Total Synthesis of Dysidiolide

Abstract

The cdc25A protein phosphatase inhibitor dysidiolide (1) has been synthesized enantioselectively, starting from the enantiomerically pure ketal enone 2 and using a cationic rearrangement as the key step to produce the fully substituted bicyclic core of the natural product. Once the central portion of 1 was established, elaboration of the side chains was accomplished expediently via steps that included (1) vinyl cuprate displacement of an iodide to complete the C-1 side chain, (2) a highly diastereoselective oxazaborolidine-catalyzed (CBS) reduction to form carbinol 11, and (3) photochemical oxidation of 11 to generate the γ-hydroxybutenolide functionality of 1. Additionally, this synthesis proves the absolute stereochemistry of dysidiolide (1).

Compound library development guided by protein structure similarity clustering and natural product structure

“…The ketones and the secondary alcohols subsequently were further transformed by addition of Grignard or aryl lithium reagents. Conversion of the furans into hydroxybutenolides was effected by means of cycloaddition with photochemically generated singlet oxygen and regioselective opening of the intermediate cycloadducts (25,26). ␣,␤-Unsaturated lactones were readily obtained by treatment of different aldehydes with 2-(trimethylsilyloxy)furan in the presence of a Lewis acid (27).…”

Synthetic approaches toward sesterterpenoids

“…57 Not surprisingly, a large number of synthetic chemists were drawn to dysidiolide (88) as a target, which culminated in several total and formal total syntheses. As a detailed discussion of all these approaches would exceed the range of this review, we will focus in the following on three successful syntheses by Corey, 58 Dani shefsky 59 and Forsyth. 60 Just one year after its isolation, Corey's group presented the first route to ( ) dysidiolide (88).…”

“…60 Just one year after its isolation, Corey's group presented the first route to ( ) dysidiolide (88). 58 They commenced their synthesis from the Wieland Miescher ketone analogue 89, that was readily available in enantiomerically pure form (Scheme 11). A second quaternary stereogenic center was incorporated by Birch reduction and trapping of the resulting lithium enolate with allyl bromide, after which an enone was introduced by means of a sulfoxide elimination.…”

Natural Product‐Like Combinatorial Libraries

“…The marine sesterterpene dysidiolide, 147 whose absolute configuration has been established by total synthesis, 148 is the first naturally occurring inhibitor of the dual-specificity cdc25 protein phosphatase family, which plays a crucial role in the regulation of the cell cycle. To determine if the solid-phase synthesis delivered biologically active analogues, 6-epi-dysidiolide 121a and four other diastereomers were synthesized on a Merrified resin by means of a Diels-Alder cycloaddition route.…”