Alfano, Antonella Ilenia (2022) Low carbon footprint routes to privileged scaffolds. [Tesi di dottorato]

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Abstract

This PhD thesis was focused on the development of greener and more sustainable organic reactions for the preparation of privileged scaffolds in medicinal chemistry. In most of the examples reported in the present thesis, the newly conceived protocols relied upon the use of flow chemistry in its sustainable declination. In particular, during these three years, I focused my attention on indoline-based structures, that have always deserved particular importance, being embedded in medicinally relevant compounds of natural and synthetic origins. Fischer indolisation and its variation (interrupted Fischer) still represent the preeminent methods for synthesizing the indole and the indolenine rings. In our quest towards the development of a reliable methodology avoiding or at least minimizing the issues associated to the synthesis of (spiro)indolenines, I reported a telescoped sustainable synthesis of 3,3-disubstituted indolenines through the use of flow chemistry. This newly developed protocol displayed the potential to turn into an effective coupling point for additional flow reactions for multistep syntheses. Accordingly, we sought to investigate the usefulness of (spiro)indolenines as substrates for the generation of peptidomimetic frameworks through a Joulliè-Ugi multicomponent reaction. A telescoped flow approach coupling interrupted Fischer reaction and subsequent Joulliè-Ugi was established, using small amounts of solvent and requiring limited reaction times. The generated peptidomimetic derivatives were evaluated as anti-biofilm agents, thus also fostering further scaffold diversification through the developed methodology. Flow-based approaches are also amenable for organocatalytic applications. While many examples of catalytic asymmetric Strecker are reported on acyclic imines, the same reaction is barely studied on cyclic imines. I applied asymmetric catalysis in flow to (spiro)indolenine substrates in order to develop a fast, sustainable and highly enantioselective Strecker synthesis of cyclic α-amino-nitriles. Furthermore, I recently developed indoline-based metallo-β-lactamase (MBL) inhibitors to be potentially used in synergy with beta-lactam antibiotics to overcome microbial resistance. Inspired by the structure of the drug Captopril, behaving as a weak MBL inhibitor,4 we developed a flow protocol for the fast and diversity-oriented generation of new derivatives, in high yields and optical purities, thus guaranteeing fast structure-activity relationships studies and a focused optimization process. Furthermore, I spent a 6-month period working in the Noël research group, directed by Professor Timothy Noël, University of Amsterdam. I had the possibility to apply the flow chemistry world to the photocatalysis, studying a new methodology for the classic Giese reaction. The aim was the development of a simple and straightforward protocol for hydroalkylation of an electron poor olefin with unactivated alkyl bromides.

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