Chiral asymmetric Michael addition of dimethyl malonate and nitromethane to azoalkenes generated in-situ from α-chlorohydrazones

Enantiomers of a chiral drug interacts differently in vivo. Hence, the ability to conduct stereoselective reactions producing predominantly one enantiomer over the other is of much importance in synthetic organic chemistry. The concept of asymmetric organocatalysis is a relatively young in the field of catalysis. However, it has proven to be an extremely handy synthetic strategy to control the enantioselectivity of a reaction. Asymmetric organocatalysts offers several advantages including operational simplicity, their availability, and low toxicity which confer a direct benefit in the production of pharmaceuticals and contribution to green chemistry. This thesis project aims to obtain small, highly functionalised chiral molecules by means of a phase transfer catalysis, using cinchona alkaloid quaternary ammonium salt derivatives as catalyst. The research plan includes the synthesis of series of cinchona alkaloid derivatives, as well as various hydrazones, which will be obtained through a single step reaction between hydrazine and their corresponding α-haloketone. These hydrazones will then serve as precursors to generate azoalkenes in situ, which will promptly interact with an enolate derivative. The presence of the cinchona-based catalyst will facilitate this process, leading to the formation of the target chiral compounds. These target chiral molecules will be characterised using 1H-NMR, 13C-NMR, COSY, NOESY, chiral HPLC and LC-MS. Literature studies have shown that our targeted intermediates can be subsequently transformed into important scaffolds, or even into active principal ingredients by means of Pd/C reduction or an intramolecular cyclization in the presence of TFA.