Organic chemistry

Short cuts to complexity

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The credit crunch is forcing people to tighten their belts, but chemists have long known the benefits of being economical with atoms. The latest synthesis of an anticancer agent shows how effective parsimony can be.

Nature produces an almost infinite number of structurally complex organic compounds that have fascinating — and potentially useful — biological properties. This has inspired generations of synthetic chemists to make not only the naturally occurring compounds, but also structurally modified analogues that have tailored properties and functions. Marine organisms are a particularly rich source of natural products, but so far only one such class of compound has entered clinical trials: bryostatins, which have anticancer activity in vivo1. Reporting in this issue (page 485), Trost and Dong2 describe a synthetic route to a particular bryostatin — bryostatin 16 — that drastically reduces the longest sequence of consecutive steps from the previous best of 40 down to a much more manageable 26. This might open the door to a practical process for preparing the compound, and provide ready access to bryostatin analogues for drug discovery.

The bryostatin family of compounds is derived from the bryozoan Bugula neritina3 (Fig. 1), and encompasses more than 20 structurally related natural products. Not only do these compounds exhibit anticancer properties, but they have also been shown to improve cognition and enhance memory in animals4, making them interesting leads for drug-discovery efforts targeting Alzheimer's disease. But the concentration of bryostatins in B. neritina is low, so extraction from bryozoans is not a viable means of producing these compounds — at least, not in quantities that would allow a complete evaluation of their biological profiles.

Figure 1: The natural source of bryostatins.
figure1

SOUTHEASTERN REGIONAL TAXONOMIC CENTER/SOUTH CAROLINA DEPT NAT. RES.

Approximately 1 tonne of the marine organism Bugula neritina is needed to isolate 1 gram of bryostatin anticancer agents.

Bryostatins have therefore long been synthetic targets of choice for chemists — not only because of the need to find a practical way of making them, but also because the structural complexity of the compounds provides a perfect opportunity to test new synthetic methods. Despite intensive efforts, only three total syntheses of bryostatins have been reported5,6,7. These achievements were rightly hailed as landmarks in organic chemistry, but they required lengthy sequences of consecutive synthetic steps (at least 40), making them impractical for the preparation of more than milligram quantities of material.

So what is it that makes bryostatins such interesting synthetic targets? A rule of thumb in synthetic chemistry is that the more chemical groups are squeezed into a small molecule, the more difficult that molecule will be to prepare. In this respect, the core structure of bryostatin features three rings (designated A, B and C; Fig. 2a) that are densely populated with chemical groups. Furthermore, two of these rings, B and C, contain motifs known as exo-cyclic trisubstituted alkenes (alkenes are distinguished by carbon–carbon double bonds). In the previous syntheses of bryostatins5,6,7, controlling the geometry of the groups attached to these alkenes was a truly formidable challenge, for which ingenious solutions had to be invented. Equally difficult to prepare, on the basis of the experiences of the previous syntheses, is another alkene group in the molecule, which forms part of the linker between rings B and C.

Figure 2: Catalytic steps in the synthesis of bryostatin 16.
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a, Bryostatin 16 has been prepared in a remarkably short synthesis by Trost and Dong2. The molecule contains several rings, including three designated A, B and C. The large ring highlighted in purple was constructed in the palladium-catalysed reaction shown in c. The structure also has two exo-cyclic trisubstituted alkenes (circled in red) and a disubstituted trans-alkene (circled in blue) that are difficult to prepare. The authors used three pivotal transition-metal-catalysed steps in their synthesis. b, A ruthenium-catalysed reaction was used to construct the B ring. c, d, The C ring was made in two steps: a palladium-catalysed reaction (c) followed by a gold-catalysed reaction (d). All three reactions are perfectly atom economical — all of the atoms in the starting materials are present in the products. Me represents a methyl group; R1 to R5 represent fragments of bryostatin (or of synthetic precursors to bryostatin).

Multi-step syntheses of complex molecular targets will be efficient and practical only if as many of the required reactions as possible are 'atom economical'. In an optimal atom-economical process, all of the atoms in the reactants end up in the desired product. This idea is one of twelve accepted criteria used to quantify how environmentally friendly chemical reactions are, and has been fully implemented by Trost and Dong2 in their synthesis of bryostatin 16. The authors deliberately chose this molecule as their target because it could serve as a precursor to produce many other bryostatins. Their strategy relied on coupling three fragments of the molecule at a late stage in the synthesis.

They made the B ring using a spectacular ruthenium-catalysed coupling reaction8 between an alkene and an alkyne (a compound that contains a carbon–carbon triple bond). Although both fragments contain an array of potentially reactive chemical groups, the ruthenium catalyst binds selectively to the alkene and the alkyne, so inducing the formation of a new carbon–carbon bond (Fig. 2b). Such chemoselectivity is essential to obtaining efficient synthetic routes because it avoids the use of protecting groups — chemical groups that are attached temporarily to reactive parts of molecules to prevent them from interfering in desired reactions. Not only does the ruthenium-catalysed reaction form the B ring with the correct three-dimensional arrangement of substituents, it also controls the geometry of the potentially troublesome exo-cyclic alkene. Furthermore, the reaction is perfectly atom-economical: all of the atoms found in the starting materials (bar the catalyst) are present in the coupled product.

Trost and Dong2 prepared the C ring in a two-step process involving two different transition-metal catalysts. The first step is a palladium-catalysed coupling9 of two alkynes (Fig. 2c), which not only sets the scene for the formation of the C ring, but also forms the characteristic large ring present in bryostatins. This reaction is remarkable, both because it is perfectly atom-economical and because it is the first demonstration that such a large ring structure (containing 22 atoms) can be made using this kind of carbon–carbon bond-forming reaction. Such 'macrocyclizations' are notoriously problematic, so Trost and Dong have effectively added a useful entry to the existing roster of possible reactions.

The authors completed the synthesis of the C ring using a gold-catalysed reaction to form a carbon–oxygen bond between an alcohol group (OH) and the alkyne produced in the previous step (Fig. 2d). Gold catalysts activate alkynes selectively10 in the presence of a wide variety of other chemical groups, a useful property that is used here to great effect. The authors' reaction could, in principle, yield two products, either the desired C ring that contains six atoms, or a smaller ring made up of five atoms. Indeed, when the authors tried a palladium catalyst for the reaction, a mixture of the two rings formed. But the gold catalyst provided the six-membered ring alone.

Trost and Dong's synthesis2 of bryostatin 16, by far the shortest to date, is a remarkable achievement. Nevertheless, more atom-economical and chemoselective methods are still needed to generate complex molecular targets with minimal effort. In particular, the development of chemoselective reactions is pivotal to reducing the need for temporary protecting groups, because every protecting group used in a synthesis generally adds two steps to the route — one to put the group on, and another to take it off. By drastically reducing the total number of steps previously required to make bryostatins, Trost and Dong's work clearly demonstrates the huge difference that chemoselective, atom-economical strategies can make.

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Charette, A. Short cuts to complexity. Nature 456, 452–453 (2008) doi:10.1038/456451a

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