β-Keto-dioxinones and β,δ-Diketo-dioxinones in Biomimetic Resorcylate Total Synthesis

Abstract

Resorcylates are a large group of bioactive natural products that are biosynthesized from acetate and malonate units via the intermediacy of polyketides. These polyketides undergo cyclization reactions to introduce the aromatic core. The bioactivities of the resorcylates including resorcylate macrocyclic lactones include anticancer, antimalarial, mycotoxicity, antifungal, and antibiotic properties, and several compounds in the series are already in use in medicine. Examples are prodrugs derived from mycophenolic acid as immunosuppressants and the Hsp-90 inhibitor, AT13387, which is in phase-II clinical trials for the treatment of small cell lung cancer and melanoma. In consequence of these biological activities, methods for the concise synthesis of diverse resorcylates are of considerable importance. In natural product chemistry, biomimetic total synthesis can have significant advantages including functional group tolerance in key steps, the minimization of the use of protection and deprotection reactions and the shortening of the total number of synthetic steps. This Account provides a description of our adaption of the dioxinone chemistry of Hyatt, Clemens, and Feldman for the synthesis and retro-Diels-Alder reactions of diketo-dioxinones. Such dioxinones, which were synthesized by a range of C-acylation reactions, were found to undergo retro-Diels-Alder reactions on heating to provide the corresponding triketo-ketenes with the loss of acetone. The ketene reactive intermediates were rapidly trapped both inter- and intramolecularly with alcohols to provide the corresponding β,δ,ζ-triketo-esters. These compounds, which consist of keto-enol mixtures, readily undergo cycloaromatization to produce resorcylate esters and macrocyclic lactones. We have established the use of diketo-dioxinones as key general intermediates for the synthesis of diverse resorcylate natural products and for the synthesis of new classes of compounds for the generation of medicinal chemistry lead structures. Many of the methods used were found to be tolerant of multiple sensitive functional groups. These include enolate C-acylations with acyl chlorides, 1-acyl-benzotriazoles, acyl imidazolides, or Weinreb amides to prepare diketo-dioxinones and their subsequent use to prepare β,δ,ζ-triketo-esters and lactones and hence resorcylates. In addition, in most cases, phenol protection was avoided. As an alternative to the synthesis of β,δ,ζ-triketo-esters, diketo-dioxinones were also found to undergo cycloaromatization with retention of the ketal entity via a nonketene pathway. Finally, diketo-dioxinones with an allyl, prenyl, geranyl, or other 2-alkenyl carboxylate esters at the γ-carbon underwent decarboxylative rearrangement with tetrakis(triphenylphosphine)palladium catalysis to produce α-substituted diketo-dioxinones and resorcylates with 3-allyl, prenyl, geranyl, or other 2-alkenyl groups. Such diketo-dioxinone chemistry was used in the total synthesis of natural products including aigialomycin, cruentaren A, and the oligomeric resorcylate ant...

Recent advances in ketene chemistry

“…Applications of ketenes generated by dioxinone thermolysis in synthesis have been reviewed; 78 in the example of the synthesis of zearalenone (93, Scheme 42) 79 the ketene intermediate 92 reacts with alcohol 91, followed by cyclization of the side chain after the esterification step. Dioxinone thermolysis also provides a useful route to carboxy-substituted ketenes, as in the generation of the simple carboxyketene from Meldrum's acid, probably via its enolic form.…”

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

“…Inspired by the pioneering work of Harris, Harris and Hyatt, our group has developed a general approach over the past decade to access diverse resorcylate natural products using diketo-dioxinones as a masked triketo-ketenes. [6][7][8] During the synthesis of aigialomycin D, a highly regioselective decarboxylative allylic rearrangement catalyzed by palladium(0) was observed. 9 Application of this fortuitous side reaction led to the development of a general approach to access meroterpenoids with diverse substitution patterns.…”

Applications of Mitsunobu Reaction in total synthesis of natural products

“…Resorcyclic acid lactones (RALs) are known the unique class of polyketide‐derived macrolides with a wide range of biological properties such as anti‐malarial, anti‐fungal, mycotoxic and anti‐bacterial as well as anti‐cancer activities . Novel RALs, Neocosmosin ( 249 ) isolated from a fungus Neocosmospora sp.…”