Synthetic Studies Towards Spirangien A and Total Synthesis of (+)-Ascosalipyrone and ent-Micropyrone

Author: Claire Gregg

Gregg, Claire, 2011 Synthetic Studies Towards Spirangien A and Total Synthesis of (+)-Ascosalipyrone and ent-Micropyrone, Flinders University, School of Chemical and Physical Sciences

Terms of Use: This electronic version is (or will be) made publicly available by Flinders University in accordance with its open access policy for student theses. Copyright in this thesis remains with the author. You may use this material for uses permitted under the Copyright Act 1968. 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.


Polyketides are considered not only the largest class of secondary metabolites that share a common biosynthesis, but are also one of the most interesting classes of natural products due to their enormous structural diversity and broad spectrum biological activities. Chapter one introduces the reader to polyketide natural products, including their origin, structure and activity. This is followed by an overview of the aldol reaction, a highly useful synthetic tool in the biomimetic construction of polyketide motifs. The aldol reaction will feature extensively in the studies to follow. Chapter two describes studies towards the synthesis of spirangien A (1), a highly cytotoxic and antifungal polyketide metabolite, isolated from the myxobacterium sorangium cellulosum. The synthetic approach to spirangien A exploited the obvious C22-C23 acetate aldol disconnection in linear precursor 158. Model studies were conducted which showed that the diastereoselectivity of this aldol reaction is highly substrate controlled and depends heavily of the hydroxyl protecting group strategy. This model system lacked the C17 stereocentre of the natural product, which evidently exhibited strong 1,7-stereoinduction, therefore the model was concluded to be an inadequate representation of the natural product system. The aldehyde coupling partner 150 was synthesised in 10 steps (10% yield), utilising a highly efficient cross-coupling of zinc homoenolate 144 with (E)-2-bromo-2-butene (48) to install the C28 stereocentre and two successive Evans syn aldol reactions to give the desired C24-27 stereotetrad and differential protection of the resulting hyroxyl groups. Ketone coupling partner 130 was synthesised from (R)-Roche ester (R)-32 in 16 steps (22 % yield), using a mercury catalysed hydration of the terminal alkynyl functionality derived from ethynylmagnesium bromide (35) to afford the methyl ketone, and a syn,syn selective aldol reaction with (S)-Roche ester derived dipropionate equivalent (S)-10 to give the C14-17 stereotetrad. Coupling of the resulting aldehyde 150 and ketone 130 was achieved using a LiHMDS aldol to give 1.2-2.5:1 ds in favour of the desired product 158. The relative configuration of aldol adduct 158 was assigned by conversion to the corresponding hemiacetal, and subsequent nOe analysis. Spirocyclisation of the major product hemiacetal gave 165, from which stereochemical assignment was confirmed. Further manipulation of 165 in 3 steps (removal of the TBS groups, re-protecting with TES groups and finally cleavage of the PMB ether) would result in a formal synthesis of spirangien A, however limited availability of material prevented completion of the total synthesis. Chapter three details the total synthesis of (+)-ascosalipyrone [(6S,8S)-4] and ent-miropyrone [(6S,8S)-5]. Ascosalipyrone (4), isolated from the obligate marine fungus A. salicorniae, and micropyrone (5), isolated from the plant H. italicum, are two novel, structurally related polyketide natural products. Both compounds have the same 4-hydroxy-a-pyrone containing core structure, differing only by an extra methyl group at C4 in micropyrone (5). Ascosalipyrone was reported as an inseparable mixture of diastereomers, while micropyrone was reported as a single isomer with an optical rotation. The synthesis of two potential diastereomers of each natural product from a common intermediate was achieved. A highly diastereoslective syn aldol reaction between both the (R)-77 and (S)-77 enantiomers of Evans' auxiliary and chiral aldehyde 178 was exploited to produce aldehydes (6R,7S,8S)-177 and (6S,7R,8S)-177. The linear precursors (6R,7S,8S)-192 and (6R,7S,8S)-193 were constructed by addition of b-ketoesters 175 or 176 respectively to aldehyde (6R,7S,8S)-177, with DBU promoted cyclisation to install the 4-hydroxy-a-pyrone ring system. Removal of the protecting groups and Jones oxidation gave two possible isomers of each ascosalipyrone and micropyrone. No epimerisation of the a-stereocentre was observed for the micropyrone isomers but partial epimerisastion (3:1) was seen for ascosalipyrone isomers. This was attributed to less steric congestion for ascosalipyrone, which lacks one pyrone methyl. Comparison of the NMR and specific rotation assigned the structure of (+)-ascosalipyrone [(6S,8S)-4] and micropyrone [(6R,8R)-5].

Keywords: spirangien,aldol reaction,spiroacetal,polyketide,pyrone

Subject: Chemistry thesis

Thesis type: Doctor of Philosophy
Completed: 2011
School: School of Chemical and Physical Sciences
Supervisor: Michael V. Perkins