Im Rahmen der Arbeit werden hierarchisch strukturierte Silikakompositfasern präsentiert, deren Bildung ähnlich zu natürlichen Silifizierungsreaktionen verläuft. Als Analoga zu Proteinfilamenten in Silika Morphogeneseorganismen werden selbstorganisierte, funktionale Polyethylenoxid-Peptid-Nanobänder eingesetzt. Mit der Isolierung einheitlicher Nanokompositfasern wird gezeigt, dass die PEO-Peptid-Nanobänder eine starke Bindungsaffinität gegenüber Kieselsäure besitzen, diese aus sehr stark verdünnten Lösungen anreichern und deren Kondensation zu Silikanetzwerken kontrollieren können. In höheren Konzentrationen entstehen durch die peptidgeleitete Silifizierung der PEO-Peptid-Nanobänder spontan makroskopische Kompositfasern mit sechs Hierarchieebenen. Diese verbinden Längen von bis zu 3 cm und Durchmesser von 1-2 mm mit einer definierten Feinstruktur im Submikrometerbereich. Als Resultat der komplexen inneren Struktur und der Kontrolle der Grenzflächen zwischen Nanobändern und Silika wird eine Nanohärte erreicht, die schon ~1/3 der Härte von Bioglasfasern darstellt. Für die Elastizität (reduziertes Eindrückmodul) dagegen konnte durch den relativ hohen Anteil (~40%) an verformbaren, organischen Komponenten ein ~4-mal größer Wert im Vergleich mit Bioglasfasern bestimmt werden. Des Weiteren wird die Prozessierung der makroskopischen Kompositfasern in einem 2D-Plotprozess vorgestellt. Mit Verwendung der PEO-Peptid-Nanobänder als „Tinte“ können Kompositobjekte in beliebigen Formen geplottet werden, deren Linienbreite sowie anisotrope Ausrichtung der Nano- und Submikrometerstrukturelemente direkt mit der Plotgeschwindigkeit korrelieren. Außerdem können die Kompositobjekte als Vorstufen für orientierte, mesoporöse Silikaobjekte verwendet werden. Nachdem Calcinieren werden Silikastrukturen mit einer hohen spezifischen Oberfläche und in Plotrichtung ausgerichteten zylindrischen Poren erhalten. Im Kontrast zu den anorganisch-bioorganischen Kompositfasern sollten unter Ausnutzung ionischer Wechselwirkungen oder Metallkoordination Kompositmaterialien mit anderen mechanischen Eigenschaften dargestellt werden. Es wird gezeigt, dass durch Variationen in der Aminosäuresequenz des Peptidkerns, die Oberflächen der PEO-Peptid-Nanobänder gezielt mit funktionellen Gruppen versehen werden können. Eine gerichtete Vernetzung dieser modifizierten Nanobänder wurde nicht erreicht, dafür könnten die imidazolfunktionalisierten Nanobänder als eindimensionale Protonenleiter, die mit photochromen Gruppen (Spiropyran) funktionalisierten Nanobänder für die Modifizierung von Oberflächenpolaritäten oder für gerichtete Kristallisationsprozesse eingesetzt werden. / In this work hierarchical structured silica-composite fibers are presented, whose formation is similar to natural silicification processes. Self-assembled, functional poly(ethylene oxide) (PEO) peptide nanotapes were utilized as analogue to protein filaments in silicamorphogenese organism. Isolation of homogenous nano composite fibers demonstrates that the PEO peptide nanotapes have a high affinity to bind silicic acid. They are able to enrich silicic acid from very dilute solution and can control the silica condensation process. Macroscopic composite fibers spontaneously arise if the PEO peptide nanotapes in a higher concentration were mixed with the silica precursor. These exhibit six distinguishable levels of hierarchical order, spanning length scales from the nanometer up to millimeters in lateral and even centimeters in longitudinal dimensions. As a result of the inner structure, reinforced composite fibers were obtained, exhibiting 1/3 of the mechanical hardness of natural glass sponge spicules. The elasticity, which is considered as one limiting factor in optical glass fibers, could be enhanced 4-times due to the incorporation of an increased amount of polymer peptide nanotapes (~40%). In addition a 2D-plot process is introduced, in which the polymer peptide nanotapes acts as an ink. By injecting a solution of the nanotapes into a diluted silicic acid solution composite objects can be plotted in any desired way. The width of the plotted lines as well as the anisotropic orientation of the nano- and sub micrometer structure elements correlates directly to the plotting speed. Besides the composite objects can be utilized as precursors for oriented, mesoporous silica objects. After a calcination procedure silica structures with cylindrical pores, aligned in plot direction, and a high specific surface area were received. In contrast to the inorganic-organic composite fibers other composite materials with different mechanical properties should be created exploiting ionic interactions or metal coordination. A variation in the amino acid sequence of the peptide core leads to an aimed functionalisation of the nanotape surfaces. A directed networking of such nanotapes was not observed, but imidazole functionalised nanotapes could maybe be used as one dimensional proton conductors. The nanotapes, which were tagged with photo chromic spiropyran units, have the ability to be used for controlled crystallization processes or the modification of surface polarities.

The conjugation of a small organic molecule to synthetic polypeptides from a designed set has been shown to give rise to binders with high affinity and selectivity for the phosphorylated model proteins α-casein and β-casein but not for ovoalbumin. The small organic molecule that was used for this purpose is comprised of two di-(2-picolyl)amine groups assembled on a dimethylphenyl scaffold, and is capable of complexing two Zn2+ ions to form chelates that bind the phosphate ion. The designed polypeptides used for binder construction have no precedence in nature and do not show any prior selectivity favouring any single protein. The polypeptide conjugate binders showed high affinity towards the model protein α-casein, the binder molecule 4C15L8-PP1 bound α-casein with a dissociation constant KD of 17 nM, although the di-(2-picolyl) amine based chelate in the presence of Zn2+ bound phosphate ion with dissociation constants in the low mM range. The observed affinity is due to interactions between the Zn2+ chelate and the phosphate groups of α-casein and also to interactions between the polypeptide scaffold and α-casein. The binder was found to selectively extract α-casein from buffer, bovine milk and human serum spiked with α-casein. The flexible construction of the binder permits for flexible modifications like attachment of fluorophores for titrations and quantifications. The binders were shown to efficiently capture α-casein from human serum when immobilized on solid support in a continuous flow system and to release the captured α-casein upon a simple change of pH using 0.1% acqueous trifluoroacetica acid. The developed technology brings new opportunities in investigating posttranslational phosphorylation events that are involved in signaling cascades and triggering many biologically relevant functions. A new chemical linker technology has also been developed for the purpose of conjugating biomolecules taking advantage of amino groups for the conjugation. By combining two esters with different reactivities, separated by an aliphatic chain, a molecular tool was developed that allows for controlled conjugation of biomolecules. The two esters react at different rates and can therefore be separated and allowed to react under different conditions in each step, thereby allowing for selective linkage formation between the subunits. The size of the spacer can be varied by selecting the appropriate dicarboxylic acid. The developed technology was shown to provide specificity in heteroconjugate formation in the assembly of a variety of heteroconjugates where polypeptides were combined with other peptides, carbohydrates and proteins.

The thesis entitled ‘Studies on the Chemistry of Carbonates and Carbamates’ comprises of seven chapters. Chapter 1 The reactivity of propargyloxycarbonyl (Poc) derivatives of amines and alcohols with various sulphur nucleophiles is addressed in this chapter. The chapter is divided into three different parts. Part 1: The difference in reactivity of propargyloxycarbonyl (Poc) derivatives of amines and alcohols with benzyltriethylammonium tetrathiomolybdate [(PhCH2NEt3)2MoS4, 1] is studied in detail and the results are discussed. It has been shown that amino alcohols can be protected as their diPoc derivatives using 2 equiv of propargyloxycarbonyl chloride (2). The selective deprotection of the O-Poc group using 1 equiv of 1 without affecting the N-Poc group is achieved (Scheme 1). Scheme 1 Part 2: The reactivity of propargyloxycarbonyl derivatives of various alcohols, phenols and primary and secondary amines with benzyltriethylammonium tetrathiomolybdate (1) is compared with the reactivity of these Poc derivatives with other sulphur nucleophiles such as sodium thiophenoxide, lithium sulphide, hydrogen sulphide and ammonium sulphide. The study reveals that tetrathiomolybdate (1) is the best sulphur nucleophile for the deprotection of Poc group. Poc derivatives of primary amines cyclized to the corresponding 4-methylene-2-oxazolidinones when treated with other sulphur nucleophiles (Scheme 2). Scheme 2 Part 3: The reaction between different propargyloxycarbonyl derivatives of alcohols and benzyltriethylammonium tetrathiomolybdate (1) is studied. It is found that propargyloxycarbonyl derivatives can be made more reactive towards tetrathiomolybdate by substituting the propargyl system with electron withdrawing substituents. Chapter 2 The application of propargyloxycarbonyl group for the protection of the side chain hydroxyl groups of serine, threonine and tyrosine is discussed. The O-Poc derivatives are shown to be stable to a variety of acidic and basic conditions and the applications of these derivatives in solution phase peptide synthesis is addressed. The easy and effective deprotection of the O-Poc group provides a new strategy for the synthesis of peptides bearing the hydroxy amino acid residues: serine, threonine and tyrosine. Scheme 3 Chapter 3 Development of a novel C2-symmetric protecting group for amines and amino acids is described in this chapter. But-2-ynyl-1,4-bisoxycarbonyl chloride (BbcCl, 3) is synthesized from 1,4-dihydroxybut-2-yne and used as a reagent for protecting amines as biscarbamates (Scheme 4). These biscarbamates (Bbc derivatives) are deblocked using benzyltriethylammonium tetrathiomolybdate (1) to get the amines back. Scheme 4 The orthogonal stability of the Bbc group with Boc, Cbz and Fmoc groups is established. It is also shown that Bbc group can be deblocked to the corresponding amines using resin-bound tetrathiomolybdate. The application of Bbc protected amino acids in solution phase peptide synthesis is demonstrated (Scheme 5). Scheme 5 Chapter 4 The simultaneous protection and activation of amino acids using various pentafluorophenyl carbonates is described in two parts. Part 1: A very efficient and high yielding method for the simultaneous protection of the amino group and activation of carboxylic acid group using propargyl pentafluorophenyl carbonate (PocOPfp, 4) is discussed. Treating amino acids with 2 equiv of 4 protects the amino group as a propargyl carbamate and activates the carboxylic acid group as a pentafluorophenyl ester (Scheme 6). Scheme 6 Part 2: The generality of the methodology developed for the simultaneous protection and activation of amino acids using PocOPfp (4) is studied with five different pentafluorophenyl carbonates viz. AlocOPfp, CbzOPfp, BocOPfp, EocOPfp and TrocOPfp. The studies reveal that the effectiveness of the methodology depends on the nature of the pentafluorophenyl carbonates and on the nature of the amino acids. Sterically bulky pentafluorophenyl carbonates such as BocOPfp reacted slowly with amino acids while electron deficient pentafluorophenyl carbonates such as TrocOPfp reacted faster and gave the N-protected active esters in very good yields. Amino acids bearing longer aliphatic side chains reacted better than the other amino acids. Chapter 5 The chapter describes results of the detailed studies on the base catalyzed cyclization of N-alkyl and N-aryl-O-propargyl carbamates to the corresponding 4-alkylidene-2-oxazolidinones. The effect of various bases and solvents on these cyclization reactions is studied systematically to design the most suitable conditions. The best results were obtained using catalytic amount of LiOH in DMF. The cyclization reactions of N-aryl-O-propargyl carbamates were faster than the cyclization of N-alkyl-O-propargyl carbamates. The effect of substitutions on the propargyl group in these reactions is studied by preparing various substituted propargyl carbamate derivatives from the corresponding amines and propargyl chloroformates (Scheme 7). Scheme 7 Chapter 6 An efficient procedure for the synthesis of dehydroalanine and dehydroamino butyric acid derivatives from the preformed carbonate derivatives of serine and threonine respectively, by treating with K2CO3 in DMF is discussed in this chapter. The reaction proceeds stereoselectively through a trans E2-elimination pathway to give only the Z-isomer of dehydroamino butyric acid derivatives from the carbonate derivatives of threonine. The methodology offers an easy access to dehydropeptides and proceeds without racemization of other stereogenic centers present in the peptide (Scheme 8). Scheme 8 Chapter 7 This chapter describes the use of propargyloxycarbonyl derivatives of lysine as an efficient tool for the synthesis of peptide conjugates using a click chemistry approach. The Cu(I) catalyzed cycloaddition reaction between azides and alkynes is employed in the synthesis of conjugates of lysine. Peptides bearing an Nε-Poc Lysine residue can be synthesized using traditional strategies and these peptides can be easily conjugated with azide derivatives of sugars and amino acids (Scheme 9). Scheme 9 The efficiency of the method is demonstrated by carrying out more than one click reaction in one pot using di and tri-propargyl derivatives of lysine. A dendritic core (6) is prepared from a tri-propargyl derivative (5) of lysine and an azide derived from leucine (Scheme 10). Scheme 10 The abbreviations used in the thesis are consistent with those reported in J. Org. Chem. 2007, 71, 23A. Less common abbreviations are defined, the first time they are mentioned in the thesis.

Chapter 1: Facile entry into triazole fused tetrahydropyrazinones from amines and amino acids. In this chapter, A practical and high yielding regioselective synthesis of several new, enantiopure 4,5,6,7-tetrahydro[1,2,3]triazolo[1,5-a]pyrazin-6-ones is described starting from primary amines in a three step reaction sequence (alkylation, acylation, one-pot displacement with azide followed by cycloaddition) employing constrained intramolecular ‘click’ reaction as the key step. The method obviates chromatographic purification of products. This methodology was also extended to the synthesis of diverse triazole fused tetrahydropyrazinones derived from amino acids. The scope of this methodology was extended by varying the alkyl as well as acyl components which furnished other triazole fused novel heterocycles. Chapter 2: Facile entry into triazole fused heterocycles via sulfamidate derived azido-alkynes. Direct synthesis of condensed triazoles from diverse sulfamidates by ring opening of sulfamidates with sodium azide followed by one-pot propargylation and cycloaddtion furnished title compounds. The methodogy in general has been demonstrated on diverse sulfamidates derived from amino acids, amino acid derivatives to obtain a variety of triazole fused scaffolds. In one example, a condensed triazole containing amino acid has been synthesized by ring opening of a sulfamidate derivative with propargyl amine. This methodology has also been extended to the synthesis of condensed triazoles derived from D-glucose. Chapter 3: ‘Click Chemistry’ Inspired Synthesis of Novel Ferrocene-Amino acid, Peptide Conjugates. In this chapter synthesis of a wide range of ferrocene-amino acid and peptide conjugates in excellent yield is presented. Conjugation is established via copper catalyzed Huisgen 1,3-dipolar cycloaddition. Two complementary strategies were employed for conjugation, one involving cycloaddition of amino acid derived azides with ethynyl ferrocene and the other involving cycloaddition between amino acid derived alkynes with ferrocene derived azides. Labeling of amino acids at multiple sites with ferrocene is discussed. A new route to 1, 1’ unsymmetrically substituted ferrocene conjugates is reported. A novel ferrocenophane is accessed via bimolecular condensation of amino acid derived bis alkyne with azide. The electrochemical behavior of a few selected ferrocene conjugates has been studied by cyclic voltammetry. Chapter 4: Click Chemistry inspired Synthesis of Ferrocene Amino acids and other derivatives. This work reports the synthesis of a wide range of ferrocenyl-amino acids and other derivatives in excellent yield. Diverse amino acid containing azides were synthesized and ligated to ferrocene employing click reaction to access ferrocenyl amino acids. Chiral alcohols, esters, diols amines containing azido group were tagged to ferrocene via click reaction to generateferrocene derived chiral derivatives. A novel strategy for direct incorporation of ferrocene into a peptide and a new route to 1, 1’ disubstituted ferrocene amino acid derivative are reported. Synthesis of mono and disubstituted ferrocene derivatives employing ferrocene derived azides is also described. Chapter 5: Convenient synthesis of Ferrocene Conjugates mediated by Benzyltriethylammonium Tetrathiomolybdate in a multi-step tandem process. The synthesis of a wide range of ferrocene derived sulfur linked mono and disubstituted Michael adducts and conjugates mediated by benzyltriethylammonium tetrathiomolybdate in a tandem process is reported. New route to access acryloyl ferrocene and 1,1’-bis acryloyl ferrocene is discussed. Conjugation of amino acids to ferrocene is established via their Nand Ctermini and also via side chain employing conjugate addition as key step to furnish monovalent and divalent conjugates. This methodology has also been extended to access several ferrocene carbohydrate conjugates. The electrochemical behavior of a few selected ferrocene conjugates has been studied by cyclic voltammetry. Finally, 1,1’-bis acryloyl ruthenocene was synthesized and it was utilized for the preparation of ruthenocene-carbohydrate conjugate in good yield. Chapter 6: Formation of Intramolecular S-Se bond mediated by tetrathiomolybdate. In this chapter, we have disclosed our preliminary results on reactivity of tetrathiomolybdate towards compounds containing both thiocyanate and selenocyanate functionalities. Several such compounds have been synthesized from the corresponding dibromides in two steps. We have observed selective reductive dimerization of selenocyanate over thiocyanate. In all the cases we also obtained seleno-sulfides via disulfide diselenide exchange reaction upon addition of excess tetrathiomolybdate. In the case of substrates on benzene scaffold, disulfide and diselenide bridged macrocycles were obtained apart from seleno sulfides whereas in the case of ferrocene derived substrates, formation of macrocycles was not observed. A tentative mechanism for the formation of these novel seleno sulfides is also discussed.(For structural formula pl see the pdf file)

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