A ring expansion strategy towards the total synthesis of manzamine A

Meier, Gregor Paul (2018) A ring expansion strategy towards the total synthesis of manzamine A. PhD thesis, University of Glasgow.

Due to Embargo and/or Third Party Copyright restrictions, this thesis is not available in this service.
Printed Thesis Information: https://eleanor.lib.gla.ac.uk/record=b3339171

Abstract

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

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: Total synthesis, natural products.
Subjects: Q Science > QD Chemistry
Colleges/Schools: College of Science and Engineering > School of Chemistry
Supervisor's Name: Clark, Professor J. Stephen
Date of Award: 2018
Embargo Date: 17 January 2021
Depositing User: Dr Gregor Meier
Unique ID: glathesis:2018-40907
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 17 Jan 2019 14:59
Last Modified: 23 Apr 2019 16:05
URI: http://theses.gla.ac.uk/id/eprint/40907
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