RESEARCH NEWS & VIEWS is strong enough to mask the effect. Importantly, the authors found that the altered gene expression followed a consistent pattern, with increased and decreased geneexpression levels alternating across large chromosomal segments. The discovery of these up- and downregulated segments, which Letourneau et al. call gene expression dysregulation domains (GEDDs), supports mounting evidence that chromosomes contain functional domains that may help to provide cells with access to the genetic information at the appropriate place and time. The positions of the GEDDs align with chromosome domains defined by other structural and functional properties, such as domains that associate with nuclear lamina proteins (lamina-associated domains; LADs4) or that are replicated at different times during the DNA-synthesis phase of the cell-division cycle5. These findings strengthen the idea that chromosome functions reflect underlying structural domains. The authors also report the presence of GEDDs in mice that carry an extra piece of chromosome 16 (the mouse counterpart to most of human chromosome 21) and that show several features of Down’s syndrome6. The GEDDs were observed throughout the mouse genome at positions corresponding to their locations on human chromosomes. Furthermore, the authors demonstrate that the domains were largely preserved after the human twins’ cells were artificially reprogrammed to a developmental state resembling that of embryonic stem cells (induced pluripotent stem cells)7. The authors understandably focus on the similarities between GEDDs before and after this reprogramming. However, the differences that they observed may correspond to the changes in replication timing, or perhaps lamina association, that occur during reprogramming5. Intriguingly, Letourneau and colleagues show that GEDDs with increased expression corresponded to otherwise repressed genomic domains, whereas GEDDs with decreased expression corresponded to domains normally characterized by active transcription (Fig. 1). This means that there is a diminished difference between expressed and repressed genes in people with Down’s syndrome, suggesting that the extra chromosome 21 interferes with the cell’s ability to regulate transcriptional output. The authors made several attempts to understand the mechanism behind GEDDs, but they found no significant changes in LADs or in patterns of DNA methylation — a modification that affects gene-transcription rates. They did find that levels of trimethylation at amino-acid residue lysine 4 on histone H3 correlated well with the transcriptional changes seen in GEDDs (histones are proteins around which DNA is wound in the nucleus, forming a complex called chromatin), but this is to be expected because such post-translational histone modification tracks with expressed

genes8. The results of the authors’ investigation of chromatin accessibility within GEDDs (the accessibility of chromatin to gene-transcription machinery also regulates expression levels) were difficult to interpret. So how could the addition of a single, relatively small chromosome — chromosome 21 is the smallest human chromosome and accounts for less than 2% of the genome — dampen transcriptional differences across the genome? Two kinds of mechanism seem most plausible. First, and perhaps most simply, it is possible that the increased dosage of one or more genes on chromosome 21 is responsible. For example, human chromosome 21 and mouse chromosome 16 carry the HMGN1 gene, the product of which competes9 with histone H1 for access to the linker DNA between nucleo­ somes, the repeating units of chromatin. Because H1 is associated with less-accessible chromatin, an increase in dosage of HMGN1 would be consistent with an increase in global chromatin accessibility. Increased access to normally inaccessible chromatin would be expected to dilute the activity of factors that switch on genes in other parts of the genome, or release factors that repress genes in active regions, or both, with the net effect of flattening gene-expression levels genome-wide. An obvious experiment would be to examine the effect of controlled overexpression of HMGN1 on global transcription levels. A second, much less defined possibility is that the phenomenon described by Letourneau et al. results from the extra DNA content, for example by sequestering factors that regulate expression10. This hypothetical mechanism

need not be specific to chromosome  21 and could be explored further by comparing monozygotic twins that differ in other trisomies. Although less common, most other trisomies do cause some of the clinical features of Down’s syndrome, and extra copies of larger chromosomes are associated with more-extreme effects11. Sex chromo­ somes, which are much more benign in a trisomic context, are the exception11. Letourneau and colleagues have used a set of well-controlled, carefully performed and reproducible experiments to report a provocative new phenomenon. Their findings raise more questions than they answer, and open the door to exciting further research. ■ Benjamin D. Pope and David M. Gilbert are in the Department of Biological Science, Florida State University, Tallahassee, Florida 32306, USA. e-mails: [email protected]; [email protected] 1. LeJeune, J., Gautier, M. & Turpin, R. C.R. Hebd. Séanc. Acad. Sci. 248, 602–603 (1959). 2. Letourneau, A. et al. Nature 508, 345–350 (2014). 3. Dahoun, S. et al. Am. J. Med. Genet. A 146A, 2086–2093 (2008). 4. Guelen, L. et al. Nature 453, 948–951 (2008). 5. Hiratani, I. et al. PLoS Biol. 6, e245 (2008). 6. Davisson, M. T. et al. Prog. Clin. Biol. Res. 384, 117–133 (1993). 7. Takahashi, K. & Yamanaka, S. Cell 126, 663–676 (2006). 8. Li, B., Carey, M. & Workman, J. L. Cell 128, 707–719 (2007). 9. Catez, F., Brown, D. T., Misteli, T. & Bustin, M. EMBO Rep. 3, 760–766 (2002). 10. Liu, X., Wu, B., Szary J., Kofoed, E. M. & Schaufele, F. J. Biol. Chem. 282, 20868–20876 (2007). 11. Hassold, T. & Hunt, P. Nature Rev. Genet. 2, 280–291 (2001).

O R GA N I C C HE M I ST RY

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 J A M E S P. M O R K E N

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he 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

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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

NEWS & VIEWS RESEARCH C4

a

Path 1 C1

C4

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C3

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Me

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Pd(MeCN)2(OTs)2 Cu(OTf)2

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–).

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 enantio­ selective 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. 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 poly­ merization 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. ■ James P. Morken is in the Department of Chemistry, Boston College, Chestnut Hill, Massachusetts 02467, USA. e-mail: [email protected] 1. Mei, T.-S., Patel, H. H. & Sigman, M. S. Nature 508, 340–344 (2014). 2. Das, J. P. & Marek, I. Chem. Commun. 47, 4593–4623 (2011). 3. Alexakis, A., Bäckvall, J. E., Krause, N., Pàmies, O. & Diéguez, M. Chem. Rev. 108, 2796–2823 (2008). 4. Harutyunyan, S. R., den Hartog, T., Geurts, K., Minnaard, A. J. & Feringa, B. L. Chem. Rev. 108, 2824–2852 (2008). 5. Hoveyda, A. H., Hird, A. W. & Kacprzynski, M. A. Chem. Commun. 1779–1785 (2004). 6. Lu, Z. & Ma, S. Angew. Chem. Int. Edn 47, 258–297 (2007). 7. Zhang, P., Le, H., Kyne, R. E. & Morken, J. P. J. Am. Chem. Soc. 133, 9716–9719 (2011). 8. Du, X. et al. Org. Lett. 3, 3313–3316 (2001). 9. Mizoroki, T., Mori, K. & Ozaki, A. Bull. Chem. Soc. Japan 44, 581 (1971). 10. Heck, R. F. & Nolley, J. P. Jr J. Org. Chem. 37, 2320–2322 (1972). 11. Johnson, L. K., Killian, C. M. & Brookhart, M. J. Am. Chem. Soc. 117, 6414–6415 (1995). 12. Kochi, T., Hamasaki, T., Aoyama, Y., Kawasaki, J. & Kakiuchi, F. J. Am. Chem. Soc. 134, 16544–16547 (2012). This article was published online on 9 April 2014. 1 7 A P R I L 2 0 1 4 | VO L 5 0 8 | NAT U R E | 3 2 5

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