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Volume 92 Issue 31 | p. 9 | News of The Week
Issue Date: August 4, 2014

Getting To The Core In One Step

Drug Discovery: Single-step annulation could ease access to key natural-product analogs
Department: Science & Technology
News Channels: Organic SCENE, JACS In C&EN
Keywords: polyprenylated acylphloroglucinols, PPAPs, drug discovery, hyperforin, St. John’s wort, organic synthesis, annulation

A family of natural products called polyprenylated acylphloroglucinols (PPAPs) may not have a euphonious name, but they have been found to have promising biological effects, including anticancer and antidepressant properties. The drug discovery community would love to be able to evaluate close relatives of PPAPs, but they haven’t been able to do so because the naturally occurring substances and their analogs have been difficult to make synthetically.

Now researchers have made an end run around that problem by synthesizing the core structure of PPAPs in a single step. The core structure can be decorated with diverse functional groups to conveniently make a wide range of PPAP analogs for drug discovery.

Scores of PPAP natural products have been isolated over the years from a variety of plant sources. The most well-known PPAP is hyperforin, the primary active ingredient in the antidepressant medicinal herb St. John’s wort. The biological activities of PPAPs spring from their complex core, a bicyclic structure with three keto groups, three quaternary carbon centers, and several side chains.

A number of PPAP total syntheses have been developed. Some are more efficient than others, but they are all fairly lengthy processes, and the natural products are not easy to derivatize to study variations on the basic structure. So PPAP total synthesis has not been practical for medicinal chemistry use.

Exemplifying the maxim “less is more,” John A. Porco Jr. and coworkers Alexander J. Grenning and Jonathan H. Boyce at Boston University have devised a technique called “dearomative conjunctive allylic annulation” to produce the PPAP core structure in one step (J. Am. Chem. Soc. 2014, DOI: 10.1021/ja5060302). A provisional patent on the technique has been filed.

The method uses palladium catalysis to react aromatic desoxyhumulone substrates with a “conjunctive” (bond-forming) reagent to create a new ring, forming the PPAP bicyclic core structure. It yields grams of material, and the product can be diversified for drug testing.

The technique “represents a significant advance in the systematic, practical, and rapid production of a large array of PPAP analogs,” comments PPAP-synthesis specialist David Yu-Kai Chen of Seoul National University, in South Korea. It “will facilitate more in-depth investigations and understanding of PPAPs, both chemically and more importantly as potential therapeutic agents.”

The core structure’s potential as a building block for medicinal chemistry makes the study a breakthrough in the field, says another PPAP expert, Bernd J. Plietker of the University of Stuttgart, in Germany. “I would like to have had the same idea, but I didn’t, so I have to give John Porco the credit.”

[+]Enlarge
Palladium-catalyzed reaction combines desoxyhumulone substrate and bond-forming “conjunctive” reagent to form the core structure of PPAPs such as hyperforin (top), the active ingredient in St. John’s wort.
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Palladium-catalyzed reaction combines desoxyhumulone substrate and bond-forming “conjunctive” reagent to form the core structure of PPAPs such as hyperforin (top), the active ingredient in St. John’s wort.
 
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