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Title: A ring expansion strategy towards the total synthesis of manzamine A
Author: Meier, Gregor Paul
ISNI:       0000 0004 7654 950X
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 2018
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The manzamines are a family of marine alkaloids isolated from various sponge species native to the Pacific Ocean. They possess an intricate polycyclic structure of fused 5-, 6-, 8-, and 13-membered rings. The highly functionalised core of the parent compound manzamine A bears a β-carboline unit, two tertiary amines, and a tertiary alcohol group. The complex structure combined with various reported biological activities make this molecule an appealing target for total synthesis. The common biosynthetic origins of several related manzamine alkaloids, such as nakadomarin A, suggest the possibility of a synthetic strategy targeting multiple natural products from a common late-stage intermediate. In this thesis, the synthetic efforts to explore this strategy are described. The key transformation to allow the construction of the carbon skeleton of manzamine A from the common late-stage intermediate is ring expansion of a cyclopentanone to a cyclohexanone subunit. In the first part of this work, a second-generation route towards the previously established common late-stage intermediate is established. The objective of this work was to increase the scale, robustness and cost effectiveness of the route by circumventing the use of costly reagents. In the second part, investigations of several strategies for the crucial ring expansion are reported. Silyl enol ether formation and subsequent cyclopropanation to introduce the additional carbon unit was found to be incompatible with the substrate. Ketone acylation and subsequent halomethylation was not accomplished. However, successful ring expansion was achieved by a sequence of diazoester addition, transition metal catalysed rearrangement and a modified decarboxylation protocol. Following this strategy, two separate regioisomers of cyclohexanones representing the tetracyclic manzamine core were synthesised.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QD Chemistry