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Synthesis

Catalysis Across A Ring

Catalytic transannular Diels-Alder reaction is highly selective

by Rachel Petkewich
September 24, 2007 | APPEARED IN VOLUME 85, ISSUE 39

ring crossing
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An optimized catalyst (in which R = 2-fluorophenyl) mediates this asymmetric transannular Diels-Alder reaction.
8539notw4_scheme2.gif
An optimized catalyst (in which R = 2-fluorophenyl) mediates this asymmetric transannular Diels-Alder reaction.

BONDING SPECIFIC carbon centers across sterically congested rings can be nearly impossible without the right catalyst.

Chemistry professor Eric N. Jacobsen and graduate student Emily P. Balskus at Harvard University report the first transannular Diels-Alder reaction to occur with the help of a highly selective asymmetric catalyst. They used it to catalyze a key step in the total synthesis of a sesquiterpene natural product (Science 2007, 317, 1736).

Organic chemist Erik J. Sorensen at Princeton University comments that the work "will stimulate other creative applications of this method in complex chemical synthesis." In some instances, he adds, the chiral catalyst can even override the intrinsic selectivity bias of a substrate.

Thomas R. Hoye, a synthetic organic chemist at the University of Minnesota, Twin Cities, says that "the results serve as an elegant demonstration of the power of synthetic design that can follow from insightful analysis of critical structural details."

Oxazaborolidine-based Lewis acid compounds are known to effectively catalyze intermolecular and acyclic intramolecular Diels-Alder reactions. To achieve high selectivity for transannular reactions, Balskus and Jacobsen synthesized and tested various derivatives of these catalysts. An ortho-fluorinated phenyl ring on the boron provided the best conversion and selectivity.

Balskus notes they were careful to choose macrocyclic substrates that would be amenable to catalysis but would not spontaneously undergo a transannular Diels-Alder reaction in the absence of a catalyst or at room temperature.

Jacobsen says, "We observed consistently high enantioselectivity, and that makes us very optimistic that this type of chemistry might be applied to a wide range of substrates and maybe even different types of reactions." He and his colleagues started with the Diels-Alder reaction because it is a well-studied reaction and they could build on extensive previous work related to asymmetric catalysis, Jacobsen adds.

After establishing that the catalyst would react with a broad range of macrocycles, the researchers applied their synthetic method to a more elaborate substrate, namely, a sterically congested sesquiterpene natural product called 11,12-diacetoxydrimane. In eight steps from a known ketoaldehyde, they first synthesized the desired substrate for the transannular Diels-Alder reaction. Then, they used the optimized catalyst to convert that intermediate, a silicon-containing macrocyclic ketone, to a tricyclic compound. Six additional steps led to the desired product.

The Harvard researchers note that the tricyclic compound provides access to other interesting natural products that, due to steric demands, are inaccessible by traditional inter- or intramolecular Diels-Alder reactions.

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