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Title: One-pot nitro-Mannich cascade reactions : new methodologies and synthetic applications
Author: Pelletier, Sophie Marie-Clémentine
ISNI:       0000 0004 2743 9494
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2011
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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.
Supervisor: Dixon, Darren Sponsor: EPSRC ; MSD
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Organic chemistry ; nitro-Mannich ; cascade ; multi-component reaction ; methodology ; Slaframine ; enantioselective ; diastereoselective