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Applications of radical reactions for the synthesis of β-amino acids and carbonyl compounds

Abstract : In this thesis, we focus on the application of xanthate based radical chemistry for the synthesis of ketones, esters and β2-amino acids derivatives. This research overcomes many drawbacks associated with alkylation of ketones and esters when using enolate method, and complement the methods of dialkylation of unsaturated ketones. The xanthate transfer process also offers a convergent route to potential bioactive amino acids.We firstly summarize the utility and synthetic strategies of amino acids, then we describe a convergent route to β2-amino acids derivatives by adopting the xanthate transfer process. The xanthate can bear either an ester or free carboxylic acid group. When the α-xanthyl-β-amino ester is used as starting xanthate, almost all reactions were performed neat and provided the desired adducts in good to excellent yield. When the xanthate was bearing a free acid group, the addition to hetero-rings was accompanied with spontaneous decarboxylation to afford the N-protected heteroarylethylamines. In some cases, the unexpected vinyl products were separated and the plausible mechanism is also discussed.Then we briefly introduce the previously reported methods for alkylation of ketones, and then move on to our own research. By replacing enolates and enolate equivalents with α-ketonyl radicals, many disadvantages of alkylation of ketones such as aldol condensation, lack of regioselectivity, O-alkylation and polyalkylation can be minimized. Then we focus on the dialkylation of α, β-unsaturated ketones. In contrast with traditional ionic methods which have to use organocopper and alkyl halides, our new method incorporates both ionic and radical process which avoid the use of aforementioned organometallic agents and alkyl halides. It is noteworthy that the Michael addition step was significantly affected by stereochemistry while the radical addition step was little affected. Based on this methodology, various dialkylated cyclopentanones were rapidly synthesized including ring-fused compounds which are commonly present in natural products. Finally, in order to generalize the alkylation of carbonyl compounds, α-alkylation of esters was also investigated. In the scope extension section, we test the radical additions to different functionalized alkenes. All reactions proceeded smoothly and show a broad functional group tolerance. Reactions using lactones as substrates were also performed with the same conditions and were shown to be equally efficient.In summary, we used this xanthate transfer process as a powerful tool to synthesize many useful ketones, esters and amino acid derivatives. This metal-free method features mild reaction conditions, excellent functional group compatibility and good substrate scope which we anticipate will be, especially useful in the late-stage functionalization of natural products and drugs.
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Xuan Chen. Applications of radical reactions for the synthesis of β-amino acids and carbonyl compounds. Organic chemistry. Institut Polytechnique de Paris, 2020. English. ⟨NNT : 2020IPPAX042⟩. ⟨tel-02983194⟩

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