Asymmetric Phase-Transfer Catalysis: Synthetic Applications and Mechanistic Insights

This thesis involves three different published manuscripts (Chapter 2 submitted to peer review, Chapters 3 and 4 published) and unpublished data (Chapter 5) in the area of organocatalysis and Phase-Transfer Catalysis: mechanistic insights, synthetic applications and new catalyst syntheses are reported. These chapters are preceded by an introductory overview (Chapter 1) of the two common themes found throughout the projects: Phase-Transfer Catalysis (PTC) and Sulfonic Acids.

PTC is the most exploited organocatalysis due to its benefits such as simple experimental procedures, mild reaction conditions, inexpensive and environmentally benign reagents and solvents, and possible scale-up. Among the chiral catalysts used for asymmetric PTC reactions, Cinchona alkaloid derivatives are undoubtedly the most common because of their efficiency and convenience. Alongside their development carried out in recent decades, many theories and studies have arisen to shed light upon the nature of their interaction with the substrates of a reaction, which leads to the enantioselective outcomes of reactions. In Chapter 2, we report a deep mechanistic insight into this interaction, revealing a crucial role played by the N⁺CHs of the quaternary catalyst. When observed in solution and with neutral species, thanks to ¹H-NMR titrations of Cinchona alkaloid PTC bromides with different neutral hydrogen bond acceptors, the interactions between catalyst and substrates were elicited as H-bonds. The correspondent BArF salts were also titrated, showing a different pattern of H-bonding. When studied in solution and in solid state with negatively charged substrates, thanks to ¹H-NMR and X-ray data of probes bearing ammonium and sulfonate or enolate groups within the same framework, catalyst and substrate surrogates interacted via ion-dipole interactions. The high directionality exerted by both H-bonds and ion-dipole interactions between catalysts and substrates could rationally explain how these interactions are pivotal to the enantioselectivity. The findings were further confirmed by appropriate computational studies.

In Chapter 3 and Chapter 4 two examples of synthetic applications of asymmetric organocatalyses are reported, involving the use of bifunctional thiourea catalysts and Cinchona-alkaloid PTCs respectively.

In Chapter 3, the mild procedure previously reported by Adamo’s group for the asymmetric addition of sodium bisulfite to olefins catalysed by Cinchona-thiourea catalysts, was exploited. This allowed us to synthesise for the first time enantioenriched ginge and shogasulfonic acids in natural and unnatural configurations. These compounds are recognised as the active principles of Ginger rhizome, exhibiting antiemetic and stomach protecting effects. The same sulfonylation methodology was also involved in Chapter 2 for synthesising the ammonium-sulfonate probe.

In Chapter 4, a new procedure for the enantioselective synthesis of 3,4-dihydropyran-2-ones is reported. The optimized reaction proceeded via PTC addition-cyclisation of acetylacetone to cinnamic thioesters, catalysed by N-phenylquininium bromide and the system base/phenol. Mechanistic insights concerning the catalytic cycle of reaction are also indicated.

Finally, we decided to synthesise a new class of potential PTCs that could combine the main features of the most efficient catalysts reported in the literature: chiral ammonium betaine scaffold, Cinchona alkaloid derivatization, and ammonium-sulfonate interaction. The synthetic approaches and the characterization of the final designer products are reported in Chapter 5.

Complete abstracts of the projects are reported as distinct paragraphs in each chapter.