Synthesis of high-value small molecules through new cascade reactions

Providing non-traditional disconnections has been recently highlighted as one of the “Key messages for organic chemistry when it comes from drug discovery” by scientists from GSK, Pfizer, and AstraZeneca. Apart from the possibility to unlock the access to previously unattainable chemical matter, the establishment of a novel synthetic approach could furnish new solutions in terms of cost, safety, eco-sustainability and time-consuming of a synthetic process. In the realm of ideal synthesis, cascade reactions are well known for their efficiency in building up molecular complexity starting from simple available starting materials or easily accessible building blocks. Hydroxy cyclobutanone HCB derivatives, thanks to their inherent ring strain and their rich chemical reactivity portfolio are important intermediates in organic synthesis. However, at the outset of my PhD, there were limited reported examples of highly functionalized HCB structures thus, since the beginning, I was engaged in their photochemical synthesis. Further investigations in this sense, allowed us to establish a robust procedure for continuous flow cyclization of 1,2 diketones enabling the efficient production of a large amount of these precious building blocks. These novels substrates were methodically reacted with various nucleophiles, enclosing the route to a whole gamut of important functionalized cyclopropane and heterocyclic derivatives always through cascade rearrangements. During the investigations concerning the preparation of the precursor for those cascade processes, a new photocatalyzed radical cascade transformation has been discovered. Radical chemistry provides useful synthetic transformations when controllable product distribution is achieved. The mild and controlled conditions provided by photoinduced electron transfer catalysis procedures are, in many cases, a key to the success of selective radicals cascade transformations. Photoredox catalysis alleviates the use of harsh condition or extra and sometimes not selective radical initiators. Moreover, the employment of organic photocatalyst, low-cost LEDs and 3D Printed technologies can strongly contribute to enhance the sustainability of the synthetic process. Driven by these concepts, a 3D Printed Cap with controlled air and reagents feeds, allow us to tune the photon flux air supply and reagents ratio to guaranteeing a mild aerobic oxidative environment thus disfavouring over oxidation side reactions and instead favouring an efficient outcome of the reaction. This synthetic method allows transforming a series of internal alkyl alkynes into useful and different functionalized aryl-thio-enones through a novel visible-light mediated metal-free radical cascade reaction.