This thesis addresses the challenge of constructing the ergoline scaffold, a tetracyclic indole alkaloid core that underlies numerous biologically active natural products, including ergot alkaloids of pharmacological and toxicological relevance. Despite the long-standing interest in ergoline derivatives, their structural complexity, particularly the stereodefined tetracyclic framework, continues to make their synthesis a demanding task. The work presented explores a novel biomimetic cyclization strategy as a central step toward the total synthesis of ergoline, with the ultimate aim of providing a generalizable approach that bypasses some of the limitations encountered in conventional synthetic routes. The study begins with a detailed review of alkaloids, emphasizing those derived from tryptophan, including ergot alkaloids, aspects of biosynthesis and their historical and biomedical importance. Special attention is given to ergoline as a fundamental structural unit, whose preparation is not only of academic interest but also opens potential for the development of new derivatives with therapeutic value. The discussion of biomimetic cyclizations, inspired by natural biosynthetic cascades, establishes the conceptual foundation of this work. Recent studies have demonstrated the feasibility of cascade reactions activated by iridium-acyl nitrenoid species to generate complex δ-lactam frameworks. Building on these insights, the thesis investigates the use of copper (II) as a catalyst, specifically tetrakis(pyridine)copper (II) triflate, as a more sustainable and accessible catalyst compared to iridium-based systems. The experimental work is structured in two major parts. First, the synthesis of the pre-cyclization substrate is pursued, exploring both phenyl and 3,5-dimethoxyphenyl variants to evaluate the influence of electronic effects on the outcome of the cyclization. The retrosynthetic analysis identifies a Suzuki coupling between a styrene derivative and a vinyl iodide ester as a pivotal step, enabling the assembly of the linear precursor required for the biomimetic cascade. Despite the apparent simplicity of the transformations, practical challenges – such as low yields, instability of intermediates, and difficulties in purification – necessitated multiple iterations and optimization of reaction conditions. These difficulties underscore the practical complexity of translating retrosynthetic logic into laboratory reality, particularly when dealing with sensitive vinyl iodide substrates. The second part of the study focuses on the post-functionalization of the cyclized product, with particular emphasis on achieving selective benzylic oxidations as key transformations for the progression toward ergoline. The development of conditions for these oxidations is shown to be crucial, as they establish the synthetic link between the biomimetically generated polycyclic lactam and the ergoline framework. Although this step proved problematic and limited the of the post-functionalization study, the discouraging results do not rule out the possibility that the copper-catalyzed biomimetic cyclization could be a viable entry point to the ergoline core. In conclusion, the thesis demonstrates the potential of copper-based biomimetic cyclizations as an alternative to iridium-catalyzed systems for constructing complex alkaloid frameworks. While the work does not yet achieve a full synthesis of ergoline, it lays the groundwork for future developments. Future efforts directed at refining post-functionalization strategies, expanding substrate scope, and developing asymmetric catalytic systems will be essential to fully realize the promise of this approach.
La tesi affronta la sfida della costruzione dell’impalcatura dell’ergolina, un nucleo indolico tetraciclico che costituisce la struttura portante di numerosi prodotti naturali biologicamente attivi, tra cui gli alcaloidi dell’ergot, di rilevanza sia farmacologica sia tossicologica. Nonostante il consolidato interesse per i derivati dell’ergolina, la loro complessità strutturale, in particolare l’assetto stereodefinito del core tetraciclico, continua a rendere la loro sintesi un compito estremamente impegnativo. Il lavoro presentato esplora una nuova strategia di ciclizzazione biomimetica come passaggio centrale verso la sintesi totale dell’ergolina, con l’obiettivo di fornire un approccio generalizzabile che superi alcune delle limitazioni tipiche delle vie sintetiche convenzionali. Lo studio prende avvio da una rassegna sugli alcaloidi, con particolare attenzione a quelli derivati dal triptofano, inclusi gli alcaloidi dell’ergot, affrontando aspetti di biosintesi, oltre che il loro rilievo storico e biomedico. In particolare, ci si focalizza sull’ergolina quale unità strutturale fondamentale, la cui preparazione non rappresenta soltanto un interesse di carattere accademico, ma apre anche la possibilità di sviluppare nuovi derivati a potenziale valore terapeutico. La discussione sulle ciclizzazioni biomimetiche, ispirate alle cascate biosintetiche naturali, costituisce il fondamento concettuale del lavoro. Studi recenti hanno dimostrato la fattibilità di reazioni a cascata attivate da complessi iridio-acilnitrenoidi, in grado di generare strutture δ-lattamiche. Sulla base di tali premesse, la tesi indaga l’impiego del rame (II), in particolare del tetrakis(piridina)rame (II) triflato, come catalizzatore più sostenibile e accessibile rispetto ai sistemi basati sull’iridio. L’attività sperimentale è articolata in due sezioni principali. Nella prima parte, è stata perseguita la sintesi del substrato pre-ciclizzazione, esplorando sia la variante fenilica sia quella 3,5-dimetossifenilica al fine di valutare l’influenza degli effetti elettronici sull’esito della ciclizzazione. L’analisi retrosintetica individua come passaggio cruciale un coupling di Suzuki tra un derivato dello stirene e un estere vinil ioduro, che consente l’assemblaggio del precursore lineare necessario all’avvio della cascata biomimetica. Nonostante l’apparente semplicità delle trasformazioni, difficoltà pratiche quali basse rese, instabilità degli intermedi e problematiche di purificazione, hanno reso necessarie ripetute iterazioni e l’ottimizzazione delle condizioni di reazione. Tali problematiche evidenziano la complessità intrinseca nel tradurre la logica retrosintetica in pratica di laboratorio, soprattutto in presenza di vinil ioduri particolarmente sensibili. La seconda parte dello studio è incentrata sulla post-funzionalizzazione del prodotto ciclizzato, con particolare attenzione al conseguimento di ossidazioni benzliche selettive, trasformazioni chiave per ottenere la struttura dell’ergolina. Lo sviluppo delle condizioni per tali ossidazioni si rivela cruciale, in quanto consente di stabilire il collegamento sintetico tra il lattame policiclico e lo scheletro ergolinico. Sebbene questo passaggio si sia rivelato problematico, limitando l’estensione dello studio di post-funzionalizzazione, i risultati poco incoraggianti non escludono la possibilità che la ciclizzazione biomimetica rappresenti una via d’accesso valida alla moleola target. In conclusione, la tesi dimostra il potenziale delle ciclizzazioni biomimetiche basate sul rame come alternativa ai sistemi catalizzati dall’iridio per la costruzione di strutture alcaloidiche complesse. Il lavoro pone le basi per futuri sviluppi. Sarà fondamentale indirizzare gli sforzi verso il perfezionamento delle strategie di post-funzionalizzazione, l’ampliamento dello spettro dei substrati e lo sviluppo di sistemi catalitici asimmetrici.
STUDIO DI STRATEGIE SINTETICHE PER LA PREPARAZIONE DELL’ERGOLINA MEDIANTE CICLIZZAZIONI BIOMIMETICHE
RINI, EDOARDO
2024/2025
Abstract
This thesis addresses the challenge of constructing the ergoline scaffold, a tetracyclic indole alkaloid core that underlies numerous biologically active natural products, including ergot alkaloids of pharmacological and toxicological relevance. Despite the long-standing interest in ergoline derivatives, their structural complexity, particularly the stereodefined tetracyclic framework, continues to make their synthesis a demanding task. The work presented explores a novel biomimetic cyclization strategy as a central step toward the total synthesis of ergoline, with the ultimate aim of providing a generalizable approach that bypasses some of the limitations encountered in conventional synthetic routes. The study begins with a detailed review of alkaloids, emphasizing those derived from tryptophan, including ergot alkaloids, aspects of biosynthesis and their historical and biomedical importance. Special attention is given to ergoline as a fundamental structural unit, whose preparation is not only of academic interest but also opens potential for the development of new derivatives with therapeutic value. The discussion of biomimetic cyclizations, inspired by natural biosynthetic cascades, establishes the conceptual foundation of this work. Recent studies have demonstrated the feasibility of cascade reactions activated by iridium-acyl nitrenoid species to generate complex δ-lactam frameworks. Building on these insights, the thesis investigates the use of copper (II) as a catalyst, specifically tetrakis(pyridine)copper (II) triflate, as a more sustainable and accessible catalyst compared to iridium-based systems. The experimental work is structured in two major parts. First, the synthesis of the pre-cyclization substrate is pursued, exploring both phenyl and 3,5-dimethoxyphenyl variants to evaluate the influence of electronic effects on the outcome of the cyclization. The retrosynthetic analysis identifies a Suzuki coupling between a styrene derivative and a vinyl iodide ester as a pivotal step, enabling the assembly of the linear precursor required for the biomimetic cascade. Despite the apparent simplicity of the transformations, practical challenges – such as low yields, instability of intermediates, and difficulties in purification – necessitated multiple iterations and optimization of reaction conditions. These difficulties underscore the practical complexity of translating retrosynthetic logic into laboratory reality, particularly when dealing with sensitive vinyl iodide substrates. The second part of the study focuses on the post-functionalization of the cyclized product, with particular emphasis on achieving selective benzylic oxidations as key transformations for the progression toward ergoline. The development of conditions for these oxidations is shown to be crucial, as they establish the synthetic link between the biomimetically generated polycyclic lactam and the ergoline framework. Although this step proved problematic and limited the of the post-functionalization study, the discouraging results do not rule out the possibility that the copper-catalyzed biomimetic cyclization could be a viable entry point to the ergoline core. In conclusion, the thesis demonstrates the potential of copper-based biomimetic cyclizations as an alternative to iridium-catalyzed systems for constructing complex alkaloid frameworks. While the work does not yet achieve a full synthesis of ergoline, it lays the groundwork for future developments. Future efforts directed at refining post-functionalization strategies, expanding substrate scope, and developing asymmetric catalytic systems will be essential to fully realize the promise of this approach.| File | Dimensione | Formato | |
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https://hdl.handle.net/20.500.14239/31423