The 2-acyl-1,3-cyclohexanediones are an important class of polyketide natural products found in plants belonging to the family Piperacae (peppers) and insects of the order Lepidoptera (moths and butterflies). Many of these compounds serve as chemical signaling agents in insects, regulating activities such as oviposition. In 2014, Kato and coworkers isolated alatanones A and B from the perennial herb Peperomia alata and trineurones A–E from Peperomia trineura. When tested for biological activity, the alatanones significantly inhibited the growth of the pathogens C. cladosporioides and C. sphaerospermum, with activities two to four times greater than the control antifungal agents nystatin and miconazole. In addition, trineurone E exhibited modest cytotoxicity against the K562 and Nalm-6 leukemic cell lines. Herein we report the first total syntheses of alatanones A and B and trineurones A–E utilizing a one-pot C-acylation reaction to couple 1,3-cyclohexanediones with the appropriate carboxylic acids. This key transformation proceeds via an initial carbodiimide-mediated O-acylation followed by a DMAP-catalyzed Claisen–Haase rearrangement, resulting in O to C acyl migration. Our synthetic routes have produced sufficient amounts of these scarce natural products to enable further biological testing and have also allowed for the preparation of several unnatural analogs of these compounds.

Synthesis of antifungal alatanone and trineurone polyketides

251st National Meeting (2016)

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