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Title: Synergistic catalysis : merging amino catalysis and metal Lewis acid activation of azaarenes : Green chemistry : first organophotocatalytic approach to the synthesis of phosphoramidates
Author: Meazza, Marta
ISNI:       0000 0004 5923 7694
Awarding Body: University of Southampton
Current Institution: University of Southampton
Date of Award: 2016
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The art of building complex chemical scaffolds in a totally stereoselective manner is one of the cornerstones for Organic Chemists. The quest for new catalytic methodologies that fulfil the requirements of efficiency, green chemistry and predictable stereochemical outcome have become the Holy Grail for synthetic chemists. In the present thesis we investigated new catalytic strategies for the enantioselective synthesis of azaarene scaffolds. Alkyl-azaarenes are common motifs in natural products and pharmaceutical compounds, however few methodologies are devoted to their functionalisation in an enantioselective manner. The major part of the approaches are based on the use of stoichiometric strategies and chiral auxiliaries due to the difficulty to activate the methylene position of alkylazaarenes. Our innovative approach relies on the use of a synergistic strategy where a Lewis acid activates the azaarene moiety making it a nucleophile while a Lewis base catalyst activates the electrophile. This dual activation presents several advantages such as an easy optimisation of each catalytic cycle and a greater decrease of the activation energy required for the reaction, allowing the use of low temperatures and soft conditions. In Chapter 4 we demonstrate the proof of concept of this approach by joining transition metal catalysis (Lewis acid) and secondary amine catalysis (Lewis base, iminium activation) achieving the enantioselective addition of alkyl-benzoxazoles and related heterocycles to enals in good yields and reasonable stereoselectivity levels. In Chapter 5 we expanded this new concept in the application of cascade reactions. We designed a cascade reaction consisting in the Michael addition of chloromethylbenzoxazoles to enals followed by a 3-exo-trig cyclisation to furnish cyclopropanes in good yields and enantioselectivities. The value of the present work is not only the development of these methodologies for the synthesis of chiral azaarenes (aldehyde derivatives and cyclopropanes) but also to demystify some misconceptions such as that metal Lewis acid could not coexist with secondary amine catalysis. This pioneering work is an open gate to generate new methodologies using a synergistic approach that tries to take the best of two of the pillars of catalysis: the high activity and rich chemistry of transition metal catalysis with the affordable and easy stereochemical prediction of secondary amine catalysis, avoiding the use of extreme reaction conditions or the use of chiral ligands.
Supervisor: Rios Torres, Ramon Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available