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Title: A novel biomimetic synthesis of resorcylic acid lactones, via macrolactonization and transannular aromatization
Author: Miyatake Ondozabal, Hideki
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2012
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Resorcylic acid lactones (RALs) are biologically active polyketide natural products with typically a large macrocyclic ring fused to a resorcylic unit.i This thesis outlines novel biomimetic syntheses of such natural products utilizing intramolecular capture of acylketenes for macrolactonization and subsequent transannular aromatization to form resorcylic cores in a one-pot procedure. This strategy is sufficiently concise for analogue synthesis and therefore has potential use for pharmaceutical applications. One of the RAL family, namely (S)-zearalenone (5), was successfully synthesized following our developed strategy. The key acylketene precursor 3 was prepared in eight steps from norbonene 1 via alkene 2 in excellent E/Z selectivity. Thermolysis of 3 provided macrocycle 4 by retro-Diel-Alder fragmentation which in turn underwent ketal deprotection and transannular aromatization to give the natural product 5 in high yields.ii [Molecular structure diagrams appear here. To view, please open pdf attachment] Following the successful synthesis of (S)-zearalenone (5), this methodology was applied to a more complex target, LL-Z1640-2 (9). The synthesis of diketo-dioxinone 7 was achieved via Weinreb amide 6 in eight steps. The key transformations included selective Lindlars reduction of alkyne 6 and the incorporation of keto-dioxinone unit 10 by dianion chemistry. Upon heating a hydroxy-keto-dioxinone 7, macrocyclic triketo-ester was generated which smoothly aromatized to afford resorcylate 8 in a one-pot procedure. Further three steps of manipulation on resorcylate 8 furnished TAK-kinase inhibitor 9.iii [Molecular structure diagrams appear here. To view, please open pdf attachment] Extensive studies have been carried out towards the racemic synthesis of dimeric dihydroisocoumarin, known as tragoponol (16). Our aim included the use of inter- and intra-molecular ketene trapping which would be followed by two separate aromatizations to construct its dilactone structure. The left hand side resorcylate unit rac-14 was synthesized in seven steps starting from commercially available β-keto-ester 11 through a ketene trapping and an aromatization sequence utilizing diketo-dioxinone rac-12 and alcohol rac-13. The incorporation of keto-dioxinone unit was achieved by C-acylation of dilithium enolate derived from keto-dioxinone 10 with Weinreb amide rac-14 to give diketo-dioxinone rac-15 in high yield. [Molecular structure diagrams appear here. To view, please open pdf attachment] The final part of this thesis describes the studies carried out on a recently isolated RAL called paecilomycin B (21). A unique tetrahydropyran unit within the macrocyle is one of its attractive structural features. The key precursors 18 were successfully synthesized in five steps from alcohol 17. The introduction of four stereogenic centres was controlled by a diastereoselective aldol reaction, a CBS-reduction, and a directed epoxidation of an allylic alcohol. [Molecular structure diagrams appear here. To view, please open pdf attachment] (i) Schirmer, A.; Kennedy, J.; Murli, S.; Reid, R.; Santi, D. V. PNAS, 2006, 103, 4234. (ii) Miyatake-Ondozabal, H.; Barrett, A. G. M. Tetrahedron 2010, 66, 6331. (iii) Miyatake-Ondozabal, H.; Barrett, A. G. M. Org. Lett. 2010, 12, 5573.
Supervisor: Barrett, Anthony Sponsor: Engineering and Physical Sciences Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available