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
antibiotics ent-W1278 A, B, and C. Additionally, tandem use of the decarboxylative rearrangement process and cycloaromatization was used in the total synthesis of natural products including the methyl
ester of
cristatic acid,
mycophenolic acid, and
hongoquercin B. The methodology was also applied to the synthesis of 9,10-anthraquinones, o-aminoalkyl resorcylates, dihydroxyisoindolinones, oligomers, and resorcinamides. The development of this methodology is described in this Account, showcasing its applicability and versatility for the synthesis of complex resorcylate products.