Extending the boundaries of the resorcylates and dioxinones

• Main Author: Patel, Bhavesh
• Other Authors: Barrett, Anthony
• Published: Imperial College London 2012
• Subjects: 540
• Online Access: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.749146

The conversion of various carboxylate derivatives ii,iv and dioxinone i (Scheme A1) into C-6-substituted resorcylates vii,(a) related dihydroxy-isoindolinones viii,(a),(b) C-5-substituted dioxinone-resorcylates x, and resorcinol amides xi, without the use of phenolic protection is described. The key diketo- v and formyl-keto- ix dioxinone intermediates were prepared from keto-dioxinones iii utilizing a crossed Claisen condensation reaction mediated by diethylzinc. The aromatic unit was constructed via late stage cyclization and aromatization. The substrate scope of this synthesis was good and some selected examples are shown in Figure A1. Several of these resorcylate related compounds displayed promising biological activities against a selection of kinases and receptors including CDKs and LRH-1. The synthesis of Hsp90 inhibitor AT13387 (xiv) currently in clinical trials,(c) is reported using our biomimetic aromatization approach, with generation of key intermediates xii and xiii (Scheme A2), and in an improved overall yield (13.4%, compared to 2.6%). Thermolysis of double dioxinone xv with methanol gave a triketo-ester which subsequently aromatized to provide a synthetically useful homophthalate ester xvi (Scheme A3).(d) Enolate C-acylation with diethylzinc was used to form double diketo-dioxinones xvii, which on cyclization, aromatization and dioxinone ring opening gave double resorcylates xviii. The synthesis of various 6-substituted-4-hydroxy-2-pyridinones xxi is also described (Scheme A4).(e) The functionalized keto-dioxinones xix have been transformed into the corresponding enamine-dioxinones xx. Subsequent thermolysis and intramolecular ketene trapping efficiently provided the pyridinone unit.