Enolates Go Radical. Stereoselective Radical Alkylation Reactions of Titanium Enolates from N-Acyl Oxazolidinones with Carboxylic Acid Derivatives. Synthesis of Umuravumbolide
[eng] This thesis consists in the development of a new methodology of α-alkylation of carbonyl compounds and its application to the synthesis of small molecules with therapeutic interest. In this context, the alkylation of carbonyl compounds is usually achieved by alkylation of nucleophilic metal en...
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| Tipo de documento: | tese |
| Estado: | Versão publicada |
| Data de publicação: | 2022 |
| País: | España |
| Recursos: | Universidad de Barcelona |
| Repositório: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/187870 |
| Acesso em linha: | https://hdl.handle.net/2445/187870 http://hdl.handle.net/10803/674908 |
| Access Level: | Acceso aberto |
| Palavra-chave: | Química orgànica Titani Estereoquímica Organic chemistry Titanium Stereochemistry |
| Resumo: | [eng] This thesis consists in the development of a new methodology of α-alkylation of carbonyl compounds and its application to the synthesis of small molecules with therapeutic interest. In this context, the alkylation of carbonyl compounds is usually achieved by alkylation of nucleophilic metal enolates with alkyl halides through a SN2 substitution mechanism. This approach entails a limited scope in terms of alkylating agent since the alkyl halide should be activated enough to undergo such substitution. In this thesis, a radical alternative which uses titanium(IV) enolates is presented. In fact, titanium enolates are found in equilibrium between a nucleophilic species, the titanium(IV) enolate, and a biradical species, the titanium(III). This equilibrium is the result of a valence tautomerism that lies in an electron transfer from the ligand (the enolate) to the metal center (titanium), which is reduced to titanium(III). As a consequence of this redox process, the enolate becomes an open shell species with three electrons in the acyl moiety instead of four, which grants the enolate with radical reactivity. In chapter one, this reactivity is exploited to achieve the radical alkylation of titanium(IV) enolates from chiral N-acyl oxazolidinones with diacyl peroxides. When mixed with the enolate, these species break homolytically to give an acyloxy radical, which upon decarboxylation, generates an alkyl radical that recombines with the titanium enolate to give a single diastereomer of the alkylated product. The high reactivity of alkyl radicals permits us to perform the alkylation with deactivated primary and secondary alkyl groups, a transformation that is difficult to achieve by other established methodologies. A broad scope of primary and secondary diacyl peroxides including different functional groups such as unsaturations, phenyl or esters is described. In addition, the alkylation can be performed on a vast range of titanium enolates, which can also include such functionalities as well as an oxygen, nitrogen or chlorine in the α position. This methodology is finally applied to the straightforward synthesis of arundic acid. In chapter two, the total synthesis of umuravumbolide, a substituted pyrone extracted from a medicinal plant, is described. The synthesis includes the abovementioned alkylation of a titanium enolate derived from glycolic acid to furnish the stereocenter in the side chain. Other key steps are the formation of a Z double bond and an asymmetric allylation of a sensitive aldehyde intermediate. Chapter three describes an analogous alkylation procedure to that one investigated in the first chapter, only this time, tert-butyl peresters are used instead of diacyl peroxides. This change allows the alkylation of titanium enolates derived from chiral N-acyl oxazolidinones with secondary and even tertiary alkyl groups, a transformation that is rarely reported in the literature. A broad scope of secondary and tertiary peresters is described for this transformation. And similarly to chapter one, different titanium enolates including functional groups such as esters, unsaturations or heteroatoms can be used for such alkylation procedure. Finally, in chapter four other alkylating agents that are able to render an alkyl radical are investigated. However, the alkylation product is not obtained in any of the examples tested against titanium enolates. Therefore, the substitution of titanium for another metal that can render biradical enolates but at the same time can be used in catalytic amounts is attempted. For that, a screening of different metals in various oxidation states is performed. In this case, TEMPO is used to trap a putative biradical enolate. |
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