Browsing by Author "Petersen, Wade"

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    Chiral acyl radicals generated by visible light enable stereoselective access to 3,3-disubstituted oxindoles: application toward the synthesis of (–)- and (+)-physovenine
    (2024) Späth, Josef; Petersen, Wade; Hunter, Roger
    Radical species serve as powerful tools for carbon-carbon bond formation in synthetic organic chemistry. Such species can be formed in an efficient and environmentally friendly manner by way of photoredox catalysis, which uses a photocatalyst in conjunction with visible light (typically) to generate the necessary environment for radical generation under extremely mild conditions. This work outlines the development of a novel imidazolidinone-derived acyl radical, generated under photoredox catalysis, and its application toward the stereoselective synthesis of 3,3- disubstituted oxindoles via an additional-cyclisation cascade sequence to acrylamide precursors. 6 oxindoles were produced in up to 85% yield, with moderate diastereoselectivity of up to 2.2:1, but which could be easily separated by standard chromatography to yield pure diastereomers. Mechanistic studies, by virtue of TEMPO-trapping experiments provided strong support for the existence of the proposed acyl-radical, and further synthetic utility of the research was demonstrated in formal synthesis of the natural product (–)-physovenine, a member of the biologically active cyclotryptamine alkaloids.
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    New explorations in visible-light mediated energy and single electron transfer for nitrogen heterocycle synthesis
    (2024) Oddy, Meghan Jessica; Petersen, Wade
    With the recent push toward green chemistry, photocatalysis has emerged as a powerful alternative for reactions that might otherwise need high temperatures, poor atom economy or harsh reactants to proceed. This thesis explores the use of visible-light mediated photocatalysis for the synthesis of biologically important nitrogen containing heterocycles, investigating both single electron transfer and energy transfer methods. The results section of this thesis is presented in three chapters, each focusing on a different ring size, namely 4, 5 and 6 membered nitrogen heterocycles. Chapter two explores the use of photocatalysis to enable stereoselective access to 3,3-disubstitued oxindoles via newly developed N-acyl chiral auxiliaries, serving as chiral C1 radical synthons. These acyl radicals are generated under visible-light mediated single electron transfer to N-hydroxyphthalimido esters, which then undergo a radical addition–cyclisation sequence with N-phenyl acrylamides. A model 3,3-disubstitued oxindole is isolated as separable diastereomers in 81% yield with 2.2:1 dr. This advanced intermediate could be telescoped toward the formal synthesis of the natural cyclotryptamine alkaloid, physovenine. Chapter three describes an efficient thioxanthone-catalysed triplet energy transfer process for the synthesis of 3,4-dihydroquinolin-2-ones from N-acrylamides. This work features a rare example of a metal-free formal C(sp2)–H/C(sp3)–H arylation mediated by visible-light. Using 450 nm light with 2 chlorothioxanthone in 2,2,2-TFE:CHCl3, a selection of 23 substituted 3,4-dihydroquinolin-2-ones are isolated in moderate to excellent yields (16–97%). The reaction is amenable to gram-scale synthesis, and the 3,4-dihydroquinolin-2-ones obtained are easily oxidized to the corresponding quinolin-2-ones, ultimately producing facile access to two privileged bioactive scaffolds. The reaction mechanisms presented are supported by Stern-Volmer plots as well as deuterium labelling studies. Finally, chapter four explores the synthesis of 2-azetidinones (β-lactams) from simple acrylamide starting materials by visible-light-mediated energy transfer catalysis. The reaction features a C(sp3)−H functionalisation via a variation of the Norrish–Yang photocyclisation involving a rare carbon-to-carbon 1,5-hydrogen atom transfer. The proposed mechanism is supported by deuterium labelling and DFT calculations. The optimised reaction conditions use 2-chlorothioxanthone under irradiation with 405 nm light which enables the synthesis of 30 substrates in moderate to excellent yields (40–98%), mostly as 2 separable diastereomers (generally 1.5:1 dr).
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    Photochemical synthesis of dihydroquinolinones and their investigation toward macrocycle synthesis via ring expansion
    (2023) Magura, Chipo; Petersen, Wade
    There are several macrocyclic drugs that are currently on the market. As representative examples, erythromycin and azithromycin are currently approved antibiotics. Macrocycles are also used to treat other infectious diseases, for example, natamycin and amphotericin B are used as antifungal agents and ivermectin is used as an antiparasitic agent.1 The synthesis of macrocyclic compounds is typically done using an end-to-end macrocyclization approach. However, challenges arise due to competing intermolecular reactions leading to the use of high dilution conditions. It is therefore important that synthetic chemists develop general and modular methods for their synthesis in order to produce the next generation of therapeutic macrocyclic drugs. One such method is the Successive Ring Expansion (SuRE) protocol developed by Unsworth and co-workers at the University of York, offering an innovative and straightforward way to access such compounds. With this methodology, a cyclic starting material such as a lactam, is coupled to a N-protected β-amino acid fragment which is then deprotected to yield the ring-expanded cyclic product following rearrangement. Given our group's interest in the development of dihydroquinolinones (DHQs) and realizing that their suitability for SuRE had not yet been investigated, we recognised an opportunity to collaborate with the Unsworth group, as it would enable the synthesis of more diversely functionalised macrocyclic molecules. Visible-light mediated triplet energy transfer has enabled the synthesis of N-substituted DHQs by our group and others through a formal C(sp2)-H/C(sp3)-H hydroarylation.2–5 However, none of these methods have reported such syntheses producing the N-unsubstituted DHQ — which is required for the SuRE. Thus we first set out to optimise this photochemical cyclisation to enable the direct formation of Nunsubstituted DHQs. Gratifyingly, this reaction was successfully developed, requiring the use of an iridium photocatalyst, and was able to provide a diverse range of unprotected DHQs that could be investigated in the SuRE In application towards the synthesis of macrocycles using the SuRE methodology, a model DHQ was first investigated. Unfortunately, in the event, the N-unsubstituted DHQ was obtained instead of the ring-expanded product.After facing this challenge, Conjugate Addition or Ring Expansion (CARE) method, also developed by the Unsworth and coworkers was considered6, however the acylation to generate the key starting material was unsuccessful. To overcome the acylation, and in a third strategy (returning to a SuRE approach), we thought to replace the amide linker with an alkyl chain instead and effect a SuRE macrocyclization following a Staudinger deprotection in the presence of triphenylphosphine. The intermediate was successfully synthesised, and while a trial reaction revealed promising results, this is still under investigation. Analysis of the product mixture by NMR suggested the desired product formation, however residual triphenylphosphine oxide (TPPO) complicated this analysis. Time constraints prevented further investigation, however methods to remove or avoid the formation of TPPO will be a topic of future work. Since our direct DHQ synthesis requires an expensive iridium photocatalyst, we considered a demethylation strategy for the synthesis of N-unsubstituted DHQs from N-methyl DHQs — as these can be accessed using inexpensive thioxanthone photosensitisers.3 A related demethylation of amides was reported by Yi et al using a Cu catalyst and NFSI as an oxidant7 and in our attempt to use this procedure to produce the unprotected DHQ, we obtained the unsaturated quinolinone, instead. Quinolinones are important biological molecules and are used as antiviral, anticancer, antiulcer, and antihistaminic agents in medicinal chemistry, and thus we were very pleased with this result. These relatively mild oxidation conditions also offer opportunities for late-stage functionalization.8 Ultimately, through the use of photocatalysis, we could develop this oxidation chemistry to avoid the need for a metal — favouring a thioxanthone photosensitiser over a copper catalyst, and the reaction could be conducted at ambient temperature, rather than at 80 oC as per Yi et al's conditions. This methodology is of great importance because existing methods for this transformation make use of expensive transition metals such as Pd8–10 and Pt11 or require even higher temperatures.12
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    Radical decarboxylation strategies for the synthesis of nitrogen-containing heterocycles
    (2023) Mazodze, Crispen Munashe; Petersen, Wade
    Nitrogen-containing heteroaromatics are ubiquitous in nature. In addition, 75% of FDA-approved drugs currently on the market are based on these compounds, establishing them and their analogues as a primary source of therapeutic agents in the pharmaceutical industry. The structural complexity exhibited by these nitrogen-based moieties necessitates the development of innovative strategies that demand mastery beyond routine and traditional organic chemistry that most synthetic chemists typically cultivate. The second chapter of this thesis describes the use of novel delayed radical precursors in Mn (OAc)3·2H2O mediated oxidative radical cyclization-fragmentation-dimerization processes from Banilides. The first part presents a sequential oxidative radical cyclization-decarboxylative-dimerization process from β-oxoacids, forming three bonds in a one-pot manner. This approach was successful with a diverse range of 3,3′-bisoxindoles substrates obtained in up to 96% yield. The second part of chapter two details a complementary and closely related sequential one-pot oxidative radical cyclization-deformation-dimerization process from β-oxoanilides, this motion was also applicable to a wide array of 3,3′-bisoxindoles with up to 98% yield. There are no clear-cut distinctions between the decarboxylative and deformylation approaches as they appear to be highly complementary to each other. The chapter concludes with a further demonstration of the utility of this methodology, in the formal synthesis of the calycanthaceae alkaloid, (±)-folicanthine via to the best of our knowledge the shortest linear route. The third chapter of this thesis describes a general extension of the second chapter, which involves an atom-efficient silver-catalysed double decarboxylative strategy for the one-step synthesis of quinolin2-ones. This is achieved via an oxidative radical addition–cyclisation–elimination cascade sequence of oxamic acids to acrylic acids, mediated either thermally or photochemically. The reaction proved to be successful with a wide range of 32 quinolin-2-ones synthesized in of up to 84% yield. The method features an elegant double-disconnection approach, which constructed the quinolin-2-one core through the formal and direct addition of a C(sp2)–H/C(sp2)–H olefin moiety to a phenyl formamide precursor. The theme of the thesis is centred around the synthesis of nitrogen-containing heteroaromatics using facile and efficient protocols that offer catalyst, atom and energy efficiency, while also providing substantial economic advantages. Additionally, the thesis presents systematic and in-depth mechanistic studies on both developed protocols to support and offer compelling evidence for the proposed mechanistic cycles. These studies provide insights into the reaction pathways and help establish a more comprehensive understanding of the radical synthetic pathways.