Biomimetic Approaches to the Synthesis of Polyketide Derived Marine Natural Products; (-)-Maurenone and the Spiculoic Acids


Crossman, Julia Stephanie, 2007 Biomimetic Approaches to the Synthesis of Polyketide Derived Marine Natural Products; (-)-Maurenone and the Spiculoic Acids, Flinders University, School of Chemistry, Physics & Earth Sciences

This electronic version is made publicly available by Flinders University in accordance with its open access policy for student theses. Copyright in this thesis remains with the author. This thesis may incorporate third party material which has been used by the author pursuant to Fair Dealing exceptions. If you are the owner of any included third party copyright material and/or you believe that any material has been made available without permission of the copyright owner please contact with the details.


This thesis describes the total synthesis of the polyketide derived marine natural product (-)-maurenone (14) and synthetic studies of a model system for the marine polyketides, the spiculoic acids (20, 22-24). A biomimetic approach involving cyclisation of linear polyketide precursors to install the complex chemical frameworks was employed. Maurenone is a polypropionate derived metabolite isolated from pulmonate molluscs collected off the coast of Costa Rica. While structural assignment following isolation revealed a relatively uncommon tetra-substituted dihydropyrone moiety the only stereochemical information deduced was the trans-relative relationship between the C8 and C9 protons. The total synthesis of a series of eight stereoisomeric putative structures was achieved in order to assign the stereochemistry of (-)-maurenone (14), as that depicted above. A time and cost efficient strategy was developed utilising common intermediates providing access to the eight stereoisomeric structures in a convergent manner. Six key fragments, four aldehydes (109) and two ketones (110), were synthesised using highly diastereoselective syn- and anti-boron aldol reactions and were coupled using a lithium-mediated aldol reaction. Trifluoroacetic acid-promoted cyclisation/dehydration enabled installation the -dihydropyrone ring. All eight isomers of one enantiomeric series were synthesised by coupling two ketones with each of four aldehydes. By comparison of the NMR data for the eight isomers with that reported for the natural product, the relative stereochemistry was established as shown. The (-)-enantiomer of maurenone was synthesised in nine linear steps (13 % overall yield) from (R)-2-benzylpentan-3-one ((R)-40) and (R)-2-benzoyloxypentan-3-one ((R)-39). The spiculoic acid family of polyketide derived natural products, isolated from plakortis sponges, possess a unique [4.3.0]-bicyclic core which is proposed to be formed via an enzyme catalysed Intramolecular Diels-Alder (IMDA) cycloaddition reaction of linear polyene precursors 25. Model linear precursors (114), possessing various olefin geometries at C2 and both stereochemical orientations of the C5 stereocentre, were synthesised in order to examine stereoselectivity of the thermally induced IMDA cycloaddition reaction. The two alternative C4-C6 stereotriads of the linear precursors 114 were achieved by employing highly diastereoselective substrate-controlled aldol reactions; an anti-boron aldol reaction, controlled by the facial preference of (R)-2-benzoyloxypentan-3-one ((R)-39), and a syn-titanium aldol reaction, under the control of chiral N-acylthiazolidinethione ((R)-43a). The diene and dienophile moieties were installed using either standard Wittig, H.W.E. or modified Julia olefination reactions. A thorough stereochemical assignment of the cycloadducts of the thermally induced IMDA reaction of each linear precursor was accomplished employing 2D NMR techniques. Comparison of the stereochemistry of each of the cycloadducts with the spiculoic acids revealed that the linear precursor (2E,5S)-114 produced a cycloadduct 232 with stereochemistry analogous to the natural products in 94 % diastereoselectivity. Thus, a synthetic approach to the spiculoic acids via synthesis of a linear precursor 285 possessing a TBS ether at C5 in the S configuration was proposed. Unfortunately, problems encountered in the synthesis of the proposed linear precursors to the spiculoic acids ultimately prevented the total synthesis from being achieved.

Keywords: stereoselective synthesis, total synthesis, Diels-Alder Reaction, Aldol Reaction, marine natural products, biomimetic synthesis
Subject: Chemistry thesis

Thesis type: Doctor of Philosophy
Completed: 2007
School: School of Chemical and Physical Sciences
Supervisor: Unknown