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Creating Chirality

Selective reaction turns achiral symmetric diols into chiral products

by Stu Borman
September 11, 2006 | A version of this story appeared in Volume 84, Issue 37

Credit: Boston College
Researchers (from left) Snapper, Yu Zhao, Jason Rodrigo, and Hoveyda developed a new enantioselective catalyst that can create chiral products from achiral symmetric diols.
Credit: Boston College
Researchers (from left) Snapper, Yu Zhao, Jason Rodrigo, and Hoveyda developed a new enantioselective catalyst that can create chiral products from achiral symmetric diols.

In work that provides potential new capabilities for chemical synthesis, researchers have identified a simple amino-acid-based catalyst that can add a silyl protecting group to one of two hydroxyl groups in a symmetric diol.

The procedure can protect one of the two very similar secondary alcohol groups in such achiral diols to yield chiral products. The process makes it possible to elaborate each hydroxyl group separately to yield a range of desired synthetic products.

The procedure was developed by chemistry professors Amir H. Hoveyda and Marc L. Snapper and coworkers at Boston College (Nature 2006, 443, 67). Although they demonstrated the reaction initially only on symmetric diols, they note that in principle it is also applicable to the selective silylation of compounds with more than two hydroxyls.

No biological model for the catalyst exists, as there are no known enzymes that catalyze silylation. The method is also unique in organic synthesis, where silylation is a ubiquitous protection strategy. Researchers had developed silylation procedures for resolving diol racemic mixtures into enantiomers and had devised ways to add other types of protecting groups to achiral symmetric diols. But there were no previous catalytic techniques for creating chiral silylated products from achiral diols.

Hoveyda, Snapper, and coworkers developed the new small-molecule catalyst by analyzing the mechanism of diol protection reactions and evaluating candidates having structural properties they predicted would be needed to catalyze those reactions. They found one agent that accelerated the desired process with slight enantioselectivity and then optimized it structurally until they found a catalyst that was more efficient and enantioselective. Using that catalyst, they were able to carry out enantioselective silylations with yields up to 96% and with enantiomeric ratios as high as 98%.

The new method requires that a large amount of catalyst be used, and typical reaction times are lengthy-two to three days. However, the catalyst is inexpensive, easy to make, recoverable, and reusable, and the Boston College group is refining the efficiency and applicability of the technique.

The new reaction "is a wonderful piece of work," says chemistry professor Martin Oestreich of the University of Münster, in Germany, whose group developed an earlier technique to resolve racemic diols. "Protection of a hydroxyl as its silyl ether is of particular importance, since the O-Si linkage is almost indispensable in multistep organic synthesis." For symmetric diols, "this is the first reaction of its kind, and it will certainly influence further developments in this area. A significant aspect of this novel methodology is its practicability—even nonexperts in this area will be able to reproduce and use it."

Chemistry professor E. J. Corey of Harvard University says it's "an original, interesting, and thought-provoking finding. If it proves to be of general applicability, it will find use by synthetic chemists."

In a Nature commentary, chemistry professor Scott E. Denmark of the University of Illinois, Urbana-Champaign, says the new procedure "is likely to have a significant impact on the efficiency and cost of constructing single-enantiomer products."



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