Mange biologisk aktive molekyler indeholder et eller flere nitrogen atomer. Derfor er dannelse af C-N bindinger et yderst vigtigt felt indenfor udvikling af medicin. Hoveddelen af denne afhandling omhandler miljøvenlige synteser af forskellige nitrogenindeholdende byggeblokke. Iridium og ruthenium katalysatorer er blevet anvendt til N-alkylering af aminer med enten alkoholer eller aminer. Syntese af sekundære aminer Selvkondensation af primære aminer gav sekundære aminer in gode eller høje udbytter. Reaktionen er katalyseret af det kommercielt tilgængelige [Cp*IrCl2]2 kompleks. Proceduren er miljøvenlig, da den udføres uden tilstedeværelse af solvent eller additiver, og det eneste biprodukt er ammoniak. Ydermere er oparbejdningsmetoden en simpel destillation af produktet direkte fra reaktionsblandingen. Syntese af piperaziner I Madsen-gruppen er det tidligere blevet påvist, at kondensation af diaminer og dioler katalyseret af [Cp*IrCl2]2 giver piperaziner, og det eneste biprodukt er vand. Substrattolerancen er blevet udvidet og begrænsningerne af reaktionen er blevet undersøgt. Det blev fastslået, at Thorpe-Ingold effekten spiller en central rolle i reaktionen, da ethylenglykol og 1,2-ethylendiamin ikke som forventet gav piperazine. Indførelse af en C-substituent på det ene eller begge af udgangsstofferne gav Csubstituerede piperaziner i høje udbytter. Syntese af N-benzylpiperazin ud fra ethylenglykol og N-benzylethylendiamin var ligeledes succesfyldt. Selvkondensation af ethanolamin til piperazin fejlede pga. polymerisering af udgangsstoffet. o-Phenylethylendiamin var et vanskeligt udgangsstof, da det gav en ækvimolær blanding af 1,2,3,4-tetrahydroquinoxalin og 2-benzimidazolmethanol i reaktion med ethylenglykol. Ammonium tetrafluoroborat som nitrogenkilde gav i reaktion med 1,2-cyklohexandiol morfolinderivatet. Endeligt blev det forsøgt at anvende ruthenium katalyse, men det var uden succes, da hverken et RuCl3-PPh3 kompleks eller et RuCl3-xantphos kompleks var i stand til at katalysere reaktionen mellem 1,2-diamincyclohexan og ethylenglykol. Mekanistiske eksperimenter af de iridiumkatalyserede reaktioner afslørede at Voigt isomeriseringen af α-iminoalkohol-intermediatet til den tilsvarende α-iminoketon spiller en væsentlig rolle. Syntese af indoler Reaktion mellem aniliner og vicinale dioler under tilstedeværelse af et rutheniumkompleks (RuCl3 med PPh3 eller xantphos) gav indoler i gode udbytter. I dette tilfælde er vand og dihydrogen de eneste biprodukter. Når asymmetriske dioler blev anvendt, var den tilsvarende indol med den største substituent i 2-positionen favoriseret. Det menes at forløbe via et Bischler-ligende reaktionsforløb. Mekanistiske eksperimenter blev udført og understregede vigtigheden af Voigt reaktionen under dannelsen af produktet. Proteinfoldning Under et eksternt ophold ved The Scripps Research Institute, San Diego, Californien, USA blev foldning af det velkendte protein CI2 studeret. Adskellige mutanter blev syntetisk fremstillet via foldningsassisteret ligering. Det ene segment blev syntetisert som en Cterminal thioester via Boc-fastfase peptid syntese og det andet som en C-terminal syre via Fmoc-fastfase peptid syntese. Alle de muterede enheder er at finde i proteinets α-helix, og valget af mutant var alanin eller Aib, som begge besider en høj tilbøjelighed til at danne α-helixer. Hermed var det antaget, at mere stabile proteiner ville kunne opnås. Foldning af mutanterne med henblik på termodynamik og kinetik blev undersøgt gennem guanidinhydroklorid denaturering monitoreret af fluorescens. Desværre var resultaterne uanvendelige pga. fejl i spektrofluorometeret.Many biologically active molecules contain one or more nitrogen atoms. Consequently, CN bond formation is a crucial area in the development of pharmaceuticals. The main part of this thesis is devoted to environmentally benign syntheses of different nitrogen scaffolds. Iridium and ruthenium catalysts have been employed for the N-alkylation of amines with either alcohols or amines. Synthesis of secondary amines Self-condensation of primary amines afforded secondary amines in good to high yields. The reaction is catalyzed by the commercially available [Cp*IrCl2]2 complex. The procedure is environmentally benign as it is performed in the absence of both solvent and additives and the only by-product is ammonia. Additionally, the work-up procedure is a simple distillation of the product directly from the reaction mixture. Synthesis of piperazines In the Madsen group it has previously been demonstrated that condensation of diamines and diols catalyzed by [Cp*IrCl2]2 furnishes the piperazine skeleton. The only by-product of the reaction is water. The substrate scope was extended and the limitations of the reaction were studied. It was established that the Thorpe-Ingold effect plays a central role in the reaction, as ethyleneglycol and 1,2-ethylenediamine failed to produce piperazine. Introduction of a C-substituent on one or both of the starting materials gave Csubstituted piperazines in high yields. Synthesis of N-benzylpiperazine from ethyleneglycol and N-benzylethylenediamine was also successful. Self-condensation of ethanolamine was unsuccessful due to polymerization of the starting material. o-Phenylenediamine was a difficult substrate as it furnished an equimolar mixture of 1,2,3,4-tetrahydroquinoxaline and 2-benzimidazolemethanol in the reaction with ethylene glycol. Ammonium tetrafluoroborate as the nitrogen source in reaction with 1,2-cyclohexanediol afforded the morpholine derivative. Finally, attempts to switch to ruthenium catalysis were unsuccessful since neither a RuCl3-PPh3 complex nor a RuCl3-xantphos complex was able to catalyze the reaction between 1,2-diaminocyclohexane and ethylene glycol. Mechanistic experiments of the iridium catalyzed reactions revealed that the Voigt isomerization of the α-imino alcohol intermediate to the corresponding α-imino ketone plays a significant role. Synthesis of indoles Anilines and vicinal diols were reacted in the presence of a ruthenium complex (RuCl3 with PPh3 or xantphos) to give indoles in good yields. In this case water and dihydrogen are the only by-products. When unsymmetrical diols were employed the corresponding indole with the largest substituent in the 2-position was favoured. It is believed to proceed through a Bischler-like reaction pathway. Mechanistic experiments were conducted and emphasized the importance of the Voigt reaction in the formation of the product. Protein folding During an external stay at The Scripps Research Institute, San Diego, California, USA, folding of the well-known protein CI2 was studied. Several mutants were synthetically prepared via folding assisted ligation. One segment was synthesised as the C-terminal thioester by Boc-SPPS and the other segment as a C-terminal acid by Fmoc-SPPS. The sites of mutation were all in the α-helical region of the protein and the mutation choices were alanine and Aib, which both posses a high α-helical propensity. Hereby, it was believed that more stable proteins would be obtained. Folding of the mutants was studied in terms of thermodynamics and kinetics by guanidine hydrochloride denaturation monitored by fluorescence. The results were unfortunately unreliable due to errors in the spectrofluorometer.</p
