Koovits, PJ; (2013) Development of an enantioselective reductive nitro-Mannich reaction using thiourea catalysis. Doctoral thesis , UCL (University College London).

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Abstract

The introductory chapter of this thesis describes in detail the chemistry of the nitro-Mannich reaction from its inception to the current “state of the art”. Additionally, the products of the nitro-Mannich reaction and their uses in synthesis are also discussed. The final section of the introduction deals with the use of thiourea organocatalysis and its application in synthetic transformations using imines or nitroalkenes as electrophiles. The results and discussion initially focuses on the development of a racemic reductive nitro-Mannich reaction. It has been found that when using SuperhydrideTM as a hydride source, a variety of nitroalkenes underwent selective reduction. The corresponding nitronates formed then underwent an in situ nitro-Mannich reaction upon addition of an N-para-methoxy phenyl (PMP) protected imine and trifluoroacetic acid to form β-nitroamines in excellent conversion (>90%) and high diastereoselectivities (75:25 to >95:5 dr). These products were then protected by reaction with trifluoroacetic anhydride and pyridine, to enable isolation of the products as trifluoroacetamides in good to excellent yields (58-87%) and diastereoselectivity (>90:10 dr). The second part details the development of an enantioselective variant using thiourea organocatalysis. It was discovered that the desired reductive nitro-Mannich reaction could be promoted with excellent levels of stereocontrol using a Hantzsch ester as the hydride source and a simple thiourea catalyst derived from L-valine. The reaction worked well for a variety of different nitroalkenes and N-PMP protected imines using toluene as a solvent at -20 oC. The resultant products could be isolated after protection as trifluoroacetamides in moderate to excellent yields (32-84%), high diastereoselectivity (>90:10 dr) and good to excellent enantioselectivity (73-99% ee). The final part of this chapter discusses progress towards the synthesis of 1,2-diamine containing natural product Eudistomidin B, using a reductive nitro-Mannich reaction as the key step. The conclusions of the research and potential future work are also presented along with analytical data. Detailed preparative methods for all compounds synthesised in this research are also described. Finally an appendix section is included, which contains a list of abbreviations, a table of coupling constants and a comprehensive list of references.

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