Neutral, heteroleptic copper(i)-4H-imidazolate complexes: synthesis and characterization of their structural, spectral and redox properties.

Facile synthetic access to four novel, neutral, heteroleptic copper(i)-complexes, incorporating 4H-imidazolates as well as the phosphane ligands XantPhos and DPEPhos is reported. The complexes were characterized in the solid state as well as in solution by means of single crystal X-ray diffraction as well as NMR spectroscopy, mass spectrometry and elemental analysis. The copper(i)-4H-imidazolate complexes show a broad intense absorption that spans almost the entire visible range. TD-DFT calculations revealed the charge transfer character of the underlying transitions. NMR as well as electrochemical investigations and UV-Vis absorption suggest a polarization of the complexes with the negative charge pushed towards the 4H-imidazolate moiety.

Quercinol, an anti-inflammatory chromene from the wood-rotting fungus Daedalea quercina (Oak Mazegill).

The fungus Daedalea quercina (oak mazegill) was examined for its capability of producing antioxidative and anti-inflammatory compounds. Bioactivity guided fractionation of the extract from a mycelial culture led to the isolation of quercinol, which was identified as (-)-(2S)-2-hydroxymethyl-2-methyl-6-hydroxychromene 1 by NMR and X-ray analyses. The cryptic hydroquinone 1 shows a broad anti-inflammatory activity against cyclooxygenase 2 (COX-2), xanthine oxidase (XO), and horseradish peroxidase (HRP) at micromolar concentrations.

Synthesis of radialene-shaped pyrroles by multiple-anion-capture reactions of 1,3-dianions.

A new multicomponent reaction (multiple-anion-capture reaction) of 1,3-dianions with nitriles and oxalic acid-bis(imidoyl)chlorides is reported. This process allows for an efficient and regioselective synthesis of a variety of radialene-shaped pyrroles which constitute structurally new and interesting heterocyclic systems. The cyclization products can be considered as aza-analogues of the pharmacologically relevant substance class of 3-acetyltetramic acids. A rationalization of the experimental results is given based on quantum chemical computations.

Bis(1,3,4-thiadiazolo)-1,3,5-triazinium halides. 2. Intramolecular ring transformation and synthesis of novel highly substituted guanidines.

Bis(1,3,4-thiadiazolo)-1,3,5-triazinium halides 6 can be easily attacked by nucleophiles at either the C(3a) or the C(4a) position of the central six-membered (cationic) ring. Nucleophilic attack leads to at least two reaction channels, one of which has been previously detected (pathway a) and leads to novel aminals 19. In this paper we report on a second channel (pathway b). Attack of primary or secondary amines 8 at C(3a) or C(4a) in 6 (and their analogues 7) leads to the weakly stabilized intermediates 14. A cascade of several proton shifts, ring openings, rearrangements, and ring closure processes is initiated which finally leads via 17 and 18 to novel highly substituted guanidines 9, 10, 12, and 13. Pathway b seems to be the result of well-balanced negative-hyperconjugative effects in 14 and/or 17 which control the highly selective opening of a relatively stable central 1,3,5-triazinium ring to yield the crucial intermediate 18. Some representatives of the guanidines have been characterized by X-ray analyses. Since some of the guanidines contain one or two chirality centers, an effort was made to investigate the stereochemistry of these compounds.

Copper(II) complexes of aminocarbohydrate beta-ketoenaminic ligands: efficient catalysts in catechol oxidation.

Copper(II) complexes of tridentate dianionic beta-ketoenaminic ligands derived from differently functionalized amino-deoxyglucoses were synthesized and characterized with respect to their structural, spectroscopic, and catalytic properties. The (probably dimeric) complex [1,2-O-isopropylidene-6-N-(3-acetyl-2-oxobut-3-enyl)amino-6-deoxyglucofuranoso)copper(II) Cu(3a) was a highly efficient catalyst for the catechol-oxidase-like oxidation of 3,5-di-tert-butylcatechol (dtbc) into 3,5-ditert-butylquinone (dtbq) by molecular oxygen (kcat=2.63s(-1)). In contrast to this magnetically "normal" complex Cu(3a), the analogous dinuclear complex [[Cu(2a)]2], derived from the isomeric amino sugar 5-amino-5-deoxyglucofuranose, forms six-membered chelate rings with the sugar moiety and has very strong antiferromagnetic-coupled copper atoms (resulting in a diamagnetic ground state). It has a rather insignificant activity (kcat < 10(-3)s(-1)). The ligand H2 1a, derived from a (protected) 6-amino-6-deoxyglucopyranose, forms a trinuclear complex [[Cu(1a)]]2.Cu(OAc)2] in which two basic formula units are bridged by one copper acetate. This compound and the complex derived from an (isomeric) aminodeoxyglucopyranose ([Cu(4a)]: kcat approximately equals 0.03 s(-1)) show moderate activity. All complexes with a peripheral ethoxycarbonyl group instead of the acetyl substituent R2, Cu(1b)-Cu(3b) and Cu(4c), are inactive. The complexes derived from 2-hydroxocyclohexylamine, Cu(5a) and Cu(5c), which were used as models of the active complex Cu(3a), have the typical "cubane-like" tetranuclear structure known from many copper complexes with derivatives of saturated 2-aminoalcohols. They are inactive with respect to the activation of dioxygen.

Structures of a tetradentate ferrocenyl ligand and its oxorhenium(V) complex in solution and in the solid state.

The novel ferrocenyl ligand rac-1,6-diferrocenyl-N,N'-bis(2-hydroxypropyl)-2,5-diazahexane (1, H(2)L) was synthesized from ferrocenylcarboxaldehyde and ethylenediamine followed by the reduction of the Schiff base with LiAlH(4) and subsequent N-alkylation with 1,2-propyleneoxide. The dianion of H(2)L reacted with [ReO(PPh(3))(2)Cl(3)], and the product was treated with NH(4)PF(6) to afford the complex [ReO(L-N(2)O(2))PPh(3)]PF(6) (2). Both the ferrocenyl ligand and the complex were characterized in solution by NMR spectroscopy and in the solid state by single-crystal X-ray diffraction studies. NMR investigations reveal two solvent-dependent isomers for the ferrocenyl ligand in solution of which the major form is the more ordered one. The cation of 2 displays a nonsymmetrically coordinated N(2)O(2) ligand.

Direct transformation of silyl enol ethers into functionalized allenes.

The first elimination reactions of silyl enol ethers to lithiated allenes are reported. These reactions allow a direct transformation of readily available silyl enol ethers into functionalized allenes. The action of three to four equivalents of lithium diisopropylamide (LDA) on silyl enol ethers results in the formation of lithiated allenes by initial allylic lithiation, subsequent elimination of a lithium silanolate, and finally, lithiation of the allene thus formed. Starting with amide-derived silyl imino ethers, lithiated ketenimines are obtained. A variety of reactions of the lithiated allenes with electrophiles (chlorosilanes, trimethylchlorostannane, dimethyl sulfate and ethanol) were carried out. Elimination of silanolate is observed only for substrates that contain the hindered SiMe2tBu or Si(iPr)3 moiety, but not for the SiMe3 group. The reaction of 1,1-dilithio-3,3-diphenylallene with ketones provides a convenient access to novel 1,1-di(hydroxymethyl)allenes which undergo a domino Nazarov-Friedel-Crafts reaction upon treatment with p-toluenesulfonic acid.

Reversible fixation of carbon dioxide at nickel(0) centers: a route for large organometallic rings, dimers, and tetramers.

The reaction between bis(cycloocta-1,5-diene)nickel(0), carbon dioxide and benzaldehyde-N-furfurylideneimine (A) in 1,4-dioxane or THF results in the formation of the 24-membered organometallic macrocycles of the type [(A)Ni(-CH(R1)-N(R2)-COO-)]6(solv)n (R1: phenyl, R2: furfurylidene, solv: 1,4-dioxane in 1a, THF in 1b). According to the X-ray analyses, six monomeric nickelacyclic units are connected through six Ni-mu2-OCO-Ni bridges in these macrocycles. The cavities of the metallomacrocycles (diameter: 9.410(1) A in 1a, 9.250(1) A in 1b) each contain one solvent molecule. Reaction of 1b with Me3P results in the displacement of the peripheral ligands A by the phosphine to form the 24-membered organometallic macrocycle 1c. Both 1a and 1b isomerize in benzene to form the dimeric complex [(A)Ni(-CH(R1)-N(R2)-COO-)]2(solv)n (2). The X-ray crystal structure reveals that 2 consists of the same monomeric units as found in 1a and 1b. However two Ni-mu2-O-Ni bonds link the carboxylato groups. The solvent-dependent isomerization of 1b yielding 2 is a reversible reaction. Furthermore, the macrocycle 1b partially eliminates carbon dioxide above 20 degrees C, followed by elimination of half of the monodentately coordinated Schiff base ligands to form the planar tetrameric complex 6. This is also a reversible process.

Studies on modified estrogens: towards the synthesis of novel 14,15-cyclopropa[a]estra-1,3,5(10),8-tetraenes.

To improve the ratio of non-hormonal to hormonal activity, estrogens 3 and 4 were modified at various molecule positions. Isomerization of the 14 alpha,15 alpha-methylene bridge, controlled 3-methoxy group cleavage with respect to the 14 alpha,15 alpha-methylene bridge stereochemistry, reduction of the 8-double bond, and substitution of the oxyfunctionality at C-17 by a methylene and a difluoromethylene moiety were in the focus. As a result of in vivo and in vitro tests, compounds 27 and 29 were selected as potential follow-up candidates of lead 3.

Conformational design for 13alpha-steroids

The diastereomeric 16-bromo- and 16-azido-17-alcohols 5-8, 11, 12, 16, and 17 and 17-ketones 3, 4, 9, and 10 of the 13alpha-estra-1,3, 5(10)-triene series were synthesized as precursors for biologically active compounds and chiral ligands for metal complexation. Conformational investigations of these and some other compounds via X-ray analysis and (1)H NMR spectroscopy show the existence of compounds with the classical steroid conformation (ring C chair, restricted conformation of ring D) and such with an atypical ring C twist-boat and a flexible ring D conformation. It could be shown that 17beta-substituents or flattening of the D-ring are responsible for the twist-boat conformation, whereas compounds containing a 17alpha-substituent or 17-keto group possess the classical conformation. By varying the substituents, compounds with either of these conformations can be intentionally synthesized. MO calculations confirmed the relative stability of the twist-boat conformation.

Stereoselective synthesis of 2-alkylidene-3-iminoindoles by reaction of 1,1-dianions with oxalic acid bis(imidoyl) chlorides

Treatment of dilithiated nitriles and sulfones with oxalic acid bis(imidoyl) chlorides resulted in a new cyclization reaction which provided a variety of (3-imino-2, 3-dihydro-1H-indol-2-ylidene)acetonitriles and -sulfones in good yields. The reactions proceeded by condensation of the dianions with the first imidoyl chloride group of the bis(imidoyl) chloride, subsequent intramolecular attack of the ortho carbon of the arylimino group onto the second imidoyl chloride group, and final aromatization. Excellent stereoselectivities were observed in most cases.

Reactions of the four diastereomeric 16-amino-17-hydroxy-3-methoxy-estra-1,3,5(10)-trienes with aromatic ortho-hydroxy and heteroaromatic alpha-aldehydes and with 1, 3-dicarbonyl compounds-molecular structures of condensation products and of copper(II) complexes.

Vicinal amino alcohols of steroids have been used as starting materials for the synthesis of chiral ligands with defined arrangements of functional groups. Condensation of the four diastereomeric 16,17-steroid amino alcohols 1a-1d with aromatic o-hydroxy and heteroaromatic alpha-aldehydes afforded the Schiff bases 2-6. When the 16,17-substituted compounds 2d, 5d, 6a, and 6d were in solution, the isomeric oxazolidines were detectable by (1)H NMR spectroscopy. The formation of oxazolidines could be avoided by using bulky aldehydes. Reduction of the Schiff bases (also in mixtures with oxazolidines) with NaBH(4) yielded the new N-substituted amino alcohols 12-15. The condensation products of 1a-1d with 1,3-dicarbonyl compounds (7 and 8) exhibited the 1-enamino-3-oxo structure ((1)H NMR spectroscopy). By means of X-ray analysis of 2a-2d, 3d, 7a, and 7c, the torsion angles for the 16N, 17O substituents, which are important for a participation of the 17O substituent in the complexation of metal ions, have been determined. Furthermore, a preferred arrangement between the chelate ring and the steroid plane existed in all investigated condensation products attributable to torsion angles 16H-C16-16N-C of 5-61 degrees. This arrangement was also preserved in the copper(II) complex 11 with 16alpha,17beta-trans configuration of the bidentate steroid ligand and a ratio of 2:1 for ligand: copper in contrast with dimeric copper(II) complexes with a tridentate steroid ligand of 16beta, 17beta-cis configuration (ratio of 1:1 for ligand:copper). The crystal structures of the condensation products are also discussed. In most cases, intermolecular hydrogen bonds between 17-hydroxy groups and the chelate oxygen caused polymeric strands.

New Building Blocks for the Design of Oligonuclear Copper Complexes Based on Amino Carbohydrates.

Remarkably high magnetic coupling and O(2)-activation ability analogous to that of catechol oxidase are characteristics of the first structurally defined, low-symmetry oligonuclear copper complexes of tridentate beta-oxoenamine ligands based on amino carbohydrates (the structure of a bis(acetylbutenonylaminoglucosidato)bis(µ-acetato)tricopper(II) complex is shown).

Novel (N-ferrocenylmethyl)amines and (N-ferrocenylmethylen)imines derived from vicinal steroid amino alcohols and amines: synthesis, molecular structure, and biological activity.

Novel steroidal (N-ferrocenylmethyl)amines with potential biologic activity and of potential interest as chiral ligands for metal complexation were synthesized. The new compounds were screened in vitro for their potential as antimicrobial agents. The synthesis of the new steroidal ferrocenes, including two X-ray crystal structures and biologic assays, are described. The 16-(ferrocenylmethyl)amino-estratrienes 4a-d, 7b, and 10b exhibited outstanding broad antimicrobial activity particularly against mycobacteria and multi-resistant staphylococci. Thus, they can be considered as new lead structures. In contrast, the analogous 3 alpha-(ferrocenylmethyl)amino-cholestanes 12 possessed only weak activity. The reaction of the four isomeric amino alcohols 1a-d (Scheme 1) with ferrocenecarbaldehyde was studied. 1b and 1c with 16/17-trans configuration yielded nearly quantitatively the (E)-Schiff bases 2b and 2c (Scheme 2). In contrast to the trans-compounds, condensation of the cisconfigurated amino alcohols 1a and 1d furnished tautomeric mixtures of the Schiff bases (2a and 2d, respectively) and their corresponding 1,3-oxazolidines (3a and 3d, respectively). The novel (N-ferrocenylmethyl)amines 4a-d were obtained in excellent yields by reduction of the tautomer mixtures and the uniform Schiff bases with sodium borohydride in ethanol. Starting with the 16 beta-hydroxy compound 5a, the synthesis of 16 beta- and 16 alpha-amino-3-methoxy-estra-1,3,5(10)-triene (6b, 9b) is described. The corresponding 16-(N-ferrocenylmethyl)amines 7b and 10b and the 3 alpha-(N-ferrocenylmethyl)amino-cholestanes 12 were synthesized (Scheme 3) for comparison in biologic tests.

Ionic hydrogenation of 3-methoxy-14 alpha,15 alpha-methylenestra-1,3,5(10),8-tetraen-17 alpha-ol: a correction.

3-Methoxy-14 alpha,15 alpha-methylenestra-1,3,5(10),8-tetraen-17 alpha-ol on hydrogenation with triethylsilane/trifluoroacetic acid yielded 3-methoxy-14 beta,15 beta-methylenestra-1,3,5(10)-trien-17 alpha-ol, not the 14 alpha,15 alpha-methylene-9 beta product as previously described.