Pyrrolidine and pyrrolidinone rings are common motifs found in many biologically active natural products and drugs. Accordingly, our work focuses on the development of new methodologies for their one-pot synthesis. An efficient diastereoselective nitro-Mannich / lactamisation reaction cascade of methyl 3-nitropropanoate with cyclic and acyclic imines for the direct preparation of trans-monocyclic and fused tricyclic pyrrolidinone derivatives was developed. The reaction is easy to perform, broad in scope and tolerates a wide variety of functional groups. For the monocyclic methodology, 28 examples with a very good average yield of 72% and excellent diastereocontrol (typical dr >98:2) were obtained using optimized conditions and varying the amine and the aldehyde reagents. The methodology has been extended to the synthesis of 1,3,5-trisubstituted 4-nitropyrrolidinone derivatives using α-substituted 3-nitropropanoate. Using a one-pot protocol, 22 derivatives were synthesised in good yields (65% average) and diastereomeric ratios ranging from 3:1 to 30:1 in favor of the trans/trans diastereoisomer. In addition, the nitro-Mannich / lactamisation cascade of methyl 3-nitropropanoate was developed further to allow the rapid synthesis of 5-isopropyl-4-nitropyrrolidin-2-one from reaction with ammonium acetate and 1-butyl-4-nitropyrrolidin-2-one from reaction with formaldehyde. Also, the synthetic utility of the nitro-pyrrolidinones formed was exemplified through various functional group modifications: the selective reduction of the lactam carbonyl, the reduction of the nitro group in the presence or absence of a carbonyl group and the reductive removal of the nitro group. The development of an enantioselective version of the cascade under chiral Brönsted acid catalysis provided promising results (up to 90% ee). Moreover, various studies were undertaken to understand the mechanism of the reaction and the nitro-Mannich / latamisation cascade is now well understood. Furthermore, a formal synthesis of rac-Slaframine in 8 steps and 15% overall yield was achieved and it inspired additional work towards a nitro-Mannich / epoxide ring opening cascade.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:580896 |
| Date | January 2011 |
| Creators | Pelletier, Sophie Marie-Clémentine |
| Contributors | Dixon, Darren |
| Publisher | University of Oxford |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://ora.ox.ac.uk/objects/uuid:283641bf-bb4e-48a8-8a28-2e048b8c4ea6 |
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