The development of nitro-Mannich/hydroamination cascades for the synthesis of substituted N-heterocycles

Thesis

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.

Authors: Barber, D; David Barber

• Publication date: 2013
• DOI: 10.5287/ora-44nd9zybk
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: Oxford University, UK
• Language: English
• Keywords: alkyne; cascade; hydroamination; nitro-Mannich; tetrahydropyridine; piperidine; synthesis; asymmetric; chemistry; pyrrole; nitro; heterocycle; pyrrolidine; catalysis; organocatalysis; organic; allene; gold
• Subjects: Synthetic organic chemistry; Asymmetric catalysis; Organic chemistry; Catalysis; Organic synthesis; Heterocyclic chemistry