NEWS & VIEWS CATALYSIS
Gold unleashes the power of three Gold in the +3 oxidation state is scarcely used in catalysis, because the oxidants employed to generate it can damage reactants. An oxidant-free route to gold(iii) catalysts reveals their potential. See Article p.449 CHRISTOPHER M. B. K . KOURRA & NICOLAI CRAMER
a
A
key challenge for organic chemists is to selectively synthesize structurally complex target molecules for the pharmaceutical, agrochemical and materials industries in a rapid, cost-effective manner. Catalysis has attracted considerable attention as a way of achieving this, because of its ability to probe unexplored chemical reactivity, and therefore to enable short synthetic routes to target compounds. On page 449 of this issue, Wu et al.1 report the design and application of catalysts based on gold in the +3 oxidation state (Au(iii) catalysts), and describe their use in promoting reactions that are complementary to existing catalytic processes. Chemists strive to use catalysis to orchestrate the assembly of demanding molecules in a controlled and selective manner. Over the past few decades, game-changing advances in catalysis have focused mainly on transition metals in low oxidation states. By contrast, catalysis that uses transition metals in high oxidation states — such as Au(iii) — remains largely underdeveloped2. This situation is particularly evident for gold: Au(i) catalysis3 is a burgeoning field, behind which Au(iii) catalysis lags considerably. The reasons are twofold. First, it is difficult to access the Au(iii) oxidation state using ‘mild’ conditions (that is, conditions compatible with the desired catalytic process), and second, Au(iii) catalysts have poor stability4,5. The successful development of such catalysts therefore requires striking a fine balance between catalytic activity and stability. Progress will continue to be limited until ligand molecules can be developed that stabilize Au(iii) metal centres. Wu and colleagues set out with the lofty ambition of developing a mild strategy that not only allows the generation of stable and active Au(iii) catalysts, but also allows the catalysts to be easily prepared and tuned for particular reactions. The central element of their plan was to form Au(iii) species by inserting an existing Au(i) catalyst into a carbon–carbon (C–C) bond, a process known as oxidative addition. This avoids the use of any strong oxidants, which are usually required to
iPr N iPr
iPr N iPr
Cut and insert here
N iPr
Au(I)
Au(III)
Biphenylene
+
iPr N iPr
iPr
Pocket for oxygen binding
Cl Gold(I) compound Gold(III) catalyst
b
OTMS β
iPr
OTMS β
OiPr
OH O OiPr
iPr Conventional catalysts, including gold(I) catalysts
O
OiPr H
Carbonyl carbon atom
Gold(III) catalyst
O iPrO iPr β
O H
Figure 1 | Preparation and application of a gold(iii) catalyst. a, Wu et al.1 report that the gold atom (Au) of a gold(i) compound inserts into a carbon–carbon single bond of biphenylene under mild conditions (at room temperature and without the need for oxidants) to form a gold(iii) catalyst. The bulky ligand molecules in the catalyst shield most of the gold atom, but create a pocket in which oxygen atoms of organic molecules can bind to the metal. iPr, isopropyl group (CH(CH3)2). b, The gold(iii) complex promotes catalytic reactivities that are complementary to those obtained using gold(i) catalysts or other conventional catalysts. In this example, a silyl enol ether (blue) reacts with an α,β-unsaturated aldehyde (green) at the carbonyl carbon atom (newly formed bond is shown in red) in the presence of a conventional catalyst, but at the β position in the presence of the gold(iii) catalyst. TMS, trimethylsilyl group (Si(CH3)3).
access Au(iii) catalysts, and which can be detrimental to chemical groups in the substrates used for the reactions. The authors knew that several transition metals undergo oxidative addition to a compound called biphenylene6 — these reactions occur readily because they alleviate strain in biphenylene molecules. Sure enough, when they reacted a Au(i) compound with biphenylene, the metal inserted into the latter’s C–C single bond, generating a Au(iii) catalyst containing a stabilizing biphenylene ligand (Fig. 1a). The reaction was straightforward to perform and surprisingly mild (occurring at room temperature). The authors used a simple procedure to convert their catalyst into a compound from which the active catalyst itself can be easily generated in reactions. Crucially, this catalyst precursor can be stored and handled easily without the need to exclude moisture and oxygen. The next task was to apply this Au(iii) catalytic system to solve persistent unanswered chemical problems. Au(iii) catalysts have a high affinity for oxygen atoms, unlike
4 4 0 | N AT U R E | VO L 5 1 7 | 2 2 JA N UA RY 2 0 1 5
© 2015 Macmillan Publishers Limited. All rights reserved
their Au(i) counterparts, and thus promote a complementary set of reactions. Wu and co-workers envisaged that they could use the bulky ligands around the gold centre to guide oxygen atoms on reaction substrates into a small, defined pocket in which they would bind to the metal. Crucially, the ligands provide a protective shield that induces the substrate to react with a particular regio selectivity (preferentially at a particular atom), thus avoiding the formation of an undesired mixture of products. Wu et al. tested their catalyst in six types of reaction in which molecules add (form a bond) to the C–C double bonds of compounds known as α,β- and α,β,γ,δ-unsaturated aldehydes. They observed that it overrides the regioselectivity generally obtained using previously reported methods7,8 (Fig. 1b). In other words, the bulky ligands force substrates to react at only the most remote modifiable position from the aldehyde’s oxygen atom. Good product yields were obtained for all the reactions reported, demonstrating the broad applicability and reliability of the Au(iii) catalyst.
NEWS & VIEWS RESEARCH A particularly exciting element of this work is that it opens up the possibility of using Au(i)and Au(iii)-catalysed processes in tandem, thus combining the best of both worlds. Wu and colleagues exemplified this approach by performing a known reaction9 using an Au(i) catalyst and then simply adding biphenylene to the reaction mixture, generating the Au(iii) catalyst in situ. A second reaction catalysed by the Au(iii) compound consequently occurred. The results are a major breakthrough for chemists aiming to master selective reactions at remote positions of molecules that contain several possible sites of modification. The authors’ innovative strategy for accessing Au(iii) catalysts in a mild, reliable manner, without the use of harsh oxidants, is revolutionary. But there is more to be done. The work currently examines
the reactions of just one class of compound from the large family of molecules that contain carbonyl (C=O) groups. The effects of the Au(iii) catalyst on other carbonyl-containing compounds should now be investigated. It also remains to be seen whether the catalyst can be successfully applied to molecules that contain heteroatoms (atoms that are not carbon or hydrogen) other than oxygen. These are exciting times: the door to Au(iii) catalysis has been kicked wide open, and chemists are poised to exploit its full potential. ■ Christopher M. B. K. Kourra and Nicolai Cramer are at the Ecole Polytechnique Fédérale de Lausanne (EPFL), Institute of Chemical Sciences and Engineering, SB ISIC LCSA, BCH 4305,
C E LL D IVISIO N
Hold on and let go The discovery and functional analysis of the protein MEIKIN in mice leads to an evolutionarily conserved model of how chromosome segregation is regulated during a specialized type of cell division called meiosis I. See Article p.466 K I K U Ë TA C H I B A N A - K O N W A L S K I
T
he movements of sister chromosomes during cell division can be compared to those of figure skaters on an ice rink. During most divisions, a pair of skaters stand back-to-back at the centre of the ice and, as the music starts, skate away from each other, separating forever. In a division that leads to the production of eggs or sperm, however, the two skaters stand side-by-side, back-to-back with another couple. Each couple holds hands as the two teams separate, and the skaters make their way across the ice together. Letting go of a partner too early could result in abnormal chromosome segregation and infertility, but the mechanisms that encourage chromosomes to hold on and separate together in this setting have long been a mystery. In this issue, Kim et al.1 (page 466) identify the first key regulator of this process in mammals, illuminating a molecular pathway that seems to be evolutionarily conserved from yeast to humans. Cell division that produces two identical daughter cells is called mitosis. Before mitosis, each chromosome in the cell is duplicated to produce an identical sister — in humans, 46 chromosomes (23 pairs of ‘homologous’ chromos omes, one set from each parent) become 92. Duplicated chromosomes called sister chromatids are held together along chromosome arms and at specialized domains, the centromeres, by complexes of cohesin protein. Protein structures called kinetochores are built back-to-back (bi-oriented) on the
centromeres of sister chromatids. Kinetochore bi-orientation facilitates sister-chromatid separation during the anaphase stage of division. At this time, cohesin is destroyed, and spindle fibres that extend from each pole of the cell attach to the facing kinetochore and pull sisters apart, partitioning an identical sister into each daughter cell (Fig. 1a). a Mitosis
1015 Lausanne, Switzerland. e-mail: [email protected] 1. Wu, C.-Y., Horibe, T., Jacobsen, C. B. & Toste, F. D. Nature 517, 449–454 (2015). 2. Hickman, A. J. & Sanford, M. S. Nature 484, 177–185 (2012). 3. Corma, A., Leyva-Pérez, A. & Sabater, M. J. Chem. Rev. 111, 1657–1712 (2011). 4. Gaillard, S., Salwin, A. M. Z., Bonura, A. T., Stevens, E. D. & Nolan, S. P. Organometallics 29, 394–402 (2010). 5. Wolf, W. J., Winston, M. S. & Toste, F. D. Nature Chem. 6, 159–164 (2013). 6. Perthuisot, C. et al. J. Mol. Catal. A 189, 157–168 (2002). 7. Yamamoto, H. (ed.) Lewis Acids in Organic Synthesis (Wiley, 2000). 8. Akagawa, K., Sen, J. & Kudo, K. Angew. Chem. Int. Edn 52, 11585–11588 (2013). 9. Pennell, M. N., Unthank, M. G., Turner, P. & Sheppard, T. D. J. Org. Chem. 76, 1479–1482 (2011).
By contrast, during meiosis, non-identical sperm or eggs (germ cells) are produced from two rounds of division, meiosis I and II. Meiosis follows chromosome duplication like mitosis, but DNA exchange, known as meiotic recombination, occurs between homologous chromosomes to ensure that germ cells have a mix of genetic material from each parent. Unlike mitosis, cohesin is maintained at centromeres during anaphase of meiosis I. Kinetochores on sister chromosomes face the same direction — they are mono-oriented — and are thus captured and pulled by spindle fibres from the same pole (Fig. 1b). Chromosome segregation in meiosis II proceeds in a similar manner to mitosis, separating the sisters into forming germ cells. How kinetochore mono-orientation is regulated in meiosis I is a long-standing b Meiosis I
Cohesin Kinetochore
Sister chromatids
Homologous chromosomes
Figure 1 | Chromosome orientation in mitosis and meiosis. Before cell division, identical chromosome copies called sister chromatids are held together by cohesin protein. How the chromatids segregate during division is determined by the orientation of protein structures called kinetochores — each chromatid is pulled towards the pole of the cell that the kinetochore faces (indicated by arrows). a, In mitosis, kinetochores sit back-to-back on sister chromatids (they are bi-oriented), and chromatids are pulled to opposite poles. b, In meiosis I, homologous chromosomes are linked as a consequence of meiotic recombination. The kinetochores of the homologous chromosomes face in opposite directions, but those of sister chromatids are mono-oriented and are pulled to the same cell pole. 2 2 JA N UA RY 2 0 1 5 | VO L 5 1 7 | N AT U R E | 4 4 1
© 2015 Macmillan Publishers Limited. All rights reserved
Gold unleashes the power of three Gold in the +3 oxidation state is scarcely used in catalysis, because the oxidants employed to generate it can damage reactants. An oxidant-free route to gold(iii) catalysts reveals their potential. See Article p.449 CHRISTOPHER M. B. K . KOURRA & NICOLAI CRAMER
a
A
key challenge for organic chemists is to selectively synthesize structurally complex target molecules for the pharmaceutical, agrochemical and materials industries in a rapid, cost-effective manner. Catalysis has attracted considerable attention as a way of achieving this, because of its ability to probe unexplored chemical reactivity, and therefore to enable short synthetic routes to target compounds. On page 449 of this issue, Wu et al.1 report the design and application of catalysts based on gold in the +3 oxidation state (Au(iii) catalysts), and describe their use in promoting reactions that are complementary to existing catalytic processes. Chemists strive to use catalysis to orchestrate the assembly of demanding molecules in a controlled and selective manner. Over the past few decades, game-changing advances in catalysis have focused mainly on transition metals in low oxidation states. By contrast, catalysis that uses transition metals in high oxidation states — such as Au(iii) — remains largely underdeveloped2. This situation is particularly evident for gold: Au(i) catalysis3 is a burgeoning field, behind which Au(iii) catalysis lags considerably. The reasons are twofold. First, it is difficult to access the Au(iii) oxidation state using ‘mild’ conditions (that is, conditions compatible with the desired catalytic process), and second, Au(iii) catalysts have poor stability4,5. The successful development of such catalysts therefore requires striking a fine balance between catalytic activity and stability. Progress will continue to be limited until ligand molecules can be developed that stabilize Au(iii) metal centres. Wu and colleagues set out with the lofty ambition of developing a mild strategy that not only allows the generation of stable and active Au(iii) catalysts, but also allows the catalysts to be easily prepared and tuned for particular reactions. The central element of their plan was to form Au(iii) species by inserting an existing Au(i) catalyst into a carbon–carbon (C–C) bond, a process known as oxidative addition. This avoids the use of any strong oxidants, which are usually required to
iPr N iPr
iPr N iPr
Cut and insert here
N iPr
Au(I)
Au(III)
Biphenylene
+
iPr N iPr
iPr
Pocket for oxygen binding
Cl Gold(I) compound Gold(III) catalyst
b
OTMS β
iPr
OTMS β
OiPr
OH O OiPr
iPr Conventional catalysts, including gold(I) catalysts
O
OiPr H
Carbonyl carbon atom
Gold(III) catalyst
O iPrO iPr β
O H
Figure 1 | Preparation and application of a gold(iii) catalyst. a, Wu et al.1 report that the gold atom (Au) of a gold(i) compound inserts into a carbon–carbon single bond of biphenylene under mild conditions (at room temperature and without the need for oxidants) to form a gold(iii) catalyst. The bulky ligand molecules in the catalyst shield most of the gold atom, but create a pocket in which oxygen atoms of organic molecules can bind to the metal. iPr, isopropyl group (CH(CH3)2). b, The gold(iii) complex promotes catalytic reactivities that are complementary to those obtained using gold(i) catalysts or other conventional catalysts. In this example, a silyl enol ether (blue) reacts with an α,β-unsaturated aldehyde (green) at the carbonyl carbon atom (newly formed bond is shown in red) in the presence of a conventional catalyst, but at the β position in the presence of the gold(iii) catalyst. TMS, trimethylsilyl group (Si(CH3)3).
access Au(iii) catalysts, and which can be detrimental to chemical groups in the substrates used for the reactions. The authors knew that several transition metals undergo oxidative addition to a compound called biphenylene6 — these reactions occur readily because they alleviate strain in biphenylene molecules. Sure enough, when they reacted a Au(i) compound with biphenylene, the metal inserted into the latter’s C–C single bond, generating a Au(iii) catalyst containing a stabilizing biphenylene ligand (Fig. 1a). The reaction was straightforward to perform and surprisingly mild (occurring at room temperature). The authors used a simple procedure to convert their catalyst into a compound from which the active catalyst itself can be easily generated in reactions. Crucially, this catalyst precursor can be stored and handled easily without the need to exclude moisture and oxygen. The next task was to apply this Au(iii) catalytic system to solve persistent unanswered chemical problems. Au(iii) catalysts have a high affinity for oxygen atoms, unlike
4 4 0 | N AT U R E | VO L 5 1 7 | 2 2 JA N UA RY 2 0 1 5
© 2015 Macmillan Publishers Limited. All rights reserved
their Au(i) counterparts, and thus promote a complementary set of reactions. Wu and co-workers envisaged that they could use the bulky ligands around the gold centre to guide oxygen atoms on reaction substrates into a small, defined pocket in which they would bind to the metal. Crucially, the ligands provide a protective shield that induces the substrate to react with a particular regio selectivity (preferentially at a particular atom), thus avoiding the formation of an undesired mixture of products. Wu et al. tested their catalyst in six types of reaction in which molecules add (form a bond) to the C–C double bonds of compounds known as α,β- and α,β,γ,δ-unsaturated aldehydes. They observed that it overrides the regioselectivity generally obtained using previously reported methods7,8 (Fig. 1b). In other words, the bulky ligands force substrates to react at only the most remote modifiable position from the aldehyde’s oxygen atom. Good product yields were obtained for all the reactions reported, demonstrating the broad applicability and reliability of the Au(iii) catalyst.
NEWS & VIEWS RESEARCH A particularly exciting element of this work is that it opens up the possibility of using Au(i)and Au(iii)-catalysed processes in tandem, thus combining the best of both worlds. Wu and colleagues exemplified this approach by performing a known reaction9 using an Au(i) catalyst and then simply adding biphenylene to the reaction mixture, generating the Au(iii) catalyst in situ. A second reaction catalysed by the Au(iii) compound consequently occurred. The results are a major breakthrough for chemists aiming to master selective reactions at remote positions of molecules that contain several possible sites of modification. The authors’ innovative strategy for accessing Au(iii) catalysts in a mild, reliable manner, without the use of harsh oxidants, is revolutionary. But there is more to be done. The work currently examines
the reactions of just one class of compound from the large family of molecules that contain carbonyl (C=O) groups. The effects of the Au(iii) catalyst on other carbonyl-containing compounds should now be investigated. It also remains to be seen whether the catalyst can be successfully applied to molecules that contain heteroatoms (atoms that are not carbon or hydrogen) other than oxygen. These are exciting times: the door to Au(iii) catalysis has been kicked wide open, and chemists are poised to exploit its full potential. ■ Christopher M. B. K. Kourra and Nicolai Cramer are at the Ecole Polytechnique Fédérale de Lausanne (EPFL), Institute of Chemical Sciences and Engineering, SB ISIC LCSA, BCH 4305,
C E LL D IVISIO N
Hold on and let go The discovery and functional analysis of the protein MEIKIN in mice leads to an evolutionarily conserved model of how chromosome segregation is regulated during a specialized type of cell division called meiosis I. See Article p.466 K I K U Ë TA C H I B A N A - K O N W A L S K I
T
he movements of sister chromosomes during cell division can be compared to those of figure skaters on an ice rink. During most divisions, a pair of skaters stand back-to-back at the centre of the ice and, as the music starts, skate away from each other, separating forever. In a division that leads to the production of eggs or sperm, however, the two skaters stand side-by-side, back-to-back with another couple. Each couple holds hands as the two teams separate, and the skaters make their way across the ice together. Letting go of a partner too early could result in abnormal chromosome segregation and infertility, but the mechanisms that encourage chromosomes to hold on and separate together in this setting have long been a mystery. In this issue, Kim et al.1 (page 466) identify the first key regulator of this process in mammals, illuminating a molecular pathway that seems to be evolutionarily conserved from yeast to humans. Cell division that produces two identical daughter cells is called mitosis. Before mitosis, each chromosome in the cell is duplicated to produce an identical sister — in humans, 46 chromosomes (23 pairs of ‘homologous’ chromos omes, one set from each parent) become 92. Duplicated chromosomes called sister chromatids are held together along chromosome arms and at specialized domains, the centromeres, by complexes of cohesin protein. Protein structures called kinetochores are built back-to-back (bi-oriented) on the
centromeres of sister chromatids. Kinetochore bi-orientation facilitates sister-chromatid separation during the anaphase stage of division. At this time, cohesin is destroyed, and spindle fibres that extend from each pole of the cell attach to the facing kinetochore and pull sisters apart, partitioning an identical sister into each daughter cell (Fig. 1a). a Mitosis
1015 Lausanne, Switzerland. e-mail: [email protected] 1. Wu, C.-Y., Horibe, T., Jacobsen, C. B. & Toste, F. D. Nature 517, 449–454 (2015). 2. Hickman, A. J. & Sanford, M. S. Nature 484, 177–185 (2012). 3. Corma, A., Leyva-Pérez, A. & Sabater, M. J. Chem. Rev. 111, 1657–1712 (2011). 4. Gaillard, S., Salwin, A. M. Z., Bonura, A. T., Stevens, E. D. & Nolan, S. P. Organometallics 29, 394–402 (2010). 5. Wolf, W. J., Winston, M. S. & Toste, F. D. Nature Chem. 6, 159–164 (2013). 6. Perthuisot, C. et al. J. Mol. Catal. A 189, 157–168 (2002). 7. Yamamoto, H. (ed.) Lewis Acids in Organic Synthesis (Wiley, 2000). 8. Akagawa, K., Sen, J. & Kudo, K. Angew. Chem. Int. Edn 52, 11585–11588 (2013). 9. Pennell, M. N., Unthank, M. G., Turner, P. & Sheppard, T. D. J. Org. Chem. 76, 1479–1482 (2011).
By contrast, during meiosis, non-identical sperm or eggs (germ cells) are produced from two rounds of division, meiosis I and II. Meiosis follows chromosome duplication like mitosis, but DNA exchange, known as meiotic recombination, occurs between homologous chromosomes to ensure that germ cells have a mix of genetic material from each parent. Unlike mitosis, cohesin is maintained at centromeres during anaphase of meiosis I. Kinetochores on sister chromosomes face the same direction — they are mono-oriented — and are thus captured and pulled by spindle fibres from the same pole (Fig. 1b). Chromosome segregation in meiosis II proceeds in a similar manner to mitosis, separating the sisters into forming germ cells. How kinetochore mono-orientation is regulated in meiosis I is a long-standing b Meiosis I
Cohesin Kinetochore
Sister chromatids
Homologous chromosomes
Figure 1 | Chromosome orientation in mitosis and meiosis. Before cell division, identical chromosome copies called sister chromatids are held together by cohesin protein. How the chromatids segregate during division is determined by the orientation of protein structures called kinetochores — each chromatid is pulled towards the pole of the cell that the kinetochore faces (indicated by arrows). a, In mitosis, kinetochores sit back-to-back on sister chromatids (they are bi-oriented), and chromatids are pulled to opposite poles. b, In meiosis I, homologous chromosomes are linked as a consequence of meiotic recombination. The kinetochores of the homologous chromosomes face in opposite directions, but those of sister chromatids are mono-oriented and are pulled to the same cell pole. 2 2 JA N UA RY 2 0 1 5 | VO L 5 1 7 | N AT U R E | 4 4 1
© 2015 Macmillan Publishers Limited. All rights reserved
