Development of novel MHAT C-C coupling reactions inspired by morphan-containing anticancer compounds

Abstract

[eng] Natural products have long served as a cornerstone of drug discovery, not only as therapeutic agents but also as key drivers of innovation in organic synthesis. Their intricate structures and remarkable biological activities have inspired the development of new synthetic strategies that enable the efficient construction of complex molecular frameworks. However, the complexity that makes natural products valuable also limits their practical accessibility, often requiring lengthy, low-yielding routes with reduced scalability. To overcome these limitations, two complementary approaches have emerged: function-oriented synthesis (FOS), which simplifies natural product structures while preserving bioactivity, and the development of new synthetic methodologies, allowing for more efficient and selective access to complex molecular architectures In this context, radical-based transformations have gained increasing attention due to their ability to streamline molecular assembly under mild conditions, expand chemical space, and enable transformations that are difficult to achieve using traditional ionic chemistry. Among these, metal-catalyzed hydrogen atom transfer (MHAT) reactions have emerged as a powerful tool for selective C–C bond formation, proceeding under non-toxic conditions with high site- and chemoselectivity. Despite their advantages, their full potential remains underexplored, particularly in terms of radical precursors and acceptor groups.This thesis aims to expand the utility of MHAT chemistry for the synthesis of bioactive compounds and complex natural products by developing new transformations and disconnection strategies. Firstly, in the context of the synthesis of the core of madangamine alkaloids, a novel MHAT C–C coupling was developed to form a key bond, enabling access to the tricyclic scaffold after classical approaches proved unsuccessful. The reaction involved a Giese addition of electron-deficient alkynes to neutral alkenes (Scheme 2), introducing a new disconnection approach to electron-deficient alkenes. This methodology exhibited broad functional group tolerance and proceeded under mild, non-toxic conditions with high atom efficiency and scalability. Furthermore, it enabled control over alkene geometry, favoring the cis isomer, which could be readily isomerized to the trans form. The method also allowed olefin installation near sterically hindered centers, offering a key advantage over conventional olefination techniques and expanding the synthetic toolbox to access complex molecular frameworks. Secondly, with the ultimate goal of achieving the total synthesis of aspernomine, a convergent strategy was proposed, focusing on the preparation of its heterocyclic and terpenic components for late-stage coupling (Scheme 3a). Given the complexity of this task, the first step was to apply a function-oriented synthesis strategy to simplify the structure while retaining bioactivity. This approach focused on the synthesis of the 3,4-benzomorphan core, obtained through a base-mediated reductive cyclization of nitrophenyl ketones (Scheme 3b). The method provided a concise four-step approach, achieving high yields of up to 87% in the key cyclization step. Biological evaluation of the analogs showed that their cytotoxicity was generally lower than that of aspernomine, indicating that additional structural elements beyond the core are critical for the full bioactivity of the natural product. Notably, however, the introduction of an enone moiety in the analogs enhanced antiproliferative activity, suggesting that the enone fragment may function as a key pharmacophore, similar to other Michael acceptor-based drugs. Further efforts were directed toward the total synthesis of aspernomine, with a novel MHAT-based methodology proposed to facilitate the coupling of the heterocyclic component to the terpenic fragment, ultimately advancing the synthesis toward its final stages. To achieve this transformation, a new class of redox-active esters (RAEs) was designed by incorporating an alkene fragment into the classical N-hydroxyphthalimide framework, facilitating decarboxylation under MHAT conditions (Scheme 3c). This modification allowed carboxylic acids to be utilized as radical precursors in MHAT reactions for the first time, expanding the scope of radical sources and broadening the applications of MHAT processes. The strategy also facilitated the generation of primary radicals and enabled the first-ever formation of linearly coupled products under MHAT conditions, complementing the branched products obtained from alkene-based precursors. The versatility of the RAEs was evaluated through Giese-type couplings with electron-deficient alkenes, generating a broad range of radicals. Then, they were further applied in a variety of well-established MHAT reactions, underscoring their potential for diverse synthetic applications.

[cat] Els productes naturals han estat una font d’inspiració en la química orgànica i el desenvolupament de fàrmacs gràcies a la seva complexitat estructural i activitat biològica. No obstant això, aquesta complexitat dificulta la seva síntesi, requerint rutes llargues i poc escalables. Per superar aquestes limitacions, han sorgit dues estratègies: la síntesi orientada a la funció (FOS), que tracta de simplificar estructures mantenint-ne la bioactivitat, i el desenvolupament de noves metodologies sintètiques per a un accés més eficient a estructures complexes. En aquest context, les transformacions radicalàries han guanyat rellevància per la seva capacitat d'aconseguir acoblaments sota condicions suaus. Entre elles, les reaccions de transferència d’hidrogen catalitzades per metalls (MHAT) han demostrat ser eines versàtils per a la formació selectiva d’enllaços C–C. Malgrat els seus avantatges, encara hi ha marge per ampliar el seu potencial, especialment en l'exploració de nous precursors radicalaris i grups acceptors. Aquesta tesi busca ampliar l’abast de la química MHAT mitjançant el desenvolupament de noves transformacions per facilitar la síntesi de compostos bioactius i productes naturals. D’una banda, es va desenvolupar una nova metodologia d’acoblament C–C mitjançant MHAT basada en una addició de Giese entre alquins deficients d’electrons i alquens neutres, amb l’objectiu de sintetitzar el nucli tricíclic dels alcaloides de tipus madangamina. Aquesta metodologia va permetre el control de la geometria de l’alquè i va oferir una nova via per sintetitzar alquens electrodeficients. D’altra banda, es va plantejar una estratègia convergent per a la síntesi de l’aspernomina. En primer lloc, per tal de sintetitzar el fragment de 3,4-benzomorfà es va desenvolupar una ciclació reductiva de nitrofenil cetones, amb una posterior avaluació de les propietats biològiques del nucli tricíclic que va indicar que la seva activitat era més baixa que la del producte natural. Posteriorment, per tal d’unificar el fragment heterocíclic i el fragment terpènic del producte natural es va proposar l’ús d’una nova classe d’èsters redox-actius (RAEs) adaptats a condicions MHAT per fer un acoblament descarboxilatiu. Aquest disseny va permetre, per primer cop, l’ús d’àcids carboxílics com a precursors radicalaris en reaccions MHAT, fent possible així l’accés a productes d’acoblament lineal.