Steroids are perhydrocyclopentanephenanthrene compounds, consisting of three six-membered rings and one five-membered ring, differently substituted. In general, these substituents are located on the first six-membered ring (A) and on the five-membered ring (D), although their presence on the other two rings (B and C) cannot be excluded. The different classes of steroids are categorized into 11 types according to the basic carbon skeleton and, in nature, they serve as starting frameworks for the formation of a wide variety of compounds. A synthetic methodology was developed to derivatize selected steroidal structures using highly reactive classical nucleophiles, such as hydrazines, hydrazides, and hydroxylamines, which selectively react with the carbonyl functionalities of the steroids investigated in this study. Nucleophiles bearing heterocyclic moieties were employed, and the reactions afforded excellent results, providing good yields and generally high purities. These transformations can therefore be exploited for the functionalization of a broad class of steroids, leading to heterocyclic derivatives with potential biological activity. The outcome of this preliminary rapid functionalization study of steroids appears particularly promising also for the introduction of complex functionalities, including commercially available ones, thereby drastically reducing the number of synthetic steps required to achieve the desired goal. Despite the preliminary synthetic success, these derivatives have not yet been evaluated from a pharmacological standpoint; however, the literature reports numerous studies on steroidal derivatives, different from those described here, suggesting a possible and variable biological activity. The reactivity of Norethisterone acetate was also investigated in 1,3-dipolar cycloaddition processes involving nitrile oxides. The structure of Norethisterone acetate is particularly well suited for this study, as it contains both C=C double bonds and C≡C triple bonds capable of acting as dipolarophilic systems in these reactions. Isoxazole chemistry, dating back several decades, has proven to be valuable and promising for the introduction of heterocyclic modifications into steroidal frameworks, with potential effects on the biological activities of known compounds or newly designed molecules sharing a steroidal scaffold. Based on previously reported results obtained in the presence of aromatic nitrile oxides, the 1,3-dipolar reaction of Norethisterone acetate with acetonitrile oxide was examined and afforded, in addition to isoxazoline derivatives with defined regiochemistry and different stereochemistry, the bis-cycloadduct for the first time, in which both the C=C double bond and the C≡C triple bond were simultaneously derivatized by acetonitrile oxide. The methodology can be applied by exploiting the structural diversity of 1,3-dipoles generated from aldehydes as starting materials. In this work, we demonstrated the possibility of expanding the application of 1,3-dipolar cycloaddition reactions in order to obtain a set of readily derivatizable steroids. In parallel, the procedure can be easily employed to design and prepare new steroids with tunable and variable biological activities. This study also revealed a remarkable selectivity outcome: the steroidal scaffold governs both regio- and stereochemistry, leading to structures that are readily predictable on the basis of the well-established selection rules of 1,3-dipolar cycloaddition chemistry. Design, synthesis, and application: these aspects can be effectively synchronized, and new derivatives are currently under continuous development.
Gli steroidi sono composti peridrociclopenteno-fenantreni, costituiti quindi da tre anelli esaciclici e un anello pentaciclico, differentemente ramificati; in linea generale, queste ramificazioni sono posizionate sul primo anello esaciclico (A) e sull’anello pentaciclico (D), ma non è da escludere la loro presenza sugli altri due anelli (B e C). Le diverse classi di steroidi sono classificate secondo 11 tipologie dello scheletro base ed in natura sono utilizzate come reattivo di partenza per la formazione di una moltitudine di composti differenti. È stata messa appunto una metodologia sintetica al fine di derivatizzare alcune strutture steroidee con classici nucleofili molto reattivi, quali idrazine, idrazidi e idrossilammine, che vanno a installarsi sulle funzioni carboniliche degli steroidi oggetto del presente studio. Sono stati utilizzati nucleofili contenenti strutture eterocicliche e le reazioni condotte hanno portato ad ottimi risultati con buone rese e purezze tendenzialmente elevate. Queste reazioni, pertanto, possono essere sfruttate per la funzionalizzazione di un’ampia classe di steroidi, formando derivati eterociclici potenzialmente attivi biologicamente. L’esito di questo studio preliminare di funzionalizzazione rapida degli steroidi sembra particolarmente promettente anche per l’introduzione di funzionalità complesse, anche disponibili commercialmente, riducendo in questo modo in maniera drastica il numero di passaggi sintetici richiesti per raggiungere l’obbiettivo desiderato. Nonostante il preliminare successo sintetico, questi derivati devono ancora essere valutati dal punto di vista farmacologico; in letteratura, però, sono presenti moltissimi lavori di valutazione di derivati steroidei, diversi da quelli presentati in questo lavoro, che portano a presuppore una conseguente possibile e variabile attività biologica. È stata inoltre studiata la reattività del Noretisterone acetato nei processi di cloaddizione 1,3-dipolare di nitril ossidi. La struttura del Norestisterone acetato si presta molto bene a questa indagine in quanto contenente legami C-C doppi e tripli in grado di agire come sistemi dipolarofili in queste reazioni. La chimica degli isossazoli, risalente a molti decenni fa, sembra essere promettente e preziosa per l'introduzione di modifiche eterocicliche nelle strutture steroidee, con potenziali effetti sulle attività biologiche di composti noti o composti nuovi che condividono uno scheletro steroideo. Sulla base dei risultati precedentemente ottenuti in presenza di nitril ossidi aromatici, è stata studiata la reazione 1,3-dipolare del Noretisterone acetato con acetonitril ossidi che ha fornito, oltre ai derivati isossazzolinici con regiochimica definita e diversa stereochimica, per la prima volta il bis-cicloaddotto in cui contemporaneamente il doppio legame C=C e il triplo legame C≡C sono stati derivatizzati dall’acetonitril ossido. La metodologia può essere applicata sfruttando la varietà di strutture degli 1,3-dipoli aventi le aldeidi come composti di partenza. In questo lavoro, abbiamo dimostrato la possibilità di espandere l'applicazione delle reazioni di cicloadizione 1,3-dipolare al fine di ottenere un gruppo di steroidi facilmente derivatizzabili. Parallelamente, la procedura è facilmente applicabile per progettare e preparare nuovi steroidi con attività biologiche variabili e modulabili. Da questo studio è emerso un risultato di selettività notevole: lo scheletro steroideo orienta sia la regio- sia la stereochimica, portando a strutture facilmente prevedibili sulla base delle regole di selezione imposte e ben note dalla chimica delle cicloaddizioni 1,3-dipolari. Progettazione, sintesi e applicazione: questi aspetti possono essere sincronizzati e nuovi derivati sono costantemente in preparazione.
Steroidi come elettrofili e dipolarofili
LAGRASTA, ERIKA
2024/2025
Abstract
Steroids are perhydrocyclopentanephenanthrene compounds, consisting of three six-membered rings and one five-membered ring, differently substituted. In general, these substituents are located on the first six-membered ring (A) and on the five-membered ring (D), although their presence on the other two rings (B and C) cannot be excluded. The different classes of steroids are categorized into 11 types according to the basic carbon skeleton and, in nature, they serve as starting frameworks for the formation of a wide variety of compounds. A synthetic methodology was developed to derivatize selected steroidal structures using highly reactive classical nucleophiles, such as hydrazines, hydrazides, and hydroxylamines, which selectively react with the carbonyl functionalities of the steroids investigated in this study. Nucleophiles bearing heterocyclic moieties were employed, and the reactions afforded excellent results, providing good yields and generally high purities. These transformations can therefore be exploited for the functionalization of a broad class of steroids, leading to heterocyclic derivatives with potential biological activity. The outcome of this preliminary rapid functionalization study of steroids appears particularly promising also for the introduction of complex functionalities, including commercially available ones, thereby drastically reducing the number of synthetic steps required to achieve the desired goal. Despite the preliminary synthetic success, these derivatives have not yet been evaluated from a pharmacological standpoint; however, the literature reports numerous studies on steroidal derivatives, different from those described here, suggesting a possible and variable biological activity. The reactivity of Norethisterone acetate was also investigated in 1,3-dipolar cycloaddition processes involving nitrile oxides. The structure of Norethisterone acetate is particularly well suited for this study, as it contains both C=C double bonds and C≡C triple bonds capable of acting as dipolarophilic systems in these reactions. Isoxazole chemistry, dating back several decades, has proven to be valuable and promising for the introduction of heterocyclic modifications into steroidal frameworks, with potential effects on the biological activities of known compounds or newly designed molecules sharing a steroidal scaffold. Based on previously reported results obtained in the presence of aromatic nitrile oxides, the 1,3-dipolar reaction of Norethisterone acetate with acetonitrile oxide was examined and afforded, in addition to isoxazoline derivatives with defined regiochemistry and different stereochemistry, the bis-cycloadduct for the first time, in which both the C=C double bond and the C≡C triple bond were simultaneously derivatized by acetonitrile oxide. The methodology can be applied by exploiting the structural diversity of 1,3-dipoles generated from aldehydes as starting materials. In this work, we demonstrated the possibility of expanding the application of 1,3-dipolar cycloaddition reactions in order to obtain a set of readily derivatizable steroids. In parallel, the procedure can be easily employed to design and prepare new steroids with tunable and variable biological activities. This study also revealed a remarkable selectivity outcome: the steroidal scaffold governs both regio- and stereochemistry, leading to structures that are readily predictable on the basis of the well-established selection rules of 1,3-dipolar cycloaddition chemistry. Design, synthesis, and application: these aspects can be effectively synchronized, and new derivatives are currently under continuous development.| File | Dimensione | Formato | |
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Descrizione: Tesi sperimentale sulla sintesi di derivati steroidei
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https://hdl.handle.net/20.500.14239/33984