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Title: Diastereocontrolled synthesis of hetero- and carbocycles via manganese(III) and copper(II) : towards a novel prostaglandin total synthesis
Author: Docherty, Paul Henry
ISNI:       0000 0001 3426 8126
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2008
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The prostaglandins are a unique family of natural products found in all mammalian life, including humans. Their biological significance is profound, and they are responsible for a vast array of bodily functions. This importance, coupled with their low concentration in vivo, has made them attractive targets for total chemical synthesis. The work herein describes synthetic efforts towards their synthesis using an oxidative radical cyclisation to construct the key [3.3.0]-bridged bicyclic lactone, from which the prostaglandin skeleton may be derived. Key to this was the development of manganese(III) acetate and copper(II) triflate as optimal reagents for this cyclisation of unsaturated malonate/malonic acid derivatives. To study this, several model substrates for this crucial cyclisation were synthesised, and their cyclisation analysed. Chapter 5 describes the design and synthesis of several model substrates containing malonate groups for the oxidative radical cyclisation. The results of the cyclisation with manganese(III) and various copper(II) salts influenced the design of the substrates, and led to the use of malonic acids as more effective substrates for the formation of [3.3.0]-bicyclic lactones. A catalytic process, in which atmospheric oxygen is the terminal oxidant was also developed. Chapter 6 describes the studies towards a total synthesis of the prostaglandin family. Two potential routes are followed, the first of which used a key asymmetric epoxidation to install asymmetry. A Suzuki coupling was used to deliver the desired diene required for the cyclisation substrate, which was successfully cyclised using manganese(III) acetate and copper(II) triflate, creating the desired [3.3.0]-bicyclic lactone in good yield and with excellent diastereomeric control. A second, shorter route to the same lactone was also developed, using a novel asymmetric deconjugative aldol condensation to establish asymmetry. Cyclisation of this analogous substrate was also successful, delivering the same lactone after olefin metathesis.
Supervisor: Burton, Jonathan Sponsor: EPSRC ; AstraZeneca
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Organic synthesis ; Organic chemistry ; Natural products ; Heterocyclic chemistry ; Catalysis ; Asymmetric catalysis ; Synthetic organic chemistry ; manganese acetate ; radical reactions ; natural product synthesis ; cyclisation reactions