and its binding ligands are upregulated in CNV. The initiating event in CNV might be a physical response of the choroid to micro-scopic fractures in Bruch’s membrane — the supporting basement membrane of the retinal pigmented epithelium — with repositioning of a single choroidal vessel that feeds new ves-sel formation. Could such repositioning result in endothelial expression of CCR3? Or do the endothelial progenitor cells that are incorpo-rated into the new CNV vessels express CCR3? Evaluation of CCR3 expression on circulating endothelial progenitor cells and measurement of the amounts of circulating CCR3 ligands could address this question and possibly iden-tify people who are at risk of AMD.

Disturbed blood-vessel formation is involved in the development of other diseases, including cancer13, and it would be interesting to explore whether CCR3 is differentially expressed in tumour vasculature. As Takeda et al.3 point out, a search for variations in the gene encod-ing CCR3 or in related genes in populations with AMD may also aid our understanding of what causes AMD.

The findings of Takeda and colleagues3

suggest that the same anti-CCR3 antibodies used to detect CNV in its earliest stages could be used to treat patients with AMD before blood vessels have fully infiltrated the central macula and caused vision loss. By identifying a unique signature for CNV, the authors have triggered a paradigm shift in AMD research and have pro-vided a wealth of questions to be answered. ■

Maria Grant is in the Department of

Pharmacology and Therapeutics, University of

Florida, Gainesville, Florida 32610, USA.

e-mail: grantma@ufl.edu

1. Smith, W. et al. Ophthalmology 108, 697–704 (2001).

2. Rein, D. B. et al. Arch. Ophthalmol. 127, 533–540 (2009).

3. Takeda, A. et al. Nature 460, 225–230 (2009).

4. Rosenfeld, P. J. et al. N. Engl. J. Med. 355, 1419–1431 (2006).

5. Saint-Geniez, M. et al. PLoS One 3, e3554 (2008).

6. Ma, W. et al. J. Clin. Invest. 109, 621–628 (2002).

7. Humbles, A. A. et al. Proc. Natl Acad. Sci. USA 99, 1479–

1484 (2002).

8. Harrington, P. M. et al. Int. J. Exp. Pathol. 80, 177–185 (1999).

9. Zhou, J. et al. Mol. Vis. 11, 414–424 (2005).

10. Sakurai, E., Anand, A., Ambati, B. K., van Rooijen, N. &

Ambati, J. Invest. Ophthalmol. Vis. Sci. 44, 3578–3585

(2003).

11. Ambati, J. et al. Nature Med. 9, 1390–1397 (2003).

12. Nozaki, M. et al. Proc. Natl Acad. Sci. USA 103, 2328–2333

(2006).

13. Carmeliet, P. Nature 438, 932–936 (2005).

ORGANIC CHEMISTRY

Forgotten hydrocarbons preparedHenning Hopf

Dendralene hydrocarbons have a reputation for being difficult — it seemed that these molecules couldn’t easily be made. A practical synthesis of dendralenes opens them up for study, and reveals some surprises.

The presence of unsaturation — double or triple bonds — in molecules often largely determines their structural properties and chemical behav-iour. Unsaturated hydrocarbons are well known to chemists, but one class, known as dend-ralenes, has been neglected, in part because the compounds were thought to be unstable. In Angewandte Chemie, Payne et al.1 report a prac-tical synthesis of dendralenes, and find that they are stable after all. Intriguingly, the physical and chemical properties of the compounds depend on whether there is an odd or even number of double bonds in the molecules.

There are six different ways in which carbon–carbon double bonds (C=C bonds) can be assembled to form unsaturated hydrocar-bons2. The simplest is to connect these C=C bonds using carbon–carbon single bonds, to produce chain-like molecules known as acyclic conjugated polyolefins (Fig. 1a). Some crucial naturally occurring compounds, such as vita-min A and β-carotene, are derivatives of this class, whereas polymeric versions are familiar to materials scientists as ‘organic metals’ — so-called because of their conducting properties.

Alternatively, C=C bonds may be con-nected together using single bonds to form

ring-shaped, or cyclic, molecules (Fig. 1b). The resulting hydrocarbons, known as annu-lenes, are either aromatic (for those with an odd number of C=C bonds), or antiaromatic (for flat molecules that have an even number of C=C bonds). Annulenes have had pivotal roles in the development of theories of the structure and reactivity of organic molecules. More prac-tically, the aromatic hydrocarbons benzene, toluene and xylene are important feedstocks for the chemical industry.

Then there are the radialene3 and fulvene2 classes of hydrocarbons, which have more exotic-looking structures. In radialenes, C=C bonds ‘radiate’ from a central ring of carbon atoms that is formed from carbon–carbon single bonds (Fig. 1c), whereas, in fulvenes, C=C bonds radiate from annulene-like rings (Fig. 1d). Dendralenes4 (Fig. 1e) are chain-like versions of radialenes — on paper, dendralene structures look like radialenes in which a sin-gle bond has been broken (although it isn’t actually possible to convert a radialene to a dendralene). The final structural arrangement of hydrocarbons occurs when two or more C=C bonds share a common carbon atom; allenes contain two C=C bonds, whereas cumulenes

contain three or more5 (Fig. 1f).Although dendralenes exhibit a curious

electronic phenomenon known as cross-conjugation — a feature also found in numer-ous organic dyestuffs — they have long been neglected by organic chemists. The reason is simple: the compounds could not be made readily in sufficient amounts for further study, and were assumed to be too unstable to han-dle under normal laboratory conditions (on the basis of what was known from the few reported examples of dendralenes4). Payne et al.1 show that this assumption is wrong. They devised a general method for the preparation of dendralenes, and used it to make the first six members of the family. Their synthetic route provides more than enough material for fur-ther studies of the reactivity and structures of these mysterious compounds.

Payne et al. constructed their compounds from molecular building blocks that already contained one or more C=C bonds. For exam-ple, they used a magnesium-containing reagent (easily made from a commercially available compound) as the source of a diene fragment, which contains two C=C bonds connected by a single bond (Fig. 2a). They reacted this with other double-bond-containing compounds — various vinyl halides — in a nickel-catalysed process6,7 that ‘stitched’ together the unsatu-rated hydrocarbon groups. In this way, Payne and colleagues prepared dendralenes contain-ing three to five C=C bonds in good yields. The authors prepared higher oligomers (containing up to eight C=C bonds) using similar proc-esses, providing each member of the series in gram quantities and as analytically pure sub-stances. Previously, only milligram quantities could be made.

Like annulenes, the physical and chemical

Conjugated

polyolefins

Radialenes

Dendralenes

Fulvenes

a b

Annulenes

c d

e f

Allene

Cumulenes

Figure 1 | Six varieties of unsaturation. a–f, Carbon–carbon double bonds can be assembled in six different ways to construct distinct families of unsaturated hydrocarbons, examples of which are shown. In f, the first member of the family is known as allene, whereas the others are known as cumulenes. Carbon atoms shared by two double bonds are represented as bold dots.

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properties of the newly prepared dendralenes depend on the number of C=C bonds in the molecule: the properties of the even-numbered members of the series are distinctly different from those of its odd-numbered members. A good example is the thermal stability of the compounds. Dendralenes that have an even number of C=C bonds can be kept at room temperature for weeks without any significant decomposition, whereas their odd analogues have much shorter half-lives. A similar dichot-omy occurs for the electronic spectra of these compounds, and in their chemical behaviour.

Perhaps the most likely initial use of dend-ralenes will be in organic synthesis, acting as sources of dienes in ‘cycloaddition’ reactions. The most widely used cycloaddition reaction is the Diels–Alder addition, because this is the best method for preparing rings of six carbon atoms. When dendralenes are used in Diels–Alder additions, the reaction product will contain a new diene fragment, which can in principle undergo another Diels–Alder addi-tion, and so on, until no more diene units can be generated (Fig. 2b). Such ‘diene-transmis-sive Diels–Alder processes’8 allow the rapid generation of molecular complexity from relatively simple starting materials in a one-pot operation.

Payne et al.1 found that the reactivity of dendralenes in Diels–Alder additions again depends on the number of C=C bonds in the molecule: odd-numbered dendralenes react faster than their even-numbered counterparts. Furthermore, only the endmost dienes of odd-numbered dendralenes take part in reactions,

MgCl

ClClCl

Br

a

b

Diels–Alder

reaction

Diels–Alder

reaction

Nickel catalyst

Figure 2 | Preparation and reactions of selected dendralenes. Payne et al.1 have prepared dendralenes by stitching together unsaturated hydrocarbon fragments from other compounds. a, In these examples, the diene fragment (red) of a magnesium-containing compound is coupled in nickel-catalysed reactions to hydrocarbon fragments (various colours) of halogen-containing compounds, to make the first three members of the dendralene family. b, The authors also investigated the reactivities of dendralenes in Diels–Alder additions. In these reactions, a diene fragment (red) reacts to form a six-membered ring. Another diene is formed in the product, which can, in principle, take part in another Diels–Alder reaction. The cycle continues until no more dienes are formed.

whereas diene subunits throughout the even-numbered dendralenes react. The authors rationalized this surprising chemical effect using quantum mechanical calculations, which suggest that the geometries of the bonds in the

dendralenes are at least partly responsible. In the odd-numbered dendralenes, the endmost diene subunits adopt a conformation that has long been known to be optimal for Diels–Alder reactions. These subunits therefore react quickly, and preferentially to the other diene subunits. But all of the diene subunits in the even–numbered dendralenes adopt an unfa-vourable conformation for Diels–Alder addi-tions; their reactions are therefore slower than in the odd-numbered dendralenes, and no particular diene subunit reacts preferentially to the others.

With the dendralenes now available in sufficient amounts for further study, we can expect the discovery of many new reactions. The resulting products should show interesting chemical and structural properties, and would not have been available using conventional methods of synthesis. ■

Henning Hopf is at the Institute of Organic

Chemistry, Technical University Braunschweig,

Hagenring 30, D-38106 Braunschweig, Germany.

e-mail: h.hopf@tu-bs.de

1. Payne, A. D., Bojase, G., Paddon-Row, M. N. & Sherburn,

M. S. Angew. Chem. Int. Edn 48, 4836–4839 (2009).

2. Hopf, H. Classics in Hydrocarbon Chemistry (Wiley-VCH,

2000).

3. Maas, G. & Hopf, H. Chemistry of Dienes and Polyenes Vol. 1

(Ed. Rappoport, Z.) 927–977 (Wiley, 1997).

4. Hopf, H. Angew. Chem. Int. Edn 23, 948–960 (1984).

5. Krause, N. & Hashmi, A. S. K. (Eds) Modern Allene

Chemistry Vol. 1 & 2 (Wiley-VCH, 2004).

6. Corriu, R. J. P. & Masse, J. P. J. Chem. Soc. Chem. Commun.

144a (1972).

7. Tamao, K., Sumitani, K. & Kumada, M. J. Am. Chem. Soc.

94, 4374–4376 (1972).

8. Tsuge, O., Wada, E. & Kanemasa, S. Chem. Lett. 12, 1525–1528 (1983).

IMMUNOLOGY

B cells break the rules Marilyn Diaz and Janssen Daly

A study of lymphocytes that lack a DNA-repair enzyme challenges long-standing dogma about the spatial separation of processes that rearrange antibody genes, and provides clues about the origins of B-cell cancers.

Long-lived organisms are constantly being attacked by a myriad of pathogens that have evolved mechanisms to evade the host immune system. To counter this onslaught, vertebrate T and B lymphocytes have an extraordinar-ily diverse repertoire of surface receptors that recognizes an array of foreign antigens. The generation of this wide range of surface B-cell receptors (membrane-bound immunoglobu-lin) takes place in developing B lymphocytes in the bone marrow through a process that involves breakage and recombination of vari-able (V), diversity (D) and joining (J) segments of immunoglobulin genes. Mature B cells in peripheral tissues (the spleen and lymph nodes) also rearrange immunoglobulin genes by DNA breakage and repair, but through a different

mechanism — class-switch recombination. In an exciting study in this issue (page 231),

Wang et al.1 find that a special type of V(D)J recombination — receptor editing — can take place in the periphery in mature B cells that are simultaneously undergoing class-switch recombination. In the absence of a DNA-repair enzyme, these cells experienced frequent chromosome translocations at the sites of immuno globulin genes. These find-ings refute the long-standing belief that recep-tor editing and class-switch recombination are restricted to distinct anatomical locations and specific stages of B-cell development, and provide insight into the mechanism of gene translocations.

The immunoglobulin molecule (antibody)

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