Organic chemistry

Triumph for unnatural synthesis

Nature crafts many molecules from common precursors, but this approach isn't always possible in chemical synthesis. A strategy for synthesizing a family of natural products succeeds by ignoring nature's blueprint. See Article p.461

Polyphenols are a group of structurally diverse compounds found in fruits, vegetables and plant-based food products such as tea, wine and chocolate. Because many polyphenols are antioxidants, they have been acclaimed as natural health-protecting agents, although the benefits to humans have yet to be proven. Nevertheless, some polyphenols have biological activities that make them potentially useful leads in the search for drugs against illnesses such as heart disease, cancer and Alzheimer's disease. Pharmaceutical research has been thwarted, however, by the fact that the most complex polyphenols are available from their natural sources in only limited quantities.

An obvious solution would be to prepare large quantities of polyphenols using chemical synthesis. This might seem a trivial task, given that many polyphenols are oligomers derived from just one or two precursor molecules, of which resveratrol (Fig. 1) is perhaps the best-known example. In fact, the structural complexity of resveratrol oligomers makes their chemical synthesis a daunting challenge. But on page 461 of this issue, Snyder et al.1 describe a major advance in polyphenol research: a daring but clever synthetic strategy that has enabled them to prepare a series of resveratrol trimers and tetramers — the highest-order resveratrol oligomers prepared to date.

Figure 1: A synthetic strategy for making resveratrol-derived polyphenols.
figure1

Nature constructs a family of oligomeric polyphenol compounds from resveratrol, but this approach does not work well for the chemical synthesis of these compounds. Snyder et al.1 report a three-stage strategy for making resveratrol oligomers that starts from an alternative precursor molecule. In the first stage, the precursor is converted into a resveratrol dimer, such as permethylated ampelopsin F. The second stage involves introducing a bromine atom (Br) at selected positions in the dimer; the two examples shown were achieved by using different bromination agents. The third stage is to introduce new resveratrol units in the form of trans-dihydrofurans (red), as shown here to make the resveratrol trimers carasiphenol B and ampelopsin G. The authors prepared other trimers and tetramers in a similar way using different resveratrol dimers.

Traditionally, strategies for total synthesis target one specific, naturally occurring compound, rather than a series of biosynthetically or structurally related compounds. Furthermore, the large number of steps involved in many classical total syntheses often makes the synthetic routes economically unviable for industrial-scale processes. Synthetic organic chemists are therefore now using their savoir faire to devise short, practical natural-product syntheses, with the additional challenge of finding routes that have minimal impact on the environment. One approach is to identify better ways of exploiting the inherent chemical reactivity of starting materials and/or synthetic intermediates2. This is the approach used by Snyder and colleagues1, although the resveratrol oligomers that they have made are not traditional targets for total synthesis — indeed, only a few chemists have attempted to make complex plant polyphenols3,4.

Although most polyphenols are biosynthetically derived from the metabolism of only one or two parent molecules, the structural diversity generated within each class of polyphenol is enormous5. A couple of hundred oligomeric constructs are known to be derived from resveratrol, for example6. The biosynthesis of these compounds presumably involves the initial dimerization of resveratrol (which can produce several structurally different dimers), structural rearrangement of the dimers and then further transformations to make higher resveratrol oligomers. But biomimetic strategies that involve making resveratrol oligomers by treating resveratrol with chemical or enzymatic oxidants have generally produced low yields of the desired products and/or led uncontrollably to complex mixtures of compounds.

Nevertheless, a few dimeric members of the resveratrol oligomer family have been made using molecular building blocks other than resveratrol. But none of those syntheses, elegant though they may be7, provides a common route that could generate multiple, structurally very different members of the family. This is what Snyder et al.1 have achieved.

Snyder's group previously reported8,9 the synthesis of several different resveratrol dimers from a common building block that is distinct from, and much more chemically controllable than, resveratrol (Fig. 1). To reach the next level of complexity1 (trimers and tetramers), the authors decided to try to attach bromine atoms to specific sites in some of the previously prepared dimeric compounds. Once installed, the bromine atoms could be used as 'handles' to introduce resveratrol-based groups known as trans-dihydrofurans, making trimers (by the addition of one trans-dihydrofuran) or tetramers (by adding two trans-dihydrofurans). This ambitious goal required the means not only to differentiate selected sites for bromination from all the other sites that shouldn't be brominated, but also to selectively brominate different positions in compounds at will, as required for the particular trimer or tetramer being targeted.

By choosing the appropriate substrates and bromination agents (a process that required extensive experimental trials), Snyder et al. successfully synthesized three naturally occurring resveratrol trimers and two tetramers in good yields. For example, when the authors reacted a commonly used bromination agent, N-bromosuccinimide, with permethylated ampelopsin F (a resveratrol dimer), they obtained a product in which a single bromine atom had become attached to the dimer (Fig. 1) — a remarkable outcome, given that this was one of four possible products. They then converted this product into a trimeric compound, carasiphenol B. But when they reacted permethylated ampelopsin F with a different brominating agent10, they obtained a product in which the bromine atom was attached to a different site in the dimer. The authors converted this into another resveratrol trimer, ampelopsin G.

Snyder and colleagues' syntheses yield products as racemic mixtures (one-to-one mixtures of mirror-image isomers), which would need to be separated into individual isomers for some applications. Even so, their work constitutes a spectacular, highly efficient and general solution to the chemical synthesis of many — if not all — resveratrol-derived polyphenols. This approach will also be useful for preparing analogues of the natural products, which could be necessary for finding compounds possessing optimal biological properties in drug development programmes. The structural diversity of resveratrol oligomers that can be prepared controllably from a simple and easily modulated starting material is truly remarkable, far surpassing what can be achieved using biosynthetic or biomimetic approaches starting from resveratrol itself. Moreover, the authors' strategy of performing divergent, site-selective reactions using lower-order oligomers might be applicable to the synthesis of other oligomeric families of natural products11.

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Correspondence to Stéphane Quideau.

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Quideau, S. Triumph for unnatural synthesis. Nature 474, 459–460 (2011). https://doi.org/10.1038/474459a

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