Photoredox-catalysed amidyl radical insertion to bicyclo[1.1.0]butanes

nature catalysis Article https://doi.org/10.1038/s41929-024-01239-9 Photoredox-catalysed amidyl radical insertion to bicyclo[1.1.0]butanes Received: 18 December 2023 Accepted: 20 September 2024 Chetan C. Chintawar 1,2, Ranjini Laskar 1,2, Debanjan Rana1, Felix Schäfer 1, Nele Van Wyngaerden 1, Subhabrata Dutta 1, Constantin G. Daniliuc 1 & Frank Glorius 1 Published online: xx xx xxxx Check for updates Replacing planar aromatic rings in drug molecules with C(sp3)-rich isosteric mimetics, such as bicyclo[n.1.1]alkanes, can significantly alter their physicochemical and pharmacokinetic properties, often leading to higher clinical success rates. However, unlike a benzene ring, the structurally rigid C(sp3)-rich isosteric mimetics of heteroaromatic rings are rare. Heterobicyclo[n.1.1]alkanes are promising in this regard, but the lack of modular synthetic methods has currently hindered their exploration. We envisioned that the strategic and selective insertion of different heteroatomic units to bicyclo[1.1.0]butanes could offer a highly modular platform to access diverse heterobicyclo[n.1.1]alkanes. Herein we report a photoredox-catalysed highly regioselective and chemoselective insertion of amidyl radicals to bicyclo[1.1.0]butanes, providing direct access to 2-oxa4-azabicyclo[3.1.1]hept-3-enes. The exit vector analysis shows a geometric resemblance of these C(sp3)-rich heterobicyclic motifs with pyridine and pyrimidine derivatives, suggesting their potential as isosteric mimetics of such medicinally important heterocycles. Additionally, various downstream transformations demonstrate their utility as versatile building blocks in synthetic chemistry. Aromatic motifs are vital components of many approved drugs as well as drugs under clinical trial1–5. A substituted benzene ring, which constitutes 63% of aromatic ring-containing small-molecule drugs, is the most prevalent ring system in pharmaceuticals (Fig. 1a)1,5. However, under physiological conditions, organic compounds with more than two substituted benzene rings often have poor solubility, low target specificity and low metabolic stability, thus halting the entry of pharmaceutical candidates into the final phases of drug development6,7. Substituting benzene rings with heteroaromatic units (for example, pyridine, pyrimidin and so on) often proves to be crucial in fine-tuning such molecular functions8–11. As a result, heteroaromatic units are being increasingly incorporated in pharmaceutical candidates. Approximately 37% of aromatic ring-containing small-molecule drugs now feature at least one heteroaromatic unit, and this count is increasing in new potential clinical trial drugs1,5. In modern medicinal chemistry, replacing planar aromatic rings with C(sp3)-rich polycyclic hydrocarbons proved to be beneficial to improve the metabolic stability, solubility and lipophilicity of potential drug candidates. Structurally rigid bicyclo[n.1.1]alkanes (n = 1, 2 or 3) and cubanes having well-defined exit vectors (the three-dimensional geometric arrangement of all the substituents around a molecular skeleton) emerged as highly successful isosteres of differently substituted benzene rings (Fig. 1b)12,13. By stark contrast, structurally rigid isosteric mimetics of heteroaromatic compounds with well-defined exit vectors are very rare. Recently, Mykhailiuk and coworkers showed that by replacing the parent pyridine ring of an antihistamine drug— rupatidine—with a 3-azabicyclo[3.1.1]heptane (3-aza-BCHep) unit (Fig. 1c), marked improvement in physicochemical properties such as solubility, lipophilicity and metabolic stability could be achieved14, clearly highlighting the promising avenue of heterobicyclo[n.1.1] Organisch-Chemisches Institut, Universität Münster, Münster, Germany. 2These authors contributed equally: Chetan C. Chintawar, Ranjini Laskar. e-mail: 1 Nature Catalysis Article a https://doi.org/10.1038/s41929-024-01239-9 b Aromatic-ring-containing small-molecule drugs C(sp3)-rich isosteres of aromatic rings Drugs with benzene ring 63% Drugs with aromatic units Potency Polarity Solubility Ar Het Ar Het Selectivity Metabolism 37% Effects of heteroaromatic replacements on drug efficiency Drugs with at least one heteroaromatic ring c d 3-Azabicyclo[3.1.1]heptane as an isostere of pyridine N Cl Rupatidine Antihistamine N Me Unknown Cl Improved solubility, metabolic stability and lipophilicity Challenge: limited methods to access multiply substituted heterobicyclo[n.1.1]alkanes of desired ring size e Insertion of heteroatomic units to BCBs N N Me Isosteres of heteroaromatic rings — under-explored N Me N Isosteres of benzene — well-explored = N, O or S = C, N O or S Well-known Rare examples BCBs as precursors to access diverse heterobicyclo[n.1.1]alkanes? Insertion of amidyl radicals to BCBs under photoredox catalysis (this work): O N Challenges R O N R 1 I 3′ (not observed) + O R PC N R O N 2 O R O NH N II = Leaving groups R R O N III 3 (observed) Fig. 1 | Heterobicyclo[n.1.1]alkanes: prospects in medicinal chemistry and motivation for the present work. a, Abundance and importance of heteroaromatic (Het) rings in small-molecule drugs. Ar, aromatic. b, Current status of the saturated isosteres of aromatic and heteroaromatic rings. c, 3-Azabicyclo[3.1.1]heptane, an example of a pyridine isostere. d, Insertion of heteroaromatic units to BCBs as a platform for accessing heterobicyclo[n.1.1] alkanes. e, This work explores the insertion of amidyl radicals into BCBs under photoredox catalysis (PC, photocatalyst). alkanes in medicinal chemistry. However, further exploration of such opportunities is currently hampered by the scarcity of methods that enable access to such heterobicyclic motifs. In recent years, bicyclo[1.1.0]butanes (BCBs) have garnered commendable attention as versatile building blocks in organic synthesis15,16. The high ring strain17 resulting from their inter-bridgehead C1–C3 bond has proven instrumental in various transformations18–20. More interestingly, the insertion of one, two or three carbon atoms to this strained bond via a formal [n+2] cycloaddition reaction emerged as a powerful approach to access substituted bicyclo[1.1.1]pentanes (BCPs)21–23, bicyclo[2.1.1]hexanes (BCHs)24–29 and bicyclo[3.1.1]heptanes (BCHeps)30,31. While numerous elegant transformations have been reported for the synthesis of such bicyclo[n.1.1]alkanes, the methods for accessing related heterobicyclo[n.1.1]alkanes remain under-explored. Analogous to carbon atom insertions, the strategic development of efficient methods for the highly selective insertion of different heteroatomic units into BCBs could be an ideal approach to access diverse heterobicyclo[n.1.1]alkanes (Fig. 1d). However, mitigating the undesired pathways associated with the reaction of heteroatomic precursors with BCBs, such as a nucleophilic ring-opening or Nature Catalysis Article an isomerization reacti (...truncated)