This dissertation describes work towards two marine alkaloid natural products of the manzamine family. The total synthesis of (–)-nakadomarin A, via two conceptually different strategies is described along with the development of a novel nitro-Mannich-Mannich cascade reaction, which has been applied in a synthesis of the diazatricyclic core of the madangamines. A short and highly stereoselective synthesis of (–)-nakadomarin A has been developed. A sequential alkyne ring-closing metathesis/syn selective reduction strategy enabled the stereoselective construction of the Z-configured alkene in the fifteen-membered macrocycle of the molecule. ‘Matched’ catalyst and substrate control facilitated a highly diastereoselective nitro olefin Michael addition to fix two of the four stereocentres in one key step. Furthermore, a nitro-Mannich/lactamization cascade, furan N-acyl iminium ion cyclisation and alkene ring-closing metathesis enabled the total synthesis of the natural product in 19 steps. In collaboration with Prof. Amir Hoveyda and Prof. Richard Schrock, an alternative approach to a highly Z-selective macrocyclic ring closure in the synthesis of (–)-nakadomarin A has been developed. Three diene substrates were prepared and the Z-selectivity of alkene ring-closing metathesis investigated using a range of molybdenum MAP (monoaryloxide pyrrolide) catalysts. Initial studies using these catalysts produced promising results (Z:E = ~1.2:1), relative to commercially available ruthenium metathesis catalysts (Z:E = 2:3). Using a recently developed chiral tungsten MAP complex, alkene ring-closing metathesis was found to proceed in excellent yield (90%) with exceptional Z:E-selectivity (Z:E ~1.2:1) and requiring only low catalyst loadings (5 mol%). A novel nitro-Mannich-Mannich cyclisation cascade has been developed allowing access to highly functionalized piperidines. Application of this unprecedented mode of reactivity using a substrate derived from a Michael-addition of methylcyanoacetate to a functionalized cyclic nitro olefin allowed the preparation of a cis-fused 6,6’-bicycle in excellent yield. Further elaboration of this 6,6’-bicycle enabled the synthesis of the diazatricyclic core of the madangamine alkaloids to be achieved.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:580987 |
| Date | January 2012 |
| Creators | Kyle, Andrew F. |
| Contributors | Dixon, Darren J. |
| Publisher | University of Oxford |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://ora.ox.ac.uk/objects/uuid:43e8044f-6860-47a2-9850-5f42990d4a68 |
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