Resumen de Carboxylic acids as directing groups for intramolecular catalytic oxidation of unactivated c(sp3)-h bonds with bioinspired catalysts
The lack of reactivity of largely abundant hydrocarbons makes the few practical processes capable of converting them in more valuable compounds, highly desired. This aspect confers to catalytic Carbon-Hydrogen (C-H) bond oxidation a privileged place in modern organic chemistry, since this powerful reaction installs oxygen atoms into ubiquitous and notoriously poorly-reactive C-H bonds thus, enabling straightforward product diversification. After intense investigation of the catalytic action of enzymatic C-H bonds oxidations, the scientific community has turned its attention towards bioinspired Fe and Mn coordination complexes as promising candidates to reproduce such naturally occurring oxidations, in presence of H2O2 and carboxylic acids as co-ligands. Despite some progresses on oxidation-site predictability and chemoselectivity have been achieved with these artificial systems, enantioselective oxidation of aliphatic C-H bonds, capable to produce chirality at the forged C(sp3)-O bond, remains limited to enzymatic transformations. Realization of this goal would require conceptual innovations in order to address the chemo-, site- and stereo-selectivity challenges associated with the formation of chiral C(sp3)-O bond from a specific non-activated alkyl C-H bond. In this scenario, the aim of this thesis is the discovery of innovative methodologies precisely designed for this challenging task.
Therefore, in Chapter III we developed a protocol for the intramolecular oxidation of prochiral secondary C-H bonds in which carboxylic acids, acting as directing groups for the oxidant species, promoted a highly site-selective and lactone product chemoselective oxidation. The versatility and general applicability of the reaction is witnessed by the successful oxidation of 25 substrates involved in this study, of note, even at strong primary C-H bonds. The data collected concerning the reaction stereoselectivity acquired in this chapter were fundamental for the development of the highly enantioselective C-H lactonization described in Chapter IV. Here, rational catalyst design and judicious choice of the substrates enabled the first example of non-enzymatic, chiral C(sp3)-O bond-forming catalytic reaction from an unactivated C-H bond. Mechanistic considerations are collected in Chapter V, where rationally designed experiments unveiled the single contribution of reagents and solvents to the reaction efficiency. More interestingly, isotopic labelling experiments bring to light a carboxylate rebound pathway, unprecedented in the mechanistic landscape of Fe and Mn bioinspired oxidations.
