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Title: The development of nitro-Mannich/hydroamination cascades for the synthesis of substituted N-heterocycles
Author: Barber, David M.
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2013
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This thesis describes the development of nitro-Mannich/hydroamination cascade reactions for the synthesis of N-heterocycles, which are important motifs found in a variety of biologically active natural products and pharmaceuticals, such as atorvastatin (Lipitor®). Chapter 2 outlines the development of an efficient synthesis of 2,5-disubstituted pyrroles using a nitro-Mannich/hydroamination cascade. Starting from easily prepared N-protected imines and nitroalkyne substrates, a compatible combination of KOtBu (10 mol%) and AuCl3 (5 mol%) was used to afford the desired pyrrole products, after an alkene isomerisation/HNO2 elimination reaction sequence. Chapter 3 describes the extension of this methodology to the diastereo- and enantioselective synthesis of 1,2,3,4-tetrahydropyridine derivatives using a nitroalkyne substrate with an extended carbon chain. The sequential addition of a bifunctional Brønsted base/H-bond donor organocatalyst and a gold complex was found to facilitate the desired cascade reaction affording substituted 1,2,3,4-tetrahydropyridine products. We then established that highly substituted pyrrolidine compounds could be prepared by replacing the nitroalkyne substrate with a nitroallene substrate (Chapter 4). The combination of KOtBu (5 mol%) and a gold catalyst derived from Au(PPh3)Cl (10 mol%) and AgSbF6 (20 mol%) was found to give an efficient diastereoselective synthesis of pyrrolidine derivatives after an additional nitro group epimerisation step. In addition, the nitro-Mannich/hydroamination cascade using nitroallene substrates was developed into an enantioselective variant using the previously employed bifunctional Brønsted base/H-bond donor organocatalyst. This afforded enantioenriched pyrrolidine derivatives.
Supervisor: Dixon, Darren J. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Organic chemistry ; Organic synthesis ; Synthetic organic chemistry ; Heterocyclic chemistry ; Catalysis ; Asymmetric catalysis ; organic ; chemistry ; synthesis ; cascade ; nitro-Mannich ; hydroamination ; gold ; organocatalysis ; alkyne ; allene ; nitro ; asymmetric ; heterocycle ; pyrrole ; pyrrolidine ; piperidine ; tetrahydropyridine