(+)-Hongoquercin A and B were synthesized from commercially available trans,trans-farnesol in six and eleven steps, respectively, using dual biomimetic strategies with polyketide aromatization and subsequent polyene functionalization from a common farnesyl-resorcylate intermediate. Key steps involve Pd(0)-catalyzed decarboxylative allylic rearrangement of a dioxinone β,δ-diketo ester to a β,δ-diketo dioxinone, which was readily aromatized into the corresponding resorcylate, and subsequent polyene cyclization via enantioselective protonation or regioselective terminal alkene oxidation and cationic cyclization of enantiomerically enriched epoxide to furnish the tetracyclic natural product cores. Analogues of the hongoquercin were synthesized via halonium-induced polyene cyclizations, and the meroterpenoid could be further functionalized via saponification, hydrolytic decarboxylation, reduction, and amidation reactions.

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...

In recent years, H2 activation at non‐transition‐metal centers has met with increasing attention. Here, a system in which H2 is activated and transferred to aldimines and ketimines using substoichiometric amounts of lithium bis(trimethylsilyl)amide is reported. Notably, the reaction tolerates the presence of acidic protons in the α‐position. Mechanistic investigations indicated that the reaction proceeds via a lithium hydride intermediate as the actual reductant.

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