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Title: New methods for the diastereoselective construction of vicinal quaternary stereocenters and their application to the total synthesis of the bioactive (±)-dehalo-perophoramidine
Author: Wilkie, Ross Philip
ISNI:       0000 0004 5917 1875
Awarding Body: University of St Andrews
Current Institution: University of St Andrews
Date of Award: 2015
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This thesis describes a novel total synthesis of (±)-dehalo-perophoramidine (a dehalogenated analogue of the natural product perophoramidine). The key synthetic transformation involves the construction of vicinal quaternary stereocenters which were installed diastereoselectively. A Claisen rearrangement was used to install the first quaternary stereocenter then a Corey-Chaykovsky-type reaction and a Hosomi-Sakurai-type reaction were used to install the second quaternary stereocenter. Investigations directed towards the total synthesis of the communesin family of natural products are also described. In Chapter 1, the natural products perophoramidine and the communesins are introduced and their related biosynthesis is discussed. The isolation, architectural motifs and biological properties of the natural products are described and discussed. Previously reported approaches to perophoramidine and the communesins are reviewed focussing on how the vicinal quaternary stereocenters are formed in each case. Chapter 1 concludes with the retrosynthetic plan used to form dehalo-perophoramidine. In Chapter 2, previous research from the Westwood group is reviewed focusing on an asymmetric Claisen rearrangement which could potentially be used to install a quaternary stereocenter asymmetrically. A previously reported novel Cope rearrangement, potentially useful for a communesin synthesis, is optimised using microwave, neat and high-temperature flow conditions and leads to the synthesis of an intermediate containing two allyl substituents. In Chapter 3, attempts to functionalise selectively the two allyl substituents are described which was eventually achieved by a regioselective iodoetherification reaction. This leads to the synthesis of two relatively advanced intermediates for a communesin synthesis. Although the total synthesis of the communesins was not achieved, a proposed route from the advanced intermediates to the natural products is described. In Chapter 4, a novel method to construct vicinal quaternary stereocenters is disclosed using a Corey- Chaykovsky-type reaction and a Hosomi-Sakurai-type reaction. A regioselective iodolactonisation, analogous to that presented in Chapter 3, is used to functionalise selectively two allyl substituents that culminates in the preparation of a pentacyclic lactam. In Chapter 5, the total synthesis of (±)-dehalo-perophoramidine is completed and its structure is confirmed by a NMR doping experiment with an authentic sample. The biological activity of dehalo- perophoramidine is investigated and compared to that of perophoramidine. Chapter 5 culminates in an attempted synthesis of the natural product perophoramidine using the route that was used to make dehalo-perophoramidine.
Supervisor: Westwood, Nicholas James Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QP801.I45W5 ; Indole alkaloids--Synthesis