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Publication Neuartige Kupfer-katalysierte und übergangsmetallfreie Methoden zum Aufbau von Heterocyclen(2022) Rekowski, Szymon; Beifuss, UweHeterocycles are the backbones of numerous drugs and are therefore of great importance in medicinal chemistry. As a result, there is an inevitably high demand for methods to synthesize heterocycles. The requirements for new methods for the synthesis of heterocycles are nowadays very high, as they must not only be efficient and selective, but also sustainable. These prerequisites can be met by both transition metal-free and transition metal-catalyzed reactions. Thus, the transition metal-free preparation of a variety of different heterocycles can be achieved by radical, cationic and anionic cyclizations as well as by pericyclic reactions. Recently, the importance of electrochemical and photochemical methods in heterocyclic synthesis has been increasing very rapidly. In transition metal-catalyzed heterocycle synthesis, Pd- and Cu-catalysts in particular play a prominent role. For the Pd-catalyzed assembly of N-heterocycles, the intramolecular Buchwald-Hartwig amination is especially noteworthy. It is now known that many Pd-catalyzed reactions can also be carried out with Cu-catalysts. In view of the fact that Cu-catalysts are much cheaper due to the higher abundance of Cu, and that expensive ligands can usually be omitted to carry out Cu-catalyzed reactions, their enormous importance in heterocyclic synthesis is easy to understand. For example, many N-heterocycles can be prepared by intramolecular Ullmann reactions with excellent yields and high selectivities. Here, bisfunctionalized substrates with two centers of different reactivity play a major role. The aim of the present work was to develop new efficient and highly selective synthetic methods for the construction of relevant N- or O-heterocycles. In particular, Cu-catalyzed reactions with bisfunctionalized substrates were to be developed. The investigation included determining whether the corresponding reactions can also be carried out in the absence of transition metal catalysts. Benzodioxines and 2,3-dihydrobenzodioxines exhibit many interesting biological properties, but the possibilities available nowadays for their synthesis are limited. Therefore, the first part of this dissertation deals with the development of a new method for the diastereospecific construction of (Z)-2-arylidene-2,3-dihydrobenzodioxines (Z)-80 (Scheme 50) by reacting 3-aryl-substituted (Z)-1,2-dibromoarylpropenes (Z)-82 with catechols 83. While the model substrate (Z)-82a (R1 = Ph) can be prepared by reduction and subsequent bromination of a-bromocinnamaldehyde, the remaining substrates (Z)-82 were prepared in three steps from the corresponding benzaldehydes. Subsequent optimization of the model reaction under a wide variety of reaction conditions showed that the best results could be obtained under transition metal-free conditions. The highest yield of (Z)-80a was obtained when 1 equivalent of (Z)-82a (R1 = Ph, R2 = H) was reacted with two equivalents of 83a (R2 = H) in the presence of four equivalents of Cs2CO3 in DMF for 18 h at 140 °C. Remarkably, this transition metal-free domino reaction, which consists of an intermolecular O-allylation followed by an intramolecular O-vinylation, is highly diastereospecific: the use of (Z)-1,2-dibromo-3-phenyl-2-propene [(Z)-82a] exclusively delivers (Z)-2-benzylidene-2,3-dihydrobenzodioxines [(Z)-80a]. This high diastereospecifity was also observed in the reactions of all other substrates (Z)-82. The 2-arylidene-2,3-dihydrobenzodioxins (Z)-80 were obtained in yields up to 89%. This method tolerates different substituents on the aromatic moiety of (Z)-82 as well as different disubstituted catechols 83. DFT calculations conducted in collaboration with Prof. Bharatham, NIPER Nagar (Mohali), suggest that the intramolecular O-vinylation proceeds via an alkene intermediate rather than an alkyne intermediate. The diastereoselective conversion of the E-configured substrate (E)-82a (R1 = Ph) to the corresponding (E)-2-benzylidene-2,3-dihydrobenzodioxine [(E)-80a] supports this assumption. The second part of this work is devoted to the intramolecular Cu(I)-catalyzed cyclization of o-haloarylideneguanylhydrazone salts (E)-86 for the direct construction of N-1 unsubstituted 1H-indazoles 84 (Scheme 51). The synthesis of indazoles of this type is of particular interest to medicinal chemistry because they form the backbone of some important anticancer drugs. Substrates (E)-86 were prepared by condensation of o-halobenzaldehydes with aminoguanidine hydrochloride in yields up to 90%. Subsequent cyclization using 10 mol% CuI, 30 mol% DMEDA and 0.5 equivalents of Cs2CO3 afforded the 1H-indazoles 84 in yields up to 75%. The reactions were carried out at 120 °C in DMF for 5 h in a sealed glass tube. The method tolerated a full range of substituents on the aromatic moiety of the substrates. Based on DFT calculations done in collaboration with Prof. Bharatham, NIPER Nagar (Mohali), it is reasonable to assume that E/Z isomerization of substrate 86 occurs first, followed by metal complexation with subsequent C,N bond formation. The final hydrolysis of the 1H-indazole-1-carboximidamide yields the N-1 unsubstituted 1H-indazole 84.Publication Metalloporphyrine als potentiell präbiotische Moleküle und chemische Biosignaturen(2022) Pleyer, Hannes Lukas; Strasdeit, HenryThis doctoral thesis addresses two important astrobiological aspects of metalloporphyrins. First, the possible abiotic origin of metalloporphyrins under prebiotically plausible conditions, and second, metalloporphyrins as possible molecular biosignatures in the context of the search for extraterrestrial life. This two-pronged approach allowed us to obtain a more comprehensive overview of metalloporphyrins in an astrobiological context. In presently known living organisms, metal complexes of porphyrins and porphyrinoids occur ubiquitously, whereas free base porphyrins scarcely matter. Among the best known examples are chlorophylls (magnesium complexes), which are crucially involved in photosynthesis, and the heme group, for example as a cofactor of cytochromes, which play an important role in cel¬lular respiration. In terms of evolution, porphyrinoid cofactors appear to be very old, and indeed 1.1 billion-year-old geoporphyrins have been found in sedimentary rocks. Ancestors of current porphyrinoid cofactors, simple metalloporphyrins, may have been present in the first organisms or even earlier in abiotic protometabolisms. Furthermore, the wide distribution of porphyrinoid cofactors among known organisms, as well as their participation in basic biological functions, suggests that metalloporphyrinoids may also be present in potential life forms beyond Earth. Thus, metalloporphyrinoids could be useful as chemical biosignatures in the search for life on Mars, Europa, Enceladus and beyond. The first objective of this work was to investigate whether complex formation with selected metals (Fe, Mg, Co, Ni, and Cu) is possible under prebiotically plausible conditions. Based on a prebiotic synthesis of octaalkylporphyrins at simulated primordial volcanic coasts, which has been previously described by our group, the influence of wet-dry cycles on octaethylporphyrin (OEP) and selected metal sources was to be studied. For this purpose, first a novel, automated apparatus had to be developed that allowed the simulation of conditions on the early Earth, especially at primordial volcanic coasts. In particular, this apparatus had to ensure strict exclu-sion of atmospheric oxygen and allow fluctuating changes between wet and dry phases (simu-lation of tides or rainfall). Initially, experiments were conducted to test the new apparatus. It was shown that the appa-ratus worked completely automatically and reliably over a longer period of time. In further experiments, it was tested whether oxidation-sensitive substances can be handled in the apparatus. Indeed, it was shown that it is possible to strictly exclude oxygen. Thus, the apparatus proved to be suitable for investigating the formation of metal complexes from OEP and various metal sources under the influence of alternating wet-dry cycles. Metal sources used included metal(II) chlorides, metal sulfides, basalt, and iron meteorites. The focus was on iron sources. Indeed, it was shown that iron, magnesium, cobalt, nickel and copper complexes formed with the corresponding metal sources in an unusual reaction (completely water-insoluble OEP reacted with partly also insoluble metal sources), whereby wet-dry cycles turned out to be essential. Yields ranging from 20 to 78% (relative to the porphyrin) were obtained in fresh water. In addition, the influence of artificial seawater and low pH values on complex formation was investigated. In the second part of the thesis, the stability of metalloporphyrins was investigated using the compound chlorido(octaethylporphyrinato)iron(III), [FeCl(oep)], as a model. Potentially de-structive conditions relevant to metalloporphyrins as possible chemical biosignatures were selected for the experiments performed, as well as conditions that presumably prevailed on primordial volcanic coasts. Extensive series of experiments demonstrated, among other things, that (a) the iron OEP core is stable over a pH range of 0.0 to 13.5, (b) [FeCl(oep)] is stable up to ca. 250 °C in an inert atmosphere, (c) a salt matrix protects [FeCl(oep)] from X-ray radiation but not from iron particle radiation, and (d) hypochlorite, hydrogen peroxide, chlorate, and nitric acid oxidatively decompose [FeCl(oep)] (oxidation power in descending order). On the other hand, perchlorate, which is often mentioned in connection with its occurrence in the Martian regolith, did not show any oxidation effect. Finally, the importance of metalloporphyrins as potential biosignatures is discussed in the presented work, particularly in the light of their stability and possible abiotic synthetic pathways for these compounds.Publication Thermal behavior of amino acids in inorganic matrices : relevance for chemical evolution(2013) Dalai, Punam; Strasdeit, HenryThe onset of life on Earth was preceded by an abiotic chemistry in which complex molecules were formed from simpler ones. In the presence of energy sources such as UV radiation, lightning and geothermal energy, a wide range of organic compounds probably formed on the young Earth. Stanley Miller was the first to study this scenario experimentally. He showed that amino acids were synthesized under simulated conditions of the primitive Earth?s atmosphere. Initially, it was believed that the Earth?s early atmosphere contained high concentrations of CH4, NH3, CO, and H2 and was thus strongly reducing. However, later it was assumed that the early atmosphere was redox neutral and was composed of N2, CO2, and H2O as main constituents. Isotopic data from zircons indicate that liquid water might have been present already around 4.2 billion years ago. So called banded iron formations confirm the presence of liquid water at least 3.8 billion years ago. The early geological histories of Earth and Mars were probably very similar. About 4 billion years ago, both planets had liquid water, volcanoes, and a dense atmosphere without free oxygen, and they experienced intense meteoritic and cometary impacts. Therefore, the simulation experiments described in the present thesis may also be relevant to the early Mars. Among the possible prebiotic molecules, amino acids are generally considered especially important for the origin of life. The main reason for this is that they serve as building blocks of proteins which are the pillars of metabolism in all organisms. There is practically no doubt that amino acids were present on the young Earth. They originated from endogenous and exogenous (i.e. extraterrestrial) sources. Glycine is the most abundant amino acid in carbonaceous meteorites and Miller-type experiments. In the present work, the deep black residue was studied that forms when glycine is heated at 200 °C. Similar residues have been named ?thermo-melanoid? by others. The experiments were performed under a pure nitrogen atmosphere in order to simulate the oxygen-free early atmosphere of the Earth. It was found that the formation of the thermomelanoid from neat glycine started at 160 °C and was relatively fast and complete at 200 °C. However, the residues that formed at high temperatures (250?350 °C) were different from the thermo-melanoid. The thermo-melanoid was also present in the residues obtained by heating the glycine homopeptides 2,5-diketopiperazine (DKP), diglycine, triglycine, and tetraglycine at 200 °C. In contrast, penta- and hexaglycine remained almost unreacted at this temperature. Deuterolysis experiments revealed that C=C bonds are a characteristic structural feature of the thermo-melanoid. These bonds form by an unusual condensation reaction between C=O and CH2 groups. Glycine, DKP, and diglycine were released during hydrolysis of the thermomelanoid in water at 100 °C. In these experiments, the thermo-melanoid slowly dissolved. After 10 days, for example, a mass loss of ~75 % was observed. Therefore, the thermomelanoid can be regarded as a kind of storage form of glycine and glycine oligopeptides. The lower solubility of the thermo-melanoid as compared to glycine and its homopeptides may have influenced the distribution of glycine units on the early Earth. Moreover, additional experiments have shown that the thermo-melanoid mixed with soil continuously produced a higher amount of CO2 during a six-months period than samples without the thermo-melanoid. Obviously, the thermo-melanoid was decomposed in the soil. The decomposition was probably caused by microorganisms. Therefore, one can hypothesize that the thermomelanoid could have served as nutrient for early heterotrophic (pre-)organisms. The salt concentration of the late Hadean/early Archean ocean was at least twice as high as the concentration in the present-day oceans. There are good reasons to assume that the ions were Na+, K+, Ca2+, Mg2+, and Cl?. SO4 2? and PO4 3? were possibly not present in significant concentrations as the early atmosphere of the Earth was anoxic. In relation to this, the thermal behavior of glycine was investigated in the presence of various salts. It was found that glycine changed from the initial α- to the γ-modification when it crystallized together with NaCl and NaCl?KCl mixtures. At 200 °C, the glycine that was embedded in the NaCl or NaCl?KCl salt crusts transformed into the thermo-melanoid and a small amount of DKP. Only ~5 % of unreacted glycine was left after seven days in the presence of NaCl. The results showed that the presence of these salts and the change in the modification were nearly ineffective in protecting glycine from transformation into the thermo-melanoid. In contrast to NaCl and KCl, CaCl2 formed a coordination compound with glycine, namely CaCl2(Hgly) ⋅ H2O, when solutions of CaCl2 ⋅ 2H2O and glycine were evaporated. It was found that more than 90 % of the glycine were still present in CaCl2(Hgly) ⋅ H2O after heating at 200 °C for seven days. The coordination of glycine to Ca2+ prevented the transformation of glycine into the thermo-melanoid up to 250 °C. Yusenko et al. reported that at 350 °C, small volatile N-heterocycles such as pyrroles formed from CaCl2(Hgly) ⋅ H2O. Pyrroles are the building blocks of porphyrin-type biomolecules such as cytochromes and chlorophylls. CaCl2(Hgly) ⋅ H2O was also identified in mixtures of glycine with artificial sea salt (AS) prepared from NaCl (705 mmol), KCl (15 mmol), MgCl2 ⋅ 6H2O (80 mmol), CaCl2 ⋅ 2H2O (15 mmol), and glycine (10 mmol). About 84 % of the initial glycine had survived after heating an AS?Hgly mixture for seven days at 200 °C. In contrast, neither complex formation nor change in the modification of glycine was observed in gypsum?Hgly and MgCO3?Hgly mixtures. Clay minerals are mainly produced by the weathering of volcanic rock. They are not only found on Earth, but also on Mars. A possible role of clay minerals in chemical evolution was first suggested by Bernal more than half a century ago. In the present work, the thermal behavior of glycine embedded in smectites (Ca-montmorillonite, Na-montmorillonite, and nontronite) and kaolinite was investigated. The glycine-loaded clay minerals were heated at 200 and 250 °C for two days. HPLC and MALDI?TOF/TOF MS analyses of glycine-loaded Ca-montmorillonite that had been heated at 200 °C showed the presence of unreacted glycine, DKP, and linear peptides up to decaglycine. The comparison between the smectite clay minerals revealed that glycine was best protected by Ca-montmorillonite. ~63 % of the amino acid survived in its free form at 200 °C. This was followed by Na-montmorillonite (~53 %) and nontronite (~39 %) under similar experimental conditions. These results demonstrated that smectite clay minerals protect glycine from complete decomposition and sublimation, partly by promoting its polymerization. In contrast to smectites, kaolinite has no interlayer spaces available for intercalation. Therefore, glycine is only attached to the surface of the kaolinite particles. Sublimation of glycine and newly formed DKP was observed when kaolinite mixed with glycine was heated at 200 and 250 °C. All investigated clay minerals prevented the transformation of glycine into the thermo-melanoid during thermal treatments. Various heating experiments were conducted with mixtures of glycine and volcanic rock (basaltic sand from the island of La Réunion, Indian Ocean) or Martian soil simulants (JSC Mars-1A, P-MRS, and S-MRS). Glycine and DKP were identified in the residues and sublimates after heating basaltic sand?Hgly and JSC Mars-1A?Hgly at 200 °C for two days. Additionally, the thermo-melanoid was found in the residue of basaltic sand?Hgly. JSC Mars-1A contains mainly volcanic glass. Forsterite (Mg2SiO4) was identified as the major crystalline mineral in the basaltic sand. Glycine cannot be intercalated in JSC Mars-1A and basaltic sand as they have no clay minerals. As a result, glycine in these two matrices undergoes thermal alterations similar to neat glycine. In contrast, glycine, DKP, and linear peptides from di- to hexaglycine were detected after heating a P-MRS?glycine mixture. This observation can be easily explained by the fact that P-MRS contains 70 % of clay minerals that protect the amino acid from complete decomposition and thus allow the formation of larger peptides. The S-MRS?glycine residue contained only DKP, glycine, and diglycine, obviously because the mineral matrix consisted only of rock, anhydrous iron oxides, and gypsum, but not clay minerals. These experiments again demonstrated the influence of clay minerals on the behavior of glycine when exposed to higher temperatures. Another focus of the work was on the thermal behavior of chiral amino acids intercalated in Ca-montmorillonite. The heating experiments were conducted with different L-enantiomeric excesses (ee) of alanine [L-ee = 0 (i.e. racemic), 4, 20, 50, and 100 %] under a pure nitrogen atmosphere. The residues were analyzed by GC-MS/FID after derivatization. It was found that the racemization process was fast during the first 2?3 days and thereafter slowed down considerably. After eight weeks at 200 °C, the residues still contained 17.5?25.0 % of the respective starting L-ee. Complete racemization of L-alanine was not observed even after 24 weeks of heating. It was also found that, as expected, Camontmorillonite did not have any specific preference for the formation of either the D- or L-enantiomer. Interestingly, it could be observed that L-isovaline influenced the racemization of alanine. The presence of L-isovaline increased the rate of formation of D-alanine. In addition, higher temperatures greatly accelerated the racemization. For instance, after eight weeks at 220 °C, 85 % of the initial L-ee of alanine had been lost by racemization, whereas at 120 °C only 25 % racemization was observed. These experiments made use of the fact that Ca-montmorillonite largely protects amino acids from sublimation. In contrast, neat amino acids such as alanine undergo considerable sublimation in a few hours or less, depending on the temperature. Using a racemization kinetics model, it was estimated that L-alanine can survive in Ca-montmorillonite at elevated temperatures for years. In the literature, there are several reports on enantiomeric excesses of certain amino acids in meteorites. In relation to this, experiments were performed to demonstrate the enantiomeric enrichment of amino acids by partial sublimation. After 3 and 24 hours at 200 °C, the L-ee of alanine and valine increased in the sublimation residue, whereas the L-ee of the sublimates was lower than the initial one. Thus, it seems that racemic alanine and racemic valine crystals are more volatile than enantiomerically pure crystals. It may be assumed that similar processes take place during the atmospheric entry of meteorites and in the aqueous alteration phase of asteroids. The experimental results described in the present thesis suggest that various modes of interaction of amino acids with inorganic matrices such as salt mixtures and clay minerals existed on the young Earth. These results may help to better understand some of the processes of the prebiotic chemical evolution.Publication Influence of microwave irradiation and ionic liquids on multi component reactions(2013) Mert-Balci, Fadime; Beifuss, UweThe present thesis focuses on the influence of microwave irradiation and ionic liquids on the outcome of two well-known three component reactions, the Groebke reaction and the Povarov reaction. The first part of the thesis deals with the influence of microwaves and ionic liquids on the Groebke reaction. The reaction of 2-aminopyridines with aldehydes and isocyanides using montmorillonite as a catalyst in toluene under microwave conditions at 160°C delivers the corresponding imidazo[1,2-a]pyridines within only seven minutes with yields ranging from 16 to 98%. The organic solvent can be replaced by ionic liquids like imidazolium and guanidinium salts. With guanidinium salts, it is possible to perform the Groebke reaction in the absence of any other catalyst and solvent under microwave conditions. The second part of this work is about the extension of the scope of typical Groebke reactions by replacing the aldehyde component with a bifunctional 2-carboxybenzaldehyde. The reaction of 2-aminopyridines with isocyanides and 2-carboxybenzaldehydes with 20 mol% methanesulfonic acid as a catalyst in toluene under microwave conditions at 160°C affords the corresponding pyrido[2?,1?:2,3]imidazo[4,5-c]isoquinolin-5(6H)-ones with yields ranging between 35 and 68%. The new method can easily be performed, is robust, and highly efficient. The third part of the thesis is focused on the intermolecular Povarov reaction. Using the reaction between aniline, benzaldehyde, and 2,3-dihydrofuran as a model reaction, the influence of ionic liquids, such as imidazolium and guanidinium salts, and microwaves on the outcome of the Povarov reaction was evaluated. It was established that the model reaction can be promoted by imidazolium salts like [bmim]BF4 under thermal as well as under microwave conditions. The reaction temperature has a strong impact on the chemical yield and the diastereoselectivity of the model reaction. At lower temperatures the formation of the endo-isomer is favored. However, the influence of microwave irradiation on yield and selectivity is not very pronounced. The Povarov reaction can also be promoted by a great number of guanidinium salts. Reactions that were performed under thermal conditions in a sealed vial demonstrated that both the chemical yield and the diastereoselectivity of the reaction are strongly influenced by a) the structure of the guanidinium ion and the nature of the anion of the guanidinium salt, and b) the concentration of the guanidinium salt. Remarkably, the Povarov can also be performed successfully in the presence of only catalytic amounts of a guanidinium salt. Finally, it was demonstrated that the guanidinium salts can be recycled and reused several times without loss of reactivity.Publication Selektive und effiziente Laccase-katalysierte oxidative Phenolkupplungen(2012) Constantin, Mihaela-Anca; Beifuss, UweThe oxidative phenolic coupling is one of the fundamental reactions of organic chemistry. In contrast to its major role in the biosynthesis of numerous natural compounds the oxidative phenolic coupling is only of little importance in organic synthesis so far. This is due to its frequent lack of regio- and stereoselectivity. Laccases are oxidases which can be employed, amongst others, for the catalysis of oxidative phenolic couplings using O2 as the oxidant. This study highlights three examples which clearly demonstrate that laccases can be used as catalysts for regio- and stereoselective oxidative couplings of phenolic compounds. The first example deals with the laccase-catalyzed oxidative dimerization of (E)-2-propenylsesamol to carpanone (a). The oxidative cyclization starts with a phenolic oxidation, which is followed by a radical coupling and an intramolecular hetero-Diels-Alder reaction. Experiments with laccases and a number of other catalysts indicate that the diastereoselectivity of the carpanone formation doesn´t depend on the nature of the catalyst but on the double bond geometry of the substrate. With (E)-2-propenylsesamol as the substrate, a 9:1-mixture of carpanone (a) and its diastereoisomer c was formed, irrespective of the catalyst used. When (Z)-2-propenylsesamol was used as the substrate, the formation of a 5:1:4-mixture of three diastereoisomers, i.e. a, c and d, was observed. When the oxidation of (E)-2-propenylsesamol with O2 as the oxidant was run in the absence of any catalyst the diastereoisomeric benzopyrans a and b were obtained in a 3:2-ratio. From a mechanistic point of view, this reaction proceeds as a Domino oxidation/intermolecular hetero-Diels-Alder reaction. The second example selected was the laccase-catalyzed oxidative coupling of sesamol, a naturally occurring phenolic antioxidant. Here, a so far unknown trimer was formed as the main product in good yield. Experiments with different catalysts indicated that the course of the oxidative coupling of sesamol depends strongly on the catalyst chosen. Finally, the laccase-catalyzed phenolic coupling of di- and trisubstituted vanillidene derivatives with O2 as the oxidant was studied. The dimerization of (E)-ferulic acid proceeded as a 8,8?-coupling with formation of a dilactone. When the disubstituted vanillidene derivatives were reacted, the diastereoselective formation of the racemic dihydrobenzo[b]furans which can be understood as the products of a 5,8?-coupling mode were formed. In contrast to the disubstituted vanillidene derivatives, the laccase-catalyzed reaction of the trisubstituted vanillidene derivatives exclusively yielded biphenyls as the result of a 5,5?-coupling.Publication Laccase-katalysierte Dominoreaktionen von Brenzcatechinen und Hydrochinonen mit 1,3-Dicarbonylverbindungen(2012) Hajdok, Szilvia; Beifuss, UweIn the present work novel domino reactions have been described which are based on the laccase-catalyzed oxidation of catechols and hydroquinones to the corresponding o- and p-quinones and their subsequent reactions with 1,3-dicarbonyl compounds. In the first part of this thesis an efficient approach to 3,4-dihydro-7,8-dihydroxy-2H-dibenzofuran-1-ones has been developed. The method includes a laccase-initiated domino reaction between cyclohexane-1,3-diones and catechols using air as an oxidant. The reactions can be carried out under mild reaction conditions without using toxic reagents. The products were obtained in yields ranging from 70 to 97% and with high purity. Byproducts were not formed. The structures of all products were unambiguously elucidated by NMR spectroscopic methods. In the second part of this work laccase-initiated domino reactions between catechols and heterocyclic 1,3-dicarbonyls have been presented. Using pyridinones, quinolinones and thiocoumarin as substrates, the corresponding benzofuropyridinones, benzofuroquinolinones and thiocoumestans were being obtained. The reactions could be easily performed to deliver the products regioselctively in yields ranging between 55 and 98%. In contrast, polycyclic dispiropyrimidinones were exclusively formed when barbituric acid derivatives were employed as substrates. The unambiguous and complete structure elucidation of all products has been achieved by NMR spectroscopic methods (HSQMBC and band-selective HMBC) as well as by X-ray crystal structure analysis. In the third part of this work laccase-catalyzed transformations between differently substituted hydroquinones and 1,3-dicarbonyls have been studied. These reactions provide a new and highly selective method for the formation of quinone bisadducts with two adjacent 1,3-dicarbonyl substituents. The only exception is the reaction of 2-chlorohydroquinone with 4-hydroxycoumarin which delivers a trisadduct. It is noteworthy that under different conditions the reaction between hydroquinones and 1,3-dicarbonyls resulted in the formation of benzofuran derivatives. The unambiguous structure elucidation of all products has been achieved by NMR spectroscopic methods including spin pattern analysis of the long-range coupled C=O carbons and 13C satellites analysis in 1H NMR spectra. The domino reactions presented in this thesis allow for the efficient and selective synthesis of numerous heterocyclic systems as well as substituted p-benzoquinones under mild reaction conditions. In most cases the products can be isolated in good to very good yields and with high purity. For the structure elucidation of the products a wide range of NMR methods was used.Publication Selective transformations of substituted aryl compounds to fluorenes and phosphoramidates : synthetic and spectroscopic studies(2010) Haggam, Reda; Beifuss, UweBecause of their diverse biological properties and their high potential for the development of new drugs the synthesis of fluorenes and related systems such as benzo[b]fluorenes is of great interest in the fields of organic and medicinal chemistry. The most relevant benzo[b]fluorenes include the naturally occurring kinamycins. Recently, two fluorene derivatives have been isolated from the sweat of hippopotamus (Hippopotamus amphibius). The biological function of the two dyes named hipposudoric acid (4) and norhipposudoric acid (5) is still unknown. For the synthesis of fluorenes a number of synthetic approaches have been developed. Among the most important methods there are the intramolecular electrophilic substitution, the Pschorr cyclization and palladium-mediated intramolecular cyclizations. The first part of the present study focusses on the construction of fluorenes carrying several methoxy groups by employing the Pschorr cyclization and the palladium-mediated intramolecular cyclization of suitable substrates. A comparison of the two methods is also presented. In addition, the cleavage of the methyl ethers 203 into the corresponding hydroxy-substituted fluoren-9-ones 206 is also included in the first part. To begin with, the synthesis of hydroxy- and alkoxy-substituted fluoren-9-ones through Pschorr cyclizations was studied. For the preparation of the substrates 233 the bromides 229 were first lithiated with t-butyllithium and then reacted with the aldehydes 231. Using this method it was possible to prepare the secondary alcohols 233a-e with excellent yields ranging from 87 to 98 % (Scheme 74). Treatment of the secondary alcohols 233a-e using K2Cr2O7 as an oxidant gave the corresponding ketones 234a-e with very good yields (85 to 92 %; Table 16). Reduction of the nitro group of the substituted ketones 234a-e using iron powder resulted in the formation of substituted 2-aminobenzophenones 235a-e with very good results (Table 17). The compounds 235a-e were cyclized to furnish the methoxy-substituted fluoren-9-ones by Pschorr cyclizations. For this purpose the substituted 2-aminobenzophenones 235a-e were oxidized to the corresponding diazonium salts with n-amylnitrite in glacial acetic acid at 0 °C which underwent cyclization to give the methoxy-substituted fluoren-9-ones 236a-e with yields ranging from 72 to 86 % (Table 18). Ether cleavage of the methoxy-substituted fluoren-9-ones 236a-e performed using boron tribromide resulted in the formation of the hydroxy-substituted fluoren-9-ones 242a-e with yields between 60 and 84 % (Table 19). These results show that the Pschorr cyclization allows for the preparation of substituted fluoren-9-ones in four steps from readily available starting materials. Palladium-mediated reactions play a very important role in current organic synthesis. Therefore, it was studied whether the palladium-mediated cyclizations of 2-iodo-substituted benzophenones 243 can be employed for the efficient synthesis of fluoren-9-ones. It was of great interest to learn whether this method is superior to the Pschorr cyclization approach. For this purpose, the 2-iodobenzophenone derivatives 243a-f were synthesized. They were obtained by reaction of the 2-amino-substituted benzophenones 235 with n-amylnitrite followed by treatment with KI. Following this procedure, the iodides 243a-e could be obtained with yields between 65 and 73 % (Table 20). Compound 243f was synthesized by intermolecular Friedel-Crafts acylation of 228 with 244 in 97 % yield (Scheme 75). It turned out that the best results for the palladium-mediated cyclization of the iodides 243a-c,e,f could be achieved when PdCl2(PPh3)2 was used as a palladium reagent in the presence of NaOAc as a base and DMA as a solvent. Heating at 130 °C afforded the fluoren-9-ones 236a-c,e,f with yields in the range between 31 and 86 % (Scheme 76). On the whole, it can be concluded that the palladium-catalyzed intramolecular arylations of 243 suffer from high palladium-loadings, high reaction temperatures and long reaction times. In addition, in a few cases the yields for the palladium-mediated cyclizations are not sufficient. Compared to the results of the Pschorr cyclizations the palladium-mediated cyclizations need an extra step; i.e. the transformation of the 2-aminobenzophenones 235 into the corresponding 2-iodobenzophenones 243. This is why the Pschorr cyclization is more efficient for the synthesis of fluoren-9-ones 236 than the palladium-mediated cyclization. In addition, attempts were undertaken to cyclize the substituted 2-nitrobenzophenones 234b,c to the corresponding acridinones 205. When the benzophenones were treated with triethyl phosphite (161) the unexpected formation of diethyl N-arylphosphoramidates 251b (59 % yield) and 251c (62 % yield) was observed. With these unexpected results in hand it was decided to develop a new synthetic protocol for the efficient conversion of nitroarenes into the corresponding phosporamidates. Phosporamidate oligonucleotides play an important role in medicinal chemistry because they have been considered for diagnostic as well as therapeutic applications within the antisense field. The preparation of phosphoramidate substituted nucleoside analogues is also of great interest as many of them exhibit anticancer, antiviral (anti-HIV) and spermicidal activities. Therefore, the second goal of this thesis was to develop a practical and efficient method for the synthesis of dialkyl N-arylphosphoramidates by reaction of readily available nitroarenes with tervalent phosphorous reagents such as triethyl phosphite or trimethyl phosphite under both thermal and microwave conditions. In order to evaluate the scope of this conversion it was necessary to study the effects of substitution on the aromatic ring at different positions. It was found that nitroarenes 255a-o can easily be transformed into the corresponding diethyl N-arylphosphoramidates 256a-o by treatment with an excess of triethyl phosphite (161) or trimethyl phosphite (257). Yields were in the range of 52 to 79 % (Table 21). The results obtained clearly indicate that ? in contrast to previous reports ? the reaction of nitroarenes with trialkyl phosphites is a practical and efficient method for the selective preparation of dialkyl N-arylphosphoramidates in one synthetic operation. The structures of all compounds prepared during this study have been elucidated unambiguously by analytical and spectroscopic methods including NMR spectroscopy, mass spectrometry, UV spectroscopy, IR spectroscopy and elemental analysis.Publication Studien zur Synthese von Pyripyropenen und Strukturanaloga durch Cyclisierungen(2007) Schmidt, Dietmar; Beifuss, UweIn 1993 Omura et al. isolated from the culture broth of Aspergillus fumigatus FO 1289 a new class of compounds that exhibit a polyoxygenated sesquiterpene and α-pyrone and therefore was called pyripyropenes. Up to now pyripyropenes represent the most potent inhibitors of the enzyme cholesterol-O-acyl transferase (ACAT) that plays a key role in human fat metabolism. For example, arteriosclerosis have its origin in a fat digestion disorder and therefore ACAT-inhibiting agents like pyripyropenes shows a new promising approach in the treatment of this cholesterol level depending diseases. In the beginning preliminary studies were performed on improving the synthesis of pyripyropene E according to literature known procedures. From the big difficulties arriving from the synthesis of the key compounds this work focussed on: a) selective γ-acylation of 2-substituted aceto acetic esters, b) effective conversion of β, δ-diketo carboxylic acids into 4-hydroxy-2H-pyran-2-ones, c) optimized cyclization of epoxyolefine substituted 6-pyridyl-4-hydroxy-2H-pyran-2-ones by variation of different parameters like Lewis acids, solvents and temperature, d) design of a new efficient method for the synthesis of 6-substituted 4-hydroxy-2H-pyran-2-ones and related heterocycles, e) application of the in a) to d) elaborated results on the efficient total synthesis of three naturally occurring compounds with a 4-hydroxy-2H-pyran-2-on skeleton. The cyclization substrate in the geranyl series, the 3-[7-(2,3-epoxy-2,3-dihydrogeranyl)]-6-(3-pyridyl)-4-hydroxy-pyran-2H-pyran-2-one, was synthesized in a nine step sequence starting from geraniol with 18 % overall yield. In the following experiments this epoxide was cyclized in liquid sulphur dioxide with twelve different Brønsted and Lewis acids. Dependent on the Lewis acid up to four products were isolated: a pyrano[4,3-b]chromen-1-one (α-pyrone), a pyrano[2,3-b]chromen-4-one (γ-pyrone), a 7-oxa-bicyclo[2.2.1]hept-2-ane and a diol generated from opening of the epoxide function. The structure of the diol was unambiguously determined by total synthesis. In the farnesyl series the cyclization substrate was assembled in total analogy to that one of the geranyl series in a nine step sequence with 20 % overall yield starting from (E,E)-farnesol. After the cyclization experiments an inseparable mixture of eight different isomers were obtained. During a series of iodocyclization experiments 3-(7-geranyl)-6-pyridyl-4-hydroxy-2H-pyran-one was reacted with iodine in acetonitrile without a base. In another experiment the corresponding enolate anion was generated by deprotonation with potassium carbonate and then was brought to reaction with iodine. Without base the iodo substituted pyrano[2,3-b]pyran-4-one derivative (γ-pyrone) was formed. The reaction of the enolate anion with iodine resulted in a mixture of two iodo substituted α-pyrones, a pyrano[4,3-b]pyran-5-one (endo product) and a furo[3,2-c]pyran-4-one (exo product). From the experience that was gained by the assembly of the cyclization substrates in the geranyl series a new synthesis of 6-substituted 4-hydroxy-2H-pyran-2-ones was developed: The main principle was the in situ release of the extraordinary sensitive 5-hydroxy-3-oxo-pent-4-enoic acids through protonation of their stable bispotassium salts with TFA at low temperature, followed by spontaneous lactonization of these acids in the reaction media TFAA leading to the corresponding pyrones in high yields. The effectiveness of this procedure was impressively demonstrated in twelve examples. The 5-phenyl-substituted bispotassium salt was used for the construction of heterocycles: one pyrazole and one isoxazole were synthesized in high yields. Based on the new pyrone synthesis the total synthesis of three natural products with a 4-hydroxy-2H-pyran-2-one framework was carried out. 1. The compound Sch-419560 isolated from Pseudomonas fluorescens was synthesized in a four step sequence starting from ethyl 2-hexylacetoacetate with 62 % overall yield. 2. The α-pyrone 3?,3?-dimethylallylconrauanalactone isolated from Garcinia conrauana Engl. (Guttiferae) was synthesized via a four step sequence starting from ethyl 2-prenylacetoacetate with 64 % overall yield. 3. Finally, the natural product aurantiacone isolated from Mimulus aurantiacus was synthesized via a seven step sequence starting from 2-hydroxybutyric acid with 62 % overall yield.Publication Synthesis of N-neterocycles via intramolecular reductive cyclizations of nitroalkenes(2007) Merisor, Elena; Beifuss, UweThe current work describes a new triethyl phosphite mediated domino reaction of ω-nitro-alkenes which in one step cyclize to the corresponding saturated N-heterocycles. The one-step domino reaction described in this work includes a three-step reaction, a nitroso-ene reaction being coupled with two reduction reactions. A new C-N bond is formed and saturated N-heterocycles are synthesized. The microwave irradiation of the ω-nitroalkenes has been developed as an alternative protocol, having the advantage that the formation of byproducts can be suppressed and the reaction times reduced. The reductive cyclization reaction mediated by triethyl phosphite allows preparation of a series of saturated N-heterocycles such as substituted 3,4-dihydro-2H-1,4-benzoxazines, 1,2,3,4-tetrahydroquinoxalines and 1,2,3,4-tetrahydroquinolines. The newly developed domino reaction can also occur under CO pressure using metal catalysts, allowing the formation of saturated N-heterocycles. Since the reductive cyclizations reported in this work are transition metal-catalyzed domino processes without precedent, they could be of significant interest to the field of synthetic chemistry and ?Life Sciences?.