Periodic Reporting for period 1 - Expand Flow (Expand Flow – Accessing new chemical space via a combined flash- and photochemical flow chemistry approach for the functionalisation and ring expansion of heterocycles)
Periodo di rendicontazione: 2023-10-16 al 2025-10-15
Sintesi del contesto e degli obiettivi generali del progetto
The need for development of cost-effective and efficient methodologies for the exploration of new chemical space is imperative to streamline the access to new effective drugs. This demands progress in several areas of synthetic organic chemistry, and some of those are addressed with ExpandFlow.
First, with the medicinal chemists' move away from molecular flatland towards sp3-rich chemical space with high conformational restriction, the need for the discovery and synthesis of novel strained saturated heterocycles is imperative. The importance of such novel motifs is manifold as they allow development of drug candidates outside of the already crowded intellectual property space, and may impart improved physicochemical properties, incl. lower off-target biding promiscuity, improved solubility and an increased probability of lead compounds advancing in clinical trials. ExpandFlow addresses this need in two ways. First, by developing new and improved synthetic methodologies for the introduction of already proven strained heterocycles (e.g. oxetanes, azetidines, aziridines) into functionalised molecules. This would allow the expansion of hitherto accessible chemical space and potentially path the way for the synthesis of new lead compounds. Second, ExpandFlow will develop completely new strained saturated heterocycles and investigate their potential as bioisosteres of common heterocycles found in drugs and drug candidates. The successful development of novel biologically useful heterocycles would expand the toolbox of the medicinal chemists in drug candidate development and relief some burden associated with the crowded patent space.
In a second, overarching motif, ExpandFlow's will work to address the environmental targets set by the European Commission MSCA Green Charter and the Horizon Europe missions to become climate resilient by 2030. In addition, the project addresses several environmental needs described in the 2030 Agenda for Sustainable Development: 7) Affordable and clean energy; 9) Industry, innovation and infrastructure; 12) Responsible consumption and production; and 13) Climate Action. Currently, the pharmaceutical industry contributes an estimated 4-5% of global carbon emissions, so that meeting the EU's ambitious targets requires the prioritization of sustainable production technologies. ExpandFlow will address this need from a technology standpoint. Historically, pharmaceutical production has relied on batch processes which, although simple(r) and cheap, have inherent constraints in resource use and process control. An alternative approach is continuous processing (flow chemistry),which involves continuously pumping reagents into a plug flow reactor (PFR) or continuous-stirred tank reactor (CSTR), from which product is continuously discharged. Conducting reactions in continuous flow confers additional advantages. From a safety perspective, the limited reactor volume and fewer start-up and shutdown cycles reduce exposure to hazardous or toxic reagents. In addition, superior mixing and heat transfer mitigate the risk of thermal runaway. Furthermore, greater control over key reaction parameters (temperature, pressure, and residence time) enables milder reaction conditions, making it possible to tame intermediates that are otherwise inaccessible in batch reactors. ExpandFlow will further develop this technology, also in combination with photocatalysis, and showcase its utility in the development of novel synthetic methodology.
Expand Flow thus presents a multidisciplinary project that lies in the intersection of flow chemistry (incl. photocatalysis), medicinal chemistry and computational chemistry, for the development of a selective, sustainable and applicable methodology for the functionalisation of (novel) strained heterocycles. Ultimately, its applicability to the pharmaceutical industry will be proven by the development of novel bioisosteres and their in silico and in vitro validation. Overall, this project will add a valuable tool to the synthetic chemist’s repertoire for the rapid, environmentally-friendly and cost-effective development of new drug candidates, by the versatile functionalisation of various heterocycles using flow technology. This innovative approach will have a high scientific, technological and societal impact, reinforcing the European competitiveness in the development of life-saving drugs.
First, with the medicinal chemists' move away from molecular flatland towards sp3-rich chemical space with high conformational restriction, the need for the discovery and synthesis of novel strained saturated heterocycles is imperative. The importance of such novel motifs is manifold as they allow development of drug candidates outside of the already crowded intellectual property space, and may impart improved physicochemical properties, incl. lower off-target biding promiscuity, improved solubility and an increased probability of lead compounds advancing in clinical trials. ExpandFlow addresses this need in two ways. First, by developing new and improved synthetic methodologies for the introduction of already proven strained heterocycles (e.g. oxetanes, azetidines, aziridines) into functionalised molecules. This would allow the expansion of hitherto accessible chemical space and potentially path the way for the synthesis of new lead compounds. Second, ExpandFlow will develop completely new strained saturated heterocycles and investigate their potential as bioisosteres of common heterocycles found in drugs and drug candidates. The successful development of novel biologically useful heterocycles would expand the toolbox of the medicinal chemists in drug candidate development and relief some burden associated with the crowded patent space.
In a second, overarching motif, ExpandFlow's will work to address the environmental targets set by the European Commission MSCA Green Charter and the Horizon Europe missions to become climate resilient by 2030. In addition, the project addresses several environmental needs described in the 2030 Agenda for Sustainable Development: 7) Affordable and clean energy; 9) Industry, innovation and infrastructure; 12) Responsible consumption and production; and 13) Climate Action. Currently, the pharmaceutical industry contributes an estimated 4-5% of global carbon emissions, so that meeting the EU's ambitious targets requires the prioritization of sustainable production technologies. ExpandFlow will address this need from a technology standpoint. Historically, pharmaceutical production has relied on batch processes which, although simple(r) and cheap, have inherent constraints in resource use and process control. An alternative approach is continuous processing (flow chemistry),which involves continuously pumping reagents into a plug flow reactor (PFR) or continuous-stirred tank reactor (CSTR), from which product is continuously discharged. Conducting reactions in continuous flow confers additional advantages. From a safety perspective, the limited reactor volume and fewer start-up and shutdown cycles reduce exposure to hazardous or toxic reagents. In addition, superior mixing and heat transfer mitigate the risk of thermal runaway. Furthermore, greater control over key reaction parameters (temperature, pressure, and residence time) enables milder reaction conditions, making it possible to tame intermediates that are otherwise inaccessible in batch reactors. ExpandFlow will further develop this technology, also in combination with photocatalysis, and showcase its utility in the development of novel synthetic methodology.
Expand Flow thus presents a multidisciplinary project that lies in the intersection of flow chemistry (incl. photocatalysis), medicinal chemistry and computational chemistry, for the development of a selective, sustainable and applicable methodology for the functionalisation of (novel) strained heterocycles. Ultimately, its applicability to the pharmaceutical industry will be proven by the development of novel bioisosteres and their in silico and in vitro validation. Overall, this project will add a valuable tool to the synthetic chemist’s repertoire for the rapid, environmentally-friendly and cost-effective development of new drug candidates, by the versatile functionalisation of various heterocycles using flow technology. This innovative approach will have a high scientific, technological and societal impact, reinforcing the European competitiveness in the development of life-saving drugs.
Lavoro eseguito dall’inizio del progetto fino alla fine del periodo coperto dalla relazione e principali risultati finora ottenuti
To tackle the main objectives set out above, I chose to first focus on the development of a flow protocol for the introduction of known bioisosteres into highly functionalised molecules, before investigating the development of novel bioisosteres based on strained heterocycles.
I began my investigation by studying the incorporation of the oxetane-moiety. The oxetane ring has evolved as a useful bioisostere for dimethyl and carbonyl groups for the improvement of physiochemical properties of drug candidates, yet the introduction of this motif is reliant mostly on SN2-substitution of nucleophiles on 3-halooxetanes, nucleophilic addition to oxetan-3-one, followed by reductive deoxygenation of the hydroxy group, or halogen-atom-transfer (XAT)/transition-metal-catalyzed coupling tandem protocols. Furthermore, Suzuki–Miyaura cross-couplings have been extensively applied in the academic and patent space. Interestingly, direct access to analogues deriving from reaction of nucleophilic oxetane with electrophilic partners (e.g. ketones, aldehydes, isocyanates, etc.) was unviable, as the seemingly straightforward generation of 3-oxetanyllithium remained unknown, which was a methodology gap we wanted to address. I first attempted to perform lithium-halogen exchange on 3-iodooxetane, followed by addition to benzophenone, under various batch conditions. Disappointingly and surprisingly, under external quenching conditions this failed to deliver the desired addition product. Close monitoring of the reaction by in situ NMR revealed that the 3-oxetanyllithium species is initially formed, but immediately decomposes to allyl alcohol, preventing the desired reaction from occurring. I addressed this issue using flow methodology as this allowed me to precisely control the residence time of the highly unstable 3-oxetanyllithium intermediate before introduction of the desired electrophile. I found that a residence time of 52 ms for the lithium-halogen exchange proved optimal for the generation of 3-oxetanyllithium while simultaneously preventing its decomposition. Shorter residence times led to incomplete lithium-halogen exchange, whereas with longer residence times, the decomposition pathway was dominant. During my scope investigation, I found that a range of different electrophiles (incl. ketones, aldehydes, isocyanates, Weinreb amides, disulfides etc.) are suitable to undergo this transformation. This allowed the introduction of the oxetane moiety in a wide range of compounds, incl. natural products and APIs, and allowed the synthesis of hitherto inaccessible oxetane-containing substrates. Given the importance of the oxetane-core in drug development, I expect this methodology to find rapid adoption in the medicinal community. After publication in Organic Letters, this work was highlighted in OPR&D and Synfacts as an item of interest to medicinal chemists. It also demonstrated the power of continuous processing to tame highly reactive intermediates.
Afterwards, my attention shifted to the development of a potential novel bioisostere. Strained spiro heterocycles (e.g. 2-ASE, DASE etc.) are valuable bioisosteres in medicinal chemistry for common non-strained heterocycles (e.g. piperidine, piperazine, etc.). The addition of a novel bioisostere would add possibilities to further manipulate drug candidates to the medicinal chemist's toolbox. In collaboration with a PhD student, I developed the synthesis of 1-Oxa-2,6-DiAzaSpiro[3.3]heptanE ("ODASE") - a new spiro[3.3]heptane core. Our synthetic effort relied on the formation of highly strained and unstable azabicyclo[1.1.0]butyl-lithium (ABB-Li), which is added to a nitrone to form hydroxylamines. Subsequent intramolecular strain-release of the ABB-moiety by activation of the ABB-core with various electrophiles, afforded the desired ODASE-core. In order to tame the ABB-Li intermediate we again relied on continuous flow for its synthesis and its addition to nitrones. The intramolecular spirocyclisation was subsequently performed in batch. This combined flow-batch protocol afforded the desired ODASE cores in generally high yields. We tolerated the process' tolerance for various substituents on the nitrone and for various electrophiles for the intramolecular spirocyclisation, thus allowing incorporation of ODASE into various APIs, incl. ibuprofen, flurbiprofen, indomethacin and naproxen. In collaboration with computational chemists we investigated in silico the core's potential as a bioisostere, and concluded its potential value as a bioisostere for piperazine.
Last, my focus returned to oxetane moiety for the synthesis of another hitherto inaccessible strained spiro-heterocycle: 1,5-dioxaspiro[2.3]hexane. This core had been absent from the literature. Bearing in mind the importance of such motifs in medicinal chemistry, we addressed this shortcoming by devising a mechanistically interesting route to this core. Our design plan relied on the single-electron transfer from a sterically hindered lithium amide (LiTMP) to non-enolizable, reducible ketones to form a nitrogen-centered radical and a ketyl radical anion. Selective HAT on the beta-position of 3-iodooxetane by the nitrogen-centered radical, followed by radical-radical cross-coupling and intramolecular substitution affords the 1,5-dioxaspiro[2.3]hexane cores. In a thorough scope investigation we investigated various electronically diverse benzophenones, as well as trifluoroacetophenones as suitable electrophiles. Using cyclic voltammetry, we showed that the success of the reaction is dependent on the reducibility of the ketone, and the mechanism was investigated by control experiments and in silico investigations. This work was published in 2025 in Angewandte Chemie. In line with ExpandFlow this introduced yet another hitherto inaccessible strained heterocycle, and provided novel fundamental mechanistic evidence.
I began my investigation by studying the incorporation of the oxetane-moiety. The oxetane ring has evolved as a useful bioisostere for dimethyl and carbonyl groups for the improvement of physiochemical properties of drug candidates, yet the introduction of this motif is reliant mostly on SN2-substitution of nucleophiles on 3-halooxetanes, nucleophilic addition to oxetan-3-one, followed by reductive deoxygenation of the hydroxy group, or halogen-atom-transfer (XAT)/transition-metal-catalyzed coupling tandem protocols. Furthermore, Suzuki–Miyaura cross-couplings have been extensively applied in the academic and patent space. Interestingly, direct access to analogues deriving from reaction of nucleophilic oxetane with electrophilic partners (e.g. ketones, aldehydes, isocyanates, etc.) was unviable, as the seemingly straightforward generation of 3-oxetanyllithium remained unknown, which was a methodology gap we wanted to address. I first attempted to perform lithium-halogen exchange on 3-iodooxetane, followed by addition to benzophenone, under various batch conditions. Disappointingly and surprisingly, under external quenching conditions this failed to deliver the desired addition product. Close monitoring of the reaction by in situ NMR revealed that the 3-oxetanyllithium species is initially formed, but immediately decomposes to allyl alcohol, preventing the desired reaction from occurring. I addressed this issue using flow methodology as this allowed me to precisely control the residence time of the highly unstable 3-oxetanyllithium intermediate before introduction of the desired electrophile. I found that a residence time of 52 ms for the lithium-halogen exchange proved optimal for the generation of 3-oxetanyllithium while simultaneously preventing its decomposition. Shorter residence times led to incomplete lithium-halogen exchange, whereas with longer residence times, the decomposition pathway was dominant. During my scope investigation, I found that a range of different electrophiles (incl. ketones, aldehydes, isocyanates, Weinreb amides, disulfides etc.) are suitable to undergo this transformation. This allowed the introduction of the oxetane moiety in a wide range of compounds, incl. natural products and APIs, and allowed the synthesis of hitherto inaccessible oxetane-containing substrates. Given the importance of the oxetane-core in drug development, I expect this methodology to find rapid adoption in the medicinal community. After publication in Organic Letters, this work was highlighted in OPR&D and Synfacts as an item of interest to medicinal chemists. It also demonstrated the power of continuous processing to tame highly reactive intermediates.
Afterwards, my attention shifted to the development of a potential novel bioisostere. Strained spiro heterocycles (e.g. 2-ASE, DASE etc.) are valuable bioisosteres in medicinal chemistry for common non-strained heterocycles (e.g. piperidine, piperazine, etc.). The addition of a novel bioisostere would add possibilities to further manipulate drug candidates to the medicinal chemist's toolbox. In collaboration with a PhD student, I developed the synthesis of 1-Oxa-2,6-DiAzaSpiro[3.3]heptanE ("ODASE") - a new spiro[3.3]heptane core. Our synthetic effort relied on the formation of highly strained and unstable azabicyclo[1.1.0]butyl-lithium (ABB-Li), which is added to a nitrone to form hydroxylamines. Subsequent intramolecular strain-release of the ABB-moiety by activation of the ABB-core with various electrophiles, afforded the desired ODASE-core. In order to tame the ABB-Li intermediate we again relied on continuous flow for its synthesis and its addition to nitrones. The intramolecular spirocyclisation was subsequently performed in batch. This combined flow-batch protocol afforded the desired ODASE cores in generally high yields. We tolerated the process' tolerance for various substituents on the nitrone and for various electrophiles for the intramolecular spirocyclisation, thus allowing incorporation of ODASE into various APIs, incl. ibuprofen, flurbiprofen, indomethacin and naproxen. In collaboration with computational chemists we investigated in silico the core's potential as a bioisostere, and concluded its potential value as a bioisostere for piperazine.
Last, my focus returned to oxetane moiety for the synthesis of another hitherto inaccessible strained spiro-heterocycle: 1,5-dioxaspiro[2.3]hexane. This core had been absent from the literature. Bearing in mind the importance of such motifs in medicinal chemistry, we addressed this shortcoming by devising a mechanistically interesting route to this core. Our design plan relied on the single-electron transfer from a sterically hindered lithium amide (LiTMP) to non-enolizable, reducible ketones to form a nitrogen-centered radical and a ketyl radical anion. Selective HAT on the beta-position of 3-iodooxetane by the nitrogen-centered radical, followed by radical-radical cross-coupling and intramolecular substitution affords the 1,5-dioxaspiro[2.3]hexane cores. In a thorough scope investigation we investigated various electronically diverse benzophenones, as well as trifluoroacetophenones as suitable electrophiles. Using cyclic voltammetry, we showed that the success of the reaction is dependent on the reducibility of the ketone, and the mechanism was investigated by control experiments and in silico investigations. This work was published in 2025 in Angewandte Chemie. In line with ExpandFlow this introduced yet another hitherto inaccessible strained heterocycle, and provided novel fundamental mechanistic evidence.
Progressi oltre lo stato dell’arte e potenziale impatto previsto (incluso l’impatto socioeconomico e le implicazioni sociali più ampie del progetto fino ad ora)
The work conducted within the ExpandFlow project significantly expands the state of the art in two ways. First, it further developed the use of continuous processing for the generating and taming of highly reactive and/or unstable lithiated intermediates (flash chemistry). This has societal impacts as it allows the synthesis of unknown motifs under (more) sustainable conditions without exposure to noxious reagents or transition metal catalysts. Second, hitherto inaccessible strained (spiro-)heterocycles were developed (ODASE and 1,5-dioxaspiro[2.3]hexane) which could become valuable tools within medicinal chemistry. In particular, ODASE has been investigated in silico as a piperazine bioisostere, facilitating its potential socio-economic impact by adoption in drug development. For the synthesis of 1,5-dioxaspiro[2.3]hexane on the other hand, fundamentally novel mechanistic insights were generated, opening the path for the synthetic chemistry community to adopt this underexplored reactivity mode.