New Catalytic Methods for the Synthesis of Peptides and Peptide Conjugates
Final Report Abstract
The proposed research project is centred around the discovery and development of new ways to construct organic molecules. Herein the exploitation of an innovative strategy for the synthesis of peptides is envisaged. In more detail, new concepts are explored to form peptide bonds starting from suitable nitrogen sources and substrates containing carboncarbon double bonds. This chemistry should tolerate an aqueous environment and aerobic conditions and does not involve carbonyl activation as a central reaction. In general, carbonyl activation is the key process in most well established strategies for the preparation of peptides. Due to the lability of activated carbonyl compounds these reactions are normally performed under anhydrous and anaerobic conditions. Thereby, the concept presented in this project leads to a completely new approach for making such complex molecules. In detail, this approach should yield methodology capable of creating short as well as long peptides by connecting two smaller peptide moieties by forming a new amide bond. By extending the principle further, this chemistry would open the possibility of conjugating many other biomolecules to each other by newly generated peptide bonds. Thus one of the overall aims of this project is to develop an innovative, mild and convenient technique for joining one complex molecule to another, including peptide, DNA and carbohydrate derived fragments. Within this methodology the connection of two biomolecules shall be investigated in as many different ways as possible. The primary approach towards the development of such a strategy should be based on the osmium catalysed aminohydroxylation reaction, developed by the Nobel Laureate K. B. Sharpless. So far, it was demonstrated that the aminohydroxylation approach is capable of furnishing the desired amide bond formation between a variety of different substrates, including up to now mainly peptide based substrates. Moreover, first preliminary results indicate that the concept can be extended to carbohydrate derived starting materials and the potential of DNA based fragments to serve as substrates in this transformation will be studied in the very near future. Nevertheless, the resulting products can only be isolated as mixtures of compounds, due to the fact that it has not been possible to control all parameters of reactivity and especially selectivity during the reaction thus far. Therefore, it is essential to investigate more reaction conditions and different catalyst systems in the near future that are capable of providing the products in each case in the form of one single compound. In this regard it would be ideal to have full control over the outcome of the reaction, meaning that all possible desired product molecules can be accessed with perfect selectivity by choosing the appropriate conditions. Simultaneously to the work in this area, it was decided to explore the potential of two additional closely related strategies for the preparation of amide bonds in unprecedented ways, to provide two supplementary concepts to circumvent the problems associated with the so far observed lack of control of selectivity. Since many peptide and sugar derivatives exhibit potent and diverse biological activity, arrangements have been made to test the compounds prepared in this project in the future, in particular for anti-cancer potency, via a well established collaboration within the University of Oxford.
