Chemical Synthesis and Catalysis in Germany

The strategic incorporation of boron, both as a design feature and synthetic handle, in medicinal chemistry has vastly accelerated in recent years. This reflects the unique physicochemical properties of boron motifs and the efficiency with which the C(sp2/sp3)-B bond can be functionalized. This factor has culminated in the design of state-of-the-art therapeutics, such as Bortezomib, which has recently gained blockbuster status.[1] Due to these notable strides in drug design, in combination with the overwhelming utility of boron to serve as a linchpin in synthesis,[2] expedient access to complex 3D architectures of this kind remains a core research objective in contemporary synthesis. While methods enabling direct incorporation of boron have been intensively pursued,[2] protocols that facilitate the mild functionalization of boron molecules to increase complexity and explore chemical space are comparatively underexplored.

Boron’s inimitable ability to fluctuate between two discrete hybridized forms (sp2 and sp3) of contrasting physical and electronic properties, represents an attractive platform for reaction development. Our research group focusses on boron hybridization and how these factors regulate or elicit light-driven processes.[3] Specifically, how hybridization can modulate and influence both efficiency of activation and subsequent reactivity of high-energy intermediates. Through these considerations, expedient access to α-boryl radicals of varying reactivity was realized,[4] using only light and a simple Lewis basic additive. These high-energy intermediates were leveraged for reaction development enabling the construction of complex organoboron scaffolds. Mechanistic studies reveal the pivitol role of boron hybridization for the targeted reactivity.

Electrochemistry has emerged as a transformative approach in organic synthesis, offering significant advantages such as enhanced safety and sustainability. By facilitating direct conversions through electrical energy, electrochemical methods minimize reliance on haz-ardous reagents and high-pressure conditions. A key transformation enabled by this tech-nology is the hydrogenation of nitriles to primary amines, which serve as crucial intermedi-ates in pharmaceutical, and life sciences. In our recent collaboration, we developed a scalable electrochemical method for the hydro-genation of nitriles using a nickel foam cathode in a simple two-electrode setup. This meth-od operates under galvanostatic conditions with readily available materials, ensuring ease of implementation and operational safety. We achieved yields of up to 89% for primary amines, showcasing the versatility of our technique across various nitrile substrates. A notable advancement of this method is its scalability; we successfully transitioned from milligram-scale batch reactions to multi-gram production flow-type electrolysers. The nickel foam cathode provides excellent mechanical stability and reusability, maintaining high per-formance over multiple cycles. This work highlights our electrochemical hydrogenation method as a sustainable alternative to conventional practices, contributing to greener chemical processes and expanding safety in the production of commercially relevant pri-mary amines.

Flavoenzymes are among nature’s most versatile catalysts and mediate reactions ranging from oxidations, oxygenations, ring-contractions, to reductions. However, the astonishingly broad reactivity spectrum of flavoenzymes stands in contrast to the currently limited synthetic use of molecular flavins. To bridge this gap, we focus on the design and application of molecular flavin catalysts for organic transformations. We are especially interested in sequential reactions since combining various catalytic activities allows for achieving molecular complexity with one single flavin catalyst. Current examples from our laboratory include desaturation-epoxidation sequences, which were inspired by the enzymatic formation of α,β-epoxyketones, and photochemical catalysis with ring-contracted flavins that rely on both triplet sensitization and H-atom abstraction. We could also develop reductive flavin catalysis with hydroquinoid flavins, which mimics the reactivity of DNA photolyase enzymes.

The undirected Ir-catalyzed C–H borylation typically occurs preferentially at the least hindered and more acidic C–H bonds of the aromatic ring. However, in the case of polyaromatic compounds with multiple unbiased and sterically accessible C–H bonds, the site selectivity for non-directed C–H borylation is low. In this study, we report a dramatic effect induced by the π-complexation of a chromium tricarbonyl unit on the aromatic ring in Ir-catalyzed C–H borylation. Competition experiments demonstrate that the C–H bonds of an aromatic ring bound to the chromium tricarbonyl unit react, on average, two orders of magnitude faster toward C–H borylation compared to unbound arenes. This effect enabled unprecedented site-selective C–H borylation of aromatic rings complexed with a chromium tripod across a range of polyaromatic compounds. Additionally, the chromium tripod significantly enhances the reactivity of C–H bonds, enabling the borylation to occur at room temperature with the substrate as the limiting reagent. To explain the exceptional site selectivity observed for the preferential borylation of (η6-arene)Cr(CO)3 complexes, density functional theory (DFT) calculations were employed. The DFT studies suggest that the oxidative addition of the C–H bonds has lower activation barriers when the arenes are complexed with a chromium tricarbonyl unit. This work paves the way for the development of non-directed C–H borylation using a bimetallic system to exploit the influence of non-covalent metal-arene π-type interactions on reactivity and selectivity in C–H functionalization.