Guided by nature

16 Mar 2010

The versatile chemical synthesis of natural fungal compounds should lead to new candidates for malaria treatments

Fig. 1: Cordyceps nipponica, a relative of the Cordyceps sinensis mushroom (pictured), which is used in Asian medicine, may hold the key to new antimalarial medications.

Fig. 1: Cordyceps nipponica, a relative of the Cordyceps sinensis mushroom (pictured), which is used in Asian medicine, may hold the key to new antimalarial medications.

© iStockphoto/bedo

The Cordyceps sinensis mushroom (Fig. 1) is a traditional Asian medicine with an unusual background. This parasitic fungus—originally from Tibet—propagates by invading the body of a rare caterpillar, slowly replacing tissue until new mushrooms sprout from the deceased host’s head. A related species, Cordyceps nipponica, has attracted recent scientific attention because it contains biochemical substances, known as cordypyridones A and B, which exhibit potent activity against the multidrug-resistant strain of malaria.

Now, Christina Chai and co-workers from the A*STAR Institute of Chemical and Engineering Sciences in Singapore have reported the first total synthesis of cordypyridones A and B from simple and inexpensive starting materials. The flexibility of their procedure could enable rapid development of new pharmaceutical compounds that can overcome the limitations of current malaria therapies.

The biological activity of cordypyridones is believed to arise from a distinctive molecular structure that can immobilize metal ions. This natural product contains two rings connected by a single carbon–carbon bond; one ring is based on a six-membered carbon molecule called cyclohexane, the other is a nitrogen-bearing benzene analogue known as pyridone. Constructing this complex molecular framework with the correct three-dimensional arrangement of the rings and their associated substituents was a challenging proposition.

Chai and her team employed a convergent strategy to produce their natural product. The two key halves of the molecule—the cyclohexane and pyridone rings—were synthesized using separate chemical pathways; a coupling reaction then joined the halves together. Reactions performed in this manner have higher efficiencies than traditional stepwise transformations, and are far more versatile: new components can readily be added to the rings, while retaining the same coupling procedure.

The researchers used innovative techniques, such as a custom zeolite-supported rhodium catalyst, to produce the cyclohexane and pyridone molecular fragments. For the crucial coupling step, a lithium–halogen exchange reaction transformed the pyridone into an anionic intermediate; this species then attacks a carbon–oxygen double-bonded unit known as a ketone on the cyclohexane, joining the rings together.

According to Chai, this coupling reaction tested the limits of their chemical repertoire. “We were extremely relieved when the addition to the ketone was successful—we were rapidly running out of tricks up our sleeves!”

Fully exploiting the antimalarial activity of cordypyridones requires synthesis of several structurally related analogues—a task for which Chai’s procedure is ideally suited. “With malaria developing resistance to current prophylaxis treatments, these compounds could be instrumental in the ongoing fight against such a devastating disease,” says Chai.

The A*STAR-affiliated authors in this highlight are from the Institute of Chemical and Engineering Sciences.

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Jones, I.L., Moore, F.K. & Chai, C.L.L. Total synthesis of (±)-cordypyridones A and B and related epimers. Organic Letters 11, 5526–5529 (2009). | article

This article was made for A*STAR Research by Nature Research Custom Media, part of Springer Nature