Organic chemistry

Reactions at the end of a tether

A remarkable reaction that reverses the chemical behaviour of molecules known as 1,3-diketones allows a new strategy that could be used to prepare a range of potentially useful, naturally occurring compounds. See Letter p.86

Building architecturally complex organic molecules from simple building blocks is akin to building the Taj Mahal from rough chunks of marble — with breathtaking results arising from unassuming starting materials. The process often involves making molecular building blocks called nucleophiles and electrophiles, which attract each other. Once pulled together by attraction, the blocks can react with each other, creating a new, more complex molecule. On page 86 of this issue, Leighton and colleagues1 describe some clever molecular choreography that enables them to convert a nucleophile into an electrophile, so that it can react with another nucleophilic partner. Not only is this work of fundamental scientific interest, but it also paves the way for short synthetic routes of structurally complex molecules.

Some of the most commonly used nucleophiles in organic synthesis are organometallic reagents — compounds that contain a carbon–metal bond. Organometallic reagents that contain allyl groups (CH2CH=CH2) are particularly useful. These react with aldehydes to form 'homoallylic' alcohols, which contain carbon–carbon double bonds — useful starting points for a wealth of other synthetic reactions. Perhaps the most widely used allylic nucleophiles are allylboranes, in which the allyl group is attached to a boron atom, and allylsilanes, in which the allyl group is attached to silicon (Fig. 1a).

Figure 1: Allylation reactions of aldehydes and 1,3-diketones.

a, Electrophilic aldehydes react with nucleophilic, chiral allylic metal reagents, such as the allylborane and allylsilane shown, to form homoallylic alcohols as a single mirror-image isomer (enantiomer). The allyl group transferred in the reaction is shown in red. R is an alkyl group (a saturated hydrocarbon); Ar is an aryl (benzene-containing) group. b, Unlike aldehydes, 1,3-diketones are nucleophilic, and so do not react with allylic metal reagents. This is because they exist predominantly as enol-containing isomers; the enol group is shown in blue. R groups are alkyl or aryl groups. c, Leighton and colleagues1 have reacted 1,3-diketones with an allylsilane5 previously developed in their group. The silane becomes tethered to the enol group and then takes part in an intramolecular reaction that generates a β-hydroxyketone as a single enantiomer. The tethering reaction generates HCl, an acid, which helps to promote the intramolecular reaction.

In many cases, the alcohols that form are chiral — that is, they can exist as two mirror-image isomers known as enantiomers. Chiral variants of boranes have long been used to control which enantiomer of a product forms, making these reactions a cornerstone of organic synthesis. The US chemist Herbert C. Brown won a Nobel prize for his work developing chiral boranes2,3,4, many of which are still used for the synthesis of complex molecules more than 30 years after their discovery. More recently, Leighton's group has reported5 that the members of a family of chiral allylsilanes (Fig. 1a) react with aldehydes to yield products with even higher enantioselectivity than can be achieved using Brown's reagents. These silanes are increasingly being used for synthesis.

Some of the most interesting targets of organic synthesis are compounds that contain carbonyl groups (C=O) separated from homoallylic alcohols by a single carbon atom. Such motifs could, in principle, be assembled using the strategies discussed above, except that the starting material would not be a simple aldehyde, but a 1,3-diketone — a compound in which two carbonyl groups are separated by a single carbon atom (Fig. 1b). This is problematic, because such compounds are nucleophilic rather than electrophilic. Indeed, 1,3-dicarbonyl compounds (such as 1,3-diketones) are such valuable nucleophiles that chemists often append an additional carbonyl group to lone carbonyls in synthetic intermediates to enhance the lone carbonyls' nucleophilicity for subsequent reactions.

This nucleophilicity of 1,3-diketones is a consequence of tautomerism, a phenomenon in which the compounds rapidly interconvert between an electrophilic dicarbonyl isomer and a nucleophilic isomer that contains one carbonyl group and an enol group (HO–C=C; Fig. 1b). In fact, the equilibrium state of the interconversion process ensures that most of the molecules are enol-containing isomers. So how does one coerce these isomers to behave as electrophiles? It should be possible given that they still contain a carbonyl group, albeit one that is much less electrophilic than a lone carbonyl group because of electron donation from the enol isomer.

Leighton and colleagues' solution was to tether an allylsilane to the enol group of a 1,3-diketone (Fig. 1c). The allyl group could then attack the remaining carbonyl group in an intramolecular reaction to form an alcohol — the only drawback being that, in general, such reactions are extremely slow. The authors expected this sluggishness to be offset to some degree by the fact that the reaction is intramolecular, because intramolecular reactions are generally faster than intermolecular ones. Nevertheless, they didn't anticipate that this effect alone would be enough to promote the reaction.

However, the tethering process generates acid molecules, which are known to activate the nucleophilic attack of allyl silanes on carbonyl groups6. Would this help the reaction to occur? When the authors combined 1,3-diketones with one of Leighton's allylsilanes, hey presto: they obtained homoallylic alcohols bearing a neighbouring carbonyl in high yield, and with exquisite control of the enantiomer formed during the reaction.

Leighton and colleagues went on to show that their reaction works well for a range of symmetrical 1,3-diketones. More impressively, in the case of unsymmetrical 1,3-diketones that have an alkyl group (a saturated hydrocarbon) on one side of the two carbonyls, and an aryl group (one containing a benzene ring or a benzene-like ring) on the other, the allylsilane selectively attacks the carbonyl adjacent to the alkyl. The authors observed that the reaction also discriminates between the two carbonyl groups in 1,3-diketones bearing two different aryl groups, but not between those in diketones bearing two different alkyl groups. This limitation represents a crucial challenge remaining to be solved, because reactions of dialkyl diketones are likely to be of greatest use in the synthesis of complex molecules.

The synthetic utility of the process is further enhanced by the ready availability of 1,3-diketones and of Leighton's allylsilane reagents (which are commercially available), and because the protocol required for the reaction is simple. Ultimately, it would be useful if the reactions could be conducted with chiral catalysts rather than chiral reagents, because catalysts are used in small, sub-stoichiometric quantities and so are more suitable for use in large-scale reactions.

The ability to efficiently design, synthesize and manufacture ever more complex molecules that have particular shapes and functions is important to the future needs of society. Leighton and colleagues' work is a considerable step towards this goal, and, as a master synthetic chemist7, Leighton is well placed to apply this methodology to the challenging targets presented by nature. Such application will provide the definitive challenge to test these impressive reactions.


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Correspondence to Varinder K. Aggarwal.

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Roesner, S., Aggarwal, V. Reactions at the end of a tether. Nature 487, 48–49 (2012).

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