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Title: Novel biomimetic total syntheses of resorcylate natural products utilizing late stage aromatisation
Author: Basset, Jean-Francois
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2011
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Abstract:
The β-resorcylic acid (1) unit can be found in a number of biologically active natural products including montagnetol (2), hair-growth stimulant pochonin G (3), antioxidant erythrin (4), antifungal agents 15G256b (5) and mycotoxin (S)-zearalenone (6). A conventional total synthesis of 15G256b (5), from β-resorcylic acid units, was fraught with difficulties.1 Consequently, we established a novel biomimetic strategy for the synthesis of natural product 6, by utilising a late stage aromatisation step, starting from polyketide precursor 7. Two main issues needed to be solved: a flexible synthesis to build polyketides and mild conditions to construct the aromatic ring. [Molecular structure diagrams appear here. To view, please open pdf attachment]. Diketo-dioxinone 10 was found to be an equivalent of a polyketide. Its synthesis was accomplished by reaction of deprotonated dioxinone 8 and benzotriazole derivative 9 (obtained from thermolysis of dioxinone 8 2). [Molecular structure diagrams appear here. To view, please open pdf attachment]. Mild conditions were found to construct the aromatic ring 11 using a weak base followed by an acid work-up. A strategy to build resorcylates in one step from diketodioxinone 10 was also discovered.2-3. [Molecular structure diagrams appear here. To view, please open pdf attachment]. This strategy was then applied to the total synthesis of (S)-zearalenone (6) employing dioxinone derivate 12 and alcohol 13 to afford polyketide 14. Conversion into (S)- zearalenone (6) was accomplished by aromatisation and trans-selective ring closing metathesis.3. [Molecular structure diagrams appear here. To view, please open pdf attachment]. In an analogous manner to (S)-zearalenone (6), the biomimetic total synthesis of both enantiomers of montagnetol (2) and erythrin (4) were completed, allowing assignment of their absolute stereochemical configuration.2. [Molecular structure diagrams appear here. To view, please open pdf attachment]. Similarly, an analogue of pochonin G 19 was synthetised, using a C-acylation reaction of the keto-dioxinone 16 dianion with Weinreb amide 17 followed by a cascade sequence consisting of ketene generation, alcohol 18 trapping, aromatization and ring closing metathesis. [Molecular structure diagrams appear here. To view, please open pdf attachment]. From the key diketo-dioxinone building block 10, heteroaromatic 20 as well as resorcylate 15 were synthesised.2. [Molecular structure diagrams appear here. To view, please open pdf attachment]. 1 Frederiksen M. U., PhD thesis. 2 Basset, J.-F.; White, A. J. P.; Barrett, A. G. M.; Leslie, C.; Hamprecht, D. Tetrahedron Lett. 2010, 51, 783. 3 Navarro I., Basset J. F., Hebbe S., Major M. M., Werner T., Howsham C., Bräckow J., Barrett A.G.M. J. Am. Chem. Soc. 2008, 130, 10293.
Supervisor: Barrett, Anthony Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.575994  DOI: Not available
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