<p>Methods for the ¹¹C-labeling of carbonyl compounds applicable in the preparation of radiotracers for Positron Emission Tomography (PET) are described. To this end [¹¹C]carbon monoxide at low concentration was used in transition metal- mediated reactions.</p><p>Stille couplings were employed in the synthesis of [<i>carbonyl-</i>¹¹C]ketones from methyl and aryl halides with [¹¹C]carbon monoxide. The synthesized [<i>carbonyl-</i>¹¹C]ketones were obtained from the corresponding organostannanes with analytical radiochemical yields up to 98%.</p><p>A number of synthetic routes were designed using [¹¹C]carbon monoxide and rhodium complexes. Nitrene intermediates were generated from azides and reacted via a rhodium-mediated carbonylation reaction as a general synthetic route to [<i>carbonyl-</i>¹¹C]isocyanates, versatile precursors. [<i>carbonyl-</i>¹¹C]Isocyanate reacted via nucleophilic attack of an amine to form <i>N,N’</i>-diphenyl[¹¹C]urea in 82% analytical radiochemical yield, ethyl phenyl[¹¹C]carbamate was synthesized by the same route, using ethanol as the nucleophile, in 70% radiochemical yield. [¹¹C]Isocyanate was also able to react in a [2+3] cycloaddition with ethylene oxide to form 3-phenyl[<i>carbonyl-</i>¹¹C]oxazolidin-2-one in over 80% analytical radiochemical yield. This method was applied to the synthesis of a potential efflux system tracer [¹¹C]hydroxyurea in 38% isolated radiochemical yield and the derivative 1-hydroxy-3-phenyl[¹¹C]urea in 35% isolated radiochemical yield. Carbene intermediates, generated from diazo compounds, were reacted with [¹¹C]carbon monoxide in the rhodium-mediated synthesis of [<i>carbonyl-</i>¹¹C]ketenes. [<i>carbonyl-</i>¹¹C]Ketene intermediates were utilised in the synthesis of diethyl[<i>carbonyl</i>-¹¹C]malonate, from ethyl diazoacetate and ethanol. The product was obtained with a 20% isolated radiochemical yield. Alkylation of diethyl[<i>carbonyl</i>-¹¹C]malonate, with ethyliodide and tetrabutylammonium fluoride, was successfully accomplished and diethyl diethyl[<i>carbonyl</i>-¹¹C]malonate was synthesized in 50% analytical radiochemical yield. Several (<i>carbonyl-</i>¹³C)compounds were also synthesized using the described methods as a way of characterizing the position of the label using ¹³C-NMR.</p>

This thesis describes the use of kinetic isotope effects, linear free energy relationships and stereochamical studies to distinguish between different mechanistic alternatives and to obtain information about transition state structure. In the first part fluorine and deuterium kinetic isotope effects were determined for the base promoted HF elimination from 4-fluoro-4-(4’-nitrophenyl)butane-2-on. During this work a new method for the determination of fluorine kinetic isotope effects was developed. The results from the study demonstrates that the reaction proceeds via an E1cBip mechanism. In the second part the transition state structure for the SN2 reaction between ethyl chloride and cyanide ion in DMSO was studied. Kinetic isotope effects for six different positions in the reacting system, both in cyanide and ethyl chloride, were determined. The experimental isotope effects were then compared with the theoretically predicted isotope effects. The third part describes the use of Hammett type free-energy relationships and stereochemical evidence to study the mechanism of the copper catalysed alkene aziridination. The results from the study support a model that involves the simultaneous presence of two different copper nitrene intermediates. One which reacts non-stereospecifically via a radical intermediate and one which reacts stereospecifically via a concerted mechanism. In the fourth part a mechanistic study of the Ru(aminoalcohol) catalysed transfer hydrogenation of acetophenone in isopropanol is described. Kinetic isotope effects were determined for both proton and hydride transfer. The observation of significant primary deuterium kinetic isotope effects for both proton and hydride transfer support a mechanism where the proton and hydride are transferred simultaneously in a concerted mechanism.

This thesis describes how radical cyclization chemistry can be applied for the construction of heterocyclic compounds. In the first part, a series of electron deficient α-phenylselenenylalkenes were prepared via a PhSeCl-addition/HCl-elimination sequence. Allyl- and propargylamines readily underwent conjugate addition to these species to produce pyrrolidines or dihydropyrrol derivatives, after triethylborane initiated reductive radical cyclization in the presence of tris(trimethylsilyl)silane. The second part describes a convergent synthesis of the pineal hormone melatonin. The indole nucleus is secured via a tris(trimethylsilyl)silane mediated 5-exo radical cyclization. The protocol provides convenient and simple access to compounds useful for studies of biological activity and structure activity relationships. The third part describes construction of substituted tetrahydrofuran-3-ones and pyrrolidin-3-ones. Regioselective ring-opening of epoxides or aziridines with benzeneselenolate/tellurolate, followed by Michael addition to electron deficient alkynes afforded the corresponding O/N-vinylated compounds. The tetrahydrofuran-3-ones and pyrrolidin-3-ones were secured via radical carbonylation/reductive cyclization using pressurized carbon monoxide (80 atm). The fourth part is concerned with the effect of an N-protecting group on the cyclization of 2-substituted-3-aza-5-hexenyl radicals. Relative energies for reactants and transition states were determined using density functional calculations. Reactant and transition state conformers leading to cis-product were lower in energy than those leading to trans-product. The results can be explained by the unfavorable 1,2-strain present in chair-equatorial and boat-equatorial conformers.

Peptide secondary structure mimetics are important tools in medicinal chemistry, as they provide analogues of endogeneous peptides with new physicochemical and pharmacological properties. The β-hairpin motif has been shown to be involved in numerous physiological processes, among others in regulation of eucariotic gene transcription. This thesis addresses the design, synthesis and conformational analysis of photoswitchable β-hairpin mimetics. The developmental work included the establishment of an improved procedure for cross coupling of aryl halides with terminal alkynes. Microwave mediated Sonogashira couplings in closed vessels were optimized under homogeneous and solid-phase conditions furnishing excellent yields for a large variety of substrates within 5 – 25 minutes. In addition, microwave heating was shown not to have any non-conventional effect on the reaction rate. Furthermore, the most important factors affecting β-hairpin stability were evaluated. Studies of tetrapeptide and decapeptide analogues revealed the essential role of the β-turn in initiation of hairpin folding. Moreover, hydrogen bonding was shown to be the main interchain stabilizing force, whereas hydrophobic interactions were found to be relatively weak. Nevertheless, hydrophobic packing appears to provide an important contribution to the thermodynamic stability of β-hairpins. Photoswitchable peptidomimetics were prepared by incorporation of various stilbene moieties into tetra- and decapeptides. Synthesis, photochemical isomerisation and spectroscopic conformational analysis of the compounds were performed.

The development of new aza-bicyclic structures with potential applications as ligands synthesised via an aza-Diels-Alder cycloaddition has been studied. The studies are concerning the i) development of large scale aza-Diels-Alder reaction, ii) development of a fast and simple route to bicyclic diamine ligands, iii) development of new aza-Diels-Alder adducts from different dienes, iv) development and application of bicyclic N,P ligands for catalytic Michael additions and v) development of robotized asymmetric transfer hydrogenation reactions. i) Development of large-scale aza-Diels-Alder reaction giving up to 110 g pure product, in ordinary laboratory equipment without the need of any flash chromatography. ii) Development of a new synthetic route to bicyclic diamine ligands highly useful for asymmetric rearrangement of olefin oxides to allylic alcohols and thereby shortening the ligand synthesis dramatically and moreover providing with a faster access to those ligands. iii) Expanding the scope of the aza-Diels-Alder reaction by the use of spirodienes and anthracene as dienes. iv) Development and application of a new bidentate ligands for catalytic Michael addition to cyclic enones using 5 mol % ligand giving the product in 71 % ee. v) Utilisation of Chemspeed ASW 2000 in catalytic transfer hydrogenation and solving of problems regarding use of highly air sensitive reactions in an automated environment.

This thesis describes synthesis and reactivity studies of 2-amino-2-siloxysilenes and 2-silenolates, species that are strongly influenced by reversed Si=C bond polarization, i.e. an Siδ-=Cδ+ polarization as compared to the natural Siδ+=Cδ- polarization. Because of the reversed polarization, the 2-amino-2-siloxysilenes are zwitterions and the 2-silenolates are predominantly described by the resonance structure with the negative charge at Si. Transient zwitterionic 2-amino-2-siloxysilenes are formed thermolytically from carbamylpolysilanes (tris(trimethylsilyl)silylamides) and trapped with 1,3-dienes in nearly quantitative yields. These silenes have structure and reactivity characteristics that differ from earlier studied Si=C bonded compounds. They are thermodynamically stable toward dimerization and react with 1,3-dienes to give exclusively [4+2] cycloadducts. Their reactions with 1,3-dienes proceed in accordance with inverse electron demand (IED) Diels-Alder reactions which is explained by the electron-rich nature of these silenes. The 2-amino-2-siloxysilenes are also less reactive toward alcohols than earlier silenes. Hence, alcohols do not react with 2-amino-2-siloxysilenes but with the silene precursor, the carbamylpolysilanes, leading to alkoxysilanes in high yields. The latter reaction represents a novel base-free synthetic protocol for protection of primary and secondary alcohols with the fluoride resistant but photolabile tris(trimethylsilyl)silyl group. Another class of formally Si=C bonded compounds, metal 2-silenolates, has been formed in high yields using a novel facile method. Reaction of acyl- and carbamylpolysilanes with potassium tert-butoxide in tetrahydrofurane gives potassium 2-silenolates. The potassium 2-silenolates are stable at room temperature, in contrast to earlier lithium 2-silenolates that degrade rapidly at ambient temperature. The first crystallisable complex of a 2-silenolate was formed and characterized by X-ray crystallography. This 2-silenolate has a pyramidal central Si (ΣSi = 317.8°), and an Si-C single rather than Si=C double bond (r(SiC) = 1.926 Å). The potassium 2-silenolates give exclusively Si alkylated products with alkyl halides and only [4+2] cycloadducts with 1,3-dienes.

This thesis describes mechanistic studies, rational ligand design, and synthesis of asymmetric transition metal catalysts. The topics addressed concerned [Papers I-VII]: [I] The asymmetric addition of diethyl zinc to N-(diphenylphosphinoyl)benzalimine catalyzed by bicyclic 2-azanorbornyl-3-methanols was studied. An efficient route to both diastereomers of new bicyclic 2-azanorbornyl-3-methanols with an additional chiral center was developed, in the best case 97% ee was obtained with these ligands. The experimental results were rationalized by a computational DFT-study. [II] An aza-Diels-Alder reaction of cyclopentadiene with chiral heterocyclic imines derived from (S)-1-phenylethylamine and different heteroaromatic aldehydes was developed. The cycloaddition proved to be highly diastereoselective and offers a very rapid access to possible biologically active compounds and interesting precursors for chiral (P,N)-ligands. [III] A convenient and high-yielding method for the preparation of (R)-tolterodine, utilizing a catalytic asymmetric Me-CBS reduction was developed. Highly enantio-enriched (R)-6-methyl-4-phenyl-3,4-dihydrochromen-2-one (94% ee) was recrystallized to yield practically enantiopure material (ee &gt;99%) and converted to (R)-tolterodine in a four-step procedure. [IV] The reaction mechanism of the iridium-phosphanooxazoline-catalyzed hydrogenation of unfunctionalized olefins has been studied by means of DFT-calculations (B3LYP) and kinetic experiments. The calculations suggest that the reaction involves an unexpected IrIII-IrV catalytic cycle facilitated by coordination of a second equivalent of dihydrogen. On the basis of the proposed catalytic cycle, calculations were performed on a full system with 88 atoms. These calculations were also used to explain the enantioselectivity displayed by the catalyst. [V and VI] A new class of chiral (P,N)-ligands for the Ir-catalyzed asymmetric hydrogenation of aryl alkenes was developed. These new ligands proved to be highly efficient and tolerate a broad range of substrates. The enantiomeric excesses are, so far, the best reported and can be rationalized using the proposed selectivity model. [VII] The complex formed between the quincorine-amine, containing both a primary and a quinuclidine amino function, and [Cp*RuCl]4 catalyzes the hydrogenation of aromatic and aliphatic ketones in up to 90% ee approx. 24-times faster than previously reported Ru-diamine complexes. The reason for the lower but opposite stereoselectivity seen with the quincoridine-amine, as compared to the quincorine-amine, was rationalized by a kinetic and computational study of the mechanism. The theoretical calculations also revealed a significantly lower activation barrier for the alcohol mediated split of dihydrogen, as compared to the non-alchol mediated process. A finding of importance also for the diphosphine/diamine mediated enantioselective hydrogenation of ketones.

This thesis contains two parts. In the first part, general and versatile palladium-mediated 11C-C bond forming reactions for use in the production of radiotracers for Positron Emission Tomography (PET) were explored. Two complimentarty approaches were investigated: the coupling of [11C]methyl iodide with a vinyl stannane and the reaction of a [11C]methylated stannane with various organohalides. The former approach resulted in an improved, fully automated method for the synthesis of the potential cell proliferation tracer 1-(2’-deoxy-2’-fluoro-β-D-arabinofuranosyl)-[methyl-11C]- thymine. The tracer was obtained in an isolated decay-corrected radiochemical yield of 28% at 25 min after end of radionuclide production. In the latter approach, a [11C]methylated tricyclic stannane (5-[11C]methyl-1-aza- 5-stannabicyclo[3.3.3]undecane) was synthesised in 47% decay-corrected radiochemical yield, starting from [11C]methyl iodide. This stannane was successfully employed in palladium-mediated coupling reactions with aryl, heteroaryl and vinyl halides. In the second part, effects of the osmolytes glycine betaine, trimethylamine N-oxide (TMAO) and urea on Ribonuclease A (RNase A) were investigated using Nuclear Magnetic Resonance (NMR) spectroscopy. Changes in the enzymatic activity in the presence of these osmolytes at concentrations of ≤1 M were observed by monitoring the RNase A-catalysed degradation of polyuridylic acid using 31P NMR spectroscopy. The decrease in activity caused by urea was counteracted by both glycine betaine and TMAO at a molar ratio of 1:1.4 and 1:1, respectively. To investigate if the observed activity changes were accompanied by any detectable alteration in the gross conformation of RNase A, diffusion coefficients for the enzyme in the various osmolyte solutions were measured using pulsed-field gradient NMR. A pulse sequence suitable for diffusion measurements in highly concentrated aqueous osmolyte solutions was developed and assessed. The diffusion of RNase A was measured relative to a new internal standard, 2,2,5,5,-tetramethyl-1,4-dioxane. No clear, detectable change in the relative diffusion of RNase A was observed in these media.

Methods for the 11C-labeling of carbonyl compounds applicable in the preparation of radiotracers for Positron Emission Tomography (PET) are described. To this end [11C]carbon monoxide at low concentration was used in transition metal- mediated reactions. Stille couplings were employed in the synthesis of [carbonyl-11C]ketones from methyl and aryl halides with [11C]carbon monoxide. The synthesized [carbonyl-11C]ketones were obtained from the corresponding organostannanes with analytical radiochemical yields up to 98%. A number of synthetic routes were designed using [11C]carbon monoxide and rhodium complexes. Nitrene intermediates were generated from azides and reacted via a rhodium-mediated carbonylation reaction as a general synthetic route to [carbonyl-11C]isocyanates, versatile precursors. [carbonyl-11C]Isocyanate reacted via nucleophilic attack of an amine to form N,N’-diphenyl[11C]urea in 82% analytical radiochemical yield, ethyl phenyl[11C]carbamate was synthesized by the same route, using ethanol as the nucleophile, in 70% radiochemical yield. [11C]Isocyanate was also able to react in a [2+3] cycloaddition with ethylene oxide to form 3-phenyl[carbonyl-11C]oxazolidin-2-one in over 80% analytical radiochemical yield. This method was applied to the synthesis of a potential efflux system tracer [11C]hydroxyurea in 38% isolated radiochemical yield and the derivative 1-hydroxy-3-phenyl[11C]urea in 35% isolated radiochemical yield. Carbene intermediates, generated from diazo compounds, were reacted with [11C]carbon monoxide in the rhodium-mediated synthesis of [carbonyl-11C]ketenes. [carbonyl-11C]Ketene intermediates were utilised in the synthesis of diethyl[carbonyl-11C]malonate, from ethyl diazoacetate and ethanol. The product was obtained with a 20% isolated radiochemical yield. Alkylation of diethyl[carbonyl-11C]malonate, with ethyliodide and tetrabutylammonium fluoride, was successfully accomplished and diethyl diethyl[carbonyl-11C]malonate was synthesized in 50% analytical radiochemical yield. Several (carbonyl-13C)compounds were also synthesized using the described methods as a way of characterizing the position of the label using 13C-NMR.

Structure elucidation of charge delocalised carotenoid mono- and dications by NMR and VIS/NIR spectroscopy. Studies of the nucleophilic reactions of these cations. Studies of the β,β-carotene-iodine complex. Isolation and anmalysis of new carotenoid glucoside esters from extremophilic bacteria.