Synthesis and use of Tetrahydrofuran amino acids and Reductive deoxygenation of alcohols

The first part of the thesis (chapter 1-3) describes the synthesis and use of tetrahydrofuran amino acids. In chapter 1 we summarize previous investigations followed by a more detailed description of the synthesis and conformational studies of the Cα-tetrasubstituted α-amino acid tert-butyl 2-(4-bromophenyl)-3-((tert-butoxycarbonyl)amino)tetra-hydrofuran-3-carboxylate, which is of importance for the following chapters. Chapter 2 describes the synthesis of a small series of pyrene and carboxyfluorescein labeled unnatural tetrahydrofuran amino acid building blocks. They can be incorporated into peptides to rigidify the secondary structure and at the same time introducing a fluorescent label. The fluorescent dye can be coupled to the TAA before or after its incorporation into a peptide sequence using a Suzuki-type C-C bond formation on the bromoarene substituent, which illustrates the synthetic feasibility of these compounds. Thus these building blocks combine two properties which are often of high interest in the preparation of peptide analogues. The absorption and emission spectra of the prepared building blocks and peptides were investigated. Furthermore the fluorescence quantum yields of derivatives rac-3 and rac-6 were determined (ФF = 0.24±0.03 and ФF = 0.09±0.02, respectively). Compared to literature known values of pyrene (ФF = 0.58), the quantum yield is lower. Chapter 3 reports the synthesis of a new class of NTS2 receptor selective ligands based on the structural modification of the lead structure NT(8-13) via solid phase supported peptide synthesis. The tetrahydrofuran amino acid HCl*H-TAA-OH was introduced as scaffold for Tyr11-Ile12 or Tyr11, respectively, leading to a small library of penta- and hexapeptides. For selected peptides that showed interesting biological activity when tested as mixtures of stereoisomers the crucial steps of an alternative synthetic pathway were investigated, allowing the synthesis of diastereomerically pure compounds. The biological investigations by radioligand binding assay at hNTS1 or hNTS2 receptors revealed that the prepared pentapeptides have only very low affinity and were therefore not further investigated. The Ki values for the hexapeptides showed good binding affinities and increased selectivity towards the NTS2 receptor. The most promising ligand possesses a Ki(NTS2) value of 67 ± 12 nM and a selectivity ratio of 52 in favour of the NTS2 receptor. However, the most active and selective compound for the NTS2 receptor reported so far shows a smaller Ki(NTS2) of 2.8 ± 0.69 nM and a superior selectivity ratio of 22000. The second part of this thesis (Chapter 4) deals with the reductive deoxygenation of alcohols. The method for the reduction of alcohols to hydrocarbons by using hydriodic acid and red phosphorous presented in Chapter 4, was described for the first time by Kiliani more than 140 years ago for the deoxygenation of gluconic acid. We improved this method, applying a biphasic toluene – aqueous hydriodic acid reaction medium. This allowed the separation of organic substrates, which dissolve in toluene, from the strongly acidic aqueous phase leading to milder reaction conditions and therefore being more applicable to organic synthesis. A range of primary, secondary and tertiary benzylic alcohols as well as α-hydroxycarbonyl compounds are converted in good yields and functional groups like keto, ester, amide, or ether groups are tolerated. With an access of red phosphorous as the stoichiometric reducing agent, catalytic amounts of hydriodic acid are sufficient to achieve full conversion