New designs in organocatalysis to unlock novel catalytic systems and complex chemical spaces

In Chapter 1, a general introduction to catalysis and its branches that will be encountered in this manuscript has been given. In Chapter 2, an application of a novel class of aminocatalysts for the asymmetric Michael addition of masked acetaldehyde as dimethyl acetal to β-nitrostyrenes to produce key intermediates for the synthesis of a class of APIs (Active Pharmaceutical Ingredients) will be shown. These catalysts are specifically designed to work in water acting like micelles, thus avoiding the use of polluting organic solvents, while the acetaldehyde is released using catalytic amount of Amberlyst-15, an acidic heterogeneous resin. Critical to the success is the use of chemometrics-assisted ‘Design of Experiments’ (DoE) optimization during the development, which allowed to investigate the chemical space in a rational way. An application of Asymmetric Counteranion Directed Catalysis merged with nanomaterials application will be described in Chapter 3. Indeed, a specifically designed type of Carbon Dots (a novel class of nanomaterials) functionalised with primary amine moieties has been used to perform asymmetric aminocatalysis via iminium ion recurring to a chiral phosphoric acid to transfer the chiral information in the 1,4-reduction of α,β-unsaturated-β,β-disubstituted aldehydes using dihydropyridines as reductants. A correlation between the features of the CDs’ surfaces and their catalytic performance was shown, and the catalytic activity of the employed CDs proved to be higher than simple molecular primary amines. In Chapter 4, a new route towards the synthesis of silyl-heterocycles via catalytic 1,1-carboboration is reported. Due to the shortage of methods to synthetise this scaffold, four- and five-membered silyl-heterocycles are a challenge: however, the use of catalytic carboboration reaction shows how these heterocyclic cores can be easily prepared recurring to the use of [H-B-9-BBN]2 as catalyst and pinacolborane in stoichiometric amount to regenerate the catalyst and functionalise the product, opening the path for downstream derivatisations. Mechanistic studies, including 13C-labelling, computational studies, and single-turnover experiments, suggest a reaction pathway proceeding by 1,2-hydroboration, 1,1-carboboration, and transborylation to release the alkenyl boronic ester product and regenerate the borane catalyst. In Chapter 5, a feasible synthesis of a primary metabolite of Cannabidiol (CBD), 7-hydroxy Cannabidiol, is described. Due to the wide interest the CBD had gathered in recent years, the study of its metabolites is of primary importance to understand its biological action for future clinical trials. However, the synthesis of this metabolites, is a challenge due to the many synthetic steps required and the consequent low yields they lead. In this chapter, an eight-step synthesis of 7-hydroxy Cannabidiol from CBD is described, recurring to easy reaction condition and to a final Piers–Rubinsztajn reaction as the key to enable a mild deprotection, affording the desired product in 31% overall yield. In Chapter 6, an overview of the other projects I have contributed to will be given. The first one is a review on the alkali and alkali-earth metals salts of chiral phosphoric acids to which I have contributed as main author. In this review, the developments achieved in this field since its beginning are exposed in a critical perspective, focusing on their reaction mechanism and the potential future developments. The second project, to which I have contributed as secondary author, presents the development of a new and greener synthetic method of Dibenzosuberone (DBS), an important intermediate for the preparation of active pharmaceutical ingredients (API), born from a collaboration with the pharmaceutical company Dipharma Francis.