news & views at the typical cryogenic conditions. Then, they use a refinement procedure designed to capture conformational heterogeneity 5. With this approach, they can model a loop at the entrance of the binding site in three different conformations, with occupancies of 72, 23 and 4%. Assuming that the observed populations are a natural consequence of their relative stabilities, they use the inverse Boltzmann relationship to assign relative energies (Fig. 1). Because low-population conformations can offer better binding opportunities, this seemingly simple procedure has a big impact on the outcome of docking. Without the energetic balance between conformers, the ranked list of ligands generated in a virtual screening exercise becomes dominated by high-energy states. Experimentally derived conformational energies place all ligands on common ground and improve the chances of finding active compounds while still accepting ligands that bind to diverse states. The authors go on to show that the conformation-weighted docking scores can then be used to predict how the presence of a ligand will modify the population of each conformer with good accuracy (Fig. 1). Furthermore, they use modified software to efficiently screen hundreds of thousands of compounds against this multiple-conformer model of the protein and identify new active molecules that would not be ranked

in top positions by either of the singleconformation models alone. Importantly, the authors have gone to great lengths to demonstrate that their results are robust to the choice of adjustable parameters. The method has its limitations and perhaps the biggest question is how generally applicable it will be. For instance, it is difficult to conceive that large conformational changes could coexist in the same crystal. The way in which the proteins are packed in the crystal may also affect the conformational preferences, in which case the inverse Boltzmann relationship might not hold. Occupancies below 10% can only rarely be assigned to defined atomic positions, meaning that the technique is not expected to capture conformations with an energetic penalty above 2 kcal mol−1. But the method proposed by Fraser, Shoichet and co-workers has the great strengths of being simple, elegant, and easily implemented in existing tools. Furthermore, it can be applied to many existing crystallographic structures. It is preferable if the diffraction dataset has been obtained at room temperature, but the authors have also shown that conformational diversity can be preserved at cryogenic temperatures. Nevertheless, the method has been tested on a convenient model system, and it will have to demonstrate applicability on systems of

pharmacological interest before it reaches the mainstream. As a fast and inexpensive method, molecular docking holds the promise to facilitate drug discovery and to make it possible for any research group on a low budget to screen millions of chemical compounds against novel targets. But its emphasis on throughput means that the binding event is crudely modelled. This affects not only the protein, but also the intermolecular terms and the ligand. The work by Fraser, Shoichet and colleagues serves as a reminder that the way forward is to represent each individual component in a more faithful manner and to improve the energetic balance between the different terms, reaching towards experimental data whenever possible. Only in this way can the great potential of molecular docking be achieved. ❐ Xavier Barril is in the Departament de Fisicoquímica, Facultat de Farmàcia at Barcelona University, Av. Joan XXII s/n, 08028 Barcelona, Spain. e-mail: [email protected] References 1. Fischer, M., Coleman, R. G., Fraser J. S. & Shoichet B. K. Nature Chem. 6, 575–583 (2014). 2. Salvatella, X. Adv. Exp. Med. Biol. 805, 67–85 (2014). 3. Jorgensen, W. L. Acc. Chem. Res. 42, 724–33 (2009). 4. Barril, X. & Morley, S. D. J. Med. Chem. 48, 4432–43 (2005). 5. Fraser, J. S. et al. Proc. Natl Acad. Sci. USA 108, 16247–52 (2011).

C–C BOND FORMATION

Rethinking cross-coupling

The palladium-catalysed cross-coupling of aryl- or alkenylboronates and aryl halides has proved phenomenally successful for the formation of Csp2–Csp2 bonds. Now, an alternative non-transition-metal-mediated coupling using similar reactants has been reported for the stereo-controlled formation of Csp2–Csp3 bonds.

Ho-Yan Sun and Dennis G. Hall

C

ross-coupling chemistry has changed the way small molecules are designed and synthesized in the drug discovery and development process. It forms a type of bond connection that, before it was found, was considered unachievable. The Suzuki– Miyaura cross-coupling 1 of organoboron compounds, for example, has become a workhorse for the production of flat, aromatic and heteroaromatic compounds through the coupling of sp2-hybridized carbon atoms, an example being the coupling of two benzene derivatives to make a biphenyl product. On the other hand, it often falls flat, literally, in the assembly of three-dimensional aliphatic

units through the coupling of sp3-hybridized carbon atoms. Attempts have brought to light several mechanistic issues, including undesired side reactions, such as β-hydride elimination and protodeboronation. This challenge is even greater when stereochemical control is required. In the past decade, numerous advances have been made in the preparation of chiral secondary and tertiary boronic esters. Researchers in this field are switching their attention to the cross-coupling of these chiral boronates, a goal that can provide a conceptually novel approach to establishing saturated C–C bonds with stereochemical control. While alternatives exist, such as

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stereoselective enolate alkylation chemistry, such approaches leave behind functionality (in this case a carbonyl) that may not be desired in the target molecule. The removal of such functional groups reduces the overall efficiency of target syntheses and thus more direct routes are generally preferred. To improve on a Nobel Prize-winning reaction like the palladium-catalysed Suzuki– Miyaura cross-coupling is no doubt an intimidating task and one that may require a new approach. Just such an approach — exploiting an entirely different reaction mechanism and one that does not require a metal catalyst — has now been described by Varinder Aggarwal and co-workers. 561

news & views Suzuki-Miyaura cross-coupling R1

• Stereoselective coupling is difficult • Coupling of tertiary boronate remains a challenge

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Aggarwal and co-workers’ reported coupling

Figure 1 | Cross-coupling of alkyl boronates. Common problems in the palladium-catalysed Suzuki–Miyaura coupling of alkyl boronates are shown at the top. The alternative strategy developed by Aggarwal and co-workers — starting from similar reagents and not relying on a transition metal catalyst — is shown at the bottom. NBS, N-bromosuccinimide; SEAr, aromatic electrophilic substitution.

Writing in Nature Chemistry, they describe2 the construction of stereochemically defined tertiary and quaternary carbon atoms through the notoriously difficult crosscoupling of aliphatic secondary and tertiary boronic esters. Although the products of the method developed by Aggarwal and co-workers are equivalent to a Suzuki–Miyaura crosscoupling between an aryl halide and a chiral organoboronate, the mechanisms through which the two processes proceed are entirely different. The Suzuki–Miyaura coupling typically involves oxidative addition of an aryl halide to a palladium(0) catalyst followed by transmetallation with an organoboronate, and subsequent reductive elimination to give the crosscoupled product. In contrast, Aggarwal and colleagues cleverly chose to exploit the known propensity of organoboronates to undergo stereospecific 1,2-metallate rearrangement 3 to achieve an oxidative coupling between aryl lithium reagents and optically enriched alkyl boronates, giving 562

cross-coupled products with preservation of stereochemical integrity (Fig. 1). The high stereochemical fidelity of these types of rearrangement have been welldocumented in frequently used processes such as boronate oxidation to alcohols and the seminal Matteson homologation, thus this coupling process was also expected to be highly stereoselective. By avoiding the palladium-catalysed mechanism entirely, Aggarwal and co-workers were able to eliminate the many problematic side reactions that normally plague the joining of these types of coupling partner. Related reactions of achiral boranes have been reported in the past 4,5, but the further development of this chemistry to allow for stereoselective coupling has been unsuccessful, due in part to the air-sensitivity and associated difficult handling of these borane substrates. Here, this problem is circumvented by developing reaction conditions that are suitable for the significantly more robust organoboronates6.

Although its virtues are certainly more numerous, the method presented by Aggarwal and co-workers is not without its limitations. The aryl halide coupling partner is limited to electron-rich or heteroaryl species. Furthermore, the use of aryl lithium reactants, which are both strong bases and nucleophiles, limits the types of functionality that can be tolerated under these reaction conditions. Nonetheless, the scope of this reaction does encompass a variety of chiral secondary organoboronates, including both dialkyl and benzylic boronates. Most impressive was the successful coupling of optically enriched tertiary alkyl boronates to give the corresponding quaternary stereogenic carbon centres. Historically, the coupling of optically enriched tertiary boronates through a Suzuki–Miyaura coupling has been considered unachievable. The sterically congested environment around the boron– carbon bond on these substrates results in a particularly difficult transmetallation step. With these selected examples of tertiary boronate coupling, Aggarwal and co-workers have provided an elegant means to construct stereogenic quaternary carbon centres that is complementary to other recently reported advances7,8, and thus set a firm foundation for the continued expansion of a class of methods that is still in its infancy. Methods allowing for the effective construction of optically enriched stereogenic carbon centres continue to be highly sought after, especially in the pharmaceutical industry as there is an increased recognition of the correlation between the tri-dimensionality of a drug candidate and its clinical success9. The market for enantiopure drugs itself is worth more than 200 billion dollars, and as such, efforts should continue to be made towards the advancement of methods contributing to this cause. ❐ Ho-Yan Sun and Dennis Hall are in the Department of Chemistry at the University of Alberta, Edmonton, Alberta, T6G 2G2, Canada. e-mail: [email protected] References 1. Miyaura, N. & Suzuki, A. Chem. Rev. 95, 2457–2483 (1995). 2. Bonet, A., Odachowski, M., Leonori, D., Essafi, S. & Aggarwal, V. K. Nature Chem. 6, 584–589 (2014). 3. Thomas, S. P., French, R. M., Jheengut, V. & Aggarwal, V. K. Chem. Rec. 9, 24–39 (2009). 4. Pelter, A., Williamson, H. & Davies, G. M. Tetrahedron Lett. 25, 453–456 (1984). 5. Ishikura, M., Kato, M. & Ohnuki, N. Chem. Commun. 220–221 (2002). 6. Hall, D. G. (ed.) Boronic Acids 2nd edn (Wiley-VCH, 2011). 7. Mei, T.-S., Patel, H. H. & Sigman, M. S. Nature 508, 340–344 (2014). 8. Minko, Y., Pasco, M., Lercher, L., Botoshansky, M. & Marek, I. Nature 490, 522–526 (2012). 9. Lovering, F., Bikker, J. & Humbler, C. J. Med. Chem. 52, 9752–6756 (2009).

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C-C bond formation: Rethinking cross-coupling.

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