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Studies towards a total synthesis of manzamine A

Hansen, Anna Mette (2010) Studies towards a total synthesis of manzamine A. PhD thesis, University of Glasgow.

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Abstract

Manzamine A has been isolated from various Okinawa Sponges of the genus Haliclona and was first characterised by Higa and co-workers in 1986. The unusual and synthetically challenging structure consists of a pentacyclic core containing an array of 5-, 6-, 8-, and 13-membered rings with a pendant -carboline unit. The complex structure of manzamine A combined with its biological activities has made it a highly attractive synthetic target. The synthetic endeavors in the Clark group to develop a novel approach towards the total synthesis of manzamine A (i) with the main focus on the synthesis of the ABC ring fragment as advanced intermediates will be disclosed. In the first synthetic approach towards the total synthesis of manzamnine A (i), bicyclic enone iii was constructed from amine ii and served as a model system to validate the proposed intermolecular Diels-Alder reaction. Despite several attempts utilising various dienes, the Diels-Alder adduct was not obtained and an alternative bicyclic system was investigated. After accomplishing the synthesis of the simple AB fragment v from propargylamine (iv), the Diels- Alder reaction was yet again investigated. Due to the failure of the Diels-Alder reaction, this route towards the total synthesis of manzamine A (i) was abandoned. The second approach introduces the conjugate addition reaction towards the total synthesis of manzamine A (i). Instead of the Diels-Alder approach, 1,4 addition to enone v was explored. Initial attempts to perform the 1,4-addition reaction and subsequent aldol condensation reaction afforded the dehydrated aldol condensation products vii via silyl enol ether vi. Additional investigations to prevent the dehydration reaction taking place proved unsuccessful. Thereafter, various methods for the introduction of a substituent in the position to the ketone were investigated. These included alkylation using chloromethyl phenylsulfide, halogenation using NBS or NCS, Rubottom oxidation using DMDO, direct amination using manganese(V) complexes, azidation using sodium azide and CAN as well as aziridination using PhI=NTs. A number of adducts viii-x were succesfully prepared. Finally, the last part of the thesis describes the efforts towards the synthesis of a model system resembling the CD ring-system. The macrocyles xiii and xiv were easily synthesised from dienes xi and xii, although the RCM of diene xi gave rise to isolation problems.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Subjects: Q Science > QD Chemistry
Colleges/Schools: College of Science and Engineering > School of Chemistry
Supervisor's Name: Clark, Professor James Stephen
Date of Award: 2010
Depositing User: Anna Mette Hansen
Unique ID: glathesis:2010-1775
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 10 May 2010
Last Modified: 10 Dec 2012 13:46
URI: http://theses.gla.ac.uk/id/eprint/1775

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