news & views pathways. The ability to use fluoromalonylCoA in place of malonyl-CoA would greatly expand the generality of this approach. Unfortunately, the biochemical tools currently available do not permit this swapping of substrates. It is also unclear how many fluorine substitutions are possible, or if Chang and co-workers’ methodology is compatible with a full-sized antibiotic macrolide like erythromycin. However, this is only the beginning of what
is an exciting future for biosynthesis. There is a range of possibilities for developing complementary pathways or applying these techniques to synthesizing fluorinated molecules. The foundation has now been set for the site-specific biosynthetic incorporation of fluorine into a broad spectrum of secondary metabolites. ❐ Peter A. Jordan and Bradley S. Moore are in the Center for Marine Biotechnology and Biomedicine, Scripps
Institution of Oceanography, University of California at San Diego, La Jolla, California 92093, USA. e-mail: [email protected] References 1. Müller, K., Faeh, C. & Diederich, F. Science 317, 1881–1886 (2007). 2. Hagmann, W. K. J. Med. Chem. 51, 4359–4369 (2008). 3. O’Hagan, D. Chem. Soc. Rev. 37, 308–319 (2008). 4. Furuya, T., Kamlet, A. S. & Ritter, T. Nature 473, 470–477 (2011). 5. Dong, C. et al. Nature 427, 561–565 (2004). 6. Walker, M. C. et al. Science 341, 1089–1094 (2013).
SEPARATED TANDEM CATALYSIS
It’s about time
One-pot processes in which a single catalyst carries out several reactions are attractive, but typically promote the formation of by-products as well as the desired ones, and are not amenable to optimization of the individual transformations. Now, these issues have been overcome by separating the catalytic processes in time.
Sarah Abou-Shehada and Jonathan M. J. Williams
C
12
R
H
Anti-Markovnikov alkyne hydration
O
R
Transfer hydrogenation R
OH
Yield
atalysis is one of the overarching principles of green chemistry capable of providing substantial environmental and economic benefits1. The past three decades have seen significant research dedicated to the development of novel catalytic systems, particularly in the area of transition metal catalysis. However, the impact of these advances has been limited by the current application of chemical transformations as singular events, which gives rise to by-products associated not only with the desired reaction but also with reaction auxiliaries and the purification of each intermediate. An ideal alternative would be to place all of the starting materials and catalysts in one vessel, where a series of reactions could take place to give the final product, avoiding the need for excess reaction auxiliaries, work-up and purification stages. Such an approach is known as a ‘one-pot’ process and has generated much interest within the synthetic community in an effort to enhance the efficiency of chemical synthesis. Tandem catalytic transformations are a subset of such reactions, and have been described by Fogg and dos Santos as “coupled catalyses in which sequential formation of the substrate occurs via two (or more) mechanistically distinct processes”2. Writing in Nature Chemistry, Le Li and Seth Herzon now argue that unwanted side reactions associated with one-pot processes can be removed by a temporal separation between the different catalytic cycles involved3. This decoupling of the catalytic cycles allows for each of the
Time
Figure 1 | Temporal separation of two catalytic cycles. All of the starting material (red) is converted into intermediate (green), which is then converted into the final product (yellow).
different transformations to be individually analysed and optimized. Tandem catalysis can be divided into three sub-categories: auto, assisted and orthogonal. Auto tandem catalysis involves two or more mechanistically distinct reactions that are promoted by a single catalyst, with both catalytic cycles occurring spontaneously by cooperative interaction of the species that are present from the outset of reaction. Assisted tandem catalysis also uses a single catalyst but requires a change in reaction conditions to bring about a shift from one catalytic mechanism to another; these transformations are not concurrent.
In contrast, orthogonal tandem catalysis requires the use of two or more catalysts that have distinct mechanisms operating concurrently, but, in a similar way to assisted tandem catalysis, the substrate is transformed sequentially. Auto and assisted tandem catalysis, which use a single (pre)catalyst, are more efficient in their use of the catalyst than their orthogonal counterpart. However, auto and orthogonal tandem catalysis offers higher process efficiency in terms of time and energy, as both sets of reactions occur under the same reaction conditions. The drawback to these methods is the inability
NATURE CHEMISTRY | VOL 6 | JANUARY 2014 | www.nature.com/naturechemistry
© 2014 Macmillan Publishers Limited. All rights reserved
news & views to optimize the reaction conditions for each transformation within the process; assisted tandem catalysis has the lowest overall reaction efficiency but holds the advantage of reaction-condition optimization for each intermediate generated within the process. Of the three subcategories, auto tandem catalysis is the most efficient, and several examples of such processes have been developed. They are typically challenging, however, as both the interactions between reaction intermediates and considerations of catalysts’ compatibility must be taken into account. Nonetheless, some very interesting work has come out of such efforts4–7, with some cases even including asymmetric tandem catalysed processes8,9. The simultaneous occurrence of multiple catalytic cycles make investigation and analysis of these processes rather complicated; as the rates of each step in the sequence are interrelated, the reaction substrates need be selected carefully for a particular transformation in the presence of others, and a single catalyst that can carry out the specific sequence of transformations needs to be chosen. The recent work by Li and Herzon on separating catalytic activities in time addresses such drawbacks in auto tandem catalysed processes3. Temporal separation was achieved by considering a catalyst that, for each cycle, would have a resting state — consisting of a substrate–metal complex — which would have increasing energy along
the reaction profile. In this manner, the catalyst would be limited to carrying out the first reaction cycle until all of the starting substrate is consumed — that is, it would be more energetically favourable to carry out the transformations sequentially. Building on previous work on an orthogonal tandem catalysed process10, Li and Herzon have applied this temporal separation approach to devise a tandem catalytic process in which a piano stool ruthenium catalyst carries out an antiMarkovnikov alkyne hydration followed by transfer hydrogenation (Fig. 1). The method proceeds in good yields and has a broad scope. Although this is an important transformation in its own right, the particularly interesting aspect of this work was that the researchers were not only able to optimize the reaction conditions for both transformations, but also to investigate and analyse the transformations over time. Indeed, the reaction profile unambiguously showed this separation in time between both catalytic cycles. As seen in Fig. 1, conversion of the alkyne (red) into the intermediate aldehyde (green) takes place first, and only once this process is complete does the second process take place to give the final alcohol (yellow) product. The added benefit of this temporal separation is the accumulation of intermediates during one step — these can be further functionalized by introduction of a stoichiometric reagent to divert the
system towards other reaction pathways. This functionalization possibility further increases the scope and efficiency of the catalyst. Demonstrating this approach, Li and Herzon were able to block the transfer hydrogenation pathway of their reaction and redirect it towards a Wittig olefination followed by enone reduction, in a triple-cascade tandem-catalysed system. Although this may not be the first instance in which temporal separation in tandem catalysis has occurred, it is the first time that it has been recognized and investigated. Overall, this approach provides a good strategy for developing tandem catalysis transformations by identifying suitable catalysts, modifying their reaction pathways to achieve a wider scope, and increasing the overall reaction efficiency. ❐ Sarah Abou-Shehada and Jonathan M. J. Williams are in the Department of Chemistry, University of Bath, Bath BA2 7AY, UK. e-mail: [email protected] References 1. Sheldon, R. A. Chem. Commun. 3352–3365 (2008). 2. Fogg, D. E. & dos Santos, E. N. Coord. Chem. Rev. 248, 2365–2379 (2004). 3. Li, L. & Herzon, S. B. Nature Chem. 6, 22–27 (2014). 4. Edwards, M. G. & Williams, J. M. J. Angew. Chem. Int. Ed. 41, 4740–4743 (2002). 5. Chen, J.-R. et al. Angew. Chem. Int. Ed. 47, 2489–2492 (2008). 6. Yadav, A. K. et al. Org. Lett. 15, 1060–1063 (2013). 7. Fleischer, I. et al. Angew. Chem. Int. Ed. 52, 2949–2953 (2013). 8. Kanbayashi, N,. Takenaka, K,. Okamura, T.-a. & Onitsuka, K. Angew. Chem. Int. Ed. 52, 4897–4901 (2013). 9. Chapman, C. J. & Frost, C. G. Synthesis-Stuttgart 1–21 (2007). 10. Li, L. & Herzon, S. B. J. Am. Chem. Soc. 134, 17376–17379 (2012).
BIOPHYSICAL CHEMISTRY
Strength in numbers
Replication of the HIV-1 viral genome can be inhibited by a protein known as APOBEC3G, via two seemingly contradictory mechanisms. Now, the molecular conundrum behind these two processes has been resolved.
Graeme A. King and Gijs J. L. Wuite
M
ammals have evolved a series of complex early-defence mechanisms to protect their cells against retroviral infections. These defensive processes typically focus on either attacking the invading viral capsid or destabilizing the viral genome1. The latter is mediated by a class of enzymes known as APOBEC3. One member of this family, APOBEC3G (A3G), can inhibit the HIV-1 retrovirus by restricting the replication of the viral genome2; however, the molecular mechanism behind the antiviral activity of A3G is not yet fully understood. Evidence suggests that A3G can
inhibit the HIV-1 retrovirus by two separate methods. One involves enzymatically editing the viral DNA sequence. The other requires binding to the HIV-1 genome and forming a roadblock to physically obstruct viral DNA synthesis. Whereas the first process relies on rapid binding and unbinding of the protein from the genome to swiftly sample a large number of reaction sites, the second requires that A3G is bound more strongly to the viral DNA — to ensure the roadblock remains in place. This creates a molecular conundrum: how can A3G dissociate from the viral
NATURE CHEMISTRY | VOL 6 | JANUARY 2014 | www.nature.com/naturechemistry
© 2014 Macmillan Publishers Limited. All rights reserved
genome both rapidly and slowly at the same time? As they report in Nature Chemistry, Mark C. Williams and co-workers have now resolved this issue3. Using a singlemolecule approach, they demonstrate that A3G binds and unbinds from singlestranded DNA rapidly at first, but then converts through oligomerization to a slowly dissociating complex. Williams and co-workers analysed the kinetics of A3G binding to single-stranded DNA using an optical tweezers assay in which a double-stranded DNA molecule is held between two micro-sized beads. 13
is an exciting future for biosynthesis. There is a range of possibilities for developing complementary pathways or applying these techniques to synthesizing fluorinated molecules. The foundation has now been set for the site-specific biosynthetic incorporation of fluorine into a broad spectrum of secondary metabolites. ❐ Peter A. Jordan and Bradley S. Moore are in the Center for Marine Biotechnology and Biomedicine, Scripps
Institution of Oceanography, University of California at San Diego, La Jolla, California 92093, USA. e-mail: [email protected] References 1. Müller, K., Faeh, C. & Diederich, F. Science 317, 1881–1886 (2007). 2. Hagmann, W. K. J. Med. Chem. 51, 4359–4369 (2008). 3. O’Hagan, D. Chem. Soc. Rev. 37, 308–319 (2008). 4. Furuya, T., Kamlet, A. S. & Ritter, T. Nature 473, 470–477 (2011). 5. Dong, C. et al. Nature 427, 561–565 (2004). 6. Walker, M. C. et al. Science 341, 1089–1094 (2013).
SEPARATED TANDEM CATALYSIS
It’s about time
One-pot processes in which a single catalyst carries out several reactions are attractive, but typically promote the formation of by-products as well as the desired ones, and are not amenable to optimization of the individual transformations. Now, these issues have been overcome by separating the catalytic processes in time.
Sarah Abou-Shehada and Jonathan M. J. Williams
C
12
R
H
Anti-Markovnikov alkyne hydration
O
R
Transfer hydrogenation R
OH
Yield
atalysis is one of the overarching principles of green chemistry capable of providing substantial environmental and economic benefits1. The past three decades have seen significant research dedicated to the development of novel catalytic systems, particularly in the area of transition metal catalysis. However, the impact of these advances has been limited by the current application of chemical transformations as singular events, which gives rise to by-products associated not only with the desired reaction but also with reaction auxiliaries and the purification of each intermediate. An ideal alternative would be to place all of the starting materials and catalysts in one vessel, where a series of reactions could take place to give the final product, avoiding the need for excess reaction auxiliaries, work-up and purification stages. Such an approach is known as a ‘one-pot’ process and has generated much interest within the synthetic community in an effort to enhance the efficiency of chemical synthesis. Tandem catalytic transformations are a subset of such reactions, and have been described by Fogg and dos Santos as “coupled catalyses in which sequential formation of the substrate occurs via two (or more) mechanistically distinct processes”2. Writing in Nature Chemistry, Le Li and Seth Herzon now argue that unwanted side reactions associated with one-pot processes can be removed by a temporal separation between the different catalytic cycles involved3. This decoupling of the catalytic cycles allows for each of the
Time
Figure 1 | Temporal separation of two catalytic cycles. All of the starting material (red) is converted into intermediate (green), which is then converted into the final product (yellow).
different transformations to be individually analysed and optimized. Tandem catalysis can be divided into three sub-categories: auto, assisted and orthogonal. Auto tandem catalysis involves two or more mechanistically distinct reactions that are promoted by a single catalyst, with both catalytic cycles occurring spontaneously by cooperative interaction of the species that are present from the outset of reaction. Assisted tandem catalysis also uses a single catalyst but requires a change in reaction conditions to bring about a shift from one catalytic mechanism to another; these transformations are not concurrent.
In contrast, orthogonal tandem catalysis requires the use of two or more catalysts that have distinct mechanisms operating concurrently, but, in a similar way to assisted tandem catalysis, the substrate is transformed sequentially. Auto and assisted tandem catalysis, which use a single (pre)catalyst, are more efficient in their use of the catalyst than their orthogonal counterpart. However, auto and orthogonal tandem catalysis offers higher process efficiency in terms of time and energy, as both sets of reactions occur under the same reaction conditions. The drawback to these methods is the inability
NATURE CHEMISTRY | VOL 6 | JANUARY 2014 | www.nature.com/naturechemistry
© 2014 Macmillan Publishers Limited. All rights reserved
news & views to optimize the reaction conditions for each transformation within the process; assisted tandem catalysis has the lowest overall reaction efficiency but holds the advantage of reaction-condition optimization for each intermediate generated within the process. Of the three subcategories, auto tandem catalysis is the most efficient, and several examples of such processes have been developed. They are typically challenging, however, as both the interactions between reaction intermediates and considerations of catalysts’ compatibility must be taken into account. Nonetheless, some very interesting work has come out of such efforts4–7, with some cases even including asymmetric tandem catalysed processes8,9. The simultaneous occurrence of multiple catalytic cycles make investigation and analysis of these processes rather complicated; as the rates of each step in the sequence are interrelated, the reaction substrates need be selected carefully for a particular transformation in the presence of others, and a single catalyst that can carry out the specific sequence of transformations needs to be chosen. The recent work by Li and Herzon on separating catalytic activities in time addresses such drawbacks in auto tandem catalysed processes3. Temporal separation was achieved by considering a catalyst that, for each cycle, would have a resting state — consisting of a substrate–metal complex — which would have increasing energy along
the reaction profile. In this manner, the catalyst would be limited to carrying out the first reaction cycle until all of the starting substrate is consumed — that is, it would be more energetically favourable to carry out the transformations sequentially. Building on previous work on an orthogonal tandem catalysed process10, Li and Herzon have applied this temporal separation approach to devise a tandem catalytic process in which a piano stool ruthenium catalyst carries out an antiMarkovnikov alkyne hydration followed by transfer hydrogenation (Fig. 1). The method proceeds in good yields and has a broad scope. Although this is an important transformation in its own right, the particularly interesting aspect of this work was that the researchers were not only able to optimize the reaction conditions for both transformations, but also to investigate and analyse the transformations over time. Indeed, the reaction profile unambiguously showed this separation in time between both catalytic cycles. As seen in Fig. 1, conversion of the alkyne (red) into the intermediate aldehyde (green) takes place first, and only once this process is complete does the second process take place to give the final alcohol (yellow) product. The added benefit of this temporal separation is the accumulation of intermediates during one step — these can be further functionalized by introduction of a stoichiometric reagent to divert the
system towards other reaction pathways. This functionalization possibility further increases the scope and efficiency of the catalyst. Demonstrating this approach, Li and Herzon were able to block the transfer hydrogenation pathway of their reaction and redirect it towards a Wittig olefination followed by enone reduction, in a triple-cascade tandem-catalysed system. Although this may not be the first instance in which temporal separation in tandem catalysis has occurred, it is the first time that it has been recognized and investigated. Overall, this approach provides a good strategy for developing tandem catalysis transformations by identifying suitable catalysts, modifying their reaction pathways to achieve a wider scope, and increasing the overall reaction efficiency. ❐ Sarah Abou-Shehada and Jonathan M. J. Williams are in the Department of Chemistry, University of Bath, Bath BA2 7AY, UK. e-mail: [email protected] References 1. Sheldon, R. A. Chem. Commun. 3352–3365 (2008). 2. Fogg, D. E. & dos Santos, E. N. Coord. Chem. Rev. 248, 2365–2379 (2004). 3. Li, L. & Herzon, S. B. Nature Chem. 6, 22–27 (2014). 4. Edwards, M. G. & Williams, J. M. J. Angew. Chem. Int. Ed. 41, 4740–4743 (2002). 5. Chen, J.-R. et al. Angew. Chem. Int. Ed. 47, 2489–2492 (2008). 6. Yadav, A. K. et al. Org. Lett. 15, 1060–1063 (2013). 7. Fleischer, I. et al. Angew. Chem. Int. Ed. 52, 2949–2953 (2013). 8. Kanbayashi, N,. Takenaka, K,. Okamura, T.-a. & Onitsuka, K. Angew. Chem. Int. Ed. 52, 4897–4901 (2013). 9. Chapman, C. J. & Frost, C. G. Synthesis-Stuttgart 1–21 (2007). 10. Li, L. & Herzon, S. B. J. Am. Chem. Soc. 134, 17376–17379 (2012).
BIOPHYSICAL CHEMISTRY
Strength in numbers
Replication of the HIV-1 viral genome can be inhibited by a protein known as APOBEC3G, via two seemingly contradictory mechanisms. Now, the molecular conundrum behind these two processes has been resolved.
Graeme A. King and Gijs J. L. Wuite
M
ammals have evolved a series of complex early-defence mechanisms to protect their cells against retroviral infections. These defensive processes typically focus on either attacking the invading viral capsid or destabilizing the viral genome1. The latter is mediated by a class of enzymes known as APOBEC3. One member of this family, APOBEC3G (A3G), can inhibit the HIV-1 retrovirus by restricting the replication of the viral genome2; however, the molecular mechanism behind the antiviral activity of A3G is not yet fully understood. Evidence suggests that A3G can
inhibit the HIV-1 retrovirus by two separate methods. One involves enzymatically editing the viral DNA sequence. The other requires binding to the HIV-1 genome and forming a roadblock to physically obstruct viral DNA synthesis. Whereas the first process relies on rapid binding and unbinding of the protein from the genome to swiftly sample a large number of reaction sites, the second requires that A3G is bound more strongly to the viral DNA — to ensure the roadblock remains in place. This creates a molecular conundrum: how can A3G dissociate from the viral
NATURE CHEMISTRY | VOL 6 | JANUARY 2014 | www.nature.com/naturechemistry
© 2014 Macmillan Publishers Limited. All rights reserved
genome both rapidly and slowly at the same time? As they report in Nature Chemistry, Mark C. Williams and co-workers have now resolved this issue3. Using a singlemolecule approach, they demonstrate that A3G binds and unbinds from singlestranded DNA rapidly at first, but then converts through oligomerization to a slowly dissociating complex. Williams and co-workers analysed the kinetics of A3G binding to single-stranded DNA using an optical tweezers assay in which a double-stranded DNA molecule is held between two micro-sized beads. 13
