Biomimetic total synthesis of resorcylate natural products via a decarboxylative, allyl migration and aromatisation sequence

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Title: Biomimetic total synthesis of resorcylate natural products via a decarboxylative, allyl migration and aromatisation sequence
Authors: Anderson, Katie Elizabeth
Item Type: Thesis or dissertation
Abstract: Angelico in A (I), angelicoin B (II), cristatic acid (III) and grifolic acid (IV) (Figure A1) are members of the resorcylate family of natural products which contain a common 6-alkyl-2,4-dihydroxy benzoic acid core (β-resorcylate unit). The total syntheses of angelicoin A (I) and angelicoin B (II) from 2,2,6-trimethyl-4H-1,3-dioxin-4-one V are reported using late stage aromatisation reactions via diketo-dioxinones as advanced intermediates. In the case of angelicoin A (I), biomimetic aromatisation was coupled with a highly regioselective palladium(0)-catalysed decarboxylative prenyl migration as the key step (Scheme A1).(a)(b) The palladium(0)-catalysed decarboxylative, prenylation and aromatisation sequence furnished both linear VII and branched adducts VI. Extensive optimisation of conditions to improve the ratio of linear to branched adducts involved the screening of palladium catalysts, ligands, solvents, reactions times, temperature and organic and inorganic bases.(a)(c) The regioselectivity of this novel palladium(0)- catalysed decarboxylative prenyl migration was determined unambiguously through X-ray crystallographic studies.(a)(c) Furthermore, an intermolecular mechanism is proposed after thorough mechanistic studies including cross over and variable concentration experiments, base studies and regioselectivity investigations. Two synthetic approaches towards the total synthesis of cristatic acid methyl ester are reported. The first approach investigated a one-pot reaction to install the furan moiety VIII (Scheme A2), via a Nef reaction, deprotection, decarboxylation and furan formation. The second approach attempted to perform a one-pot Pd(0)-decarboxylative allylation, TMSE deprotection and aromisation to provide the core of cristatic acid IX (Scheme A3). Finally, studies towards the total synthesis of grifolic acid (IV) are reported utilising the palladium(0)-catalysed decarboxylative allyl migration and aromatisation sequence.
Content Version: Open Access
Issue Date: Mar-2013
Date Awarded: Jul-2013
URI: http://hdl.handle.net/10044/1/39340
Supervisor: Barrett, Anthony
Department: Chemistry
Publisher: Imperial College London
Qualification Level: Doctoral
Qualification Name: Doctor of Philosophy (PhD)
Appears in Collections:Chemistry PhD theses



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