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Synthesis

Two-By-Two To Zaragozic Acid

Two-carbon reagent helps build natural product's core while reducing redox steps

by Carmen Drahl
December 22, 2008 | APPEARED IN VOLUME 86, ISSUE 51

A TRIPLE DOUBLE
Linking three copies of a two-carbon building block makes an important portion (red) of the core of zaragozic acid C.

BY TAKING A PAGE from polymer chemistry, researchers have completed a new synthesis of the natural product zaragozic acid C, a fungal metabolite named after the Spanish city Zaragoza. The new route relies on a versatile two-carbon building block and could inspire highly efficient routes to myriad natural products featuring repeating subunits.

Several research groups have synthesized zaragozic acids, which block cholesterol biosynthesis. But the highly oxygenated core ring system in these compounds remains particularly challenging to assemble. Now, David A. Nicewicz, Andrew D. Satterfield, Daniel C. Schmitt, and Jeffrey S. Johnson of the University of North Carolina, Chapel Hill, have developed a reaction that fashions the core's three adjoining chiral centers in one step (J. Am. Chem. Soc., DOI: 10.1021/ja808347q).

The key transformation was made possible by a reagent that Johnson's group had already developed—a compound that acts as a building block for glycolic acid, a two-carbon α-hydroxy acid. "We took a look at zaragozic acid and saw that its core contains a series of three consecutive glycolic acid fragments," Johnson explains.

The group's reagent, a silyl glyoxylate, has an electrophilic functional group and a latent nucleophilic group. A trigger reagent unmasks the glyoxylate's nucleophilic moiety, which can then react with a second glyoxylate molecule, leading to a chain-building cascade.

To build zaragozic acid C, the team manipulated reagent ratios to precisely control the number of glyoxylates added to the chain. Because the glyoxylate reagent is already in the correct oxidation state for building zaragozic acid C, it minimized the number of redox-related steps in the synthesis, Johnson says.

Johnson's oligomerization strategy is likely to extend to an array of natural products and analogs that have repeating motifs, says Daniel Romo, an organic chemist at Texas A&M University. "The caveat, as with most methods, is that this particular reagent is only applicable to a subset of natural products," he says. But that should inspire chemists to develop reagents that complement Johnson's versatile glyoxylate, he adds.

"The Johnson group has provided a stunning example of the power of carefully orchestrated multiple-bond-forming cascade reactions to deliver highly complex products—in this case, a major portion of the core ring system of the zaragozic acids—from extraordinarily simple starting materials," says James L. Leighton, a professor at Columbia University who has synthesized other natural products with repeating building blocks, such as polyacetates and polypropionates. "The oft-used descriptor 'elegant' is insufficient in this case to do justice to the beauty and quality of this work."

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