Organic chemistry

Catalysis marches on


A fresh take on an established chemical reaction has solved a long-standing problem in organic synthesis: how to prepare single mirror-image isomers of groups known as isolated quaternary stereocentres. See Article p.340

The production of a wide array of compounds, ranging from polymers to liquid crystals to human therapeutics, depends on stereoselective synthesis, which enables three-dimensional control over the isomer of the product that forms. Not surprisingly, the more stereoselective reactions that chemists have in their toolbox, the more efficiently they can construct these materials. One tool that is not well developed is a method for the stereoselective construction of quaternary stereocentres — in which a carbon atom is bonded to the carbon atoms of four other distinct appendages — at positions that are remote from any other groups in a molecule. In this issue, Sigman and colleagues1 (page 340) describe a process that accomplishes just that.

The handedness, or chirality, of enzymes, proteins, nucleic acids and carbohydrates results in distinct binding sites that often accommodate one mirror-image form (enantiomer) of a small-molecule substrate better than the other. Preparing effective inhibitors of biological processes is therefore dependent on our ability to selectively make one enantiomeric form of a small molecule. Such selectivity is the goal of asymmetric organic synthesis. A central dogma in this area is that optimum efficiency results from catalytic asymmetric reactions, in which the handedness of the catalyst controls the handedness of the reaction product. Asymmetric catalysis thus allows small amounts of single-enantiomer catalysts to produce large amounts of single-enantiomer products.

Even after enormous effort and significant advances in the field of chemical catalysis, there are still many more problems than there are solutions. One large obstacle is the enantioselective construction of quaternary stereocentres2. The challenge in making these features is two-fold. First, the fourth and final carbon appendage must be attached to a 'hindered' carbon centre that has three other carbon appendages arranged around it (Fig. 1a). Such carbon–carbon (C–C) bond-forming reactions face substantial energy barriers that can defy even the most reactive of reagents. The second challenge is to complete the construction in a way that gives just one enantiomer of the product. This requires the catalyst to distinguish the size, shape and properties of the three pre-existing appendages, and to do so with high fidelity.

Figure 1: Enantiomeric synthesis of quaternary stereocentres.

Many organic compounds can be arranged in mirror-image forms called enantiomers. a, The two enantiomers of chiral quaternary stereocentres are produced by different pathways that connect a fourth carbon appendage (C4) to a carbon atom bearing three others (C1, C2 and C3). This requires a catalyst (not shown), which must be reactive enough to overcome energy barriers to create the congested centre, and do so preferentially by one path. b, Sigman and colleagues1 report a palladium catalyst that enables the reaction of boronic acids with alkenyl alcohols to form quaternary stereocentres that are located remotely from any other reactive groups. Me, methyl; R, methyl, ethyl, propyl or OSiMe2CMe3, an alcohol derivative; OTs, tosylate (CH3C6H4SO3−); OTf, triflate (CF3SO3−).

A common reaction design for constructing chiral carbon centres involves adding carbon atoms to one end of a carbon–carbon double bond in an alkene molecule, using a catalyst both to facilitate bond formation and, by distinguishing between the groups attached to the double bond, to control the handedness of the product. Such discrimination is especially challenging in the synthesis of quaternary centres, however, because the groups to be distinguished are all carbon substituents and are therefore similar in size.

To accelerate such reactions, chemical groups are often attached to the reacting alkene, a manoeuvre that can also help the catalyst to discriminate between the two faces of planar alkene groups, and so render reactions more enantioselective. For example, a carbonyl group (C=O) can be attached to the alkene to enable conjugate addition, a widely used process for forming C–C bonds3,4. Alternatively, a carbon bearing a leaving group (a group that departs from a molecule as an anion during a reaction) can be attached, thereby allowing a different kind of C–C bond-forming reaction, the allylic substitution reaction5,6, which is a topic of research in my lab7. A consequence of this group-attachment manoeuvre, however, is that the newly formed C–C bond necessarily bears a neighbouring group, which might not be desired.

Sigman and colleagues now describe a palladium catalyst that facilitates C–C bond formation between trisubstituted alkenyl alcohols and boronic acids under oxidative conditions (Fig. 1b), and which leads to products that do not have appended neighbouring groups. The process is based on a known variant8 of a powerful C–C bond-forming process catalysed by a transition metal, which was developed by Tsutomu Mizoroki9 and Richard Heck. (Heck won a share of the 2010 Nobel Prize in Chemistry for work in this area10.) Sigman and colleagues describe the first such reaction that allows C–C bond formation to generate isolated quaternary centres intermolecularly and with outstanding levels of enantiomeric selectivity.

Concomitant with C–C bond formation, the double bond in the alkenyl alcohol migrates by 'walking' along the molecule's carbon chain, until it encounters an alcohol group (OH) farther down the molecule and converts it to a carbonyl group. A powerful feature of the reaction is that the chain walking can occur over many carbon atoms, and allows one to choose the spatial relationship between the newly formed quaternary centre and the resulting carbonyl. Such long-range chain-walking events have previously been observed in polymerization reactions11, but have not been widely used as a design element in organic synthesis12.

One question that Sigman and co-workers address is what happens when the catalyst, engaged in the act of chain walking, encounters a pre-existing chiral carbon centre? If the catalyst releases the alkene as chain walking occurs, then undesirable scrambling of the carbon centre to form an equal mixture of enantiomers is guaranteed. The authors find that the configuration of such chiral centres is retained with perfect selectivity, an outcome that suggests that tight binding occurs between the alkene and palladium as the catalyst speeds down the hydrocarbon backbone towards the carbonyl.

Sigman and colleagues' report sows the seeds of a new direction in asymmetric Mizoroki–Heck reactions, but there is clearly much to do for this area to grow. Currently, the reaction allows only aryl groups — benzene rings with or without other groups attached — to attach to the alkenyl alcohol. Expanding the scope of the reaction to allow the attachment of other groups, such as saturated and unsaturated hydrocarbons, will further extend its utility. It will also be interesting to learn whether groups other than alcohols can intercept the chain-walking palladium catalyst, because this might allow the reaction to be diverted in new and useful directions. Nevertheless, construction of quaternary stereocentres just became much easier.


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Morken, J. Catalysis marches on. Nature 508, 324–325 (2014).

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