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Metal catalysed asymmetric C–C bond forming reactions

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Universitat de Barcelona. Departament de Química Inorgànica i Orgànica

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[eng] This thesis presents novel methodologies for asymmetric C–C bond forming reactions, focusing on catalytic approaches involving chiral nickel(II) complexes. Chapter I introduces a new approach to direct asymmetric aldol reactions using thioimides. A new method was successfully developed to obtain TIPS-protected anti-aldol adducts with exceptional stereocontrol, achieving high diastereoselectivities (ca 80:20) and enantioselectivities up to 99% ee, using the chiral complex [(R)- Tol-BINAP]NiCl2 as the catalyst. This approach was applied to a wide range of substrates, which demonstrated the robustness of this method.
Moreover, preliminary studies with cobalt and iron complexes suggest that these metals could offer promising alternatives for future development of sustainable catalytic systems. The thesis also explores the reactivity of propargyl aldehydes, though background processes without sufficient stereochemical control hindered successful outcomes.
Additionally, the acetate aldol reactions, known to be specially challenging substrates compared to the propionate counterparts, was optimized. Unfortunately, all catalysts attempted yielded poor enantioselectivities, which forced us to discard this approach. In addition, efforts with α,β-unsaturated aldehydes struggled with regioselectivity, though it was found that using less sterically demanding Lewis acids, such as TMSOTf, favoured the 1,2 addition pathway. A special case of α,β-unsaturated aldehyde, propargyl aldehyde, was protected with a cobalt complex. This approach however presented several challenges associated with a background reaction, which eroded the enantioselectivity significantly and could not be resolved.

A significant achievement of this research was found in Chapter II. It consisted in the development of a novel asymmetric Michael addition to α,β-unsaturated aldehydes catalysed by chiral nickel(II) complexes. This method enables access to all possible stereocenters through the modification of the chiral ligand, showing excellent regioselectivity, with most substrates exhibiting a regioselectivity ratio (1,2:1,4) of over 1:99. The method proved robust in terms of enantioselectivity, consistently yielding enantiopure compounds (99% ee) in a wide range of substrates. The [(R)-DTBM-SEGPHOS]NiCl2 complex was identified as the most effective for producing syn Michael adducts with high diastereoselectivity, though limitations arose with electron- poor substrates and steric hindrance at the Cα position. On the other hand, [(R)-BINAP]NiCl2 furnished the complementary anti counterparts, and it has demonstrated broader substrate tolerance, although slight losses in diastereoselectivity were noted with electron-rich substrates.
The resultant Michael adducts provide valuable enantiomerically pure intermediates, which can be converted into various functional groups, such as esters, amides, alcohols, or aldehydes as demonstrated in Chapter III. A novel reaction was also developed to synthesize chiral lactones in high yields. Additionally, this methodology was applied to the synthesis of the commercial opioid (R,R)- tapentadol, achieving both stereocenters with high control. The six-step synthesis sequence yielded 45% overall, utilizing commercially available reagents and requiring only two chromatographic purification steps, thus offering a scalable and efficient process.
Chapter IV shifts focus to the development of new methods for producing β-amino carbonyl compounds. Direct asymmetric Mannich additions of thioimides to activated imines were attempted but without success, due to the instability of imines and their tendency to promote the formation of undesired silyl ketene acetals of thioimides. Afterwards, N,O- and N,N-aminals were used as imine surrogates. Despite poor results with most of these substrates, N,N-dibenzylaminal arised as a promising substrates for Mannich additions.
 
Finally, a stereodivergent approach using 1,3-dipolar cycloadditions of nitrones yielded excellent results. The nitrone addition to N-acryl thioimides, catalysed by either [(R)-DTBM- SEGPHOS]NiCl2 or [(S)-BINAP]NiCl2, produced cycloaddition products with endo and exo selectivity, respectively. This opens avenues for further development of highly stereocontrolled carbon-carbon bond-forming reactions from thioimides, driven by chiral nickel(II) complexes. The research offers valuable insights and lays the groundwork for future advancements in asymmetric catalysis and stereoselective synthesis.

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[spa] Esta tesis presenta nuevas metodologías para la formación asimétrica de enlaces C– C, centrándose en catalizadores basados en complejos quirales de níquel(II).
En el Capítulo I, se introduce un enfoque innovador para reacciones aldólicas asimétricas directas utilizando tioimidas, logrando aductos anti-aldólicos con un control estereoquímico excepcional (hasta 99% ee) mediante el complejo [(R)-Tol- BINAP]NiCl2. También se exploran metales alternativos como cobalto y hierro, con potencial para catalizadores sostenibles. Se estudiaron también los límites de esta metodología, como el control regioselectivo en aldehídos α,β-insaturados y la pobre enantioselectividad en sustratos difíciles como las reacciones aldólicas de acetato.

El Capítulo II destaca un logro importante: el desarrollo de una adición de Michael asimétrica a aldehídos α,β-insaturados, catalizada por complejos quirales de ní quel(II). Este método muestra alta regioselectividad y enantioselectividad (99% ee) en una amplia gama de sustratos. El complejo [(R)-DTBM-SEGPHOS]NiCl2 resulto ser el más eficaz para obtener aductos sin con alta diastereoselectividad, mientras que [(R)-BINAP]NiCl2 fue más adecuado para aductos anti.

En el Capítulo III, los aductos de Michael se convierten en diversos grupos funcionales como e steres, amidas, aldehídos o alcoholes, demostrando versatilidad de estos intermedios. Además, se aplicó esta metodología en la síntesis del opioide comercial (R,R)-tapentadol con un rendimiento global del 45% y obteniendo un solo isómero, logrando un proceso eficiente y escalable.
El Capítulo IV aborda la sí ntesis de compuestos β-amino carboní licos mediante adiciones asimtricas de Mannich, aunque enfrento problemas con la inestabilidad de las iminas. No obstante, se lograron resultados prometedores utilizando N,N- dibenzilaminales como sustitutos de iminas y a través de cicloadiciones 1,3- dipolares de nitronas, abriendo nuevas vías para el desarrollo de reacciones estereocontroladas impulsadas por complejos de níquel(II).

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Tesis Doctorals - Departament - Química Inorgànica i Orgànica

# metadata.dc.title[].value
Metal catalysed asymmetric C–C bond forming reactions