Dynamic Chemistry with Potassium Acyltrifluoroborates (KATs)

Abstract

The KAT ligation proceeds when potassium acyl trifluoroborates (KATs) couple with hydroxylamines, forming an amide bond in aqueous environment with remarkable chemoselectivity, robustness, and reaction rates. The reactivity of KAT ligation depends on both the structure of the KAT and of the hydroxylamine. Under certain circumstances, when the hydroxylamine oxygen is unsubstituted, a KAT nitrone intermediate is formed reversibly between the KAT and the hydroxylamine. From this dynamic KAT nitrone, a static amide bond can be formed upon acidification. This “two-step” KAT ligation via KAT-nitrone formation could be a candidate for building a dynamic chemical system which can be fixed by acidification. Chapter 2 of this thesis sets out to explore the properties of KAT nitrones, including their formation, spectroscopic properties, and reactivity. Mild and aqueous conditions for KAT nitrone formation were identified, which enabled the investigation of the dynamic exchange of KAT-hydroxylamine pairs, as well as conditions for converting the KAT nitrone into an amide. These findings supported our earlier hypothesis that KAT nitrone formation was dynamic, and laid the foundation for KAT-nitrones to power dynamic chemistries. Covalent Organic Frameworks (COFs) are structure-rigid, pore-persistent, highly crystalline materials with high surface areas that have found widespread applications. The formation of COFs relies on conditions for the dynamic formation of their constituent bonds, as crystallinity arises from reversible assembly. Chemical bonds with higher dynamicity form COFs with higher crystallinity, but are also more prone to hydrolysis, setting up a trade-off between COF stability and crystallinity. We hypothesized that by building COFs with KAT-nitrone bonds, the COF assembly could be performed with high dynamicity under aqueous, ambient conditions to achieve crystallinity. The resulting KAT-nitrone COF could be fixed into a permanent, chemically more resistant amide COF by its acidification. A collection of highly symmetric di-, tris-, and tetra KATs were designed and synthesized, along with the complementary bis- and tris hydroxylamines, as potential KAT-nitrone building blocks. The KAT-nitrone formation among these building blocks was facile in aqueous conditions, yet no crystalline COF products were formed in our hands. Findings related to these multivalent building block KATs and hydroxylamines were nonetheless interesting and were summarized in Chapter 3. In Chapter 4 we explored the possibility of using KAT-nitrones for creating a Dynamic Covalent Library for the search of suitable PROteolysis TArgeting Chimera (PROTAC) linkers. During the preparation of the required library building blocks, we encountered the need of a new class of alkyl KATs, α-alkoxy KATs, which could not be easily synthesized with existing methods. To overcome this, new cyclic KAT reagents that expedite the synthesis of alkyl KATs from alkyllithiums were designed, evaluated, and reported in Chapter 5. Chapter 6 collects some KAT related findings that couldn’t fit in the other chapters.