Potassium acyltrifluoroborates (KATs) are boron-containing organic salts, which became important over the past ten years due to their high utility in organic synthesis; particularly as remarkable reagents for rapid coupling reactions, such as the amide-forming ligation, and as prominent precursors for the synthesis of aminoboronic acids. Those are used as biochemical markers and as active substances in therapy, of which the most known is bortezomib. This proteasome inhibitor is indicated for the treatment of multiple myeloma. The potential of aminoboronic acids is much broader than their effect on a single target. Thus, some of the already marketed active substances from this class act on different targets. Given the wide potential of aminoboronic acids and great utility of the amide-forming ligation from KATs, there is a need to find new and advanced synthetic pathways for KATs. Therefore, structurally different KATs were synthesized according to the literature procedures, which we optimized. With the wide structural diversity of KATs we wanted to present the generality of the synthesis process for structurally different KATs. We have synthesized a library of KATs with diverse functional groups on the side chain, substituents with various electronic effects and sterically different substituents. In total, we planned the synthesis of 22 KATs; 10 aromatic and 12 aliphatic. Out of those 22, 14 KATs were already known and only 4 out of these 14 were commercially available. In the category of 8 completely new KATs, synthesis of 4 new KATs was successful. Synthetic improvements were mainly implemented in the area of a more accurate monitoring of the reaction, economic aspect and a wide structural range of substrates. We have also ensured the appropriate sequence of reagent addition and consequently lowered the formation of side products. We have discovered that all reactions are highly sensitive to the temperature, mixing and reagent quality (freshness). Even small deviations from prescribed procedure lead to the failure of the reaction. To conclude, we believe that further work should focus on closer monitoring of reactions and thus detecting critical steps and parameters. Namely, the questions of improving the synthetic procedures of aliphatic KATs, more effective prevention of the production of side products during the reaction, better isolation process and, ultimately, greater yield, remain open. Results and findings of this master's thesis represent a valuable advance in the synthesis of KATs, which can be used as precursors of aminoboronic acids – key building blocks of proteasome inhibitors.
|
