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Title: Novel approaches towards the total syntheses of pinnaic acid and matrine
Author: O'Donnell, Liam
ISNI:       0000 0004 5348 2613
Awarding Body: University of Nottingham
Current Institution: University of Nottingham
Date of Award: 2014
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This thesis describes synthetic efforts towards two natural products matrine and pinnaic acid. The strategy towards matrine focused on effecting an overall, but not necessarily concerted [4+2] cycloaddition in which a 1,4-dihydropyridine supplies the dienophile and aN-vinyl pyrldone is activated to act as the diene component. Attempts to progress an expedient route to pinnaic acid that starts with a chiral pyrrolidine cata lysed conjugate addit ion between propionaldehyde and I - nitrocyclopentene is discussed. Chapter 1 is an introduction to previous syntheses of matrine and introduces background literature examples of azadienes or dihydropyridines being used in [4+2] cycloadditions, as well as methods for constructing enamides required for the target. Chapter 2 describes our progress towards the synthesis of matrine. Significant contributions include the use of organotrifluoroborates as air and moisturestable alternatives to boronic acids in the synthesis of N-vinyl pyridones. Zincke reaction and subsequent dithionite reduction gave a high-yield ing route to install the l ,4-dihydropyridines required for the target precursors. Several studies to initiate intramolecular bond formation between these functional groups are reported. Chapter 3 provides an introduction to previous syntheses of pinnaic acid. Examples of transformations required for our proposed route are introduced including organocatalysed 1,4-addit ions of carbon nucieophiles to nitroolefins, an important stereochemistry generating step, and the vinylogous aldol reaction, which are both important components of the planned route. Chapter 4 highlights progress towards the synthesis of pinnaic acid. Significant contributions include the improvement of the diastereoselectivity of our key conjugate addition step via reduction of the in situ generated aldehyde. A panel of organocatalysts was screened for this conjugate addition step, with chiral HPLC studies confirming modest gains in e.e. when trans-4-hydroxy- L-proline was employed. This route was used to gain step-efficient access to an intermediate in Heathcock's synthesis of pinnaic acid. Further studies toward a step efficient route to pinnaic acid are described including a Friedel-Crafts acylation between a protected butynol species and chloroacetyl chloride that was demonstrated on a large scale, albeit with a slight preference for the undesired (E)-isomer. Conversion of this material to phosphonate and sulphone species, as well as its use in a model Wittig reaction, was also demonstrated.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available