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Title: Total synthesis of (–)-nakadomarin A and an approach to the diazatricyclic core of the madangamines
Author: Kyle, Andrew F.
ISNI:       0000 0004 2744 8403
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2012
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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.
Supervisor: Dixon, Darren J. Sponsor: EPSRC ; GlaxoSmithKline
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Chemistry & allied sciences ; Asymmetric catalysis ; Natural products ; Organic chemistry ; Organic synthesis ; Synthetic organic chemistry