Sequential Ketene Generation from Dioxane-4,6-dione-keto-dioxinones for the Synthesis of Terpenoid Resorcylates

Abstract

ABSTRACT:Trapping of the ketene generated from the thermolysis of 2-methyl-2-phenyl-1,3-dioxane-4,6-dione-keto-dioxinone at 50 ºC with primary, secondary, or tertiary alcohols gave the corresponding dioxinone β-keto-esters in good yield under neutral conditions. These intermediates were converted by palladium(0)-catalyzed decarboxylative allyl migration and aromatization into the corresponding β-resorcylates. These transformations were applied to the syntheses of the natural products (±)-cannabiorcichromenic and (±)-daurichromenic acid.The 6-alkyl-2,4-dihydroxybenzoic acid or β-resorcylic acid moiety is a structural entity embedded in diverse biologically active natural products. Many members of the resorcylates show useful biological effects and have complex and intriguing molecular structures. As such, resorcylates remain attractive targets for both total synthesis studies and as possible drug candidates.Over the past decade our group has developed a general strategy for the synthesis of β-resorcylates (Scheme 1).1 Palladium-catalyzed decarboxylative allylic migration and aromatization of dioxinone β-keto-esters 1 provided ß-resorcylates in which the allyl moiety was transferred specifically to the arene C-3 position giving the allyl-resorcylate 3 (Type I).2 This sequence provided diverse meroterpenoids in two steps. Alternatively, reaction of C-acylated dioxinone β-keto-esters, derived from allyl ester 1a with a palladium(0) catalyst and morpholine followed by ketene trapping with an alcohol and subsequent aromatization gave resorcylates 5 (Type II). We have employed this second process for the total synthesis of many biologically important resorcylic acid lactones. 3 Scheme 1. Biomimetic Strategies for the Synthesis of β-ResorcylatesThe use of dioxinone β-keto-esters 1 is fundamental to our strategy for the synthesis of meroterpenoids. Previously we have applied three different reactions to synthesize these key intermediates 1 (Scheme 2): (1) Claisen condensation of the lithium enolate 9 with β-keto acid derivatives (8a or 8b) (pathway A); (2) condensation of the dienolate 11 with imidazoyl carbamates 10 (pathway B); and (3) bismuth (III) triflate catalyzed Muikayama type reactions of acyl chlorides 8b with enol silane 12 (pathway C). Although we have demonstrated these methods are synthetically useful, they have limitations. Each method employed excess enolate or enol silane relative to the acyl donor. After work-up, separation of the β-keto-ester from residual dioxinone or keto-dioxinone usually required chromatography, which is inappropriate when the reaction is scaled up. In addition, these reactions resemble more classical procedures to construct 1,3-dicarbonyl systems (i.e. ketone enolate acylations); as such, yields obtained are often modest and can be capricious.4 Others have reported similar findings with enolates derived from dioxinones in Claisen condensation reactions. 5In light of our continued interest in the parallel synthesis of increasingly complex β-resoryclates in programs of medicinal ch...

Meroterpenoid total synthesis: Conversion of geraniol and farnesol into amorphastilbol, grifolin and grifolic acid by dioxinone- β -keto-acylation, palladium catalyzed decarboxylative allylic rearrangement and aromatization

“…12 In our earlier report, malonate 10 (R = Me) was employed in related chemistry. 10 However, the use of malonate 10 (R = H) was found to be superior since it is more readily synthesized from malonic acid and benzaldehyde and more easily purified by simple crystallization than malonate 10 (R = Me) from malonic acid and acetophenone. Additionally, with heating at 55 o C, the thermally induced retro-Diels-Alder reaction of malonate 10 (R = H) occurred at a similar rate to that of malonate 10 (R = Me) and selectively gave the key derived dioxinone-acyl ketene reactive intermediate, presumably due to the phenyl ring π-delocalization into the O-CO σ* orbital during fragmentation.…”

“…More recently, we developed an improved protocol for the synthesis of dioxinone β-keto esters based on the reaction of allylic alcohols with dioxinone-acylketenes generated from the selective mono-retro-Diels Alder reactions of dioxane-4,6-dione-keto-dioxinones. 10 This methodology was applied to the biomimetic total syntheses of the antibiotic (±)-cannabiorcichromenic acid and the anti-HIV agent (±)-daurichromenic acid. 10 Herein, we report very concise total syntheses of such bioactive geranyl-and farnesyl-substituted resorcinols from non-aromatic precursors without the need of phenol protection and which are appropriate for structure activity optimization.…”

“…10 This methodology was applied to the biomimetic total syntheses of the antibiotic (±)-cannabiorcichromenic acid and the anti-HIV agent (±)-daurichromenic acid. 10 Herein, we report very concise total syntheses of such bioactive geranyl-and farnesyl-substituted resorcinols from non-aromatic precursors without the need of phenol protection and which are appropriate for structure activity optimization.…”

Biomimetic Syntheses of Amorfrutin C and C‐5 Substituted Amorfrutin Analogues

“…This disconnection is significantly simplified by involving intermediate 14 directly, which we speculated could be achieved via direct deprotonation‐magnesiation and subsequent trapping with an electrophilic reagent [14] . The retrosynthetic disassembly of resorcylate 5 involves the biomimetic aromatization of β,δ‐ diketo dioxinone 20 , which would, in turn, be prepared through a regioselective C ‐acylation of dioxinone β ‐ketoester 18 , followed by palladium(0)‐catalyzed decarboxylative prenyl rearrangement (Scheme 1C) [12,13a] . Our regioselective acyl‐ketene generation would be key for the preparation of 18 from dioxinone acid 17 , derived from dioxinone 16 [13a,b] …”

A Novel Class of Plant Type III Polyketide Synthase Involved in Orsellinic Acid Biosynthesis from Rhododendron dauricum

“…DCA has attracted considerable attention because it displays various interesting pharmacological activities, including a potent anti-HIV effect ( Iwata et al, 2004 ; Hashimoto et al, 2005 ; Tokuyama et al, 2007 ; Iwata and Kitanaka, 2010 ; Lee, 2010 ). Thus, chemical syntheses of DCA have been extensively studied over the past few years ( Liu and Woggon, 2010 ; Bukhari et al, 2015 ; Luo et al, 2015 ; Elliott et al, 2016 ).…”