Pochonins

The discovery of ds-enone-containing RALs as kinase inhibitors has led to a broadened interest in these resorcyUdes, and total syntheses have been developed for all four natural products over the past decade. As the synthetic chemistry to these compounds is challenged by the ready isomerization of the ds-enone to the more stable trans-isomer, all the syntheses reported to date feature a selective allylic oxidation at a late stage in the synthesis in order to reveal the ds-enone moiety. 

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Hellwig V, Mayer-Bartschmid A, Miiller H, Greif G, Kleymann G, Zitzmann W, Tichy H-V, Stadler M (2003) Pochonins A-F, New Antiviral and Antiparasitic Resorcylic Acid Lactones from Pochonia chlamydosporia var. catenulata. J Nat Prod 66 829... 

Moulin E, Barluenga S, Totzke F, Winssinger N (2006) Diversity-Oriented Synthesis of Pochonins and Biological Evaluation Against a Panel of Kinases. Chem Eur J 12 8819... 

Scheme 21.12 Synthesis of pochonin D and analogues using polymer-supported reagents (Winssinger et al.) The letters R and S on the polymer matrix denote a polymer bound reagent and scavenger, respectively.

Barluenga S, Lopez, P, Moulin E, Winssinger N (2004) Modular Asymmetric Synthesis of Pochonin C. Angew Chem Int Ed 43 3467... 

Analogs with retained in vivo activity were prepared by converting the ketone into an oxime, a transformation that prevents the dienone to act as a Michael acceptor [11]. Nevertheless, clinical development for a radicicol oxime derivative has not been accomplished, apparently as a result of unfavorable pharmacokinetics and nonspecific toxicides. Danishefsky and coworkers [12a] proposed the use of a cyclopropane as an isosteric replacement for the epoxide and found that cycloproparadicicol (Figure 7.1) is nearly as potent as radicicol in vitro. Despite these advances, a clinical candidate based on the molecular framework of radicicol has yet to be developed. However, important results have recently been obtained based on the pochonins (see below). 

Scheme 7.11 Syntheses of pochonins by Winssinger and collaborators [32, 33, 69]. (a) Syntheses of pochonins A and D. (b) Syntheses of pochonins E and F-...

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