news & views potentially amenable to automation — a blueprint for synthesis on demand (Fig. 1). Writing in Nature Chemistry, they describe7 a conceptual strategy for the modular construction of natural products that draws clear parallels to what is now routine for the construction of the aforementioned classes of biomolecules. The methodology enabling this strategy is based on iterative cross-coupling chemistry of N-methyliminodiacetic acid (MIDA) boronates, an area pioneered by their research group8. The MIDA protecting group for boronic acids effectively ties up the vacant p-orbital on boron, rendering the boronate inert to cross-coupling conditions, and resistant to reagents/reaction conditions used in a wide range of functional group transformations. Indeed such an iterative cross-coupling approach has been employed by Burke to greatly accelerate the preparation of key probe molecules to expeditiously elucidate the mechanism of action of the natural product and antifungal drug amphotericin B (ref. 9). In the present work, Burke aims to systematize such an approach and apply it to broad classes of natural products. They first use an algorithm to retrosynthetically deconstruct the entirety of the nearly 3,000 known polyene natural products into fragments, which can then be made bifunctional (generally a halogen on one terminus and a MIDA boronate at the
other terminus) by application of their methodology. They go on to show that such fragments can be readily stitched together to access the core structural motifs of 75% of this entire family from only twelve discreet building blocks. Burke and co-workers then further demonstrate the applicability of the methods through synthesis in the forward direction of fifteen common polyene natural product motifs using this iterative cross-coupling process. Finally, the authors apply this paradigm to the efficient total syntheses of three representative natural products spanning different subclasses: polyterpene, fatty acid and polyketide, using pre-constructed readily synthesized capping groups to complete each molecule. Although, admittedly, the polyene subfamily of natural products may represent the low hanging fruit for illustration of the potential of this conceptual approach, the achievements here lay the groundwork for extension to other more complex families of natural products. Of key importance for robust application of this platform to a much wider scope of natural products will be improvements in the effectiveness of iterative enantiospecific sp3–sp3 cross-coupling methods, an area of significant ongoing investigation by many researchers in the field of synthetic chemistry 10,11. The ultimate potential of a platform such as that described in the paper by Burke and co-workers is yet
to be determined, though the possibility of being able to quickly assemble natural products and low-molecular-weight drug candidates using complex building blocks is highly intriguing. Furthermore, one could readily imagine endless recombinations of nature’s building blocks in ways evolution has not yet realized in order to make unnatural products of comparable structural diversity and potential biological activity, with the possibility to greatly expedite the chemist’s ability to produce the molecules that will answer countless questions of biological significance. ❐ Lawrence G. Hamann is in the Department of Global Discovery Chemistry at the Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA. e-mail: [email protected] References
1. Armstrong, R. W. et al. J. Am. Chem. Soc. 111, 7530–7533 (1989). 2. Nicolaou, K. C. & Aversa, R. J. Isr. J. Chem. 51, 359–377 (2011). 3. Davies, H. M. L., Du Bois, J. & Yu, J.‑Q. Chem. Soc. Rev. 40, 1855–1856 (2011). 4. Kuttruff, C. A., Eastgate, M. D. & Baran, P. S. Nat. Prod. Rep. 31, 419–432 (2014). 5. Merrifield, R. B. Angew. Chem. Int. Ed. 24, 799–810 (1985). 6. Woodward, R. B. et al. J. Am. Chem. Soc. 76, 4749–4751 (1954). 7. Woerly, E. M., Roy, J. & Burke, M. D. Nature Chem. 6, 484–491 (2014). 8. Gillis, E. P. & Burke, M. D. J. Am. Chem. Soc. 129, 6716–6717 (2007). 9. Gray, K. C. et al. Proc. Natl Acad Sci. USA 109, 2234–2239 (2012). 10. Li, J. & Burke, M. D. J. Am. Chem. Soc. 133, 13774–13777 (2011). 11. Wilsily, A., Tramutola, F., Owston, N. A. & Fu, G. C. J. Am. Chem. Soc. 134, 5794–5797 (2012).
ATMOSPHERIC CHEMISTRY
Intermediates just want to react
Many of the rate parameters used in models of tropospheric chemistry are obtained through laboratory ozonolysis experiments. Now, results on the self-reaction of an important, but long-elusive, intermediate could alter many of those inferences.
Craig A. Taatjes, Dudley E. Shallcross and Carl J. Percival
A
substantial removal mechanism for alkenes from the Earth’s troposphere is their reaction with ozone, which proceeds with the formation of reactive intermediate species, carbonyl oxides — often called Criegee intermediates (after Rudolf Criegee, who described their role in ozonolysis). Carbonyl oxides have been postulated to contribute to atmospheric HOx and NOx cycles and to participate in aerosol formation. However, it is only very recently — since the discovery 1,2 of an efficient laboratory method for producing carbonyl oxides — that gasphase Criegee intermediates could be
studied directly. Most of our knowledge about their reactivity, and about their formation in ozonolysis, relies on a long series of careful but indirect measurements, determining the effect of changing reactant concentrations on the yields of stable ozonolysis products. Ozonolysis involves a tremendously complex web of reactions (Fig. 1), so inference about any particular reaction depends on what is known or assumed about the rest of the web. Reactions that are inherent to the ozonolysis system are hence of particular importance in all indirect laboratory measurements of Criegee
NATURE CHEMISTRY | VOL 6 | JUNE 2014 | www.nature.com/naturechemistry
© 2014 Macmillan Publishers Limited. All rights reserved
intermediate reactions. Now, Lin, Lee and colleagues have made measurements and calculations that show 3 a surprisingly fast rate coefficient for one of these inherently important reactions: the self-reaction of the smallest Criegee intermediate, formaldehyde oxide (CH2OO). The reaction of CH2I radicals with O2 produces CH2OO, the infrared absorption spectrum of which is known4. Lin, Lee and colleagues now use3 time-resolved Fourier-transform infrared spectroscopy to monitor the CH2OO production and decay following pulsed-laser formation of CH2I radicals in the presence of O2. 461
news & views H HO
H
O
Formic acid
O H Formaldehyde
H H
H
H
H
O
Ethene
OH
O
–
H
+ –O O O Ozone
O
O
Hydroperoxymethyl formate
+
H
O
H
O O
O
O Dioxirane
O
H O
O
Formic anhydride
Figure 1 | A small subset of the chemical transformations that occur in ozonolysis of ethene are depicted. Determining rate coefficients for reactions of Criegee intermediates requires understanding the balance between the different reactions that form and consume CH2OO isomers (within the red circle) and other unstable unobserved species (represented by the dashed box). The reaction shown with the blue arrow, the self-reaction of Criegee intermediates, affects the interpretation of any measurement with sufficiently high CH2OO concentration.
At the time that this infrared absorption was first characterized, the rapid decay of the CH2OO signal suggested a large self-reaction rate coefficient 4,5, but actually determining that rate coefficient requires significantly more work. Because CH2OO is reacting with itself, its removal rate depends on its concentration, so the absolute amount of CH2OO must be measured. Moreover, the photolytic method of creating CH2OO also produces other molecules that can react with CH2OO, so rate coefficients must be known for all reactions that govern the loss of CH2OO in the experimental system. Lin, Lee and co-workers started by calculating 3 the initial concentration of CH2OO from literature cross-sections for photolysis of the precursors, and, because they used infrared detection, they were able to corroborate that determination (to within ~40%) by comparison of the observed absorption to the theoretical infrared crosssections. They were then able to apply these quantitative concentrations to modelling the kinetics of the system. Using literature values and new theoretical calculations, they demonstrated that their measurements were sensitive predominantly to the self-reaction, and therefore show that the reaction must be very fast, occurring essentially every time two CH2OO molecules meet. 462
This large rate coefficient is, on first consideration, surprising — the CH2OO molecule is isoelectronic with ozone and the self-reaction of O3 is very slow indeed — but an explanation is given by a calculation of the potential energy for the reaction pathway. As also shown5 by Vereecken and co-workers the initial encounter of two CH2OO molecules leads to a very strongly bound (by more than 90 kcal mol–1) association product, in which the negatively charged terminal oxygen atom of each CH2OO is attracted to the partly positively charged carbon atom of the other. The rapid self-reaction is therefore a consequence of the zwitterionic character of CH2OO. The self-reaction of CH2OO will affect any measurement in which the concentration of CH2OO is sufficiently high. For this reason the direct effect of CH2OO self-reaction in the troposphere, even with its large rate coefficient, is negligible — there simply isn’t enough CH2OO there. However, the laboratory measurements that underlie all the models of tropospheric Criegee intermediate chemistry are another story, and that is where the new measurements have tremendous impact. To even detect the reactions of interest, measurements are often made at concentrations far larger than those that occur in the troposphere,
and the rapid self-reaction of CH2OO could change the interpretation of many of these experiments. Lin, Lee and colleagues show that their results imply a significant change in the predicted product yields of ethene ozonolysis, for example. Some discrepancies between direct and indirect measurements of Criegee intermediates might be partly reconciled by inclusion of this fast self-reaction. The surprisingly large rate coefficient will of course be subject to confirmation by other investigators, perhaps employing ultraviolet detection, for which the absorption cross-section is known2,6. Moreover, because the model depends on (calculated) rate coefficients for several competing reactions, those reactions will also require corroboration. In the meantime, this rapid self-reaction of Criegee intermediates calls for the reevaluation of many of the rate-coefficient and branching-fraction determinations that have been carried out on the basis of ozonolysis experiments. This re-evaluation will again emphasize that kinetic measurements of ozonolysis rely on a network of interrelated determinations. Indeed, taking the example of ethene ozonolysis, a fast CH2OO self-reaction would reduce the relative contribution of the reaction of CH2OO with formic acid. Reconciling that change with the observed product yields therefore would imply a larger rate coefficient for the CH2OO reaction with formic acid. This is just the route suggested by new direct 7 and ozonolysis-based8 measurements of Criegee intermediate reactions with acids. ❐ Craig A. Taatjes is in the Combustion Research Facility, Mailstop 9055, Sandia National Laboratories, Livermore, California, 94551 USA. Dudley E. Shallcross is in the Biogeochemistry Research Centre, School of Chemistry, The University of Bristol, Cantock’s Close, Bristol BS8 1TS, UK. Carl J. Percival is in The Centre for Atmospheric Science, The School of Earth, Atmospheric and Environmental Science, The University of Manchester, Simon Building, Brunswick Street, Manchester M13 9PL, UK. e-mail: [email protected]; [email protected]; [email protected] References
1. Welz, O. et al. Science 335, 204–207 (2012). 2. Beames, J. M., Liu, F., Lu, L. & Lester, M. I. J. Am. Chem. Soc. 134, 20045–20048 (2012). 3. Su, Y.-T. et al. Nature Chem. 6, 477–483 (2014). 4. Su, Y.-T., Huang, Y.-H., Witek, H. A. & Lee, Y.-P. Science 340, 174–176 (2013). 5. Vereecken, L., Harder, H. & Novelli, A. Phys. Chem. Chem. Phys. 16, 4039–4049 (2014). 6. Sheps, L. J. Phys. Chem. Lett. 4, 4201–4205 (2013). 7. Welz, O. et al. Angew. Chem. Int. Ed. 53, 4547–4550 (2014). 8. Sipilä, M. et al. Atmos. Chem. Phys. Discuss. 14, 3071–3098 (2014).
NATURE CHEMISTRY | VOL 6 | JUNE 2014 | www.nature.com/naturechemistry
© 2014 Macmillan Publishers Limited. All rights reserved
other terminus) by application of their methodology. They go on to show that such fragments can be readily stitched together to access the core structural motifs of 75% of this entire family from only twelve discreet building blocks. Burke and co-workers then further demonstrate the applicability of the methods through synthesis in the forward direction of fifteen common polyene natural product motifs using this iterative cross-coupling process. Finally, the authors apply this paradigm to the efficient total syntheses of three representative natural products spanning different subclasses: polyterpene, fatty acid and polyketide, using pre-constructed readily synthesized capping groups to complete each molecule. Although, admittedly, the polyene subfamily of natural products may represent the low hanging fruit for illustration of the potential of this conceptual approach, the achievements here lay the groundwork for extension to other more complex families of natural products. Of key importance for robust application of this platform to a much wider scope of natural products will be improvements in the effectiveness of iterative enantiospecific sp3–sp3 cross-coupling methods, an area of significant ongoing investigation by many researchers in the field of synthetic chemistry 10,11. The ultimate potential of a platform such as that described in the paper by Burke and co-workers is yet
to be determined, though the possibility of being able to quickly assemble natural products and low-molecular-weight drug candidates using complex building blocks is highly intriguing. Furthermore, one could readily imagine endless recombinations of nature’s building blocks in ways evolution has not yet realized in order to make unnatural products of comparable structural diversity and potential biological activity, with the possibility to greatly expedite the chemist’s ability to produce the molecules that will answer countless questions of biological significance. ❐ Lawrence G. Hamann is in the Department of Global Discovery Chemistry at the Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA. e-mail: [email protected] References
1. Armstrong, R. W. et al. J. Am. Chem. Soc. 111, 7530–7533 (1989). 2. Nicolaou, K. C. & Aversa, R. J. Isr. J. Chem. 51, 359–377 (2011). 3. Davies, H. M. L., Du Bois, J. & Yu, J.‑Q. Chem. Soc. Rev. 40, 1855–1856 (2011). 4. Kuttruff, C. A., Eastgate, M. D. & Baran, P. S. Nat. Prod. Rep. 31, 419–432 (2014). 5. Merrifield, R. B. Angew. Chem. Int. Ed. 24, 799–810 (1985). 6. Woodward, R. B. et al. J. Am. Chem. Soc. 76, 4749–4751 (1954). 7. Woerly, E. M., Roy, J. & Burke, M. D. Nature Chem. 6, 484–491 (2014). 8. Gillis, E. P. & Burke, M. D. J. Am. Chem. Soc. 129, 6716–6717 (2007). 9. Gray, K. C. et al. Proc. Natl Acad Sci. USA 109, 2234–2239 (2012). 10. Li, J. & Burke, M. D. J. Am. Chem. Soc. 133, 13774–13777 (2011). 11. Wilsily, A., Tramutola, F., Owston, N. A. & Fu, G. C. J. Am. Chem. Soc. 134, 5794–5797 (2012).
ATMOSPHERIC CHEMISTRY
Intermediates just want to react
Many of the rate parameters used in models of tropospheric chemistry are obtained through laboratory ozonolysis experiments. Now, results on the self-reaction of an important, but long-elusive, intermediate could alter many of those inferences.
Craig A. Taatjes, Dudley E. Shallcross and Carl J. Percival
A
substantial removal mechanism for alkenes from the Earth’s troposphere is their reaction with ozone, which proceeds with the formation of reactive intermediate species, carbonyl oxides — often called Criegee intermediates (after Rudolf Criegee, who described their role in ozonolysis). Carbonyl oxides have been postulated to contribute to atmospheric HOx and NOx cycles and to participate in aerosol formation. However, it is only very recently — since the discovery 1,2 of an efficient laboratory method for producing carbonyl oxides — that gasphase Criegee intermediates could be
studied directly. Most of our knowledge about their reactivity, and about their formation in ozonolysis, relies on a long series of careful but indirect measurements, determining the effect of changing reactant concentrations on the yields of stable ozonolysis products. Ozonolysis involves a tremendously complex web of reactions (Fig. 1), so inference about any particular reaction depends on what is known or assumed about the rest of the web. Reactions that are inherent to the ozonolysis system are hence of particular importance in all indirect laboratory measurements of Criegee
NATURE CHEMISTRY | VOL 6 | JUNE 2014 | www.nature.com/naturechemistry
© 2014 Macmillan Publishers Limited. All rights reserved
intermediate reactions. Now, Lin, Lee and colleagues have made measurements and calculations that show 3 a surprisingly fast rate coefficient for one of these inherently important reactions: the self-reaction of the smallest Criegee intermediate, formaldehyde oxide (CH2OO). The reaction of CH2I radicals with O2 produces CH2OO, the infrared absorption spectrum of which is known4. Lin, Lee and colleagues now use3 time-resolved Fourier-transform infrared spectroscopy to monitor the CH2OO production and decay following pulsed-laser formation of CH2I radicals in the presence of O2. 461
news & views H HO
H
O
Formic acid
O H Formaldehyde
H H
H
H
H
O
Ethene
OH
O
–
H
+ –O O O Ozone
O
O
Hydroperoxymethyl formate
+
H
O
H
O O
O
O Dioxirane
O
H O
O
Formic anhydride
Figure 1 | A small subset of the chemical transformations that occur in ozonolysis of ethene are depicted. Determining rate coefficients for reactions of Criegee intermediates requires understanding the balance between the different reactions that form and consume CH2OO isomers (within the red circle) and other unstable unobserved species (represented by the dashed box). The reaction shown with the blue arrow, the self-reaction of Criegee intermediates, affects the interpretation of any measurement with sufficiently high CH2OO concentration.
At the time that this infrared absorption was first characterized, the rapid decay of the CH2OO signal suggested a large self-reaction rate coefficient 4,5, but actually determining that rate coefficient requires significantly more work. Because CH2OO is reacting with itself, its removal rate depends on its concentration, so the absolute amount of CH2OO must be measured. Moreover, the photolytic method of creating CH2OO also produces other molecules that can react with CH2OO, so rate coefficients must be known for all reactions that govern the loss of CH2OO in the experimental system. Lin, Lee and co-workers started by calculating 3 the initial concentration of CH2OO from literature cross-sections for photolysis of the precursors, and, because they used infrared detection, they were able to corroborate that determination (to within ~40%) by comparison of the observed absorption to the theoretical infrared crosssections. They were then able to apply these quantitative concentrations to modelling the kinetics of the system. Using literature values and new theoretical calculations, they demonstrated that their measurements were sensitive predominantly to the self-reaction, and therefore show that the reaction must be very fast, occurring essentially every time two CH2OO molecules meet. 462
This large rate coefficient is, on first consideration, surprising — the CH2OO molecule is isoelectronic with ozone and the self-reaction of O3 is very slow indeed — but an explanation is given by a calculation of the potential energy for the reaction pathway. As also shown5 by Vereecken and co-workers the initial encounter of two CH2OO molecules leads to a very strongly bound (by more than 90 kcal mol–1) association product, in which the negatively charged terminal oxygen atom of each CH2OO is attracted to the partly positively charged carbon atom of the other. The rapid self-reaction is therefore a consequence of the zwitterionic character of CH2OO. The self-reaction of CH2OO will affect any measurement in which the concentration of CH2OO is sufficiently high. For this reason the direct effect of CH2OO self-reaction in the troposphere, even with its large rate coefficient, is negligible — there simply isn’t enough CH2OO there. However, the laboratory measurements that underlie all the models of tropospheric Criegee intermediate chemistry are another story, and that is where the new measurements have tremendous impact. To even detect the reactions of interest, measurements are often made at concentrations far larger than those that occur in the troposphere,
and the rapid self-reaction of CH2OO could change the interpretation of many of these experiments. Lin, Lee and colleagues show that their results imply a significant change in the predicted product yields of ethene ozonolysis, for example. Some discrepancies between direct and indirect measurements of Criegee intermediates might be partly reconciled by inclusion of this fast self-reaction. The surprisingly large rate coefficient will of course be subject to confirmation by other investigators, perhaps employing ultraviolet detection, for which the absorption cross-section is known2,6. Moreover, because the model depends on (calculated) rate coefficients for several competing reactions, those reactions will also require corroboration. In the meantime, this rapid self-reaction of Criegee intermediates calls for the reevaluation of many of the rate-coefficient and branching-fraction determinations that have been carried out on the basis of ozonolysis experiments. This re-evaluation will again emphasize that kinetic measurements of ozonolysis rely on a network of interrelated determinations. Indeed, taking the example of ethene ozonolysis, a fast CH2OO self-reaction would reduce the relative contribution of the reaction of CH2OO with formic acid. Reconciling that change with the observed product yields therefore would imply a larger rate coefficient for the CH2OO reaction with formic acid. This is just the route suggested by new direct 7 and ozonolysis-based8 measurements of Criegee intermediate reactions with acids. ❐ Craig A. Taatjes is in the Combustion Research Facility, Mailstop 9055, Sandia National Laboratories, Livermore, California, 94551 USA. Dudley E. Shallcross is in the Biogeochemistry Research Centre, School of Chemistry, The University of Bristol, Cantock’s Close, Bristol BS8 1TS, UK. Carl J. Percival is in The Centre for Atmospheric Science, The School of Earth, Atmospheric and Environmental Science, The University of Manchester, Simon Building, Brunswick Street, Manchester M13 9PL, UK. e-mail: [email protected]; [email protected]; [email protected] References
1. Welz, O. et al. Science 335, 204–207 (2012). 2. Beames, J. M., Liu, F., Lu, L. & Lester, M. I. J. Am. Chem. Soc. 134, 20045–20048 (2012). 3. Su, Y.-T. et al. Nature Chem. 6, 477–483 (2014). 4. Su, Y.-T., Huang, Y.-H., Witek, H. A. & Lee, Y.-P. Science 340, 174–176 (2013). 5. Vereecken, L., Harder, H. & Novelli, A. Phys. Chem. Chem. Phys. 16, 4039–4049 (2014). 6. Sheps, L. J. Phys. Chem. Lett. 4, 4201–4205 (2013). 7. Welz, O. et al. Angew. Chem. Int. Ed. 53, 4547–4550 (2014). 8. Sipilä, M. et al. Atmos. Chem. Phys. Discuss. 14, 3071–3098 (2014).
NATURE CHEMISTRY | VOL 6 | JUNE 2014 | www.nature.com/naturechemistry
© 2014 Macmillan Publishers Limited. All rights reserved
