Disguise gets a reaction

Every organic molecule has a sea of carbon–hydrogen bonds, so fishing out just one of these bonds for a reaction is difficult. Using a common chemical group as bait provides a solution to the problem. See Letter p.70

The beneficial properties of many medicines, materials and consumer products composed of small organic molecules are greatly influenced by the locations and types of chemical groups within those molecules — especially 'functional' groups, such as hydroxyl or amino groups. Typically, the introduction of a desired functional group into a molecule is achieved through interconversion reactions, by which one existing reactive group is exchanged for another. However, this approach can involve many steps, making it costly and time consuming.

On page 70 of this issue, Simmons and Hartwig1 report that some functional-group interconversions can be sidestepped by using an iridium catalyst to convert certain carbon–hydrogen (C–H) bonds in molecules directly to carbon–hydroxyl (C–OH) bonds. Their finding provides an extremely useful way to convert alcohols (which contain one hydroxyl group) to 1,3-diols (which contain two hydroxyl groups separated by three carbon atoms). 1,3-Diols are important chemical motifs found in polymers and pharmaceuticals, as well as in the 'skeleton' of many structurally complex, naturally occurring compounds.

The reactions that Simmons and Hartwig report are examples of transition-metal-catalysed C–H bond functionalization2, a synthetic strategy in which otherwise unreactive hydrogen atoms in C–H bonds are replaced directly with functional groups. Such reactions are powerful tools for improving the efficiency with which complex molecules can be synthesized. In practice, however, these reactions are challenging to realize: because organic molecules generally contain many different C–H bonds3, achieving a reaction at just one bond amid all the others can be tricky. Furthermore, each C–H bond in a molecule has a different level of reactivity — although catalysts can be used to functionalize more-reactive C–H bonds in preference to less-reactive ones4, it is difficult to selectively functionalize the less-reactive bonds.

One way around this problem is to use a functional group in a molecule as a directing group — a handle to which a metal catalyst can bind and then guide a reaction to a specific C–H bond5. The drawback with this approach is that the specialized directing groups required are often not present in the target product of a synthetic route. Additional synthetic steps are therefore needed to introduce and remove the directing group.

Because of this limitation, there has been considerable interest in using functional groups that are commonly found in organic molecules, such as hydroxyls, amides or carboxylic acids, as directing groups for C–H bond functionalization reactions6,7. This strategy has proved successful for reactions of the relatively reactive C–H bonds on benzene rings7,8. But the use of these common functional groups to direct the selective functionalization of less-reactive C–H bonds in saturated hydrocarbon chains (alkyl chains) is considerably more challenging, and has been achieved only in simple molecules6.

Enter Simmons and Hartwig1, who have developed a transformation in which hydroxyl groups on alkyl chains are used to direct a highly selective iridium-catalysed C–H bond functionalization reaction (Fig. 1). This is a notable achievement because hydroxyl groups bind only weakly to transition metals (such as iridium), and have a tendency to take part in unwanted side reactions in the presence of many metal catalysts.

Figure 1: An iridium-catalysed C–H functionalization reaction.

Simmons and Hartwig1 report a reaction that converts alcohols into valuable 1,3-diols by replacing a specific C–H bond with a C–OH bond. a, The starting alcohol is first converted into a silyl ether by reaction with diethylsilane. Et, ethyl. b, c, The silyl ether forms a strong attachment to an iridium catalyst (green sphere), and directs the replacement of a specific C–H bond (blue) with a carbon–silicon bond (red). The catalyst is released as the carbon–silicon bond forms. d, A subsequent oxidation step, performed in the same flask as steps a–c without purification of the reaction product from those steps, yields the desired 1,3-diol.

The key to the approach was to 'disguise' a reactant's hydroxyl group by converting it into a silyl ether — a silicon-containing group that is known to bind to metal catalysts (Fig. 1). The silyl ether serves as a directing group by forming a strong attachment to the iridium catalyst and directing the formation of a carbon–silicon bond at a specific C–H bond elsewhere in the reactant. In a subsequent step carried out in the same reaction vessel, Simmons and Hartwig removed the silyl ether mask by oxidizing the carbon–silicon bond to a C–OH bond, liberating the desired 1,3-diol product.

The authors demonstrated the power and utility of their method by converting a variety of simple and complex alcohols to 1,3-diols. In every case, the functionalization occurred at a single C–H site three carbon atoms away from the directing group, even if more-reactive C–H bonds were present elsewhere in the molecule. Impressively, the site selectivity remained high even when Simmons and Hartwig subjected structurally complex natural products to the reactions. They were therefore able to convert readily available natural products bearing a hydroxyl group into other natural products that are more difficult to obtain, and to generate new analogues of natural products.

A particularly striking example is the authors' synthesis of methyl hederagenate (see Fig. 3b of the paper1) — a precursor of the natural product hederagenin, which has anti-inflammatory, antifungal and antitumour properties9. Although the starting material for the synthesis (commercially available methyl oleanate) contains 49 C–H bonds, only one of these bonds was selectively functionalized by their three-step reaction. Previously, the most efficient synthesis10 of hederagenin required ten steps from a starting material closely related to methyl oleanate.

Although Simmons and Hartwig's method is very useful for the functionalization of substrates that contain only one hydroxyl group, it would have even greater application if it could be used for molecules that have several hydroxyl groups. Whether selectivity can be obtained in such systems remains to be seen. Nonetheless, the authors' innovative transformation sheds light on how common chemical groups can be used to direct C–H functionalization reactions, and provides a new and efficient way to prepare 1,3-diol units in complex organic molecules.


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Correspondence to John P. Wolfe.

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Schultz, D., Wolfe, J. Disguise gets a reaction. Nature 483, 42–43 (2012).

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