CD) spectroscopy (LC–CD coupling), combined with quantum chemical CD calculations.

Preparation of new axially chiral bridged 2,2′-bipyridines and pyridyl monooxazolines (pymox). Evaluation in copper(i)-catalyzed enantioselective cyclopropanation

This work reports the synthesis of new axially chiral bridged 2,2'-bipyridines 1 and pyridylmonooxazolines (pymox) 2. The potential of these new axially chiral N,N-ligands was evaluated in asymmetric catalytic cyclopropanation of styrene derivatives 22a-c with diazoesters 21a,b. While 2,2'-bipyridines 1a-c afforded the corresponding cyclopropanes 23a-f in up to 65% ee, pymoxs 2a-e gave somewhat lower enantioselectivities (up to 53% ee). Both classes of ligands produced trans-cyclopropanes 23a-f as the major isomer, although with modest diasteroselectivities (56 : 44 to 78 : 22). A structure-stereoselectivity relationship study of ligands 1 and 2 identified the chiral biaryl axis as being mostly responsible for the enantioselective performances of these ligands.

Kinetic and thermodynamic control of axial chirality in biaryl-derived fused oxazolidine lactams exploiting a centre-axis relay of unit efficiency

The condensation of a 2-substituted-2-aminoethanol with methyl 2'-formylbiphenyl-2-carboxylate produces only two of the four possible axially chiral 6,7-dihydrodibenz[c,e]oxazolo[3,2-a]azepin-9(4bH)-ones (fused oxazolidine lactams), with kinetically controlled diastereoisomer ratios of up to 96 : 4. Within each lactam product the central chirality of the oxazolidine-fused benzylic position C(4b) is relayed to the biaryl axis with unit efficiency, the mis-matching of these stereogenic elements being prohibited due to strain, as predicted by molecular mechanics calculations. Diastereoisomeric lactam pairs can be equilibrated by heating with acid, and under these thermodynamic conditions reversed diastereoisomer ratios of up to 26 : 74 are observed.

Synthesis of the dibenzopyrrocoline alkaloid skeleton: indolo[2,1- a]isoquinolines and related analogues

The indolo[2,1- a]isoquinoline and pyrrolo[2,1- a]isoquinoline nuclei have been synthesized from N-benzylindole or ethyl 1 H-indol-1-ylacetate and N-benzylpyrrole precursors, respectively. Firstly, at C-2 of either the indole or pyrrole nucleus, aromatic rings containing a carbonyl substituent ortho to the newly formed biaryl axis were introduced using the Suzuki–Miyaura coupling reaction. Thereafter, under basic conditions the nucleophile that formed at the acidic methylene protons of the N-benzylindole, ethyl 1 H-indol-1-ylacetate or N-benzylpyrrole intermediate reacted with the internal aromatic carbonyl to yield (after the expulsion of water) the title compounds. For example, exposure of ethyl 2-(2-(2-formylphenyl)-1 H-indol-1-yl)acetate to potassium tert-butoxide resulted in the formation of ethyl indolo[2,1- a]isoquinoline-6-carboxylate.

Ancistrocladinium A and B, the First N,C-Coupled Naphthyldihydroisoquinoline Alkaloids, from a Congolese Ancistrocladus Species

The isolation and structural elucidation of three novel-type naphthylisoquinoline alkaloids, ancistrocladinium A and B (the latter along with its atropisomer), from a Congolese Ancistrocladus species collected in the habitat Yeteto is reported. Their structures, including all stereochemical features, were elucidated by spectroscopic, chemical, and chiroptical methods. Ancistrocladinium A and B are the first N,C-coupled naphthyldihydroisoquinoline alkaloids found in nature, i.e., with an iminium-aryl axis. Although ancistrocladinium A, which is N,8'-coupled, is configurationally stable at this axis, ancistrocladinum B and its rotational isomer are based on a hitherto unprecedented N,6'-coupling type, with a slow rotation about the hetero biaryl axis at room temperature; they thus occur as a 46:54 mixture of two configurationally semistable atropo-diastereomers. For the isomerization of (P)-ancistrocladinium B to its (M)-diastereomer and for the opposite direction, the Gibbs free energies of activation were determined to be DeltaG double dagger1 = 105.8 kJ mol-1 and DeltaG double dagger2 = 105.7 kJ mol-1, respectively. In addition, the compounds were shown to have promising antileishmanial activities.

Resolution, Enantiomerization Kinetics, and Chiroptical Properties of 7,7‘-Dihydroxy-8,8‘-biquinolyl

(+/-)-7,7'-Dihydroxy-8,8'-biquinolyl (6) was resolved into its enantiomorphic atropisomers via reverse phase (C18) chromatographic separation of epimeric bismenthyl carbonates, (-)-lk-9 and (+)-ul-9, derived from 6 and (+)-menthyl chloroformate. The faster eluting diastereoisomer, (-)-lk-9, was revealed to possess an (aS)-configurated biaryl axis by X-ray crystallographic analysis. Saponification of the separated bismenthyl carbonates gave enantioenriched samples of biquinolyl 6, and absolute stereochemical configurations were assigned to the two optical isomers as (-)-(aS)-6 and (+)-(aR)-6 by correlation with their respective progenitors, (-)-lk-9 and (+)-ul-9. First-order rate constants for the enantiomerization of 6 in water were obtained over the temperature range 316-366 K, and activation parameters were determined as DeltaH(++) = 34.0 kcal mol(-1) and DeltaS(++) = 18.7 cal mol(-1) K(-1) by Eyring plot analysis. A low level (AM1) computational study of the rotational dynamics of 6 showed excellent agreement with kinetic experimental data and suggested that enantiomerization occurs preferentially via a syn pathway. In common with (-)-(aS)-1,1'-bi-2-naphthol (BINOL), (-)-(aS)-6 showed positive exciton chirality in its electronic circular dichroism (CD) spectrum and gave a characteristic couplet composed of a positive maximum Cotton effect at 250 nm and a negative minimum at 234 nm (Delta Delta epsilon = +40 M(-1) cm(-1) at 64% ee).

Modular Synthesis of a New Class of Bis(amino-oxazoline) Using Palladium-Catalyzed Buchwald−Hartwig Amination Methodology

The palladium-catalyzed Buchwald−Hartwig aryl amination between 2,2‘-diaminobiphenyl and 2 equiv of 2-(2‘-bromophenyl)oxazoline has been used to prepare a new class of tetradentate bis(amino-oxazoline). The reaction between 2,2‘-diaminobiphenyl and 1 equiv of 2-(2‘-bromophenyl)oxazoline is highly selective for monoarylation, and the resulting products have been reacted in a second arylation to afford unsymmetrically substituted bis(amino-oxazolines). These new diamido/donors belong to the tropos class of ligand and exist as an equilibrium mixture of S,aS,S- and S,aR,S-diastereoisomers, which interconvert by rotation about the biaryl axis. Variable-temperature 1H NMR studies and line-shape analysis of simulated spectra gave ΔH⧧ and ΔS⧧ values of 51.5−57 kJ mol-1 and −25.9 to −57.0 J mol-1 K-1, respectively, for diastereointerconversion. Interestingly, reaction of one of the symmetrical bis(amino-oxazoline) with [Cu(MeCN)4][PF6] results in dynamic resolution to afford diastereopure (S,aS,S)-[Cu(L)][PF6], which has a highly unusual sawhorse geometry at copper with the two oxazolines occupying trans coordination sites and two weak interactions to the nitrogen atoms of the secondary amino groups. 1H and 13C NMR spectra of this copper complex are entirely consistent with a single C2-symmetric diastereoisomer in solution that shows no sign of diastereointerconversion even after standing for one week.

Biaryl Axis as a Stereochemical Relay for the Enantioselective Synthesis of Antimicrotubule Agents

Chiralität weitergereicht: Eine Biarylkonfiguration, die in einer atropselektiven Suzuki-Kupplung durch ein benzylisches Stereozentrum festgelegt wird, steuert wiederum die Konfiguration des Stereozentrums in einer dehydratisierenden SN1-Cyclisierung bei niedriger Temperatur. Auf diese Art wurden erfolgversprechende Antimikrotubuli-Biaryle hoch enantiomerenrein erhalten. TFA=Trifluoressigsäure, pin=Pinacolato.

Biaryl Axis as a Stereochemical Relay for the Enantioselective Synthesis of Antimicrotubule Agents

Biaryl Axis as a Stereochemical Relay for the Enantioselective Synthesis of Antimicrotubule Agents

New chiral tridentate ligands for asymmetric catalysis

Abstract The synthesis of new tridentate, isoquinoline-derived ligands, involving successive Suzuki cross-coupling reactions, is described. We were able to resolve 1-[3-(2-hydroxy-phenyl)-isoquinolin-1-yl]-naphthalen-2-ol via molecular complexation with N-benzylcinchonidinium chloride, whereas 1,3-bis(2-hydroxy-naphthalen-1-yl)-isoquinoline was resolved by chromatographic separation of its epimeric camphorsulfonates. Their barrier to rotation about the central biaryl axis was evaluated via racemization studies. Application of enantiopure 1,3-bis(2-hydroxynaphthalen-1-yl)-isoquinoline in the addition of diethylzinc to aldehydes proceeded in moderate yield but without asymmetric induction. A new tridentate ligand, 4-tert-butyl-2-chloro-6-[1-(2-hydroxymethyl-naphthalen-1-yl)-isoquinolin-3-yl]-phenol, was prepared in good yield and resolved by semipreparative high-performance liquid chromatography (HPLC). Its application in the addition of diethylzinc to a range of aromatic aldehydes proceeded in near perfect enantioselectivities at low ligand loadings of 1 mol %.

Atroposelective Synthesis of Axially Chiral Biaryl Compounds

AbstractFor Abstract see ChemInform Abstract in Full Text.

X‐ray Structure Determination, Absolute Configuration and Biological Activity of Phomoxanthone A

AbstractThe dimeric xanthone phomoxanthone A (1a), a cytochalasin L‐696,474 (2a), the corresponding 21‐O‐deacetyl‐L‐696,474 (2b), and 3‐nitropropionic acid (3) were isolated from the endophytic fungus Phomopsis sp. The relative configuration of phomoxanthone A (1a) was elucidated by X‐ray single‐crystal analysis. The comparison of the calculated and measured CD spectra and CD calculation of model compounds revealed that the axial chirality along the biaryl axis dominates the CD spectra of the dimeric xanthone 1a, and can thus be determined by CD calculation as (aS). Knowing the axial chirality, the absolute configurations of the stereogenic centers could be determined from the X‐ray data of 1a as (5R,6R,10aR,5′R,6′R,10a′R). In addition, it was demonstrated that in both the solid state (KBr) and solution (methanol/dichloromethane, 4:1) 1a has the same conformation, i.e. similar dihedral angles along the biaryl axis. Comparison of solid‐state CD measurement with calculation of CD data based on X‐ray coordinates was introduced for the first time. Phomoxanthone A (1a) showed activity against bacteria and phytopathogenic fungi. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

The first 6′- O-sulfated phenylanthraquinones: isolation from Bulbine frutescens, structural elucidation, enantiomeric purity, and partial synthesis

From the roots of Bulbine frutescens, the first sulfated phenylanthraquinones were isolated, together with their known sulfate-free analogs. Their structures were elucidated by spectroscopic and chiroptical methods, by acid hydrolysis or by partial synthesis. The new compounds have the usual stereo-orientation at the biaryl axis (i.e., with the acetyl portion above the anthraquinone plane) except for sodium ent-knipholone 6′- O-sulfate (and thus, also its hydrolysis product, ent-knipholone), which exhibit an opposite axial configuration. We also describe the first stereoanalysis of natural phenylanthraquinones, some of which were found to be not enantiomerically pure, some even near-racemic. We furthermore, report on the first X-ray structure analysis of a phenylanthraquinone, viz. 4′- O-demethylknipholone.

A borderline case between meso and stable C 1: an axially chiral, yet configurationally semi-stable biphenyl with two oppositely configured [10]paracyclophane portions

The synthesis of the bi[10]paracyclophanes 2 and 4 from the meso-configured bioxepine 3 is described. These compounds are stereochemically remarkable: the biaryl axis that connects the constitutionally identical, but oppositely configured planar-chiral paracyclophane portions, is configurationally semi-stable. Thus, 2 is an unprecedented borderline case of a (planar-chiral)–(axially chiral)–(planar-chiral) molecule that is right in between a meso-compound (as a macroscopical result of the—albeit slow—rotation about the central C,C-bond) and C 1-symmetry (with respect to the existence of separable—even though configurationally unstable—discrete atropo-enantiomers). Despite their restricted configurational stability, these atropo-enantiomers were resolved on a chiral phase at 5 °C and were stereochemically assigned by LC–CD coupling, in combination with quantum chemical CD calculations.

Synthesis, resolution and racemisation studies of new tridentate ligands for asymmetric catalysis

A method for the high-yielding preparation of two tridentate, isoquinoline-derived ligands, involving successive Suzuki cross-coupling reactions, is described. The first ligand could be resolved via molecular complexation with N-benzylcinchonidinium chloride, while the second was resolved by chromatographic separation of its epimeric camphorsulfonates. The barrier to rotation about the central biaryl axis was evaluated via racemisation studies, and the absolute configuration assigned by X-ray crystallography.

Saludimerines A and B, Novel‐Type Dimeric Alkaloids with Stereogenic Centers and Configurationally Semistable Biaryl Axes.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Ent-Dioncophylleine A and Related Dehydrogenated Naphthylisoquinoline Alkaloids, the First Asian Dioncophyllaceae-Type Alkaloids, from the “New” Plant Species Ancistrocladus benomensis

Three new fully dehydrogenated naphthylisoquinoline alkaloids, the 7,1'-coupled ent-dioncophylleine A (3a), the likewise 7,1'-coupled 5'-O-demethyl-ent-dioncophylleine A (4), and the 7,8'-linked dioncophylleine D (5), have been isolated from the leaves of the recently described Malaysian highland liana Ancistrocladusbenomensis. All of them lack an oxygen function at C-6; this so-called Dioncophyllaceae-type structural subclass had previously been found only in naphthylisoquinoline alkaloids from West and Central African plants. Moreover, compounds 3a and 4 are the first fully dehydrogenated, i.e., only axially chiral, naphthylisoquinoline alkaloids of this type that are optically active; compound 5, by contrast, is fully racemic, due to its configurationally unstable biaryl axis. The structural elucidation was achieved by spectroscopic and chiroptical methods. Biological activities of these alkaloids against different protozoan parasites are described.

The Absolute Configuration of Peroxisomicines A1 and A2

AbstractFor Abstract see ChemInform Abstract in Full Text.

Saludimerines A and B, Novel-Type Dimeric Alkaloids with Stereogenic Centers and Configurationally Semistable Biaryl Axes

The first biarylic bis-morphinanedienone alkaloids, saludimerines A (3a) and B (3b), isolated from a tree of Croton flavens (Euphorbiaceae) are described. These naturally occurring dimers of the known alkaloid salutaridine are joined together via a rotationally hindered biaryl axis, giving rise to atropo-diastereomers that are configurationally stable at room temperature but slowly interconvert in methanolic solution within several days. Their structures were established by spectroscopic methods and by partial synthesis, which was achieved by a highly atropo-diastereoselective biomimetic oxidative coupling of the monomeric precursor, salutaridine. Their axial configurations were elucidated by circular dichroism (CD) investigations, which succeeded despite the fact that the two atropo-diastereomers exhibit near-identical CD spectra. This remarkable phenomenon was rationalized by quantum chemical CD calculations. The configurational assignment of saludimerines A (3a) as P-axial and B (3b) as M was corroborated by atropisomer-specific NOE interactions between protons of the one molecular half with nuclei in the other.

The absolute configuration of peroxisomicines A1 and A2

Peroxisomicine A1 is a potentially antineoplastic compound isolated from the seeds of Karwinskia parvifolia. It is considered as a useful chemotype for the preparation of topoisomerase II targeted anticancer cells. Stereochemically, it is characterized by the presence of two stereocenters and a rotationally hindered and thus likewise stereogenic biaryl axis. In this contribution, the absolute configuration of peroxisomicine A1 and its epimer, peroxisomicine A2, was established by means of a five-step degradative procedure giving the respective R- and S-configured methyl 2-(2′-methyl-5′-oxotetrahydrofuryl)acetates. The configuration of the degradation product was obtained by means of optical rotation, 1H NMR analysis using a chiral displacement reagent, and by experimental and quantum chemical circular dichroism (CD) investigations. Based on the results obtained here and considering our previous work on the relative configuration at centers versus axis of these compounds, peroxisomicine A1 resulted to be the P,3 S,3′ S-isomer and peroxisomicine A2 the P,3 R,3′ S-isomer.