Programmable Regiodivergent Light-Driven Cyclisation of Acyclic 1,5-Dienes Unlocks Rigid Bicyclic Architectures

Programmable Regiodivergent Light-Driven Cyclisation of Acyclic 1,5-Dienes Unlocks Rigid Bicyclic Architectures | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Programmable Regiodivergent Light-Driven Cyclisation of Acyclic 1,5-Dienes Unlocks Rigid Bicyclic Architectures Varinder Aggarwal, Ze-Xin Zhang, KaiChen Shu, Mihai Popescu, Yiheng Guo, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8681610/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Controlling regioselectivity in radical cyclisations remains a major challenge in synthetic chemistry, hindering the efficient assembly of strained, rigid bicyclic architectures from simple acyclic precursors. Herein, we report a visible-light-mediated intramolecular [2+2] photocycloaddition of aza-1,5-dienes that successfully overcomes the classical “rule-of-five” selectivity governing radical cyclisations. By tuning the electronic properties of an easily removable amide N-substituent, we reprogram the initial energy-transfer-driven cyclisation event, diverging from the usually kinetically favoured 5-exo-trig to the 6-endo-trig pathway. As a result, closely related substrates can be selectively directed to generate either bridged bicyclo[2.1.1] or vastly underexplored fused bicyclo[2.2.0] architectures, both of which offer rich downstream derivatisation potential. Furthermore, an extensive computational study of this transformation revealed how the intricate interplay of electronic effects controls reaction regioselectivity. Overall, this work establishes a programmable, light-driven cyclisation strategy that enables precise and selective construction of distinct bicyclic frameworks within a unified reaction manifold. Physical sciences/Chemistry/Organic chemistry/Synthetic chemistry methodology Physical sciences/Chemistry/Photochemistry/Photocatalysis Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Introduction Since the discovery of benzene over 200 years ago, the pharmaceutical landscape has been dominated by aromatic rings 1 , but there is growing awareness of the success of more structurally complex, three-dimensional scaffolds that better mimic the intricacies of biological targets 2-4 . This has created an urgent need for novel architectures, particularly rigid, saturated, and metabolically stable ring systems, that can evade enzymatic degradation. Rigid, three-dimensional scaffolds with well-defined exit vectors can not only improve binding specificity by reducing entropic penalties but also enhance solubility, reduce off-target effects, and improve pharmacokinetic properties 2-4 . A growing body of evidence demonstrates that rigid fragments, such as bicyclo[2.1.1]hexane (BCH), function as effective bioisosteres of substituted benzene rings, often conferring substantial improvements in physicochemical and biological profiles 2-6 . For example, the reported BCH analogues of Axitinib 7 and Conivaptan 8 exhibit enhanced solubility, increased metabolic stability, and preserved or improved potency, underscoring the privileged nature of this rigid, saturated scaffold (Figure 1A). Despite these advantages, the synthetic inaccessibility of this and other related frameworks has hindered their adoption in drug discovery. Current strategies to access rigid bicyclic motifs typically rely on strain-release functionalisation of preassembled frameworks such as bicyclo[1.1.0]butane, [1.1.1]propellane, or [3.1.1]propellane 4,5,9 . While effective, these approaches intrinsically restrict the substitution patterns that can be accessed, thereby limiting the potential for late‑stage diversification. A far more powerful paradigm would be to start from a single, modular acyclic precursor and, through subtle changes, selectively generate distinct rigid frameworks. The photochemistry of acyclic 1,5-dienes provides a suitable platform to study this type of divergent synthesis 4,7,9-13 ; a process that has been previously leveraged in the creation of carbocyclic and, more recently, azacyclic scaffolds bearing the [2.1.1] framework 14-16 . In these cases, bridged [2.1.1] products are exclusively formed since, according to the established “rule-of-five” 17-19 , 5 -exo -trig cyclisation dominates over the alternative 6 -endo- trig (or 4 -exo -trig) cyclisation, which would lead to the alternative fused [2.2.0] products (Figure 1B). This effect arises from the markedly unfavourable orbital alignment of the 6 -endo -trig pathway, rendering it >50-fold slower than the competing 5- exo -trig closure 20 . In addition, even if the 6- endo cyclisation were to occur, the subsequent 1,4-biradical recombination would still have to overcome substantial transannular strain and bridgehead compression, making the subsequent C–C bond-forming step towards the [2.2.0] framework equally unfavourable 21,22 . This ring-closure preference is also observed in related 1,6-diene systems, where 5- exo -trig cyclisations are kinetically favoured over 6- exo -trig cyclisations, typically affording fused [2.3.0] frameworks. Despite this, we recently demonstrated that for hex-5-enal oximes, this intrinsic 5- exo -trig bias can be overridden, leading instead to bridged [3.1.1] bicyclic architectures 23 . However, overriding 5- exo -trig cyclisation in favour of the much less favourable 6- endo -trig cyclisation is highly uncommon, underscoring the significant mechanistic challenge associated with breaking the “rule-of-five” selectivity for 1,5-dienes. As a result, access to [2.2.0] scaffolds from simple 1,5-dienes has been considered effectively unattainable, despite it representing a highly strained and rigid framework of potential pharmacological value 24-27 . The only reported synthetic strategy to access aza-[2.2.0] ring systems relies on UV-light-promoted 4π electrocyclisation, a transformation that is severely limited with respect to the attainable substitution patterns 24,28,29 . Accordingly, the development of a strategy that enables pathway-controlled, selective construction of either the rule-breaking [2.2.0] or the rule-compliant [2.1.1] bicyclic framework from acyclic 1,5-dienes would be of substantial significance in synthetic methodology; however, such a capability has not yet been realised. Herein, we report that through precise electronic tuning of the nitrogen atom in a class of amide-tethered 1,5-diene precursors, we can successfully divert the reactivity from the classically favoured 5- exo -trig towards the rarely observed 6 -endo- trig pathway 30 , breaking the “rule-of-five” paradigm. Through employing an essentially common intermediate, either bridged [2.1.1] or fused [2.2.0] skeletons can be accessed selectively, providing synthetic chemists with a unified methodology for generating structurally diverse building blocks. The rigid, three-dimensional β-lactam-like 31 architecture and hydrogen-bonding capacity of these products underscore their potential for biological applications 32 . Furthermore, the rich downstream chemistry enabled by these scaffolds further highlights their synthetic utility in the construction of structurally complex molecules. RESULTS AND DISCUSSION Reaction design and optimisation Our reaction design was guided by the hypothesis that an amide-tethered 1,5-diene could bias the initial radical addition towards the β-position of the enamide through polarity matching, thereby opening access to the typically disfavoured 6-endo pathway. Therefore, we subjected N –alkylated substrate 1a (R = p- methoxybenzyl) to [Ir(dF[CF 3 ]ppy) 2 (dtbbpy)]PF 6 (1 mol%) under 427 nm irradiation in MeCN. Under these conditions, we observed that the formation of [2.1.1] product 3a , arising from the 5- exo -trig pathway, dominated the reactivity (Figure 2A). Despite this, we were encouraged by the detection of an unstable 3,4-dihydro-2-pyridone byproduct 4a (0.73:0.27 ratio), which presumably forms via an initial 6- endo cyclisation event. However, the inability of the 6- endo radical addition intermediate to undergo the desired recombination to the targeted [2.2.0] product demonstrates the challenges associated with synthesising these frameworks. To probe the influence of the nitrogen-appended substituent on cyclisation outcome, we synthesised a series of amide-tethered 1,5-dienes with varying electronic properties ( 1a-b , 2a-e ). Remarkably, we observed that as the electron-withdrawing capacity of the substituent increased, the selectivity of the reaction completely switched from 5- exo -trig to favouring the 6- endo -trig pathway (Figure 2A, PMB → Bn → Boc → Cbz → CO 2 Ph → Ac → Troc). More importantly, upon acylation of the nitrogen tether, radical recombination to generate the fused 4,4-ring system became feasible, allowing us to obtain the rarely observed [2.2.0] scaffold as the major product (see below for mechanistic discussion). This highly unexpected trend in selectivity clearly demonstrates that fine-tuning the electronic properties of the nitrogen substituent enables precise control over the reaction pathway, allowing for the selective construction of distinct bridged architectures. With this in mind, we then further probed the reaction conditions in an effort to obtain a deeper understanding of this unique system, as well as to identify a single protocol that could deliver both [2.1.1] and [2.2.0] products upon judicious choice of the substrate. We first examined the influence of the photocatalyst. The yields of 3c and 6f correlated closely with the triplet energy of the sensitiser but showed no dependence on redox potentials, supporting an energy-transfer (EnT), rather than a photoredox mechanism (Figure 2B, left) 33,34 . Additionally, both N –Bn and N –Ac systems display minimal dependence on solvent polarity, consistent with a neutral EnT process rather than a mechanism involving charge separation (Figure 2B, right) 35 . Furthermore, performing the reaction in the absence of the photocatalyst and light revealed that these elements were necessary to promote reactivity. Exploration of reaction time revealed that the transformation reaches completion within 15–30 minutes, and that yield was largely independent of concentration. Collectively, these observations highlight the intrinsic robustness of the reaction, which operates efficiently over a broad range of solvents, times, and concentrations without loss of performance. Nevertheless, to maintain consistency across substrates with differing solubilities, we adopted a 0.1 M concentration and 1.5 h irradiation time for all subsequent studies. Substrate scope Building on the discovery of programmable cyclisation regiodivergence, we explored the substrate scope with respect to both pathways. To target the [2.1.1] scaffold, a series of N –Bn 1,5-dienes was employed under our standard conditions (Figure 3). A variety of C -2 aryl-substituted precursors, encompassing electron-rich, electron-neutral, and electron-deficient arenes ( 3b-3i ), were readily transformed to the desired bridged products. Interestingly, the yield of the [2.1.1] scaffold correlated with the electronic nature of the aryl substituent: substrates bearing electron-deficient aryl groups ( 3b-3e ) generally afforded the [2.1.1] product in higher yields compared to those with electron-rich aryl substituents ( 3h , 3i ). Given that the intrinsically unstable six-membered-ring species ( 4 ) arising from the 6 -endo pathway (for N –alkyl substrates, Figure 2A) could typically be observed as a minor component of the reaction, we hypothesise that this decrease in [2.1.1] product yield likely reflects a shift in pathway selectivity driven by changes in C -2 electronics. Specifically, whereas electron-deficient aryl substituents favour the 5- exo -trig cyclisation, electron-rich aryl groups promote the 6- endo- trig closure (see below for further discussion). With respect to the nitrogen substituent, p- methoxybenzyl ( 3a ) and p- methoxyphenyl ( 3j ) groups were well tolerated. Importantly, debenzylation of 3c could be achieved under mild conditions to access the corresponding N–H substrate 3c’ . With respect to C -5 substitution, a series of 5-CF 3 -BCH analogues could be prepared in comparable yields to their 5-Me counterparts ( 3k-3p ). Additionally, the trend associated with aryl electronic effects remained consistent: electron-deficient aryl groups exhibited a higher propensity for the formation of the [2.1.1] product via a 5- exo -trig pathway. Furthermore, 5-H-BCH ( 3q ) and 5-Ph-BCH ( 3r ) products could be obtained in moderate yields. When inverting the position of the amide tether, we observed that these substrates (4-aza-1,5-dienes, 7 ) uniformly furnished the corresponding [2.1.1] scaffolds ( 8a-8h ) in good to excellent yields. Here, no evidence of 6- endo -trig cyclisation was detected, likely a consequence of the 6- endo pathway now involving a polarity-mismatched radical addition. Importantly, we demonstrated that the selective cleavage of either the amide N –substituent ( 8a’ ) or the internal amide bond ( 8a’’ ) could be achieved under acidic and basic conditions, respectively. We next investigated the scope of [2.2.0] synthesis by employing the analogous N –electron-withdrawing 1,5-dienes 2 (Figure 4). As expected based on our previous experiments, examination of the C -2 aryl substituent ( 6d , 6f-6p ) revealed a strong correlation between product distribution and aryl electronics: electron-rich aryl groups promoted the 6- endo -trig pathway with excellent levels of selectivity ( 6g-6k ), while electron-deficient aryl groups ( 6d , 6o , 6p ) partially eroded this preference. The lower selectivity observed with electron-deficient aryl groups ( 6d , 6o , 6p ) encouraged us to explore alternative conditions to see if we could override this substrate-dependent regioselectivity. Specifically, we discovered that replacing MeCN with hexafluoroisopropanol (HFIP) as the reaction solvent significantly increased the ratio of 6- endo to 5- exo products, presumably a result of partial polarisation of the enone via hydrogen bonding, providing a more polarity-matched 6- endo pathway. Heteroaryl substituents of varying electronic character ( 6q-6t ) followed the same trend and consistently afforded the [2.2.0] scaffold in good to excellent yields. When the aryl substituent at C -2 was exchanged for an ester group, the strongly electron-withdrawing effect completely switched the outcome, exclusively furnishing the [2.1.1] scaffold ( 5u ). As we had initially discovered that altering the substituent at the nitrogen tether had a pronounced impact on regioselectivity, we further explored this electronic effect by employing a range of electron-withdrawing groups. Generally, the stronger the electron-withdrawing nature of the substituent, the more the system favoured cyclisation to the challenging [2.2.0] scaffold ( 6v–6ab ). When a sterically hindered pivaloyl group was employed, the reaction delivered an unexpected six-membered-ring species 9 in high yield. This outcome can be plausibly attributed to the perpendicular orientation of the pivaloyl carbonyl relative to the six-membered-ring, which predisposes the intermediate formed from the initial 6- endo -trig cyclisation towards intramolecular acyl transfer. When an enantiomerically enriched carbonyl substituent was employed, the reaction delivered a pair of diastereomeric [2.2.0] products ( 6ad and 6ad’ ) which were successfully separated by flash chromatography, providing the potential to access enantioenriched [2.2.0] scaffolds. Varying the group at the C -5 position revealed that replacing Me with H ( 6ae - 6ag ) partially increased the contribution of the 5- exo -trig pathway, presumably due to steric effects. In contrast, bulkier alkyl groups at C -5 ( 6ah , 6ai ) were well tolerated, delivering excellent yields and high levels of selectivity. However, the introduction of an aryl group at C -5 ( 6aj ), lowered reaction selectivity as both alkene moieties can be photoexcited for this substrate. Substitution at C -1 could also be achieved, providing 6ak and 6al as a single diastereomer. However, we observed a reversal of selectivity with 6-Me-substituted substrate 6am , where steric congestion at this position disfavours the radical attack required for the 6- endo pathway. To highlight the applicability of this methodology to accessing challenging scaffolds relevant to medicinal chemistry, we applied our 1,5-diene cyclisation strategy to the synthesis of 6an , a [2.2.0] analogue of the δ-lactam-containing cognitive enhancer HT-0712. 36 Product derivatisation Having established that precise electronic tuning of this class of 1,5-dienes can enable the synthesis of challenging to access [2.2.0] scaffolds, we next sought to extend the structural diversity of these frameworks through downstream derivatisation. Deprotection of the nitrogen substituent was first targeted to access the corresponding secondary amide. Treatment of 6g with NaOMe promoted selective cleavage of the N –Ac amide bond, presumably due to lower steric hindrance relative to the strained β-lactam, affording 12 in 64% yield. This intermediate proved versatile, undergoing high-yielding transformations to give urea ( 14 ), thiourea ( 15 ), sulfonamide ( 16 ), N –alkylated ( 17 ), and N –arylated derivatives ( 18 ), thereby expanding the scope of functionalities accessible. Treatment of N –Boc [2.2.0] species 6ab under basic conditions resulted in selective cleavage of the internal amide bond to afford β-amino acid derivative 10 . Further diversification was achieved through RuCl 3 -mediated oxidation of the aryl ring, delivering the corresponding carboxylic acid ( 13 ) in excellent yield. This species was then converted to amide 19 , O -methylhydroxamic acid 20 , and redox-active ester derivative 21 . Finally, the amide carbonyl within the [2.2.0] core was reduced by Rh-catalysed hydrogenation 37 , furnishing fully saturated 2- N -[2.2.0] scaffold 11 . Computational studies To unravel the intricate effects that give rise to the observed programmable cyclisation regioselectivity, we developed a computational model using Density Functional Theory (DFT) at the Pr2SCAN50-D4/def2-TZVPPD,(SMD=MeCN)//M06-2X-D3/6-31+G(d,p),(SMD=MeCN) level of theory, based on recent benchmarking efforts (Figure 6A) 38 . We first verified the feasibility of triplet sensitisation by computing the triplet energy of model substrate 2f ( 1 A ). The dynamically vertically accessible triplet energy (DvTE) 39 of 60.8 kcal/mol closely matches that of the most efficient photocatalysts (61–65 kcal/mol), while the adiabatic triplet energy was found to be 50.9 kcal/mol ( 1 A to 3 A ). Analysis of low-energy triplet geometries showed that the spin density is localised on the styrene motif, identifying it as the primary chromophore, consistent with Stern–Volmer quenching studies (see SI for details). Upon excitation to 3 A , the system can undergo cyclisation either via a 6- endo -trig ( 3 TS-I ) or 5- exo -trig ( 3 TS-II ) transition structure (TS), both proceeding in a highly exergonic fashion. The computed selectivity favours 6- endo cyclisation ( 3 TS-I ), with a ∆∆G ‡ of 0.7 kcal/mol, in line with the observed experimental product distribution of 10:1 (∆∆G ‡ = 1.4 kcal/mol). Additionally, computed selectivity values across a range of 1,5-diene substrates (Figure 6B) were successful in reproducing the trend in 6- endo selectivities ( R 2 = 0.98). In the case of 6- endo cyclisation, we discovered that rather than forming the [2.2.0] scaffold directly via radical recombination, intersystem crossing (ISC) generates zwitterionic intermediate 1 B . This closed-shell species can then deliver [2.2.0] fused product 1 D ( 6f ) via a 4π Staudinger-like electrocyclisation with a diradicaloid TS ( 1 TS-III ), consistent with recent studies 40 . The inability of the analogous N –alkyl-substituted substrate to access the [2.2.0] scaffold (instead forming pyridone 4 , Figure 2A), can be understood by the relative increase in stability of zwitterionic intermediate 1 B , leading to a greater 4π electrocyclisation energy barrier which is less favourable than the corresponding H-shift (see SI for further details). In contrast, the reaction profile arising from 5- exo -trig cyclisation ( 3 TS-II ) leads to formation of triplet intermediate 3 C , which upon ISC to open-shell diradical 1 C (∆G = 0.1 kcal/mol), can recombine via 1 TS-IV (∆G ‡ = 0.8 kcal/mol) to give [2.1.1] bicyclic product 1 E . With a general understanding of the reaction mechanism in hand, we next examined the origins of regioselectivity. Using a model N –Bn 1,5-diene system as a reference, we calculated that the analogous N –Ac substrate displays a 1.7 kcal/mol lower 6- endo -trig ( 3 TS-I ) barrier, in full agreement with our experimental results (Figure 7A), as a result of several factors. In addition to the N –Ac system representing a better Giese acceptor due to its more electron-deficient nature, this difference can be rationalised by the increased TS planarity in 3 TS-I-Ac (ϕ 1 = 28.1°) that facilitates conjugation between the developing α-carbonyl radical and the carbonyl π-bond. This arises due to the cross-conjugation in the imide system enabling partial deconjugation of the endocyclic N–C(=O) bond, increasing conformational flexibility relative to the more rigid amide bond in 3 TS-I-Bn (ϕ 1 = 67.8°). The favourability of the N –Bn system to undergo 5- exo -trig cyclisation (∆∆G ‡ = 1.7 kcal/mol compared to N –Ac) can be explained through consideration of the spectator benzylic radical in the cyclisation TS. As well as representing the more planar system (163.0° vs 150.9°), the greater availability of the nitrogen lone pair in 3 TS-II-Bn increases benzylic radical stability via captodative effects 41,42 , stabilising the TS to a greater extent than for the corresponding N –Ac system. Indeed, analysis of the ϕ₂ dihedral change along the intrinsic reaction coordinate (IRC; Figure 7B/C) for the 5- exo pathway indicates that planarity is maximised at the TS. Moreover, this captodative stabilisation can explain the strong correlation between the electronics of the styrene fragment and reaction regioselectivity (see Figure 4). Analysing the IRC of the 6- endo -trig pathway shows that the nitrogen atom remains deconjugated from the benzylic radical throughout, suggesting that changing the electronics of the aryl substituents primarily affects the 5- exo -trig pathway. This was confirmed through computational Hammett analysis, clearly demonstrating that electron-withdrawing substituents lower the 5- exo -trig ( 3 TS-II ) barrier with a strong correlation to Hammett s+ values, while the 6- endo -trig TS was minimally impacted (Figure 7D). Conclusion In this study, we have established a programmable regiodivergent photochemical strategy that fundamentally challenges the long-standing “rule-of-five” paradigm in radical cyclisation. Through electronic modulation of an amide-tethered aza-1,5-diene, we demonstrate that the inherent kinetic preference for 5- exo -trig cyclisation can be overridden, enabling selective access to either bridged [2.1.1] or fused [2.2.0] heterobicyclic frameworks from closely related precursors. Computational investigations reveal that varying the electronics of the substrate significantly affects the relative stability of the developing and spectator radicals in the transition states, giving rise to the observed tuneable regioselectivity. The robustness of the energy-transfer process, broad substrate scope, and extensive downstream derivatisation collectively establish these heterobicycles as highly valuable building blocks. The ability to exert such precise pathway control over a strained intramolecular [2+2] cycloaddition is unprecedented and addresses multiple intrinsic energetic and geometric constraints associated with 6- endo -trig cyclisation and subsequent ring closure. We anticipate that this concept will inspire the development of new rule-breaking cyclisation strategies and accelerate the discovery of structurally novel, sp³-rich scaffolds for drug discovery and beyond. Declarations ACKNOWLEDGEMENTS We thank UK Research and Innovation (UKRI) under the UK government’s Horizon Europe funding guarantee for an ERC-approved grant (EP/Y028015/1) and the University of Bristol for support.Z.-X.Z. acknowledges support from a Leverhulme Trust Early Career Fellowship (ECF-2025-137). We gratefully acknowledge Dr Jonathan Charmant (University of Bristol) for assistance with X-ray analysis. R.S.P. acknowledges financial support from the National Science Foundation (CHE-2400056) and the Alpine high-performance computing resource, jointly funded by the University of Colorado Boulder, University of Colorado Anschutz, and Colorado State University (CSU), and ACCESS through allocation TG-CHE180056. ADDITIONAL INFORMATION Affiliations: School of Chemistry, University of Bristol, Cantock's Close, Bristol, BS8 1TS, UK; Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523-1872, USA. DATA AVAILABILITY The X-ray crystallographic coordinates for structures 3d, 5p, 6p and 8a reported in this study have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition numbers 2520219–2520222. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. All other data are available in the main text or the supplementary information. AUTHOR CONTRIBUTIONS Z-X.Z., J.L.T., and V.K.A. conceived the project; V.K.A. directed the research; Z-X.Z., M.V.P., J.L.T., R.S.P. and V.K.A. prepared the manuscript; Z-X.Z., K.S. and YH.G. performed the experimental work; M.V.P. carried out the computational analysis, supervised by R.S.P. All authors analysed the results. CORRESPONDING AUTHOR Correspondence to [email protected] and [email protected] COMPETING INTERESTS STATEMENT The authors declare no competing interests. References Shearer, J., Castro, J. L., Lawson, A. D. 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Biotechnol. 235 , 32-46 (2016). Strieth-Kalthoff, F. & Glorius, F. Triplet Energy Transfer Photocatalysis: Unlocking the Next Level. Chem. 6 , 1888-1903 (2020). Dutta, S., Erchinger, J. E., Strieth-Kalthoff, F., Kleinmans, R. & Glorius, F. Energy transfer photocatalysis: exciting modes of reactivity. Chem. Soc. Rev. 53 , 1068-1089 (2024). Birks, J. B. Excimers and Exciplexes. Nature 214 , 1187-1190 (1967). Peters, M. et al. The PDE4 Inhibitor HT-0712 Improves Hippocampus-Dependent Memory in Aged Mice. Neuropsychopharmacology 39 , 2938-2948 (2014). Zhong, F., Yue, W.-J., Yin, X.-H., Zhang, H.-M. & Yin, L. Copper(I)-Catalyzed Asymmetric Synthesis of α-Allenylamines and β-Lactams through Regioselective Mannich-Type Reactions. ACS Catal. 12 , 9181-9189 (2022). Hughes, W., Popescu, M. & Paton, R. Fundamental Study of Density Functional Theory Applied to Triplet State Reactivity: Introduction of the TRIP50 Dataset. ChemRxiv (2025). DOI: 10.26434/chemrxiv-2025-zfrhn. Popescu, M. V. & Paton, R. S. Dynamic vertical triplet energies: Understanding and predicting triplet energy transfer. Chem. 10 , 3428-3443 (2024). Popescu, M. V. et al. Photocatalysis as a mechanistic probe for the Staudinger β-lactam synthesis. Chem Catalysis 5 , 101493 (2025). Blokker, E., ten Brink, M., van der Schuur, J. M., Hamlin, T. A. & Bickelhaupt, F. M. Origin of the Captodative Effect: The Lone-Pair Shielded Radical. ChemistryEurope 1 , e202300006 (2023). Viehe, H. G., Janousek, Z., Merenyi, R. & Stella, L. The captodative effect. Acc. Chem. Res. 18 , 148-154 (1985). Additional Declarations There is NO Competing Interest. Supplementary Files Crystallographicdataforcompound3d.cif Crystallographic data for compound 3d structurefactorofcompouond5p.txt structure factor of compouond 5p checkcif.pdf Check cif ComputSIchangedJLT.pdf Comput_SI_changed_JLT Crystallographicdataforcompound8a.cif Crystallographic data for compound 8a structurefactorofcompouond6p.txt structure factor of compouond 6p Crystallographicdataforcompound6p.cif Crystallographic data for compound 6p structurefactorofcompouond8a.txt structure factor of compouond 8a SIProject2zexin23.pdf SI-Project2-ze-xin-23 structurefactorofcompouond3d.txt structure factor of compouond 3d Crystallographicdataforcompound5p.cif Crystallographic data for compound 5f GA.png Graphical Abstract Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8681610","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":602005756,"identity":"7663dd43-d04a-4b38-ada1-2b8e14a9b35e","order_by":0,"name":"Varinder Aggarwal","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABCElEQVRIiWNgGAWjYFADduZjDAwGIAaEb0BYCzNbGkidBAMz8Vp4zEAUYS0GB5gfv/xScy+xv5nn2+OKgro6fmYGxg8/GA4b49bCZmYtc6w4ccZh3u2GZwwOS0g2MzBL9jAcNsOlRbKBwcxYgi0ht+Ew7zbJBoMDEgaHGRikGRgO2+DWwv7NWOJfQu78wzzPgFrqQFqYf+PTws/AY/zwY1tC7obDPGxALcwgLWwgW3A6jJ+Zp4yZsS+hfuNhNnPDBoPDkjObGdssewzScXqfjb1988cf3xKM5Y43P3vY8KeOn5+9+fCNHxXWhg249DADncGDKsTYQCgimT/+wCs/CkbBKBgFIx4AAFl4TTleBgt0AAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0003-0344-6430","institution":"Bristol University","correspondingAuthor":true,"prefix":"","firstName":"Varinder","middleName":"","lastName":"Aggarwal","suffix":""},{"id":602005757,"identity":"199a6395-ed23-4ca6-835e-3e7f134223fe","order_by":1,"name":"Ze-Xin Zhang","email":"","orcid":"https://orcid.org/0000-0001-5515-0266","institution":"Bristol University","correspondingAuthor":false,"prefix":"","firstName":"Ze-Xin","middleName":"","lastName":"Zhang","suffix":""},{"id":602005758,"identity":"7ef69a63-022c-471a-91d9-80e06436e4ed","order_by":2,"name":"KaiChen Shu","email":"","orcid":"https://orcid.org/0009-0000-6370-7757","institution":"Bristol University","correspondingAuthor":false,"prefix":"","firstName":"KaiChen","middleName":"","lastName":"Shu","suffix":""},{"id":602005759,"identity":"b9ce390d-8e32-4d88-af5a-cadb89c77285","order_by":3,"name":"Mihai Popescu","email":"","orcid":"https://orcid.org/0000-0001-8565-7201","institution":"Colorado State University","correspondingAuthor":false,"prefix":"","firstName":"Mihai","middleName":"","lastName":"Popescu","suffix":""},{"id":602005760,"identity":"3db205fe-4962-49fc-a124-de481bb179a7","order_by":4,"name":"Yiheng Guo","email":"","orcid":"","institution":"Bristol University","correspondingAuthor":false,"prefix":"","firstName":"Yiheng","middleName":"","lastName":"Guo","suffix":""},{"id":602005761,"identity":"2c1ec6b0-ecbb-4dc6-bbf3-2aab3b925b87","order_by":5,"name":"Jasper Tyler","email":"","orcid":"","institution":"Bristol University","correspondingAuthor":false,"prefix":"","firstName":"Jasper","middleName":"","lastName":"Tyler","suffix":""},{"id":602005762,"identity":"4621517b-0ef8-475a-bc7f-7a7d6fac59e5","order_by":6,"name":"Robert Paton","email":"","orcid":"https://orcid.org/0000-0002-0104-4166","institution":"Colorado State University","correspondingAuthor":false,"prefix":"","firstName":"Robert","middleName":"","lastName":"Paton","suffix":""}],"badges":[],"createdAt":"2026-01-23 17:41:19","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8681610/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8681610/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":104210406,"identity":"a337b81b-3db8-442f-8357-1d05121c3201","added_by":"auto","created_at":"2026-03-09 07:43:03","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":491765,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThe “rule-of-five” in radical cyclisation reactions and programmable access to rigid bicyclic scaffolds. A\u003c/strong\u003e, Bicyclo[2.1.1]hexanes as saturated bioisosteres of aromatic rings in pharmaceuticals. \u003cstrong\u003eB\u003c/strong\u003e, The “rule-of-five”: kinetic preference for 5-\u003cem\u003eexo\u003c/em\u003e-trig cyclisation and the challenges associated with the alternative 6-\u003cem\u003eendo\u003c/em\u003e-trig pathway. \u003cstrong\u003eC\u003c/strong\u003e, This work: Programmable control of cyclisation pathways enables divergent access to [2.1.1] and [2.2.0] scaffolds. BCH = bicyclo[2.1.1]hexane; Sol: kinetic solubility in phosphate-buffered saline, pH 7.4 (μM); CL\u003csub\u003eint\u003c/sub\u003e: intrinsic clearance in human liver microsomes (μL min\u003csup\u003e-1 \u003c/sup\u003emg\u003csup\u003e-1\u003c/sup\u003e); EnT = energy transfer; k = rate constant.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8681610/v1/c77e87a2a860e63d0ab6788a.png"},{"id":104404226,"identity":"84254be4-9450-4d02-8b01-85b1e4c7902c","added_by":"auto","created_at":"2026-03-11 12:19:53","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":581041,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eElectronic control of cyclisation selectivity and reaction optimisation study. A\u003c/strong\u003e,\u003cstrong\u003e \u003c/strong\u003eElectronic tuning of nitrogen substituent governs 5-\u003cem\u003eexo\u003c/em\u003e/6-\u003cem\u003eendo\u003c/em\u003e cyclisation selectivity. Ratios were determined by quantitative \u003csup\u003e1\u003c/sup\u003eH NMR spectroscopy of the crude reaction mixtures. \u003cstrong\u003eB\u003c/strong\u003e,\u003cstrong\u003e \u003c/strong\u003eOptimisation of reaction parameters for selective cyclisation. The yields were determined by quantitative \u003csup\u003e1\u003c/sup\u003eH NMR spectroscopy of the crude reaction mixture using CH\u003csub\u003e2\u003c/sub\u003eBr\u003csub\u003e2\u003c/sub\u003e as the internal standard. The yields in parentheses are of isolated products. \u003csup\u003ea\u003c/sup\u003e\u0026nbsp;Under 390 nm LED irradiation. E\u003csub\u003e1/2 \u003c/sub\u003e=\u003csub\u003e \u003c/sub\u003ehalf-wave potential; E\u003csub\u003eT = \u003c/sub\u003etriplet energy; ppy = 2-phenylpyridine; dtbbpy = 4,4′-di-\u003cem\u003etert\u003c/em\u003e-butyl-2,2′-bipyridine; PMB = \u003cem\u003ep\u003c/em\u003e-methoxybenzyl; Bn = benzyl; Boc = \u003cem\u003etert\u003c/em\u003e-butyloxycarbonyl; Cbz = benzyloxycarbonyl; Ac = acetyl; Troc = 2,2,2-trichloroethoxycarbonyl; THF = tetrahydrofuran; DCM = dichloromethane.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-8681610/v1/05c2ec02c0fe82b46d65f242.png"},{"id":104210415,"identity":"e4a650a3-89f0-45dc-88e2-5d1632e4893e","added_by":"auto","created_at":"2026-03-09 07:43:03","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":634985,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSubstrate scope of bicyclo[2.1.1]hexane\u003c/strong\u003e \u003cstrong\u003esynthesis\u003c/strong\u003e. Reactions were performed using 1 mol% [Ir(dF[CF\u003csub\u003e3\u003c/sub\u003e]ppy)\u003csub\u003e2\u003c/sub\u003e(dtbbpy)]PF\u003csub\u003e6\u003c/sub\u003e in MeCN (0.1 M) under blue LED (427 nm) irradiation for 1.5 h. Yields are of isolated products. Bn = benzyl; PMB = \u003cem\u003ep\u003c/em\u003e-methoxybenzyl; Boc = \u003cem\u003etert\u003c/em\u003e-butyloxycarbonyl; Ts = \u003cem\u003ep\u003c/em\u003e-toluenesulfonyl; Oxone = potassium peroxymonosulfate; TFA = trifluoroacetic acid.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-8681610/v1/b4ddabe2b6b439133dfc70aa.png"},{"id":104210422,"identity":"c1e8116e-739e-4654-8223-bda6c4e02c4b","added_by":"auto","created_at":"2026-03-09 07:43:05","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":760969,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSubstrate scope of bicyclo[2.2.0]hexane\u003c/strong\u003e \u003cstrong\u003esynthesis\u003c/strong\u003e. Reactions were performed using 1 mol% [Ir(dF[CF\u003csub\u003e3\u003c/sub\u003e]ppy)\u003csub\u003e2\u003c/sub\u003e(dtbbpy)]PF\u003csub\u003e6\u003c/sub\u003e in MeCN (0.1 M) under blue LED (427 nm) irradiation for 1.5 h. Yields are of isolated products, while the ratios in square brackets represent the molar ratio of the [2.2.0] to [2.1.1] frameworks, as determined by quantitative \u003csup\u003e1\u003c/sup\u003eH NMR spectroscopy of the crude reaction mixture. \u003csup\u003ea\u003c/sup\u003e Reaction conducted on gram scale with 0.5 mol% [Ir(dF[CF\u003csub\u003e3\u003c/sub\u003e]ppy)\u003csub\u003e2\u003c/sub\u003e(dtbbpy)]PF\u003csub\u003e6\u003c/sub\u003e. \u003csup\u003eb\u003c/sup\u003e Reactions performed with HFIP (0.1 M). \u003csup\u003ec\u003c/sup\u003e\u0026nbsp;Benzophenone (25 mol%) was used as the photocatalyst under 370 nm LED irradiation. \u003csup\u003ed\u003c/sup\u003e Formed as a single diastereomer. Ac = acetyl; Bn = benzyl; Boc = \u003cem\u003etert\u003c/em\u003e-butyloxycarbonyl; \u003cem\u003ei\u003c/em\u003e-Pr = \u003cem\u003eiso-\u003c/em\u003epropyl; \u003cem\u003et\u003c/em\u003e-Bu = \u003cem\u003etert\u003c/em\u003e-butyl; TIPS = triisopropylsilyl; HFIP = hexafluoroisopropanol.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-8681610/v1/63a63fc3b94c917e2b63fd37.png"},{"id":104210413,"identity":"c88e2480-c44c-4ed0-9c73-ad75798a7788","added_by":"auto","created_at":"2026-03-09 07:43:03","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":266972,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eProduct diversification study. \u003c/strong\u003e(a) \u003cem\u003en\u003c/em\u003e-BuLi, phenyl isocyanate; (b) \u003cem\u003en\u003c/em\u003e-BuLi, phenyl isothiocyanate; (c) \u003cem\u003en\u003c/em\u003e-BuLi, MsCl; (d) NaH, BnCl; (e) NaH, 1-fluoro-2,4-dinitrobenzene; (f) oxalyl chloride, then Et\u003csub\u003e3\u003c/sub\u003eN, 2-(piperazin-1-yl)quinoline; (g) oxalyl chloride, then NH\u003csub\u003e2\u003c/sub\u003eOMe·HCl, NaHCO\u003csub\u003e3\u003c/sub\u003e; (h) \u003cem\u003eN\u003c/em\u003e–hydroxyphthalimide (NHPI), \u003cem\u003eN\u003c/em\u003e,\u003cem\u003eN\u003c/em\u003e′-diisopropylcarbodiimide (DIC), 4-dimethylaminopyridine (DMAP). Ac = acetyl; Boc = \u003cem\u003etert\u003c/em\u003e-butoxycarbonyl; Ms = methanesulfonyl.\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-8681610/v1/7c51af752ba6c12d1ac98b99.png"},{"id":104210419,"identity":"63080b00-62b9-4bb6-b44e-b5262329aed6","added_by":"auto","created_at":"2026-03-09 07:43:05","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":608747,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eComputed reaction mechanism\u003c/strong\u003e. \u003cstrong\u003eA\u003c/strong\u003e, Gibbs energy surface for the triplet cyclisation of \u003cstrong\u003e2f\u003c/strong\u003e (\u003csup\u003e\u003cstrong\u003e1\u003c/strong\u003e\u003c/sup\u003e\u003cstrong\u003eA\u003c/strong\u003e)\u003cstrong\u003e \u003c/strong\u003ecomputed at the Pr2SCAN50-D4/def2-TZVPPD,(SMD=MeCN)//M06-2X-D3/6-31+G(d,p),(SMD=MeCN) level of theory. \u003cstrong\u003eB\u003c/strong\u003e, Computed values of ∆∆G\u003csup\u003e‡\u003c/sup\u003e (\u003csup\u003e\u003cstrong\u003e3\u003c/strong\u003e\u003c/sup\u003e\u003cstrong\u003eTS-I\u003c/strong\u003e/\u003csup\u003e\u003cstrong\u003e3\u003c/strong\u003e\u003c/sup\u003e\u003cstrong\u003eTS-II\u003c/strong\u003e) for a series of substrates are highly correlated with experimentally derived values. \u003cstrong\u003eC\u003c/strong\u003e, Spin density plots of key biradicaloid transition structures illustrate the radical nature of \u003csup\u003e\u003cstrong\u003e1\u003c/strong\u003e\u003c/sup\u003e\u003cstrong\u003eTS-III\u003c/strong\u003e and \u003csup\u003e\u003cstrong\u003e1\u003c/strong\u003e\u003c/sup\u003e\u003cstrong\u003eTS-IV\u003c/strong\u003e. MECP = minimum energy crossing point.\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-8681610/v1/570ca058a4d51baafdf764b8.png"},{"id":104405135,"identity":"af9304d7-3eee-47d2-953f-9466da646c38","added_by":"auto","created_at":"2026-03-11 12:21:54","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":1115142,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eComputational investigations on the origin of selectivity\u003c/strong\u003e. \u003cstrong\u003eA\u003c/strong\u003e, Selectivity-determining steps showing reversal of selectivity for N–Bn and N–Ac systems, together with the key TSs. \u003cstrong\u003eB\u003c/strong\u003e, IRCs of \u003csup\u003e\u003cstrong\u003e3\u003c/strong\u003e\u003c/sup\u003e\u003cstrong\u003eTS-I/II-Ac\u003c/strong\u003e with the forming C–C bond lengths. \u003cstrong\u003eC\u003c/strong\u003e, The 5-\u003cem\u003eexo\u003c/em\u003e pathway is characterised by much greater planarity (ϕ\u003csub\u003e2\u003c/sub\u003e = C-C-N-C dihedral angle) in the TS and along the reaction coordinate than the 6-\u003cem\u003eendo\u003c/em\u003e pathway. \u003cstrong\u003eD\u003c/strong\u003e, Hammett correlation of computed activation barriers: greater structural planarity in the 5-\u003cem\u003eexo\u003c/em\u003e TS makes this pathway (blue) more sensitive to electronic effects. IRC = intrinsic reaction coordinate.\u003c/p\u003e","description":"","filename":"7.png","url":"https://assets-eu.researchsquare.com/files/rs-8681610/v1/a29bb6ddd59127c95afffc70.png"},{"id":104409148,"identity":"42a3b5e4-3558-4025-969b-c8e2251045b6","added_by":"auto","created_at":"2026-03-11 12:44:15","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":4851215,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8681610/v1/f14dcb66-511b-4363-a752-dc6d4d4a1276.pdf"},{"id":104210410,"identity":"e959df73-b73d-431f-9662-317b6c01ab52","added_by":"auto","created_at":"2026-03-09 07:43:03","extension":"cif","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":429841,"visible":true,"origin":"","legend":"Crystallographic data for compound 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6p","description":"","filename":"Crystallographicdataforcompound6p.cif","url":"https://assets-eu.researchsquare.com/files/rs-8681610/v1/d2183a3f99584c046bd56276.cif"},{"id":104210416,"identity":"927d22d6-d110-4a13-a59e-d03430d58360","added_by":"auto","created_at":"2026-03-09 07:43:03","extension":"txt","order_by":8,"title":"","display":"","copyAsset":false,"role":"supplement","size":1248114,"visible":true,"origin":"","legend":"structure factor of compouond 8a","description":"","filename":"structurefactorofcompouond8a.txt","url":"https://assets-eu.researchsquare.com/files/rs-8681610/v1/97640088a33fb89342f2f473.txt"},{"id":104210414,"identity":"580ece8a-cdbd-411a-8782-6f61fde622bd","added_by":"auto","created_at":"2026-03-09 07:43:03","extension":"pdf","order_by":9,"title":"","display":"","copyAsset":false,"role":"supplement","size":22782302,"visible":true,"origin":"","legend":"SI-Project2-ze-xin-23","description":"","filename":"SIProject2zexin23.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8681610/v1/42630751510046333164d690.pdf"},{"id":104210426,"identity":"309d8e7a-4cdd-416e-87ea-70ba026c87ec","added_by":"auto","created_at":"2026-03-09 07:43:06","extension":"txt","order_by":10,"title":"","display":"","copyAsset":false,"role":"supplement","size":407429,"visible":true,"origin":"","legend":"structure factor of compouond 3d","description":"","filename":"structurefactorofcompouond3d.txt","url":"https://assets-eu.researchsquare.com/files/rs-8681610/v1/331f440135b46ed469957614.txt"},{"id":104210417,"identity":"d3688b1d-69eb-40e3-9d22-6cdaccc38c01","added_by":"auto","created_at":"2026-03-09 07:43:04","extension":"cif","order_by":11,"title":"","display":"","copyAsset":false,"role":"supplement","size":452276,"visible":true,"origin":"","legend":"Crystallographic data for compound 5f","description":"","filename":"Crystallographicdataforcompound5p.cif","url":"https://assets-eu.researchsquare.com/files/rs-8681610/v1/5ce68f15dc0d6144bea4bfd6.cif"},{"id":104210412,"identity":"35abc01d-bdad-47c3-a17a-0b232b3b33f4","added_by":"auto","created_at":"2026-03-09 07:43:03","extension":"png","order_by":12,"title":"","display":"","copyAsset":false,"role":"supplement","size":47877,"visible":true,"origin":"","legend":"\u003cp\u003eGraphical Abstract\u003c/p\u003e","description":"","filename":"GA.png","url":"https://assets-eu.researchsquare.com/files/rs-8681610/v1/ec252907a7ecc38fc0da600d.png"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Programmable Regiodivergent Light-Driven Cyclisation of Acyclic 1,5-Dienes Unlocks Rigid Bicyclic Architectures","fulltext":[{"header":"Introduction","content":"\u003cp\u003eSince the discovery of benzene over 200 years ago, the pharmaceutical landscape has been dominated by aromatic rings\u003csup\u003e1\u003c/sup\u003e, but there is growing awareness of the success of more structurally complex, three-dimensional scaffolds that better mimic the intricacies of biological targets\u003csup\u003e2-4\u003c/sup\u003e. This has created an urgent need for novel architectures, particularly rigid, saturated, and metabolically stable ring systems, that can evade enzymatic degradation. Rigid, three-dimensional scaffolds with well-defined exit vectors can not only improve binding specificity by reducing entropic penalties but also enhance solubility, reduce off-target effects, and improve pharmacokinetic properties\u003csup\u003e2-4\u003c/sup\u003e. A growing body of evidence demonstrates that rigid fragments, such as bicyclo[2.1.1]hexane (BCH), function as effective bioisosteres of substituted benzene rings, often conferring substantial improvements in physicochemical and biological profiles\u003csup\u003e2-6\u003c/sup\u003e. For example, the reported BCH analogues of Axitinib\u003csup\u003e7\u003c/sup\u003e and Conivaptan\u003csup\u003e8\u003c/sup\u003e exhibit enhanced solubility, increased metabolic stability, and preserved or improved potency, underscoring the privileged nature of this rigid, saturated scaffold (Figure 1A). Despite these advantages, the synthetic inaccessibility of this and other related frameworks has hindered their adoption in drug discovery. Current strategies to access rigid bicyclic motifs typically rely on strain-release functionalisation of preassembled frameworks such as bicyclo[1.1.0]butane, [1.1.1]propellane, or [3.1.1]propellane\u003csup\u003e4,5,9\u003c/sup\u003e. While effective, these approaches intrinsically restrict the substitution patterns that can be accessed, thereby limiting the potential for late‑stage diversification. A far more powerful paradigm would be to start from a single, modular acyclic precursor and, through subtle changes, selectively generate distinct rigid frameworks.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe photochemistry of acyclic 1,5-dienes provides a suitable platform to study this type of divergent synthesis\u003csup\u003e4,7,9-13\u003c/sup\u003e; a process that has been previously leveraged in the creation of carbocyclic and, more recently, azacyclic scaffolds bearing the [2.1.1] framework\u003csup\u003e14-16\u003c/sup\u003e. In these cases, bridged [2.1.1] products are exclusively formed since, according to the established \u0026ldquo;rule-of-five\u0026rdquo;\u003csup\u003e17-19\u003c/sup\u003e, 5\u003cem\u003e-exo\u003c/em\u003e-trig cyclisation dominates over the alternative 6\u003cem\u003e-endo-\u003c/em\u003etrig (or 4\u003cem\u003e-exo\u003c/em\u003e-trig) cyclisation, which would lead to the alternative fused [2.2.0] products (Figure 1B). This effect arises from the markedly unfavourable orbital alignment of the 6\u003cem\u003e-endo\u003c/em\u003e-trig pathway, rendering it \u0026gt;50-fold slower than the competing 5-\u003cem\u003eexo\u003c/em\u003e-trig closure\u003csup\u003e20\u003c/sup\u003e. In addition, even if the 6-\u003cem\u003eendo\u003c/em\u003e cyclisation were to occur, the subsequent 1,4-biradical recombination would still have to overcome substantial transannular strain and bridgehead compression, making the subsequent C\u0026ndash;C bond-forming step towards the [2.2.0] framework equally unfavourable\u003csup\u003e21,22\u003c/sup\u003e. This ring-closure preference is also observed in related 1,6-diene systems, where 5-\u003cem\u003eexo\u003c/em\u003e-trig cyclisations are kinetically favoured over 6-\u003cem\u003eexo\u003c/em\u003e-trig cyclisations, typically affording fused [2.3.0] frameworks. Despite this, we recently demonstrated that for hex-5-enal oximes, this intrinsic 5-\u003cem\u003eexo\u003c/em\u003e-trig bias can be overridden, leading instead to bridged [3.1.1] bicyclic architectures\u003csup\u003e23\u003c/sup\u003e. However, overriding 5-\u003cem\u003eexo\u003c/em\u003e-trig cyclisation in favour of the much less favourable 6-\u003cem\u003eendo\u003c/em\u003e-trig cyclisation is highly uncommon, underscoring the significant mechanistic challenge associated with breaking the \u0026ldquo;rule-of-five\u0026rdquo; selectivity for 1,5-dienes.\u003c/p\u003e\n\u003cp\u003eAs a result, access to [2.2.0] scaffolds from simple 1,5-dienes has been considered effectively unattainable, despite it representing a highly strained and rigid framework of potential pharmacological value\u003csup\u003e24-27\u003c/sup\u003e. The only reported synthetic strategy to access aza-[2.2.0] ring systems relies on UV-light-promoted 4\u0026pi; electrocyclisation, a transformation that is severely limited with respect to the attainable substitution patterns\u003csup\u003e24,28,29\u003c/sup\u003e. Accordingly, the development of a strategy that enables pathway-controlled, selective construction of either the rule-breaking [2.2.0] or the rule-compliant [2.1.1] bicyclic framework from acyclic 1,5-dienes would be of substantial significance in synthetic methodology; however, such a capability has not yet been realised.\u0026nbsp;\u003c/p\u003e\u003cp\u003eHerein, we report that through precise electronic tuning of the nitrogen atom in a class of amide-tethered 1,5-diene precursors, we can successfully divert the reactivity from the classically favoured 5-\u003cem\u003eexo\u003c/em\u003e-trig towards the rarely observed 6\u003cem\u003e-endo-\u003c/em\u003etrig pathway\u003csup\u003e30\u003c/sup\u003e, breaking the \u0026ldquo;rule-of-five\u0026rdquo; paradigm. Through employing an essentially common intermediate, either bridged [2.1.1] or fused [2.2.0] skeletons can be accessed selectively, providing synthetic chemists with a unified methodology for generating structurally diverse building blocks. The rigid, three-dimensional \u0026beta;-lactam-like\u003csup\u003e31\u003c/sup\u003e architecture and hydrogen-bonding capacity of these products underscore their potential for biological applications\u003csup\u003e32\u003c/sup\u003e. Furthermore, the rich downstream chemistry enabled by these scaffolds further highlights their synthetic utility in the construction of structurally complex molecules.\u003c/p\u003e\n"},{"header":"RESULTS AND DISCUSSION","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eReaction design and optimisation\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOur reaction design was guided by the hypothesis that an amide-tethered 1,5-diene could bias the initial radical addition towards the \u0026beta;-position of the enamide through polarity matching, thereby opening access to the typically disfavoured \u003cem\u003e6-endo\u003c/em\u003e pathway. Therefore, we subjected \u003cem\u003eN\u003c/em\u003e\u0026ndash;alkylated substrate\u003cstrong\u003e\u0026nbsp;1a\u003c/strong\u003e (R = \u003cem\u003ep-\u003c/em\u003emethoxybenzyl) to [Ir(dF[CF\u003csub\u003e3\u003c/sub\u003e]ppy)\u003csub\u003e2\u003c/sub\u003e(dtbbpy)]PF\u003csub\u003e6\u003c/sub\u003e (1 mol%) under 427 nm irradiation in MeCN. Under these conditions, we observed that the formation of [2.1.1] product \u003cstrong\u003e3a\u003c/strong\u003e, arising from the 5-\u003cem\u003eexo\u003c/em\u003e-trig pathway, dominated the reactivity (Figure 2A). Despite this, we were encouraged by the detection of an unstable 3,4-dihydro-2-pyridone byproduct \u003cstrong\u003e4a\u003c/strong\u003e (0.73:0.27 ratio), which presumably forms via an initial 6-\u003cem\u003eendo\u003c/em\u003e cyclisation event. However, the inability of the 6-\u003cem\u003eendo\u003c/em\u003e radical addition intermediate to undergo the desired recombination to the targeted [2.2.0] product demonstrates the challenges associated with synthesising these frameworks.\u003c/p\u003e\n\u003cp\u003eTo probe the influence of the nitrogen-appended substituent on cyclisation outcome, we synthesised a series of amide-tethered 1,5-dienes with varying electronic properties (\u003cstrong\u003e1a-b\u003c/strong\u003e, \u003cstrong\u003e2a-e\u003c/strong\u003e).\u0026nbsp;Remarkably, we observed that as the electron-withdrawing capacity of the substituent increased, the selectivity of the reaction completely switched from 5-\u003cem\u003eexo\u003c/em\u003e-trig to favouring the 6-\u003cem\u003eendo\u003c/em\u003e-trig pathway (Figure 2A, PMB \u0026rarr; Bn \u0026rarr; Boc \u0026rarr; Cbz \u0026rarr; CO\u003csub\u003e2\u003c/sub\u003ePh \u0026rarr; Ac \u0026rarr; Troc). More importantly, upon acylation of the nitrogen tether, radical recombination to generate the fused 4,4-ring system became feasible, allowing us to obtain the rarely observed [2.2.0] scaffold as the major product (see below for mechanistic discussion). This highly unexpected trend in selectivity clearly demonstrates that fine-tuning the electronic properties of the nitrogen substituent enables precise control over the reaction pathway, allowing for the selective construction of distinct bridged architectures.\u003c/p\u003e\n\u003cp\u003eWith this in mind, we then further probed the reaction conditions in an effort to obtain a deeper understanding of this unique system, as well as to identify a single protocol that could deliver both [2.1.1] and [2.2.0] products upon judicious choice of the substrate.\u0026nbsp;We first examined the influence of\u003c/p\u003e\n\u003cp\u003ethe photocatalyst. The yields of \u003cstrong\u003e3c\u003c/strong\u003e and \u003cstrong\u003e6f\u003c/strong\u003e correlated closely with the triplet energy of the sensitiser but showed no dependence on redox potentials, supporting an energy-transfer (EnT), rather than a photoredox mechanism (Figure 2B, left)\u003csup\u003e33,34\u003c/sup\u003e. Additionally, both \u003cem\u003eN\u003c/em\u003e\u0026ndash;Bn and \u003cem\u003eN\u003c/em\u003e\u0026ndash;Ac systems display minimal dependence on solvent polarity, consistent with a neutral EnT process rather than a mechanism involving charge separation (Figure 2B, right)\u003csup\u003e35\u003c/sup\u003e. Furthermore, performing the reaction in the absence of the photocatalyst and light revealed that these elements were necessary to promote reactivity. Exploration of reaction time revealed that the transformation reaches completion within 15\u0026ndash;30 minutes, and that yield was largely independent of concentration. Collectively, these observations highlight the intrinsic robustness of the reaction, which operates efficiently over a broad range of solvents, times, and concentrations without loss of performance.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eNevertheless, to maintain consistency across substrates with differing solubilities, we adopted a 0.1 M concentration and 1.5 h irradiation time for all subsequent studies.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eSubstrate scope\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBuilding on the discovery of programmable cyclisation regiodivergence, we explored the substrate scope with respect to both pathways. To target the [2.1.1] scaffold, a series of \u003cem\u003eN\u003c/em\u003e\u0026ndash;Bn 1,5-dienes was employed under our standard conditions (Figure 3). A variety of \u003cem\u003eC\u003c/em\u003e-2 aryl-substituted precursors, encompassing electron-rich, electron-neutral, and electron-deficient arenes (\u003cstrong\u003e3b-3i\u003c/strong\u003e), were readily transformed to the desired bridged products. Interestingly, the yield of the [2.1.1] scaffold correlated with the electronic nature of the aryl substituent: substrates bearing electron-deficient aryl groups (\u003cstrong\u003e3b-3e\u003c/strong\u003e) generally afforded the [2.1.1] product in higher yields compared to those with electron-rich aryl substituents (\u003cstrong\u003e3h\u003c/strong\u003e, \u003cstrong\u003e3i\u003c/strong\u003e). Given that the intrinsically unstable six-membered-ring species (\u003cstrong\u003e4\u003c/strong\u003e) arising from the 6\u003cem\u003e-endo\u003c/em\u003e pathway (for \u003cem\u003eN\u003c/em\u003e\u0026ndash;alkyl substrates, Figure 2A) could typically be observed as a minor component of the reaction, we hypothesise that this decrease in [2.1.1] product yield likely reflects a shift in pathway selectivity driven by changes in \u003cem\u003eC\u003c/em\u003e-2 electronics. Specifically, whereas electron-deficient aryl substituents favour the 5-\u003cem\u003eexo\u003c/em\u003e-trig cyclisation, electron-rich aryl groups promote the 6-\u003cem\u003eendo-\u003c/em\u003etrig closure (see below for further discussion). With respect to the nitrogen substituent, \u003cem\u003ep-\u003c/em\u003emethoxybenzyl (\u003cstrong\u003e3a\u003c/strong\u003e) and \u003cem\u003ep-\u003c/em\u003emethoxyphenyl (\u003cstrong\u003e3j\u003c/strong\u003e) groups were well tolerated. Importantly, debenzylation of \u003cstrong\u003e3c\u003c/strong\u003e could be achieved under mild conditions to access the corresponding N\u0026ndash;H substrate \u003cstrong\u003e3c\u0026rsquo;\u003c/strong\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWith respect to \u003cem\u003eC\u003c/em\u003e-5 substitution, a series of 5-CF\u003csub\u003e3\u003c/sub\u003e-BCH analogues could be prepared in comparable yields to their 5-Me counterparts (\u003cstrong\u003e3k-3p\u003c/strong\u003e). Additionally, the trend associated with aryl electronic effects remained consistent: electron-deficient aryl groups exhibited a higher propensity for the formation of the [2.1.1] product via a 5-\u003cem\u003eexo\u003c/em\u003e-trig pathway. Furthermore, 5-H-BCH (\u003cstrong\u003e3q\u003c/strong\u003e) and 5-Ph-BCH (\u003cstrong\u003e3r\u003c/strong\u003e) products could be obtained in moderate yields. When inverting the position of the amide tether, we observed that these substrates (4-aza-1,5-dienes, \u003cstrong\u003e7\u003c/strong\u003e) uniformly furnished the corresponding [2.1.1] scaffolds (\u003cstrong\u003e8a-8h\u003c/strong\u003e) in good to excellent yields. Here, no evidence of 6-\u003cem\u003eendo\u003c/em\u003e-trig cyclisation was detected, likely a consequence of the 6-\u003cem\u003eendo\u003c/em\u003e pathway now involving a polarity-mismatched radical addition. Importantly, we demonstrated that the selective cleavage of either the amide \u003cem\u003eN\u003c/em\u003e\u0026ndash;substituent (\u003cstrong\u003e8a\u0026rsquo;\u003c/strong\u003e) or the internal amide bond (\u003cstrong\u003e8a\u0026rsquo;\u0026rsquo;\u003c/strong\u003e) could be achieved under acidic and basic conditions, respectively.\u003c/p\u003e\n\u003cp\u003eWe next investigated the scope of [2.2.0] synthesis by employing the analogous \u003cem\u003eN\u003c/em\u003e\u0026ndash;electron-withdrawing 1,5-dienes \u003cstrong\u003e2\u003c/strong\u003e (Figure 4). As expected based on our previous experiments, examination of the \u003cem\u003eC\u003c/em\u003e-2 aryl substituent (\u003cstrong\u003e6d\u003c/strong\u003e, \u003cstrong\u003e6f-6p\u003c/strong\u003e) revealed a strong correlation between product distribution and aryl electronics: electron-rich aryl groups promoted the 6-\u003cem\u003eendo\u003c/em\u003e-trig pathway with excellent levels of selectivity (\u003cstrong\u003e6g-6k\u003c/strong\u003e), while electron-deficient aryl groups (\u003cstrong\u003e6d\u003c/strong\u003e,\u003cstrong\u003e\u0026nbsp;6o\u003c/strong\u003e,\u003cstrong\u003e\u0026nbsp;6p\u003c/strong\u003e) partially eroded this preference. The lower selectivity observed with electron-deficient aryl groups (\u003cstrong\u003e6d\u003c/strong\u003e,\u003cstrong\u003e\u0026nbsp;6o\u003c/strong\u003e,\u003cstrong\u003e\u0026nbsp;6p\u003c/strong\u003e) encouraged us to explore alternative conditions to see if we could override this substrate-dependent regioselectivity. Specifically, we discovered that replacing MeCN with hexafluoroisopropanol (HFIP) as the reaction solvent significantly increased the ratio of 6-\u003cem\u003eendo\u003c/em\u003e to 5-\u003cem\u003eexo\u003c/em\u003e products, presumably a result of partial polarisation of the enone via hydrogen bonding, providing a more polarity-matched 6-\u003cem\u003eendo\u003c/em\u003e pathway. Heteroaryl substituents of varying electronic character (\u003cstrong\u003e6q-6t\u003c/strong\u003e) followed the same trend and consistently afforded the [2.2.0] scaffold in good to excellent yields. When the aryl substituent at \u003cem\u003eC\u003c/em\u003e-2 was exchanged for an ester group, the strongly electron-withdrawing effect completely switched the outcome, exclusively furnishing the [2.1.1] scaffold (\u003cstrong\u003e5u\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eAs we had initially discovered that altering the substituent at the nitrogen tether had a pronounced impact on regioselectivity, we further explored this electronic effect by employing a range of electron-withdrawing groups. Generally, the stronger the electron-withdrawing nature of the substituent, the more the system favoured cyclisation to the challenging [2.2.0] scaffold (\u003cstrong\u003e6v\u0026ndash;6ab\u003c/strong\u003e). When a sterically hindered pivaloyl group was employed, the reaction delivered an unexpected six-membered-ring species \u003cstrong\u003e9\u003c/strong\u003e in high yield. This outcome can be plausibly attributed to the perpendicular orientation of the pivaloyl carbonyl relative to the six-membered-ring, which predisposes the intermediate formed from the initial 6-\u003cem\u003eendo\u003c/em\u003e-trig cyclisation towards intramolecular acyl transfer. When an enantiomerically enriched carbonyl substituent was employed, the reaction delivered a pair of diastereomeric [2.2.0] products (\u003cstrong\u003e6ad\u003c/strong\u003e and \u003cstrong\u003e6ad\u0026rsquo;\u003c/strong\u003e) which were successfully separated by flash chromatography, providing the potential to access enantioenriched [2.2.0] scaffolds.\u003c/p\u003e\n\u003cp\u003eVarying the group at the \u003cem\u003eC\u003c/em\u003e-5 position revealed that replacing Me with H (\u003cstrong\u003e6ae\u003c/strong\u003e-\u003cstrong\u003e6ag\u003c/strong\u003e) partially increased the contribution of the 5-\u003cem\u003eexo\u003c/em\u003e-trig pathway, presumably due to steric effects. In contrast, bulkier alkyl groups at \u003cem\u003eC\u003c/em\u003e-5 (\u003cstrong\u003e6ah\u003c/strong\u003e, \u003cstrong\u003e6ai\u003c/strong\u003e) were well tolerated, delivering excellent yields and high levels of selectivity. However, the introduction of an aryl group at \u003cem\u003eC\u003c/em\u003e-5 (\u003cstrong\u003e6aj\u003c/strong\u003e), lowered reaction selectivity as both alkene moieties can be photoexcited for this substrate. Substitution at \u003cem\u003eC\u003c/em\u003e-1 could also be achieved, providing \u003cstrong\u003e6ak\u003c/strong\u003e and \u003cstrong\u003e6al\u003c/strong\u003e as a single diastereomer. However, we observed a reversal of selectivity with 6-Me-substituted substrate \u003cstrong\u003e6am\u003c/strong\u003e, where steric congestion at this position disfavours the radical attack required for the 6-\u003cem\u003eendo\u0026nbsp;\u003c/em\u003epathway. To highlight the applicability of this methodology to accessing challenging scaffolds relevant to medicinal chemistry, we applied our 1,5-diene cyclisation strategy to the synthesis of \u003cstrong\u003e6an\u003c/strong\u003e, a [2.2.0] analogue of the \u0026delta;-lactam-containing cognitive enhancer HT-0712.\u003csup\u003e36\u003c/sup\u003e \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eProduct derivatisation\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHaving established that precise electronic tuning of this class of 1,5-dienes can enable the synthesis of challenging to access [2.2.0] scaffolds, we next sought to extend the structural diversity of these frameworks through downstream derivatisation. Deprotection of the nitrogen substituent was first targeted to access the corresponding secondary amide. Treatment of \u003cstrong\u003e6g\u003c/strong\u003e with NaOMe promoted selective cleavage of the \u003cem\u003eN\u003c/em\u003e\u0026ndash;Ac amide bond, presumably due to lower steric hindrance relative to the strained \u0026beta;-lactam, affording \u003cstrong\u003e12\u003c/strong\u003e in 64% yield. This intermediate proved versatile, undergoing high-yielding transformations to give urea (\u003cstrong\u003e14\u003c/strong\u003e), thiourea (\u003cstrong\u003e15\u003c/strong\u003e), sulfonamide (\u003cstrong\u003e16\u003c/strong\u003e), \u003cem\u003eN\u003c/em\u003e\u0026ndash;alkylated (\u003cstrong\u003e17\u003c/strong\u003e), and \u003cem\u003eN\u003c/em\u003e\u0026ndash;arylated derivatives (\u003cstrong\u003e18\u003c/strong\u003e), thereby expanding the scope of functionalities accessible. Treatment of \u003cem\u003eN\u003c/em\u003e\u0026ndash;Boc [2.2.0] species \u003cstrong\u003e6ab\u003c/strong\u003e under basic conditions resulted in selective cleavage of the internal amide bond to afford \u0026beta;-amino acid derivative \u003cstrong\u003e10\u003c/strong\u003e. Further diversification was achieved through RuCl\u003csub\u003e3\u003c/sub\u003e-mediated oxidation of the aryl ring, delivering the corresponding carboxylic acid (\u003cstrong\u003e13\u003c/strong\u003e) in excellent yield. This species was then converted to amide \u003cstrong\u003e19\u003c/strong\u003e, \u003cem\u003eO\u003c/em\u003e-methylhydroxamic acid \u003cstrong\u003e20\u003c/strong\u003e, and redox-active ester derivative \u003cstrong\u003e21\u003c/strong\u003e. Finally, the amide carbonyl within the [2.2.0] core was reduced by Rh-catalysed hydrogenation\u003csup\u003e37\u003c/sup\u003e, furnishing fully saturated 2-\u003cem\u003eN\u003c/em\u003e-[2.2.0] scaffold \u003cstrong\u003e11\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eComputational studies\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo unravel the intricate effects that give rise to the observed programmable cyclisation regioselectivity, we developed a computational model using Density Functional Theory (DFT) at the Pr2SCAN50-D4/def2-TZVPPD,(SMD=MeCN)//M06-2X-D3/6-31+G(d,p),(SMD=MeCN) level of theory, based on recent benchmarking efforts (Figure 6A)\u003csup\u003e38\u003c/sup\u003e. We first verified the feasibility of triplet sensitisation by computing the triplet energy of model substrate \u003cstrong\u003e2f\u0026nbsp;\u003c/strong\u003e(\u003cstrong\u003e\u003csup\u003e1\u003c/sup\u003eA\u003c/strong\u003e). The dynamically vertically accessible triplet energy (DvTE)\u003csup\u003e39\u003c/sup\u003e of 60.8 kcal/mol closely matches that of the most efficient photocatalysts (61\u0026ndash;65 kcal/mol), while the adiabatic triplet energy was found to be 50.9 kcal/mol (\u003cstrong\u003e\u003csup\u003e1\u003c/sup\u003eA\u003c/strong\u003e to \u003cstrong\u003e\u003csup\u003e3\u003c/sup\u003eA\u003c/strong\u003e). Analysis of low-energy triplet geometries showed that the spin density is localised on the styrene motif, identifying it as the primary chromophore, consistent with Stern\u0026ndash;Volmer quenching studies (see SI for details). Upon excitation to \u003cstrong\u003e\u003csup\u003e3\u003c/sup\u003eA\u003c/strong\u003e, the system can undergo cyclisation either via a 6-\u003cem\u003eendo\u003c/em\u003e-trig (\u003cstrong\u003e\u003csup\u003e3\u003c/sup\u003eTS-I\u003c/strong\u003e) or 5-\u003cem\u003eexo\u003c/em\u003e-trig (\u003cstrong\u003e\u003csup\u003e3\u003c/sup\u003eTS-II\u003c/strong\u003e) transition structure (TS), both proceeding in a highly exergonic fashion. The computed selectivity favours 6-\u003cem\u003eendo\u003c/em\u003e cyclisation (\u003cstrong\u003e\u003csup\u003e3\u003c/sup\u003eTS-I\u003c/strong\u003e),\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003ewith a ∆∆G\u003csup\u003e\u0026Dagger;\u003c/sup\u003e of 0.7 kcal/mol, in line with the observed experimental product distribution of 10:1 (∆∆G\u003csup\u003e\u0026Dagger;\u003c/sup\u003e = 1.4 kcal/mol). Additionally, computed selectivity values across a range of 1,5-diene substrates (Figure 6B) were successful in reproducing the trend in 6-\u003cem\u003eendo\u003c/em\u003e selectivities (\u003cem\u003eR\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e = 0.98).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn the case of 6-\u003cem\u003eendo\u003c/em\u003e cyclisation, we discovered that rather than forming the [2.2.0] scaffold directly via radical recombination, intersystem crossing (ISC) generates zwitterionic intermediate \u003cstrong\u003e\u003csup\u003e1\u003c/sup\u003eB\u003c/strong\u003e. This closed-shell species can then deliver [2.2.0] fused product \u003cstrong\u003e\u003csup\u003e1\u003c/sup\u003eD\u003c/strong\u003e (\u003cstrong\u003e6f\u003c/strong\u003e) via a 4\u0026pi; Staudinger-like electrocyclisation with a diradicaloid TS (\u003cstrong\u003e\u003csup\u003e1\u003c/sup\u003eTS-III\u003c/strong\u003e), consistent with recent studies\u003csup\u003e40\u003c/sup\u003e. The inability of the analogous \u003cem\u003eN\u003c/em\u003e\u0026ndash;alkyl-substituted substrate to access the [2.2.0] scaffold (instead forming pyridone \u003cstrong\u003e4\u003c/strong\u003e, Figure 2A), can be understood by the relative increase in stability of zwitterionic intermediate \u003cstrong\u003e\u003csup\u003e1\u003c/sup\u003eB\u003c/strong\u003e, leading to a greater 4\u0026pi; electrocyclisation energy barrier which is less favourable than the corresponding H-shift (see SI for further details). In contrast, the reaction profile arising from 5-\u003cem\u003eexo\u003c/em\u003e-trig cyclisation (\u003cstrong\u003e\u003csup\u003e3\u003c/sup\u003eTS-II\u003c/strong\u003e) leads to formation of triplet intermediate \u003cstrong\u003e\u003csup\u003e3\u003c/sup\u003eC\u003c/strong\u003e, which upon ISC to open-shell diradical \u003cstrong\u003e\u003csup\u003e1\u003c/sup\u003eC\u0026nbsp;\u003c/strong\u003e(∆G = 0.1 kcal/mol), can recombine via \u003cstrong\u003e\u003csup\u003e1\u003c/sup\u003eTS-IV\u003c/strong\u003e (∆G\u003csup\u003e\u0026Dagger;\u003c/sup\u003e = 0.8 kcal/mol) to give [2.1.1] bicyclic product \u003cstrong\u003e\u003csup\u003e1\u003c/sup\u003eE\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003eWith a general understanding of the reaction mechanism in hand, we next examined the origins of regioselectivity. Using a model \u003cem\u003eN\u003c/em\u003e\u0026ndash;Bn 1,5-diene system as a reference, we calculated that the analogous \u003cem\u003eN\u003c/em\u003e\u0026ndash;Ac substrate displays a 1.7 kcal/mol lower 6-\u003cem\u003eendo\u003c/em\u003e-trig (\u003cstrong\u003e\u003csup\u003e3\u003c/sup\u003eTS-I\u003c/strong\u003e) barrier, in full agreement with our experimental results (Figure 7A), as a result of several factors. In addition to the \u003cem\u003eN\u003c/em\u003e\u0026ndash;Ac system representing a better Giese acceptor due to its more electron-deficient nature, this difference can be rationalised by the increased TS planarity in \u003cstrong\u003e\u003csup\u003e3\u003c/sup\u003eTS-I-Ac\u003c/strong\u003e (ϕ\u003csub\u003e1\u003c/sub\u003e = 28.1\u0026deg;) that facilitates conjugation between the developing \u0026alpha;-carbonyl radical and the carbonyl \u0026pi;-bond. This arises due to the cross-conjugation in the imide system enabling partial deconjugation of the endocyclic N\u0026ndash;C(=O) bond, increasing conformational flexibility relative to the more rigid amide bond in \u003cstrong\u003e\u003csup\u003e3\u003c/sup\u003eTS-I-Bn\u003c/strong\u003e (ϕ\u003csub\u003e1\u003c/sub\u003e = 67.8\u0026deg;).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;The favourability of the \u003cem\u003eN\u003c/em\u003e\u0026ndash;Bn system to undergo 5-\u003cem\u003eexo\u003c/em\u003e-trig cyclisation (∆∆G\u003csup\u003e\u0026Dagger;\u003c/sup\u003e = 1.7 kcal/mol compared to \u003cem\u003eN\u003c/em\u003e\u0026ndash;Ac) can be explained through consideration of the spectator benzylic radical in the cyclisation TS. As well as representing the more planar system (163.0\u0026deg; vs 150.9\u0026deg;), the greater availability of the nitrogen lone pair in \u003cstrong\u003e\u003csup\u003e3\u003c/sup\u003eTS-II-Bn\u003c/strong\u003e increases benzylic radical stability via captodative effects\u003csup\u003e41,42\u003c/sup\u003e, stabilising the TS to a greater extent than for the corresponding \u003cem\u003eN\u003c/em\u003e\u0026ndash;Ac system. Indeed, analysis of the ϕ₂ dihedral change along the intrinsic reaction coordinate (IRC; Figure 7B/C) for the 5-\u003cem\u003eexo\u003c/em\u003e pathway indicates that planarity is maximised at the TS. Moreover, this captodative stabilisation can explain the strong correlation between the electronics of the styrene fragment and reaction regioselectivity (see Figure 4). Analysing the IRC of the 6-\u003cem\u003eendo\u003c/em\u003e-trig pathway\u003cstrong\u003e\u003csup\u003e\u0026nbsp;\u003c/sup\u003e\u003c/strong\u003eshows that the nitrogen atom remains deconjugated from the benzylic radical throughout, suggesting that changing the electronics of the aryl substituents primarily affects the 5-\u003cem\u003eexo\u003c/em\u003e-trig pathway. This was confirmed through computational Hammett analysis, clearly demonstrating that electron-withdrawing substituents lower the 5-\u003cem\u003eexo\u003c/em\u003e-trig (\u003cstrong\u003e\u003csup\u003e3\u003c/sup\u003eTS-II\u003c/strong\u003e) barrier with a strong correlation to Hammett\u0026nbsp;s+ values, while the 6-\u003cem\u003eendo\u003c/em\u003e-trig TS was minimally impacted (Figure 7D).\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn this study, we have established a programmable regiodivergent photochemical strategy that fundamentally challenges the long-standing \u0026ldquo;rule-of-five\u0026rdquo; paradigm in radical cyclisation. Through electronic modulation of an amide-tethered aza-1,5-diene, we demonstrate that the inherent kinetic preference for 5-\u003cem\u003eexo\u003c/em\u003e-trig cyclisation can be overridden, enabling selective access to either bridged [2.1.1] or fused [2.2.0] heterobicyclic frameworks from closely related precursors. Computational investigations reveal that varying the electronics of the substrate significantly affects the relative stability of the developing and spectator radicals in the transition states, giving rise to the observed tuneable regioselectivity. The robustness of the energy-transfer process, broad substrate scope, and extensive downstream derivatisation collectively establish these heterobicycles as highly valuable building blocks. The ability to exert such precise pathway control over a strained intramolecular [2+2] cycloaddition is unprecedented and addresses multiple intrinsic energetic and geometric constraints associated with 6-\u003cem\u003eendo\u003c/em\u003e-trig cyclisation and subsequent ring closure. We anticipate that this concept will inspire the development of new rule-breaking cyclisation strategies and accelerate the discovery of structurally novel, sp\u0026sup3;-rich scaffolds for drug discovery and beyond.\u003c/p\u003e\n"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eACKNOWLEDGEMENTS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank UK Research and Innovation (UKRI) under the UK government\u0026rsquo;s Horizon Europe funding guarantee for an ERC-approved grant (EP/Y028015/1) and the University of Bristol for support.Z.-X.Z. acknowledges support from a Leverhulme Trust Early Career Fellowship (ECF-2025-137). We gratefully acknowledge Dr Jonathan Charmant (University of Bristol) for assistance with X-ray analysis. R.S.P. acknowledges financial support from the National Science Foundation (CHE-2400056) and the Alpine high-performance computing resource, jointly funded by the University of Colorado Boulder, University of Colorado Anschutz, and Colorado State University (CSU), and ACCESS through allocation TG-CHE180056. \u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eADDITIONAL INFORMATION\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAffiliations: School of Chemistry, University of Bristol, Cantock\u0026apos;s Close, Bristol, BS8 1TS, UK; Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523-1872, USA.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDATA AVAILABILITY\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe X-ray crystallographic coordinates for structures \u003cstrong\u003e3d, 5p, 6p\u003c/strong\u003e and \u003cstrong\u003e8a\u003c/strong\u003e reported in this study have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition numbers 2520219\u0026ndash;2520222. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. All other data are available in the main text or the supplementary information.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAUTHOR CONTRIBUTIONS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eZ-X.Z., J.L.T., and V.K.A. conceived the project; V.K.A. directed the research; Z-X.Z., M.V.P., J.L.T., R.S.P. and V.K.A. prepared the manuscript; Z-X.Z., K.S. and YH.G. performed the experimental work; M.V.P. carried out the computational analysis, supervised by R.S.P. All authors analysed the results.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCORRESPONDING AUTHOR\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCorrespondence to [email protected] and [email protected] \u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCOMPETING INTERESTS STATEMENT\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eShearer, J., Castro, J. L., Lawson, A. D. G., MacCoss, M. \u0026amp; Taylor, R. D. Rings in Clinical Trials and Drugs: Present and Future. \u003cem\u003eJ. Med. Chem.\u003c/em\u003e \u003cstrong\u003e65\u003c/strong\u003e, 8699-8712 (2022).\u003c/li\u003e\n\u003cli\u003eMykhailiuk, P. K. Saturated bioisosteres of benzene: where to go next? \u003cem\u003eOrg. Biomol. Chem.\u003c/em\u003e \u003cstrong\u003e17\u003c/strong\u003e, 2839-2849 (2019).\u003c/li\u003e\n\u003cli\u003eSubbaiah, M. A. M. \u0026amp; Meanwell, N. A. 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Herein, we report a visible-light-mediated intramolecular [2+2] photocycloaddition of aza-1,5-dienes that successfully overcomes the classical “rule-of-five” selectivity governing radical cyclisations. By tuning the electronic properties of an easily removable amide N-substituent, we reprogram the initial energy-transfer-driven cyclisation event, diverging from the usually kinetically favoured 5-exo-trig to the 6-endo-trig pathway. As a result, closely related substrates can be selectively directed to generate either bridged bicyclo[2.1.1] or vastly underexplored fused bicyclo[2.2.0] architectures, both of which offer rich downstream derivatisation potential. Furthermore, an extensive computational study of this transformation revealed how the intricate interplay of electronic effects controls reaction regioselectivity. Overall, this work establishes a programmable, light-driven cyclisation strategy that enables precise and selective construction of distinct bicyclic frameworks within a unified reaction manifold.","manuscriptTitle":"Programmable Regiodivergent Light-Driven Cyclisation of Acyclic 1,5-Dienes Unlocks Rigid Bicyclic Architectures","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-09 07:42:48","doi":"10.21203/rs.3.rs-8681610/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-chemistry","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"nchem","sideBox":"Learn more about [Nature Chemistry](http://www.nature.com/nchem/)","snPcode":"","submissionUrl":"","title":"Nature Chemistry","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Research","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"4a0b0372-c0c0-45ef-bde1-5ac0202cadbf","owner":[],"postedDate":"March 9th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":64067776,"name":"Physical sciences/Chemistry/Organic chemistry/Synthetic chemistry methodology"},{"id":64067777,"name":"Physical sciences/Chemistry/Photochemistry/Photocatalysis"}],"tags":[],"updatedAt":"2026-04-26T16:45:17+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-09 07:42:48","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8681610","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8681610","identity":"rs-8681610","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}