Rundell, CD; (2016) Intramolecular conjugate addition nitro-mannich reaction: Towards the synthesis of schizozygine. Doctoral thesis , UCL (University College London).

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Abstract

Part 1: The introduction of this thesis describes in detail the development of the nitro-Mannich reaction, in particular organocatalytic methodologies and its use in the synthesis of N-heterocycles. Additionally a current review of cascade cyclisations to furnish tetrahydroquinolines is detailed. The results and discussion describes the strategies involved in synthesising sensitive nitrostyrenes tethered onto an imine. It was found that classical disconnections to nitrostyrenes, involving the Henry reaction, were successful but low yielding and with poor substrate scope. An alternative disconnection involving a condensation between 2- vinylanilines and aldehydes, then subsequent nitration with AgNO2/TEMPO provided the desired nitrostyrene. It was found that this reaction sequence gave various substituted nitrostyrenes in high yields and was scalable. The cascade cyclisation was then investigated using hydride and carbon nucleophiles. This was highly selective for either the cis or cis,cis diastereomer. Use of a simple thiourea catalyst and a Hantzsch ester as the hydride source gave access to these cis-tetrahydroquinolines in high enantioselectivities (up to >99% ee). Investigation into using chiral phosphine ligands for the enantioselective addition of carbon nucleophiles, such as dialkylzincs, failed to give any stereoselectivity. Briefly an enantioselective approach to cis,cis-tetrahydroquinolines is discussed, using a standard intramolecular nitro-Mannich reaction. / Part 2: The introduction to this section describes the Schizogane family of alkaloids, the approaches to their total synthesis and a review of both the nitro-Mannich reaction and the nitro group in total synthesis. The results and discussion then details our approach to Schizozygine, the major alkaloid in the Schizogane family. Our retrosynthesis utilizes an intramolecular Pd catalyzed C-N bond formation and the enantioselective synthesis of syn,anti-nitroamines, both methodologies have been developed within our group. The main body of this work describes the approaches for an enantioselective synthesis of the syn,anti-nitroamine and its use in the synthesis of a key piperidine intermediate.

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