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A Catalyst That Multitasks To Make Complex Molecules

Organic Synthesis: Method leads to complex, biologically relevant molecules on gram scale

by Bethany Halford
September 22, 2014 | A version of this story appeared in Volume 92, Issue 38

Three men pose for a photo in front of a whiteboard with molecules drawn on it.
Credit: Christopher Soldt
Boston College chemists (from left) McGrath, Hoveyda, and Meng.

A new synthetic strategy that relies on a multitasking copper catalyst allows chemists to construct useful molecules faster and with higher yield. Experts say it promises to fast-track complicated syntheses.

Fewer steps in a chemical synthesis often translate to a better yield of the final product. Chemists therefore prize so-called multicomponent reactions that orchestrate the assembly of multiple building blocks into a complex structure in a single stroke. But getting all those pieces to come together in a precise and predictable fashion takes something of a molecular maestro.

A copper catalyst guides this multicomponent reaction.
A reaction scheme and a line structure of rottnestol.
A copper catalyst guides this multicomponent reaction.

Boston College chemists Amir H. Hoveyda, Fanke Meng, and Kevin P. McGrath demonstrate their virtuosity in this regard by using an inexpensive copper catalyst that puts together complex molecules from an allene, a diboron reagent, and an allylic phosphate. The resulting products contain a stereogenic carbon center, a monosubstituted alkene, and a tough-to-synthesize Z-trisubstituted alkenylboron (Nature 2014, DOI: 10.1038/nature13735).

“From a strategic point of view, it’s a catalyst that does a lot of things in one single operation rather than a stop-and-go installation of functional groups one at a time, which is very expensive and generates a lot of waste,” Hoveyda tells C&EN. “It generates in one fell swoop products that have multiple functional groups that are extremely important.”

In particular, Hoveyda points out, this multicomponent reaction can be used to stereoselectively generate trisubstituted olefins—a motif that has proven to be the Achilles heel of many total syntheses. Often, he says, chemists have to resort to making an isomeric mixture of tribsubstituted olefins followed by a tedious separation step. Because the Boston College route produces an alkenylboron species, Hoveyda explains, chemists have the option of making either stereoisomer of many different trisubstituted olefins. “A lot of the success of this chemistry hinges upon the incredible work that other colleagues have done in the area of organoboron chemistry,” he says.

The researchers used the chemistry to prepare the antitumor agent herboxidiene and the antibiotic rottnestol on gram scale. The yield of the new rottnestol synthesis is seven times greater than the overall yield of the next most efficient synthesis. A similar multicomponent reaction strategy from Hoveyda’s lab also uses a copper catalyst to assemble complex products from 1,3-enynes, a diboron reagent, and an aldehyde (J. Am. Chem. Soc. 2014, DOI: 10.1021/ja5071202).

Michael J. Krische, an expert in organic synthesis at the University of Texas, Austin, points out that Hoveyda’s strategy will be useful for creating polyketides, natural products that are frequently used in medicine. Most commercial polyketides are made via fermentation or semisynthesis approaches because, until recently, he says, polyketide total syntheses have relied upon stoichiometric amounts of chiral auxiliaries to achieve stereocontrol at acyclic positions.

“Auxiliary-based approaches typically require additional steps to construct, install, and remove the auxiliary and are typically deployed under cryogenic conditions, which is not ideal for use on scale,” Krische says. Hoveyda’s copper catalysts are capable of stereoselectively assembling polyketide skeletons without stoichiometric chiral auxiliaries, he adds, “contributing powerfully to what is becoming a veritable renaissance in the development of methods for polyketide construction.”


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