NEWS & VIEWS RESEARCH However, it is possible that epigenetic factors — heritable changes that do not involve DNA-sequence changes — could have had a simultaneous role6. If so, this invokes a broader question7 concerning the influence of developmental plasticity in niche differentiation: might character displacement in a diverse community initially be driven by developmental responses to resources and competitors that are later genetically assimilated as speciation occurs? The present study suggests that this challenging question could be addressed in real time with an experimental, field-based approach. Because natural communities are diverse, selective forces that emerge from interactions between many species may be unexpectedly influential factors that shape species traits. How might we conceptualize this possibility? Stable coexistence requires both character displacement and evolutionarily unavoidable trade-offs between species8,9. Such interspecific trade-offs occur only if allocation of biomass to traits that increase performance in one type of environment decreases performance in other environments. For example, plants that have greater root mass perform better in infertile soils, but those that have more leaf and stem mass — and thus are taller and capture more light — dominate fertile soils. Such trade-off ‘surfaces’ could explain how the ecological interactions that allow multi-species coexistence also influence the rate and pattern of species formation8,9 (Fig. 1b). Although the disciplines of ecosystem ecology and evolution have developed their own perspectives, if each incorporated elements of the other, both disciplines would be strengthened. It is time for a reunification of all of the branches of natural history in a renewed search for unified explanations of the patterns seen in the natural world. ■ David Tilman and Emilie Snell-Rood are in the Department of Ecology, Evolution and Behavior, University of Minnesota, St Paul, Minnesota 55108, USA. D.T. is also in the Bren School of Environmental Science and Management, University of California, Santa Barbara, USA. e-mails: [email protected]; [email protected] 1. Zuppinger-Dingley, D. et al. Nature 515, 108–111 (2014). 2. Lehman, C. L. & Tilman, D. Am. Nat. 156, 534–552 (2000). 3. Rainey, P. B. & Travisano, M. Nature 394, 69–72 (1998). 4. Grant, P. R. & Grant, B. R. Science 313, 224–226 (2006). 5. Fussmann, G. F., Loreau, M. & Abrams, P. A. Funct. Ecol. 21, 465–477 (2007). 6. Verhoeven, K. J. F., Jansen, J. J., van Dijk, P. J. & Biere, A. New Phytol. 185, 1108–1118 (2010). 7. Pfennig, D. W. et al. Trends Ecol. Evol. 25, 459–467 (2010). 8. Tilman, D. Proc. Natl Acad. Sci. USA 101, 10854–10861 (2004). 9. Tilman, D. Am. Nat. 178, 355–371 (2011). This article was published online on 15 October 2014.
O R GA N I C CH E M I ST RY
Shape control in reactions with light The report of a light-activated catalyst that dictates the three-dimensional shape — the stereochemistry — of molecules formed in an organic reaction suggests a new strategy for controlling such reactions using visible light. See Letter p.100 of such research, transecting many fields. Photochemical reactions have been used to streamline complex syntheses and to build structurally unusual organic frameworks. However, organic molecules are generally transparent to visible light — they cannot absorb its energy for use in chemical reactions. Organic photochemical reactions have typically needed ultraviolet light, which requires specialized equipment and instrumentation capable of handling high-energy ultraviolet photons. This has limited the study of photochemical synth esis to a fairly small community of specialists. But in the past several years, a variety of exciting photoreactions have been developed that use visible light, and so can be carried out with simple household light sources or even sunlight2. The key insight was that certain transition-metal complexes (typically based on ruthenium or iridium) that absorb relatively low-energy wavelengths of visible light can be used as catalysts to activate a wide range of organic substrates, thereby enabling new reactions to take place. Although this development has fuelled renewed interest in photochemical
K A Z I M E R L . S K U B I & T E H S H I K P. Y O O N
P
hotochemical reactions can occur when a molecule absorbs light. Such reactions are greatly valued by organic chemists for their ability to promote fascinating changes in molecular structure that cannot be replicated in any other way. However, the application of these reactions for syntheses has long been hindered by several practical limitations. One of the biggest is the dearth of effective strategies for controlling the threedimensional shape of the organic molecules produced. On page 100 of this issue, Huo et al.1 report an elegant approach to address this long-standing challenge. The interaction between light and matter constitutes one of the most active areas of scientific research. This year, for instance, the Nobel prizes for physics and chemistry were awarded for the development of efficient light-emitting devices and for the use of fluorescence in ultrahigh-resolution microscopy, respectively. From energy science to biomedicine to materials engineering, photochemistry is a vibrant theme Light
O 2N
NO2
α-Bromo-2,4-dinitrotoluene
Br
e– S
t-Bu
O 2N
NO2
N
O Ph
N
Ir
N
NMe
Acyl imidazole
Catalyst
N Me
+ Br –
Radical intermediate
O
N
Ph
Bottom face shielded by S catalyst
t-Bu
Enolate complex
O Ph
N
NO2
NMe
Stereochemically well-defined product
NO2
Figure 1 | Light-controlled stereoselectivity. Huo et al.1 report a general reaction in which a lightactivated iridium catalyst controls the stereochemistry of the product. In this example, an acyl imidazole forms an enolate (blue), which in turn forms a complex with the catalyst (red). Bonds shown in bold project above the plane of the page, whereas hashed bonds project behind the page. The catalyst also converts α-bromo-2,4-dinitrotoluene (a benzyl halide compound) into a radical intermediate and a _ _ bromide ion (Br ) by donating an electron (e ). The radical reacts only at the top face of the enolate, because part of the catalyst blocks the bottom face. This ensures that the stereochemistry of the product is well defined (the green group in the product projects above the page in most of the formed molecules, rather than below). Me, methyl; Ph, phenyl; t-Bu, tert-butyl (C(CH3)3, a highly bulky group); Ir, iridium; Br, bromine; the dot on the radical indicates a single electron. 6 NOV E M B E R 2 0 1 4 | VO L 5 1 5 | NAT U R E | 4 5
© 2014 Macmillan Publishers Limited. All rights reserved
RESEARCH NEWS & VIEWS synthesis, control over the three-dimensional structure of the organic products has remained a problem. This is an important problem, because the ability to form one mirror-image isomer (stereoisomer) of a molecule in preference to the other has profound ramifications in biological and pharmaceutical contexts: the two mirror-image forms often have drastically different physiological effects. Similarly, the macroscopic physical properties of polymeric organic materials can be strongly affected by the stereochemistry of their monomeric components. Stereoselective synthesis therefore remains one of the central challenges in modern synthetic chemistry. Since 2009, Eric Meggers’ research group has been developing methods for preparing ruthenium and iridium complexes as single stereoisomers3. In studying these complexes as catalysts for several organic reactions, Meggers and co-workers have demonstrated4,5 that the three-dimensional arrangement of the complexes can be transferred with exceptional fidelity to the organic products that they create. The same research group — Huo et al. — now shows that these transition-metal catalysts are also photoactive, and that this property can be exploited to perform highly stereoselective photochemical reactions. As a model system, the authors chose to study the α-alkylation of carbonyl compounds — a benchmark reaction in stereoselective synthesis (Fig. 1). The iridium catalyst first binds to an acyl imidazole compound, creating a structurally well-defined enolate complex. Photoexcitation of this complex initiates an electron-transfer process that converts a reagent (a benzyl halide) into a highly reactive radical intermediate. The geometry of the catalyst shields one face of the planar enolate from reaction (the bottom face in Fig. 1) and forces the radical to form a bond to it preferentially from the opposite face. The iridium catalyst thus serves two distinct roles: it simultaneously photoactivates one component of the reaction (the benzyl bromide) and controls the facial selectivity of the other (the enolate). These findings will attract considerable attention from synthetic chemists. Photochemical activation typically produces highly reactive intermediates whose stereochemical preferences have historically proved difficult to control6. Some of the most successful approaches have needed two catalysts, with one performing the photochemical activation and the other dictating the stereoselectivity of the reaction7,8. The discovery of a single transition-metal catalyst that fulfils both roles is a crucial conceptual step forward. Huo and colleagues’ reaction design combines the previously reported, precise stereoselective control exerted by their transition-metal complexes with the practicality of using visible light for photochemistry. Future investigations will surely build on this
impressive result. Because the products of the reported reaction could also be made by more-conventional methods, the next step will be to show that the new catalytic strategy is applicable to other classes of photoreaction for unmet synthetic applications. More broadly, this work provides inspiration for chemists to further explore how photochemistry might be used to transform organic synthesis. ■ Kazimer L. Skubi and Tehshik P. Yoon are in the Department of Chemistry, University of Wisconsin–Madison, Madison,
Wisconsin 53706, USA. e-mail: [email protected] 1. Huo, H. et al. Nature 515, 100–103 (2014). 2. Schultz, D. M. & Yoon, T. P. Science 343, 1239176 (2014). 3. Gong, L., Wenzel, M. & Meggers, E. Acc. Chem. Rev. 46, 2635–2644 (2013). 4. Chen, L.-A. et al. J. Am. Chem. Soc. 135, 10598–10601 (2013). 5. Huo, H., Fu, C., Harms, K. & Meggers, E. J. Am. Chem. Soc. 136, 2990–2993 (2014). 6. Inoue, Y. Chem. Rev. 92, 741–770 (1992). 7. Nicewicz, D. A. & MacMillan, D. W. C. Science 322, 77–80 (2008). 8. Du, J., Skubi, K. L., Schultz, D. M. & Yoon, T. P. Science 344, 392–396 (2014).
CA N C ER
Metastasis risk after anti-macrophage therapy Blocking the activity of macrophages may delay the spread of cancer. But new findings show that these immune cells can rapidly rebound to tumours after therapy withdrawal, accelerating lethal metastasis in mice. See Letter p.130 I O A N N A K E K L I KO G L O U & M I C H E L E D E PA L M A
M
acrophages are immune cells that are key players in our bodies’ defence against invading pathogens. More over, they participate in organ development, remodelling, healing and disease1. Macro phages are also found in tumours, where they seem to support tumour progression and spread by means of several mechanisms2. This has prompted the development of drugs that impair macrophage survival3,4, block their infiltration into tumours5 or reduce their protumoral functions6. In this issue, Bonapace et al.7 (page 130) report that, in mice, although the continuous blockade of macrophages constrains tumour progression, cessation of the therapy stimulates them to rapidly rebound to the tumours, unexpectedly leading to accelerated metastatic disease. Monocytes — the circulating precursors of macrophages — enter a tumour from the bloodstream and subsequently differentiate into macrophages2. The recruitment of monocytes and their differentiation into tumour-associated macrophages are regulated by signalling molecules released by the tumour or its metastases. One of these is C–C chemokine ligand 2 (CCL2), a protein that attracts monocytes expressing the receptor for CCL2, called CCR2. Blocking the binding of CCL2 to CCR2-expressing monocytes inhibits macrophage infiltration into the metastases that form in the lungs of mice with mammary tumours, delaying the progression of metastatic cancer and extending mouse survival5. In humans, both high levels of CCL2 expression
4 6 | NAT U R E | VO L 5 1 5 | 6 NOV E M B E R 2 0 1 4
© 2014 Macmillan Publishers Limited. All rights reserved
and macrophage infiltration in the tumours correlate with a poor prognosis in some cancer types, such as breast cancer5,8. Because tumour metastasis to the body’s vital organs is the main cause of cancer-associated death, blocking CCL2 may be an attractive strategy to help combat metastasis in patients with breast cancer and, possibly, other tumour types. Bonapace et al. used a neutralizing antibody against CCL2 to block the protein’s activity in mice with mammary tumours. In agreement with previous studies5, CCL2 blockade decreased macrophage recruitment to the tumours and reduced the incidence and growth of the lung metastases (Fig. 1). The authors observed that the number of circulating cancer cells shed from the primary tumour, which can travel to the lung and initiate metastases, was reduced during anti-CCL2 treatment. This suggests that CCL2 neutralization had a direct effect on the primary tumour, possibly through macrophage regulation of the growth and characteristics of tumour blood vessels9 — the first barrier encountered by cancer cells in their journey to distant organs. But the treatment may also affect the establishment and growth of newly settled metastases, for example by inhibiting macrophage production of vascular endothelial growth factor A (VEGF-A), a protein that stimulates the formation of blood vessels in tumours9. But in a dramatic twist, the authors found that interrupting anti-CCL2 therapy accelerated the development of lung metastases and death (Fig. 1). As early as 10 days after withdrawal of the therapeutic antibody, they observed abnormally increased numbers of
O R GA N I C CH E M I ST RY
Shape control in reactions with light The report of a light-activated catalyst that dictates the three-dimensional shape — the stereochemistry — of molecules formed in an organic reaction suggests a new strategy for controlling such reactions using visible light. See Letter p.100 of such research, transecting many fields. Photochemical reactions have been used to streamline complex syntheses and to build structurally unusual organic frameworks. However, organic molecules are generally transparent to visible light — they cannot absorb its energy for use in chemical reactions. Organic photochemical reactions have typically needed ultraviolet light, which requires specialized equipment and instrumentation capable of handling high-energy ultraviolet photons. This has limited the study of photochemical synth esis to a fairly small community of specialists. But in the past several years, a variety of exciting photoreactions have been developed that use visible light, and so can be carried out with simple household light sources or even sunlight2. The key insight was that certain transition-metal complexes (typically based on ruthenium or iridium) that absorb relatively low-energy wavelengths of visible light can be used as catalysts to activate a wide range of organic substrates, thereby enabling new reactions to take place. Although this development has fuelled renewed interest in photochemical
K A Z I M E R L . S K U B I & T E H S H I K P. Y O O N
P
hotochemical reactions can occur when a molecule absorbs light. Such reactions are greatly valued by organic chemists for their ability to promote fascinating changes in molecular structure that cannot be replicated in any other way. However, the application of these reactions for syntheses has long been hindered by several practical limitations. One of the biggest is the dearth of effective strategies for controlling the threedimensional shape of the organic molecules produced. On page 100 of this issue, Huo et al.1 report an elegant approach to address this long-standing challenge. The interaction between light and matter constitutes one of the most active areas of scientific research. This year, for instance, the Nobel prizes for physics and chemistry were awarded for the development of efficient light-emitting devices and for the use of fluorescence in ultrahigh-resolution microscopy, respectively. From energy science to biomedicine to materials engineering, photochemistry is a vibrant theme Light
O 2N
NO2
α-Bromo-2,4-dinitrotoluene
Br
e– S
t-Bu
O 2N
NO2
N
O Ph
N
Ir
N
NMe
Acyl imidazole
Catalyst
N Me
+ Br –
Radical intermediate
O
N
Ph
Bottom face shielded by S catalyst
t-Bu
Enolate complex
O Ph
N
NO2
NMe
Stereochemically well-defined product
NO2
Figure 1 | Light-controlled stereoselectivity. Huo et al.1 report a general reaction in which a lightactivated iridium catalyst controls the stereochemistry of the product. In this example, an acyl imidazole forms an enolate (blue), which in turn forms a complex with the catalyst (red). Bonds shown in bold project above the plane of the page, whereas hashed bonds project behind the page. The catalyst also converts α-bromo-2,4-dinitrotoluene (a benzyl halide compound) into a radical intermediate and a _ _ bromide ion (Br ) by donating an electron (e ). The radical reacts only at the top face of the enolate, because part of the catalyst blocks the bottom face. This ensures that the stereochemistry of the product is well defined (the green group in the product projects above the page in most of the formed molecules, rather than below). Me, methyl; Ph, phenyl; t-Bu, tert-butyl (C(CH3)3, a highly bulky group); Ir, iridium; Br, bromine; the dot on the radical indicates a single electron. 6 NOV E M B E R 2 0 1 4 | VO L 5 1 5 | NAT U R E | 4 5
© 2014 Macmillan Publishers Limited. All rights reserved
RESEARCH NEWS & VIEWS synthesis, control over the three-dimensional structure of the organic products has remained a problem. This is an important problem, because the ability to form one mirror-image isomer (stereoisomer) of a molecule in preference to the other has profound ramifications in biological and pharmaceutical contexts: the two mirror-image forms often have drastically different physiological effects. Similarly, the macroscopic physical properties of polymeric organic materials can be strongly affected by the stereochemistry of their monomeric components. Stereoselective synthesis therefore remains one of the central challenges in modern synthetic chemistry. Since 2009, Eric Meggers’ research group has been developing methods for preparing ruthenium and iridium complexes as single stereoisomers3. In studying these complexes as catalysts for several organic reactions, Meggers and co-workers have demonstrated4,5 that the three-dimensional arrangement of the complexes can be transferred with exceptional fidelity to the organic products that they create. The same research group — Huo et al. — now shows that these transition-metal catalysts are also photoactive, and that this property can be exploited to perform highly stereoselective photochemical reactions. As a model system, the authors chose to study the α-alkylation of carbonyl compounds — a benchmark reaction in stereoselective synthesis (Fig. 1). The iridium catalyst first binds to an acyl imidazole compound, creating a structurally well-defined enolate complex. Photoexcitation of this complex initiates an electron-transfer process that converts a reagent (a benzyl halide) into a highly reactive radical intermediate. The geometry of the catalyst shields one face of the planar enolate from reaction (the bottom face in Fig. 1) and forces the radical to form a bond to it preferentially from the opposite face. The iridium catalyst thus serves two distinct roles: it simultaneously photoactivates one component of the reaction (the benzyl bromide) and controls the facial selectivity of the other (the enolate). These findings will attract considerable attention from synthetic chemists. Photochemical activation typically produces highly reactive intermediates whose stereochemical preferences have historically proved difficult to control6. Some of the most successful approaches have needed two catalysts, with one performing the photochemical activation and the other dictating the stereoselectivity of the reaction7,8. The discovery of a single transition-metal catalyst that fulfils both roles is a crucial conceptual step forward. Huo and colleagues’ reaction design combines the previously reported, precise stereoselective control exerted by their transition-metal complexes with the practicality of using visible light for photochemistry. Future investigations will surely build on this
impressive result. Because the products of the reported reaction could also be made by more-conventional methods, the next step will be to show that the new catalytic strategy is applicable to other classes of photoreaction for unmet synthetic applications. More broadly, this work provides inspiration for chemists to further explore how photochemistry might be used to transform organic synthesis. ■ Kazimer L. Skubi and Tehshik P. Yoon are in the Department of Chemistry, University of Wisconsin–Madison, Madison,
Wisconsin 53706, USA. e-mail: [email protected] 1. Huo, H. et al. Nature 515, 100–103 (2014). 2. Schultz, D. M. & Yoon, T. P. Science 343, 1239176 (2014). 3. Gong, L., Wenzel, M. & Meggers, E. Acc. Chem. Rev. 46, 2635–2644 (2013). 4. Chen, L.-A. et al. J. Am. Chem. Soc. 135, 10598–10601 (2013). 5. Huo, H., Fu, C., Harms, K. & Meggers, E. J. Am. Chem. Soc. 136, 2990–2993 (2014). 6. Inoue, Y. Chem. Rev. 92, 741–770 (1992). 7. Nicewicz, D. A. & MacMillan, D. W. C. Science 322, 77–80 (2008). 8. Du, J., Skubi, K. L., Schultz, D. M. & Yoon, T. P. Science 344, 392–396 (2014).
CA N C ER
Metastasis risk after anti-macrophage therapy Blocking the activity of macrophages may delay the spread of cancer. But new findings show that these immune cells can rapidly rebound to tumours after therapy withdrawal, accelerating lethal metastasis in mice. See Letter p.130 I O A N N A K E K L I KO G L O U & M I C H E L E D E PA L M A
M
acrophages are immune cells that are key players in our bodies’ defence against invading pathogens. More over, they participate in organ development, remodelling, healing and disease1. Macro phages are also found in tumours, where they seem to support tumour progression and spread by means of several mechanisms2. This has prompted the development of drugs that impair macrophage survival3,4, block their infiltration into tumours5 or reduce their protumoral functions6. In this issue, Bonapace et al.7 (page 130) report that, in mice, although the continuous blockade of macrophages constrains tumour progression, cessation of the therapy stimulates them to rapidly rebound to the tumours, unexpectedly leading to accelerated metastatic disease. Monocytes — the circulating precursors of macrophages — enter a tumour from the bloodstream and subsequently differentiate into macrophages2. The recruitment of monocytes and their differentiation into tumour-associated macrophages are regulated by signalling molecules released by the tumour or its metastases. One of these is C–C chemokine ligand 2 (CCL2), a protein that attracts monocytes expressing the receptor for CCL2, called CCR2. Blocking the binding of CCL2 to CCR2-expressing monocytes inhibits macrophage infiltration into the metastases that form in the lungs of mice with mammary tumours, delaying the progression of metastatic cancer and extending mouse survival5. In humans, both high levels of CCL2 expression
4 6 | NAT U R E | VO L 5 1 5 | 6 NOV E M B E R 2 0 1 4
© 2014 Macmillan Publishers Limited. All rights reserved
and macrophage infiltration in the tumours correlate with a poor prognosis in some cancer types, such as breast cancer5,8. Because tumour metastasis to the body’s vital organs is the main cause of cancer-associated death, blocking CCL2 may be an attractive strategy to help combat metastasis in patients with breast cancer and, possibly, other tumour types. Bonapace et al. used a neutralizing antibody against CCL2 to block the protein’s activity in mice with mammary tumours. In agreement with previous studies5, CCL2 blockade decreased macrophage recruitment to the tumours and reduced the incidence and growth of the lung metastases (Fig. 1). The authors observed that the number of circulating cancer cells shed from the primary tumour, which can travel to the lung and initiate metastases, was reduced during anti-CCL2 treatment. This suggests that CCL2 neutralization had a direct effect on the primary tumour, possibly through macrophage regulation of the growth and characteristics of tumour blood vessels9 — the first barrier encountered by cancer cells in their journey to distant organs. But the treatment may also affect the establishment and growth of newly settled metastases, for example by inhibiting macrophage production of vascular endothelial growth factor A (VEGF-A), a protein that stimulates the formation of blood vessels in tumours9. But in a dramatic twist, the authors found that interrupting anti-CCL2 therapy accelerated the development of lung metastases and death (Fig. 1). As early as 10 days after withdrawal of the therapeutic antibody, they observed abnormally increased numbers of
