The development of nitro-Mannich/hydroamination cascades for the synthesis of substituted N-heterocycles
<p>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®).</p> <p>Chapter...
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| Format: | Thesis |
| Language: | English |
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2013
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| _version_ | 1817932080227549184 |
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| author | Barber, D David Barber |
| author2 | Dixon, D |
| author_facet | Dixon, D Barber, D David Barber |
| author_sort | Barber, D |
| collection | OXFORD |
| description | <p>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®).</p> <p>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. </p> <p>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.</p> |
| first_indexed | 2024-03-06T19:17:29Z |
| format | Thesis |
| id | oxford-uuid:18e7c533-3789-4800-9813-1d5c7bb4e4ea |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-12-09T03:32:13Z |
| publishDate | 2013 |
| record_format | dspace |
| spelling | oxford-uuid:18e7c533-3789-4800-9813-1d5c7bb4e4ea2024-12-01T15:31:16ZThe development of nitro-Mannich/hydroamination cascades for the synthesis of substituted N-heterocyclesThesishttp://purl.org/coar/resource_type/c_db06uuid:18e7c533-3789-4800-9813-1d5c7bb4e4eaOrganic synthesisSynthetic organic chemistryAsymmetric catalysisCatalysisOrganic chemistryHeterocyclic chemistryEnglishOxford University Research Archive - Valet2013Barber, DDavid BarberDixon, D<p>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®).</p> <p>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. </p> <p>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.</p> |
| spellingShingle | Organic synthesis Synthetic organic chemistry Asymmetric catalysis Catalysis Organic chemistry Heterocyclic chemistry Barber, D David Barber The development of nitro-Mannich/hydroamination cascades for the synthesis of substituted N-heterocycles |
| title | The development of nitro-Mannich/hydroamination cascades for the synthesis of substituted N-heterocycles |
| title_full | The development of nitro-Mannich/hydroamination cascades for the synthesis of substituted N-heterocycles |
| title_fullStr | The development of nitro-Mannich/hydroamination cascades for the synthesis of substituted N-heterocycles |
| title_full_unstemmed | The development of nitro-Mannich/hydroamination cascades for the synthesis of substituted N-heterocycles |
| title_short | The development of nitro-Mannich/hydroamination cascades for the synthesis of substituted N-heterocycles |
| title_sort | development of nitro mannich hydroamination cascades for the synthesis of substituted n heterocycles |
| topic | Organic synthesis Synthetic organic chemistry Asymmetric catalysis Catalysis Organic chemistry Heterocyclic chemistry |
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