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Enzyme zähmen Radikale

Früher galten Radikale als zu reaktiv, um mit ihnen Stereozentren zu kreieren. Nun haben Forschende Enzyme sogar dazu gebracht, enantioselektiv Radikale zu kuppeln. Für einen Reaktionstyp hält die Natur nur ein einziges Enzym bereit, aber die Menschheit inzwischen so einige. Enantioselektiv Kohle...

Blickpunkt Nachwuchs

Together with his team, Aduc prize winner John Molloy explores reactivity of boron-containing compounds using light as an activation mode.Chemists can easily convert C–B bonds into many other functionalities, making them highly relevant in modern synthesis. Here, the boron group can be activated to branch off to stereospecifically explore chemical space for the discovery of next-generation functional molecules. Together with the current drive towards 3D topologies in medicinal chemistry, this creates demand for new strategies to generate C(sp3)–B bonds. Our research group aims to harness light to synthesize 3D organoboron frameworks.<h2 type="main">Light-enabled generation of α-boryl radicals</h2>Open-shell intermediates, such as α-boryl radicals, have a rich history in organic synthesis, enabling the construction of a C–C bond with the concomitant installation of a boron motif. Many groups have pursued light-enabled generation of such radical intermediates via radical addition. In comparison, their formation via α-atom abstraction is underexplored and was limited to the use of transition metals or powerful photoredox catalysts. Because few catalyst-free strategies had been reported, we envisaged that boron, in its trigonal planar hybridization state,1) could weaken an adjacent C–I bond to enable facile bond homolysis (<link href="#nadc20254148483-fig-0001">Figure 1). Using visible light (427 nm) and 2,6-lutidine as a Lewis basic additive, we generated α-boryl radicals.2) Introducing styrenes to the reaction led to efficient addition and elimination, providing synthetically versatile allylic boronic esters. Through control reactions, we established that the boron p-orbital, the additive, and the C–I bond are important. X-ray crystallography confirmed that the C–I bond and the boron p-orbital overlap in the ground state; UV/Vis analysis identified the formation of an electron donor-acceptor (EDA) complex between 2,6-lutidine and the α-iodo boronic ester that efficiently absorbs at the incident light wavelength (427 nm). Given the catalyst-free nature of the protocol, when we reintroduced a photocatalyst, a complementary stereodivergent synthesis of (Z)-allylic boronic esters occurred.<figure xml:id="nadc20254148483-fig-0001"><figure><img alt="image" src="https://eu-central-1.graphassets.com/Aype6X9u2QGewIgZKbFflz/cmcil25czqesx07ummoixhhh0"><figcaption><label>Abb.1: </label>Photogeneration of α-boryl radicals via selective activation of C–X bonds.</figcaption></figure></figure><h2 type="main">Photogeneration of α-bimetalloid radicals</h2>Inspired by the use of multifunctional C1 building blocks in closed-shell reactivity (Figure 1, R = BPin, GeR3, SiR3), we envisaged that our mild photoactivation mode could chemoselectively activate these small fragments to in situ generate α-bimetalloid radicals. Access to open-shell intermediates would provide an orthogonal approach for the installation and subsequent functionalization of these motifs. Employing higher-energy light (390 nm) in the presence of 2,6-lutidine generated α-bimetalloid radicals.3) As a result of the additional metalloid atom the radical becomes more electrophilic, expanding the potential SOMOphile partners that could be engaged. We reacted the α-bimetalloid radicals with styrenes, dienes, silyl enol ethers, and α,β-unsaturated systems to generate 3D fragments. UV/Vis analysis highlighted that both C1 building block and 2,6-lutidine were required for efficient activation with light. Density functional calculations support the idea that an EDA complex forms at low concentration in solution. There, binding between the nitrogen lone pair of 2,6-lutidine and the σ-hole of the iodine atom results in a complex that efficiently absorbs the incident light.The barrierless homolysis of the C–X bond in the excited state enabled the efficient generation of the target radical. The 3D products generated from this platform were leveraged for chemoselective activation and stereospecific transformations.<h2 type="main">Origin of Selectivity in Energy Transfer Reactions</h2>Energy transfer (EnT) catalysis has recently reemerged in organic synthesis to construct higher-energy molecules from feedstocks such as alkenes; transformations such as [2+2] cycloaddition and geometric isomerization of styrenyl systems have been established. The use of non-symmetrical conjugated dienes in EnT, however, is comparatively less explored due to complications with selectivity (site-, regio-, and diastereoselectivity) and potential competing reaction pathways ([2+2] cycloaddition vs. geometric isomerization vs. [4+2] cycloaddition), leading to a complex distribution of products.Our ambition was to establish selective reactions for all three possible pathways using boron as a tool to reveal the origin of reaction selectivity. While calculated spin density indicates the location of electron density at both termini of the diene, [2+2] reactivity was observed with site-, regio-, and diastereoselectivity (<link href="#nadc20254148483-fig-0002">Figure 2).4) We improved reactivity by adding another boron substituent, using geminal borylated dienes. This mitigated dimerization, which was caused initially by aggregation. Extending the reaction to trienes provided a more stabilized system that afforded the typically photo-forbidden [4+2] product. Reaction monitoring revealed geometric isomerization that occurred with counterintuitive site-selectivity relative to that of [2+2] cycloaddition – this stimulated a mechanistic investigation. Theoretical investigations established that the absence of an alkene additive creates a photostationary state composition in favor of the Z-isomer. Proceeding via a Curtin-Hammett scenario, the higher-energy E-isomer has a lower barrier for reactivity with the alkene, with the more reactive boron-containing termini undergoing addition. The small 3D boron fragments were further derivatized, demonstrating their utility in synthesis.<figure xml:id="nadc20254148483-fig-0002"><figure><img alt="image" src="https://eu-central-1.graphassets.com/Aype6X9u2QGewIgZKbFflz/cmcil27o2x26607uplkkwj0jc"><figcaption><label>Abb.2: </label>Origin of reaction selectivity in competing energy transfer processes.</figcaption></figure></figure>The current focus of the research group is in establishing de novo strategies for organoboron heterocycle synthesis.5)<h2 type="main">Questions for the author: John Molloy</h2>My best ideas come to me when …I discuss science with my students. Their creativity is ultimately what leads our research group to exploring new projects and also providing solutions to problems in existing projects.What was the best piece of advice you received?To work to discover new reactivity and not only new reactions. New reactivity potentially opens up a research field; a new reaction can only complement the field.What is your favourite element and why?Well, this is an easy one. Boron is an extremely useful element in organic synthesis, enabling us to explore chemical space in a controlled manner and, more recently, invoke specific interactions with biomolecules. Despite such a rich history in science, it continues to surprise us every day.John Molloy carries out research at the Max Planck Institute of Colloids and Interfaces in the Biomolecular Systems department of Peter Seeberger. He carried out his doctoral studies at the University of Strathclyde with Allan Watson and a postdoctoral study with Ryan Gilmour at Universität Münster.<img alt="image" src="https://eu-central-1.graphassets.com/Aype6X9u2QGewIgZKbFflz/cmcil2vptqffh07um9fxk3wpx"><ul class="references" cited="no" style="numbered" xml:id="nadc20254148483-bibl-0001"><li xml:id="nadc20254148483-bib-0001">1 A. Marotta, C. E. Adams, J. J. Molloy, Angew. Chem. Int. Ed. 2022, 61, e202207067</li><li xml:id="nadc20254148483-bib-0002">2 A. Marotta, H. Fang, C. E. Adams et al., Angew. Chem. Int. Ed. 2023, 62, e202307540</li><li xml:id="nadc20254148483-bib-0003">3 L. McGhie, A. Marotta, P. O. Loftus et al., J. Am. Chem. Soc. 2024, 146, 15850–15859</li><li xml:id="nadc20254148483-bib-0004">4 H. Fang, A. García-Eguizábal, Y. Hsueh et al., Angew. Chem. Int. Ed. 2025, 64, e202418651</li><li xml:id="nadc20254148483-bib-0005">5 A. Marotta, H. Kortman, C. Interdonato, P. H. Seeberger, J. J. Molloy, Chem. Commun. 2024, 60, 13223–13226</li></ul>

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Enzyme zähmen Radikale

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