Resumen de Approaches to asymmetric catalysis mediated by ploymer-supported and homogeneous organocatalysts
Justification and needs for the research: The discovery and design of organocatalysts with better efficiency, able to promote new transformations and reaching higher turnover numbers has attracted a lot of attention in organocatalysis. This thesis focuses on the synthesis of organocatalysts, especially polymer-supported ones and their application in various asymmetric transformations.
Methodologies: My doctoral research mainly based on immobilized catalytic systems. First I synthesized different catalysts and immobilize onto polymers . After the development of immobilized catalysts, batch and continuous flow applications on asymmetric catalysis have been carried out. Application of continuous flow in an asymmetric formal [4+2] cycloaddition reaction catalyzed by a supported isothiourea catalyst has been successfully set up. ICIQ's Research Support Area provided the scientific instrument as follows: X-Ray Diffraction, High Resolution Mass Spectrometry (HRMS), Nuclear Magnetic Resonance (NMR), Chemical Reaction Technologies, Thermal Analysis and Electrochemistry, Spectroscopy, etc.
Conclusions: In this thesis, the first chapter is a general introduction of organocatalysis dealing with the concept and mechanisms. The most representative activation modes of aminocatalysis are presented in this chapter, as some of them will be exploited in this thesis.
Chapter II describes the development of a H-bond-directing aminocatalyst for the asymmetric [4+2] cycloaddition reactions of alkylidene pyrazolones with enals. The more hindered 4-hydroxy dinaphthylprolinol catalyst has been prepared and displayed higher reactivities and enantioselectivities in the [4+2] cycloadditions, affording the tetrahydropyranopyrazole derivatives containing three contiguous stereocenters with good results (up to 89% yield, 13:1 dr, and 99% ee).
Chapter III summarizes a formal [4+2] cycloadditions of unsaturated heterocycles with in situ activated arylacetic acids catalyzed by a robust, immobilized isothiourea. This annulation strategy represents an efficient approach to access a series of six- membered heterocycles and spiro-heterocycles in high yields and very high enantioselectivities (32 examples, 97% mean ee). In addition, recyclability of the immobilized isothiourea catalyst (11 cycles, accumulated TON of 76.8) and its application in continuous flow process (no decrease in yield or ee after 18 h) are also demonstrated.
Chapter IV investigates a periselective asymmetric [8+2] annulation reaction between chiral ammonium enolates (generated in situ from carboxylic acids) and azaheptafulvenes. The [8+2] annulation reactions proceeds smoothly catalyzed by the immobilized isothiourea, yielding the cycloheptatriene-fused pyrrolidone derivatives in high yields and excellent stereoselectivities (up to 85% yield, >20:1 dr, and 98% ee). Moreover, we have demonstrated the derivatization of the resulting [8+2] cycloadducts to give bridgedpolycyclic products via [4+2] cycloaddition, which represents an efficient stereoselective synthetic approach to polycyclic compounds.
Finally, Chapter V focuses on the cascade deoligomerization/cross-aldol reactions of electron-poor benzaldehydes with paraldehyde promoted by a dual catalytic system (PSdiarylprolinol catalyst and PS-sufonic acid catalyst). The dual catalytic system can be recycled ten times by simple filtration of the polymer mixture and mild acidic washing to recover full performance. To overcome the limitation of the deoligomerization/crossaldol reaction with benzaldehyde, we synthesized η6-benzaldehyde Cr(CO)3 as an alternative and successfully applied it in this cascade process. The application of the resulting diol product was proven by reductive amination reaction, affording the wellknown drug (R)-phenoperidine or intermediates of (R)-fluoxetine and (R)-atomoxetine.
