Final Report Summary - CATALYTIC METHODS (New Catalytic Methods for the Synthesis of Peptides and Peptide Conjugates) The fully formatted report incl. the graphical scheme (PublishableSummary) as well as the individual graphical scheme (Scheme1) are attached.The 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 was envisaged. In more detail, new concepts were explored to form peptide bonds 1 starting from alkenes 2 and suitable nitrogen sources (Scheme 1). This chemistry should not involve carbonyl activation as a central reaction, and thereby, should lead to a fundamentally new approach for making such complex molecules. Thus, this project should yield methodology capable of creating short as well as long peptides by connecting two smaller peptide moieties and forming a new amide bond in the process. 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 was to develop an innovative, mild and convenient technique for joining one complex molecule to another.The primary approach towards the development of such a strategy incorporated the formation of the peptide bond via the generation of a 1,2-aminoalcohol motif employing the osmium catalysed aminohydroxylation reaction. Preliminary results indicated that single amino acid based N-O reoxidants can be employed in intermolecular aminohydroxylation reactions with both electron-rich as well as electron-deficient olefins (T. J. Donohoe, C. K. A. Callens, A. Flores, S. Mesch, D. L. Poole, I. A. Roslan, Angew. Chem. 2011, 123, 11149 11152; Angew. Chem., Int. Ed. 2011, 50, 10957 10960.). Based on these findings we set out to study the corresponding transformation yielding tripeptidic derivatives in more detail (Scheme 1). The reaction only proceeds for amino acid based alkenes 3 with reasonably bulky side chains (R5) or an additional protecting group at the amide nitrogen atom (R6). The reaction with dipeptidic amide based N O reoxidants 4 (R2 = amino acid) was also investigated but no conversion of the starting material could be achieved regardless of the bulkiness of the corresponding side chains (R1 and side chain in amino acid R2). Even an additional protecting group at the amide nitrogen atom (R3) did not help to overcome this lack of reactivity. It rather seems to be the case that only the phthalimide protected mono amino acid reoxidants (R2R3N = phthalimide) are able to facilitate osmium catalysed aminohydroxylation reactions. The unique and distinguished reactivity provided by this group of compounds could not be rationalized so far. Furthermore, it is only possible to form iso-serine derivatives 5 with the aminohydroxylation strategy albeit in good regioselectivities, while it seems to be the case that the corresponding serine derivatives are not accessible by this approach in reasonable yields (Scheme 1). Although this would be a limitation of the methodology, it still would be acceptable as long as the reaction only furnishes the iso-serine derivatives as single regioisomers selectively. More importantly, the best stereoselectivities achieved within this methodology are rather moderate to good, but the most serious limitation of this approach is still the lack of reactivity of all nitrogen sources featuring a free NH at the nitrogen atom adjacent to the reoxidant motif (R3 = H). Furthermore, not only nitrogen sources with a free NH but also those with an additional functionalization at the nitrogen atom adjacent to the reoxidant motif (R3) were not tolerated.Although the aminohydroxylation approach provided methodology for the conjugation of two amino acid based substrates the aforementioned limitations did not allow for a further development of this concept. Therefore, we decided to explore the potential of one of the back-up plans, since we were not able to find suitable solutions for the problems with regard to the reaction outcome of the aminohydroxylation approach. This back-up plan concerns related chemistry and involves the formation of aziridine moieties and their subsequent ring opening (Scheme 1). All approaches within this back-up plan would start from α,β-unsaturated carbonyl derivatives 6 and yield an aziridine containing peptide 7 which would then serve as a valuable building block for nucleophilic ring opening reactions yielding derivatives containing natural as well as unnatural amino acids 8 depending on the specific nucleophiles employed. In here, it was essential to fully control the regioselectivity of this ring-opening process. In this regard, it was found that amines can open the aziridine moiety within a fully peptidic environment with high regioselectivity at the least hindered ring position without the addition of any catalyst. The scope of this very mild reaction was studied and it was revealed that besides simple amines and single amino acid derivatives also complex peptidic systems with a free amino group can be employed, all in good yields under mild reaction conditions.In conclusion, the regioselective ring opening of aziridine peptides is possible and will be further developed in the future. In particular, the conjugation of larger peptidic ensembles to each other offers diverse opportunities for applications at the interface of chemistry and biology. Therefore, this overall avenue of research, the combination of aziridination and nucleophilic ring opening, will be pursued in the future. The expected results have the potential to influence future research in the area of peptide chemistry significantly. Since peptides are ubiquitous in Nature and many peptides and derivatives exhibit potent and diverse biological activities, peptides and peptide conjugates will always play a key role in Medicinal Chemistry (e.g. peptide antibiotics and peptidic antitumour agents). That is why the development of innovative methodology to construct organic peptide derived molecules of this type is highly desirable and of great benefit to the pharmaceutical and agrochemical industries in Europe. Against the background of this medicinal relevance the project is expected to feature also socio-economic benefits (i.e. improvement of healthcare) in the future, besides the strong focus on the scientific and technological aspects. Thus, the overall outcome of the project is expected to contribute to European excellence and European competitiveness significantly.Project coordinator:Prof. Timothy J. DonohoeUniversity of OxfordChemistry Research Laboratory12 Mansfield RoadOxfordOX1 3TA Related documents final1-scheme1.pdf final1-finalsummary.pdf
