Zur Chemie der Pyrrolpigmente, 56. Mitt.

From an investigation of the ICD of bilatrienes-abc and 2,3-dihydrobilatrienes-abc induced by mixtures of CCl₄ with (+)-cis-Pinane, (–)-lactic and (+)-tartaric acid esters it is concluded that specific interactions between chromophore and the chiral reagents afford a partial resolution of the labile racemate of helices. Attaching chiral residues covalently to the chromophore induces very low resolution of the same kind in case of apolar ligands like a cholesteryl-residue. However, with polar ligands as in the case ofBoc-lysyl derivatives enantiomeric excesses up to 90% are achieved depending on the solvent used.

Herrn Prof. Dr.Karl Schlögl zu seinem 60. Geburtstag gewidmet.     

Zur Chemie der Pyrrolpigmente, 54. Mitt.: Phytochrommodellstudien: Ein 2,3-Dihydrobilatrien-abc-3-Cholesterylderivat

The diastereomeric 2,3-Dihydrobilatrienes-abc derivatives (4Z, 9Z, 15Z)-7 and (4Z, 9Z, 15E)-7 bearing a cholesterylacetate moiety in position 3 of the chromophore are prepared. The reaction sequence contains an isomerisation step providing quantitative enantioselective formation of the chiral center in position 3. Configurations and conformations of the diastereomers are elucidated using¹H- and¹³C-NMR spectra, NOE-difference spectra, 2D-NMR experiments (NOESY) and arguments from UV-VIS and CD data. It is concluded that the hydrophobic interactions between chromophore and cholesteryl-fragment yield a compact conformation where the two substructures are in close contact with each other. On the other hand these interactions seem to be too weak to induce significant changes in the chemistry, absorption spectra and conformational characterics of the bile pigment chromophore. Therefore hydrophobic interactions between chromophor and apolar amino acid residues of the protein in phytochrome should be of minor relevance for determining spectroscopic shifts.

     

Zur Chemie von Pyrrolpigmenten, 55. Mitt.

2,3-Dihydrobilatrienes-abc substituted with carboxy and amino residue bearing groups in 3- and 12-positions have been prepared. Spectrophotometric titrations of these derivatives revealed that the influence of a non-conjugated positive or negative charge in the vicinity of the chromophore has only marginal influence on the absorption spectra. Rather small hypsochromic and bathochromic shifts of the long wavelength absorption band were observed and are discussed with respect to their origin. The results indicate that the influence of non-conjugated charges is not a main reason for spectral shifts accompanying photochemical and thermal transformations of the phytochrome chromophore.

     

Beiträge zur Chemie der Pyrrolpigmente, 81. Mitt.: Kraftfeldrechnungen an Gallenfarbstoffen: Die Energiehyperfläche von 2,3-Dihydrobilin-1,19-dionen

Summary The energy hypersurface of 2,3-dihydrobilin-1,19-diones is analyzed with respect to their conformational aspects using a specialized force field. Estimations of helix interconversion energies, chiral discrimination, geometries of global minima, and relative energies and geometries of diastereomeres compare favourably with available experimental data from the literature.

     

Zur Chemie der Thioladdition an 2,3-Dihydro-3-ethylidendipyrrin-1(10H)-one—eine Modellstudie zur kovalenten Chromophor-Protein-Bindung in Biliproteiden

Addition of benzylmercaptan to 2,3-dihydro-3-ethylidenedipyrrin-1(10H)-one (Z,Z)-3 was found to be a model reaction with regard to the thioether linkage of protein and chromophore in biliproteins. Isolation and characterization of the main product4 reveals the ethylidene double bond to be attacked first by thiol according to the principles of the acid catalysed nucleophilic addition.

     

Beiträge zur Chemie der Pyrrolpigmente, 61. Mitt.

The parameters of aPPP-SCF-LCAO-MO-CI treatment adjusted earlier for studies in the bilatriene-abc series are checked by means of a 3,4-dihydropyrromethenone of known conformation. This method is then applied to the calculation of -electron densities, bond orders, reactivities and absorption spectra of the various tautomeric forms, diastereomers and conformations of the 2,3-dihydrobilatrieneabc chromophor, which is of interest as the prosthetic group of the plant photoreceptor phytochrome and of antenna pigments of algae. The results are compared to¹³C-,¹⁵N-NMR and X-ray data as well as absorption spectra of available tautomeric model compounds and diastereomers with conformations known from experiment. The monomeric nature of the absorbing species is checked in some cases by vapour pressure osmometry. In case of the 2,3-dihydrobilatrienes-abc in their N₂₃-H tautomeric form (which was consolidated experimentally earlier) isomerization of the (Z,Z,Z) configured parent compound doesnot yield significant changes of the type of absorption spectra. The stretched chromophore criterion deduced byMoscowitz et al. for bilatrienes-abc (i.e., the intensity of the long wavelength band exceeds that of the short wavelength band) is refined for the 2,3-dihydro-derivatives, as only conformational changes fromsyn toanti at the single bonds 10–11 and 14–15 yield this effect. This change at 10–11 may be discriminated from the one at 14–15 by a strong secondary band in the long wavelength region.

     

Beiträge zur Chemie der Pyrrolpigmente, 72. Mitt.

A strategy for the synthesis of bilatrienes-abc bridged between rings A and C has been developed and tested in case of a bibenzylethane bridging fragment. This strategy was then applied to the synthesis of a 2,3-dihydrobilatriene-abc bridged by a (S)-lysine moiety from ring A to ring C (positions 3 and 12) by means of peptide bonds between the two amino groups of lysine and the acetic and propionic acid side chains of the chromophoric unit. The two diastereomers resulting from the two chiral centers of the lysine residue and at position 3 of the chromophore were separated by chromatography.

     

Organocatalytic Enantioselective Synthesis of Axially Chiral N,N′-Bisindoles

This study establishes the first organocatalytic enantioselective synthesis of axially chiral N,N′-bisindoles via chiral phosphoric acid-catalyzed formal (3+2) cycloadditions of indole-based enaminones as novel platform molecules with 2,3-diketoesters, where de novo indole-ring formation is involved. Using this new strategy, various axially chiral N,N′-bisindoles were synthesized in good yields and with excellent enantioselectivities (up to 87 % yield and 96 % ee). More importantly, this class of axially chiral N,N′-bisindoles exhibited some degree of cytotoxicity toward cancer cells and was derived into axially chiral phosphine ligands with high catalytic activity. This study provides a new strategy for enantioselective synthesis of axially chiral N,N′-bisindoles using asymmetric organocatalysis and is the first to realize the applications of such scaffolds in medicinal chemistry and asymmetric catalysis.     

Beiträge zur Chemie der Pyrrolpigmente, 83. Mitt.: Zum Einfluß geladener Zentren auf die Absorptionsspektren von 1,19-Bilindionen

Summary Model systems consisting of 10-phenyl-bilin-1,19-diones substituted in 2- and 4-positions of the phenyl ring with carboxy or amino groups are synthesized by condensating appropriately substituted benzaldehydes with dipyrrinones. These systems provide a defined geometrical relation between bilin chromophore and functional group which can be charged by deprotonation or protonation. Spectrophotometrical titrations of these systems reveal that the negative charge exerts no influence on the absorption spectrum of the bilin. In the case of the positive charge problems arising from conformational and association equilibria prevent to draw such a conclusion.

     

Beiträge zur Chemie der Pyrrolpigmente, 82. Mitt.: Wasserlösliche Polymere mit kovalent gebundenen violinoiden und 2,3-dihydro-verdinoiden Gallenfarbstoffen

Summary A violinoid and a 2,3-dihydrobilindione chromophore is attachedvia an appendix anchored at rings A of the pigments by means of reacting them with the polyacryl-N-acryloxysuccinimid copolymer to yield water-soluble chromopolymers. They are characterized by a molecular mass of about 4000 to 6000 and a relation of one chromophoric unit per 6 to 22 monomers. Their absorption spectra and circular dichroism recorded in water and dimethylsulfoxide as solvents are discussed with respect to structural aspects, and in comparison with monomeric chromophore derivatives.

Herrn Prof. Dr. K. Schlögl mit den besten Wünschen zum 65. Geburtstag gewidmet     

Asymmetric [2,3]‐Wittig Rearrangement of Oxygenated Allyl Benzyl Ethers in the Presence of a Chiral di‐tBu‐bis(oxazoline) Ligand: A Novel Synthetic Approach to THF Lignans

We have accomplished highly enantioselective [2,3]‐Wittig rearrangements of functionalized allyl benzyl ethers in the presence of a chiral di‐tBu‐bis(oxazoline) ligand. In various oxygenated benzylic ethers, the reactions proceeded with excellent diastereo‐ and enantioselectivities, although the presence of a methoxy substituent at the ortho‐position on the benzyl group drastically decreased the enantioselectivity. Conversely, o‐ethyl and o‐phenyl substituents had no significant effect on the selectivity. We found that the C2‐substituent of the allylic moiety played an important role in producing high enantioselectivity. Highly enantioselective [2,3]‐Wittig rearrangement in the presence of catalytic amounts of the chiral ligands is also described.     

Conformation control of bilatrienes by peptides: A survey

Summary A variety of bilipeptides has been synthesized and investigated by UV-VIS and CD spectroscopy to explore the conformational influence of peptide ligands on the covalently bound tetrapyrrol moiety. The results obtained are complemented by those reported previously. From the comprehensive data thus available several features of the peptidic chain regulating interactions with the bilatriene moiety have been elucidated. Accordingly, the presence of three amide linkages at the ligand is prerequiste for induction of pronounced conformational changes consisting either in a complete transition ofM intoP helical bilatriene species by inversion of all torsional angles, or in a stretching of the chromophore. The kind of conformational influence can be controlled by varying the position of the prolyl entity within a given peptide.Dedicated to Prof. Dr. Kurt Schaffner on occasion of his 60th birthday     

Organic Stereochemistry. Part 6

Following the previous Part on the mechanisms of chiral recognition in pharmacology, the road was open to cover one aspect of stereoselectivity that had been evoked in Part 5 but not discussed explicitly, namely the pharmacological significance of the conformational behavior of active molecules. There, we saw how ligands and binding sites adapt to each other, but these results were not related explicitly to the conformational behavior of the ligand. The focus of the present Part is to use a few well‐known drugs, examine their conformational behavior, compare the 3D geometry of probable conformers with rigid analogs acting at the same receptor, and reflect on the concept of ‘active conformation’.     

Zur Chemie der Pyrrolpigmente, 63. Mitt.

Using hexamethylphosphoric acid triamide (HMPT) as solvent for bilatrienesabc and mainly for 2,3-dihydrobilatrienes-abc (which serve as the most suitable models for the biliproteid chromophores) a small hypsochromic shift and a dramatic change of the relative intensities of short and long wavelength absorption bands, as compared to solutions in CCl₄, is observed. Applying NMR-spectroscopic techniques (¹⁵N-,¹³C-,¹H-) a predominance of the (4Z,9E,15Z) diastereomer forming a 5syn-, 10anti-, 14syn-periplanar orclinal conformation is deduced. The stabilisation of this configuration and conformation arises from strong hydrogen bonds between the acidic protons of the bilins andHMPT. Interactions of this kind seem to be the main source of energy to stretch the otherwise coiled bilin chromophore of (4Z,9Z,15Z)-5sp,10sp,14sp geometry. Stretched systems of the type bilin-HMPT may serve as a valuable model for the natural biliproteides.

Herrn Prof. Dr.A. Eschenmoser zum 60. Geburtstag gewidmet.116, 1065 (1985).     

Beiträge zur Chemie schwefelhaltiger Heterocyclen, 2. Mitt.

Zusammenfassung 6-Nitro-benzo[b]thiophen-1,1-dioxid wurde unter verschiedenen Bedingungen hydriert. Das durchSkraupsche Synthese aus 2,3-Dihydro-6-amino-benzo[b]thiophen-1,1-dioxid gewonnene Produkt konnte auf Grund des NMR-Spektrums als 2,3-Dihydrothieno[2,3-f]chinolin-1,1-dioxid identifiziert werden.

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6-Nitro-benzo[b]thiophene-1,1-dioxide was hydrogenated under various conditions. The product prepared from 2,3-dihydro-6-amino-benzo[b]thiophene-1,1-dioxide by theSkraup synthesis was identified by nmr as 2,3-dihydro-thieno[2,3-f]quinoline-1,1-dioxide.

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1. Mitt.:F. Sauter, Mh. Chem.99, 1507 (1968).     

Chiral N‐Heterocyclic Carbene Ligands Bearing a Pyridine Moiety for the Copper‐Catalyzed Alkylation of N‐Sulfonylimines with Dialkylzinc Reagents

Amino acid‐derived chiral imidazolium salts, each bearing a pyridine ring, were developed as N‐heterocyclic carbene ligands. The copper‐catalyzed asymmetric alkylation of various N‐sulfonylimines with dialkylzinc reagents in the presence of these chiral imidazolium salts afforded the corresponding alkylated products with high enantioselectivity (up to 99 % ee). The addition of HMPA to the reaction mixture as a co‐solvent is critical in terms of chemical yield and enantioselectivity. A wide range of N‐sulfonylimines and dialkylzinc reagents were found to be applicable to this reaction.     

Studien zur Chemie von thienoanellierten O,N-und S,N-haltigen Heterocyclen, 5. Mitt.: Ein Zugang zum Thieno[2,3-b][1,4]oxazin-Ringsystem

Summary The reactivity of 5-acetyl-2-chloro-3-nitrothiophene with -hydroxyesters is described. The influence of the solvent (DMF, tetrahydrofurane, toluene) and of the used base is discussed. These reactions provide an access to substituted thiophene derivatives, which were cyclized after reduction by iron powder/glacial acetic acid to give thieno [2,3-b][1,4]oxazine derivatives.

     

Hydrophile Polymergele mit reaktiven Gruppen, 2. Mitt.: Chelatharze auf Basis von Glucose- und Saccharosemethacrylaten

A widely applicable method for the preparation of chelating resins based on glucose- and sucrosemethacrylate-gels is described. Primary aromatic amino groups were bonded to the carrier by esterification with 4-nitrobenzoylchloride and subsequent reduction of the nitro groups with sodium dithionite. Diazotation and coupling with various chelating ligands (8-hydroxyquinoline, dithizone, anthranilic acid, salicylic acid and pyrogallol) afforded chelating resins with capacities of max. 1.7 mmol/g. Sucrosemethacrylate-gels were etherified with 4-nitrobenzylchloride, epichlorohydrin, 4-nitrophenyl glycide ether (IIb), acrylonitrile and 4-nitrophenylacrylamide (IVb). Reaction of the gels with IIb or IVb and subsequent reduction of the nitro groups yielded reactive carriers with ether-linked primary aromatic amino groups. Diazotation and coupling with 8-hydroxyquinoline yielded chelating resins. The capacities of the gels were 0.6–0.7 mmol/g and these resins were extremely stable to changes inpH.

     

Organic Stereochemistry. Part 5

This review continues a general presentation of the principles of stereochemistry with special reference to the medicinal sciences. Here, we discuss and illustrate molecular and clinical phenomena of stereoselectivity in pharmacological effects, namely activity differences between stereoisomers, principally enantiomers. The review begins with didactic models of chiral recognition, with a main focus on the early model of Easson and Stedman. There follows a Molecular Modeling (MM) and Molecular Dynamics (MD) depiction of the differential interaction of the enantiomers of hyoscyamine with cholinergic muscarinic receptors. The next section is devoted to various rationalizations in stereoselective pharmacological activity, e.g., the influence of optical purity on enantioselectivity, Pfeiffer's rule, and eudismic analysis. The review ends with selected examples taken from various fields of preclinical and clinical pharmacology, of differences between stereoisomers in terms of drug absorption, distribution, and excretion. The influence of conformational factor in molecular pharmacology will be discussed in Part 6, while stereoselective aspects of xenobiotic metabolism will be reviewed in Parts 7 and 8.