REFERENCES
1. C. M. Rico et al., Environ. Sci. Pollut. Res. Int. 10.1007/ s11356-015-4243-y (2015). 2. F. Goecke et al., Front. Microbiol. 6, 2 (2015). 3. G. Pagano et al., Ecotoxicol. Environ. Saf. 115, 40 (2015). 4. J. Li, M. Hong, X. Yin, J. Liu, J. Rare Earths 28, 957 (2010). 5. T. Horiike, M. Yamashita, Appl. Environ. Microbiol. 81, 3062 (2015). 6. A. Pol et al., Environ. Microbiol. 16, 255 (2014). 7. Y. Hibi et al., J. Biosci. Bioeng. 111, 547 (2011). 8. E. Skovran et al., Gordon Conference on Metals in Biology, Ventura, CA, 25 to 30 January 2015. 9. E. Skovran et al., J. Bacteriol. 193, 6032 (2011). 10. A. Beck et al., PLOS ONE 9, 102458 (2014). 11. J. A. Bogart, A. J. Lewis, E. J. Schelter, Chemistry 21, 1743 (2015). 12. M. L. Wu et al., Appl. Environ. Microbiol. 81, 1442 (2014). 10.1126/science.aaa9091
ORGANIC CHEMISTRY
Streamlining amine synthesis Bulky amine groups that help make many drugs more bioavailable can be added readily to organic compounds By László Kürti
A
mines, a collective name for compounds that contain one or more nitrogen atoms, and their derivatives make up the overwhelming majority of drug molecules and agrochemicals, as well as many compounds that are produced by plants and living organisms (i.e., natural products) (1, 2). Not surprisingly, organic chemists spend a considerable amount of time with the synthesis and latestage functionalization of amines. On page 886 of this issue, Gui et al. (3) report a highly innovative iron-catalyzed cross-coupling of olefins with nitroarenes, both of which are readily available and inexpensive, to afford bulky secondary arylamines that are either very difficult to obtain or inaccessible with existing methods. Aromatic amines (also referred to as arylamines or anilines) appear as substructures in more than one-third of drug candidates (4, 5) that serve as key chemical building blocks for the preparation of biologically active compounds, especially in medicinal chemistry. There are many well-established methods (see the figure, panel A) available in a modern organic chemist’s toolbox for the synthesis of amines and, for the nonspecialist, it might appear that amines of any structural type can be quickly and reliably prepared. However, the preparation of sterically hindered (i.e., bulky) N-aryl-N-alkyl amines (structures I to IV, panel B of the figure) is still a major challenge, as none of the currently used methods allow their rapid and cost-effective synthesis. These bulky amine building blocks are highly sought-after, as the presence of the sterically demanding alkyl groups markedly improves the druglike properties of biologically active compounds, including their lipophilicity (i.e., solubility in fats, oils, and lipids) and metabolic stability toward many enzymes that are present in living organisms (6). Thus, the continued development of novel and powerful methods in synthetic organic chemistry is needed to make complex structures quickly and cost-effectively. The formal hydroamination process is operationally simple, scalable, and avoids the use of protecting groups, which tend to reduce efficiency by adding extra steps to a synthetic sequence. The scope of both cou-
SCIENCE sciencemag.org
pling partners, especially in terms of their steric and electronic properties, is exceptionally wide and renders this transformation a compelling alternative to currently utilized copper- and palladium-catalyzed cross-coupling (7) approaches that proceed with considerably reduced efficiency in the case of sterically demanding arylamine targets. The method developed by Gui et al. is orthogonal (i.e., nonoverlapping) to other arylamine syntheses and provides rapid preparative access to structurally diverse secondary amine products via a simple onepot process that takes place under mild re-
“…there can be little doubt that this new transformation will find wide applicability in both academic and industrial laboratories.” action conditions. The chemoselectivity, the preferential reaction of one functional group over others in the same molecule, is excellent, and sensitive functional groups such as ketones, free alcohols/amines, and even boronic acids are well tolerated. Aromatic C(sp2)-halogen and C(sp2)-O-triflate bonds remain unchanged, which allows product diversification via classical C-C, C-N, and C-O cross-coupling reactions (8). Key to the success of this method is the simultaneous generation of a tertiary alkyl radical (VII, panel C of the figure) from the olefin and the efficient reduction of the nitroarene to the corresponding nitrosoarene (VI). An inexpensive iron salt is used as the catalyst and a silane as the stoichiometric reducing agent, a set of conditions that Baran and co-workers had identified for the radical coupling of alkenes (9). Two equivalents of the alkyl radical (VII) add across the N=O double bond of the nitrosoarene (VI) to afford an N,O-alkylated adduct (VIII); the de-
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Address as of 1 June 2015: Department of Chemistry, Rice University, Houston, TX 77005, USA. E-mail: [email protected] 22 MAY 2015 • VOL 348 ISSUE 6237
Published by AAAS
863
Downloaded from www.sciencemag.org on May 21, 2015
sibility can be obtained by pressing various leaves onto methanol medium containing or lacking La3+ (see the figure). For some but not all leaves, addition of La3+ results in an increased number of pink-pigmented methylotrophs. Are all lanthanides equal in their ability to support XoxF function? In 2014, Pol et al. investigated the ability of lanthanides to support growth of Methylacidiphilum fumariolicum SolV, a bacterium isolated from volcanic mud pots (6). Growth of M. fumariolicum SolV in the laboratory was poor unless volcanic mud pot water was added to the growth medium. Different lanthanides such as La3+, Ce3+, Pr3+, and Nd3+ could substitute for the mud pot water, allowing rapid growth of the strain. Further, the catalytic properties of purified XoxF from M. fumariolicum SolV differed from those previously described for XoxF from Methylobacterium species: Methanol was oxidized to formate instead of formaldehyde, neutral pH was optimal for the reaction, and activation by ammonia was not required (6). XoxF crystal structure analysis and density functional theory calculations together support the hypothesis that, relative to Ca2+, lanthanides are more efficient Lewis acids in the polarization of PQQ (which is necessary for substrate activation) (6, 11). The recent isolation of a hybrid MDH containing two XoxF and two MxaI subunits from Candidatus Methylomirabilis oxyfera highlights the potential diversity of these PQQ-dependent enzymes (12). Our understanding of the biological role of lanthanides is in its early stages. It is unknown how these highly insoluble elements are acquired and transported into cells. Studies on the biological roles of lanthanides may allow researchers to isolate and culture new organisms from the environment, to engineer a wide array of dehydrogenases for use in industry, to develop bioremediation strategies for cleanup of REE mining sites, and to reduce the potential for toxicity in our food and water. ■
INSIGHTS | P E R S P E C T I V E S
Synthetic routes to amines, then and now A
R’
R’-X, base
H
N
H
R
B
H
2° N, N-Dialkyl amine
O
Then add [H] or add R-MX
R
HO
N
O
Me
N
NH
HN
Imine Ar
Arylation by C-N cross-coupling
N
Me Me
Me
NH
Cl
i. Fe(acac)3 (30 mol %) PhSiH3 (2 equivalents) EtOH, 60°C, 1 hour ii. Zn (xs), HCI (aq)
Me
O
sired bulky secondary arylamine product (V) is revealed after a simple reductive workup in which the N-O bond is cleaved. Radicals tend to react in a highly chemoselective fashion, so harsh reaction conditions can be avoided and functional group interconversions can be kept at a minimum (10). Given that an excess olefin coupling partner is needed (i.e., 3 equivalents), structurally complex and valuable olefin building blocks are not practical to use in this transformation. Nonetheless, this previously unexploited C-N bond disconnection invented by Gui et al. allows rapid synthetic access to valuable, and heretofore hard-to-prepare, bulky sec-
Cl
HIV-1 reverse transcriptase inhibitor intermediate (IV)
O
Me
N
+2
Nitrosoarene (VI)
Me
O Me
3° Alkyl radical (VII)
Me Me O Cl
Me
O
Me
N
Me
Me Me O
V (1 step, 41% yield)
Synthetic access to bulky amines. (A) Several well-established methods for the synthesis of amines are shown. (B) Examples of sterically hindered amine building blocks that are difficult to access with currently available synthetic methods. (C) Gui et al. use an inexpensive iron salt and reducing agent for one-pot cross-coupling of nitoarenes with olefins to afford bulky secondary arylamines. Two key intermediates are formed in situ: a nitrosoarene and a tertiary alkyl radical that initially afford a N,O-alkylated adduct that is later reduced to the desired product.
NBoc
N
NO2 Cl
NH Me N
F
Reactive intermediates
O
NH2
Me
Me Me
N N
Glucocorticoid receptor modulator intermediate (III)
R
(3 equivalents)
Michael addition not possible
Me
H
2° N-Aryl-Nalkyl amine
New bulky amine synthesis
CN
Medicinal chemistry building block (II)
NHBz
Me
R
Ar-X, metal catalyst
864
O
N Me H
ORL1 receptor inhibitor intermediate (I)
M = Mg, Li
Cl
BnO
Me
Reductive amination
1° Amine
C
H N
R
Alkylation
R
N
N,O-Alkylated adduct (VIII)
ondary aryl amine building blocks in which molecular complexity is built up in a single step. Since the starting materials and the reagents are inexpensive, the iron catalyst is abundant, and protecting groups are mostly unnecessary, the overall cost and material throughput of a given synthetic sequence that utilizes this new olefin hydroamination process will be vastly improved compared to existing approaches. Thus, there can be little doubt that this new transformation will find wide applicability in both academic and industrial laboratories. It is expected that modified and improved versions of this transformation will be developed that address some of the current shortcomings such as the need for multiple equivalents of olefin coupling partner and for the final reductive cleavage of the N-O bond. Moreover, the atom economy of the process would improve if the phenylsilane reducing agent could be replaced by cheaper and more abundant sources, such as H2. Functional group compatibility would improve if the combination of excess zinc metal and strong acid could be substituted with a nonmetal reduction source under neutral
conditions for the final N-O bond cleavage. The report of Gui et al. raises the intriguing possibility about potentially rendering this olefin hydroamination reaction catalytic and asymmetric, as in several of the products a new and fully substituted carbon stereogenic center is created. ■ REFERENCES
1. A. Ricci, Ed., Amino Group Chemistry: From Synthesis to the Life Sciences (Wiley-VCH, Weinheim, Germany, 2008). 2. Y. Ishihara, A. Montero, P. S. Baran, The Portable Chemist’s Consultant (iBook, Apple Publishing Group, New York, 2013). 3. J. Gui et al., Science 348, 886 (2015). 4. Z. Rappoport, Ed., The Chemistry of Anilines, Part 1 and 2. Patai Series: The Chemistry of Functional Groups (Wiley, Chichester, UK, 2007). 5. S. D. Roughley, A. M. Jordan, J. Med. Chem. 54, 3451 (2011). 6. L. Wanka, K. Iqbal, P. R. Schreiner, Chem. Rev. 113, 3516 (2013). 7. A. K. Yudin, Ed., Catalyzed Carbon-Heteroatom Bond Formation (Wiley-VCH, Weinheim, Germany, 2011). 8. A. de Meijere, S. Braese, M. Oestreich, Eds., MetalCatalyzed Cross-Coupling Reactions and More (Wiley-VCH, Weinheim, Germany, 2014), vol. 1 to 3. 9. J. C. Lo, Y. Yabe, P. S. Baran, J. Am. Chem. Soc. 136, 1304 (2014). 10. S. L. Castle, Nature 516, 332 (2014).
10.1126/science.aab2812
sciencemag.org SCIENCE
22 MAY 2015 • VOL 348 ISSUE 6237
Published by AAAS
Streamlining amine synthesis László Kürti Science 348, 863 (2015); DOI: 10.1126/science.aab2812
This copy is for your personal, non-commercial use only.
If you wish to distribute this article to others, you can order high-quality copies for your colleagues, clients, or customers by clicking here. Permission to republish or repurpose articles or portions of articles can be obtained by following the guidelines here.
Updated information and services, including high-resolution figures, can be found in the online version of this article at: http://www.sciencemag.org/content/348/6237/863.full.html A list of selected additional articles on the Science Web sites related to this article can be found at: http://www.sciencemag.org/content/348/6237/863.full.html#related This article cites 5 articles, 1 of which can be accessed free: http://www.sciencemag.org/content/348/6237/863.full.html#ref-list-1 This article appears in the following subject collections: Chemistry http://www.sciencemag.org/cgi/collection/chemistry
Science (print ISSN 0036-8075; online ISSN 1095-9203) is published weekly, except the last week in December, by the American Association for the Advancement of Science, 1200 New York Avenue NW, Washington, DC 20005. Copyright 2015 by the American Association for the Advancement of Science; all rights reserved. The title Science is a registered trademark of AAAS.
Downloaded from www.sciencemag.org on May 21, 2015
The following resources related to this article are available online at www.sciencemag.org (this information is current as of May 21, 2015 ):
1. C. M. Rico et al., Environ. Sci. Pollut. Res. Int. 10.1007/ s11356-015-4243-y (2015). 2. F. Goecke et al., Front. Microbiol. 6, 2 (2015). 3. G. Pagano et al., Ecotoxicol. Environ. Saf. 115, 40 (2015). 4. J. Li, M. Hong, X. Yin, J. Liu, J. Rare Earths 28, 957 (2010). 5. T. Horiike, M. Yamashita, Appl. Environ. Microbiol. 81, 3062 (2015). 6. A. Pol et al., Environ. Microbiol. 16, 255 (2014). 7. Y. Hibi et al., J. Biosci. Bioeng. 111, 547 (2011). 8. E. Skovran et al., Gordon Conference on Metals in Biology, Ventura, CA, 25 to 30 January 2015. 9. E. Skovran et al., J. Bacteriol. 193, 6032 (2011). 10. A. Beck et al., PLOS ONE 9, 102458 (2014). 11. J. A. Bogart, A. J. Lewis, E. J. Schelter, Chemistry 21, 1743 (2015). 12. M. L. Wu et al., Appl. Environ. Microbiol. 81, 1442 (2014). 10.1126/science.aaa9091
ORGANIC CHEMISTRY
Streamlining amine synthesis Bulky amine groups that help make many drugs more bioavailable can be added readily to organic compounds By László Kürti
A
mines, a collective name for compounds that contain one or more nitrogen atoms, and their derivatives make up the overwhelming majority of drug molecules and agrochemicals, as well as many compounds that are produced by plants and living organisms (i.e., natural products) (1, 2). Not surprisingly, organic chemists spend a considerable amount of time with the synthesis and latestage functionalization of amines. On page 886 of this issue, Gui et al. (3) report a highly innovative iron-catalyzed cross-coupling of olefins with nitroarenes, both of which are readily available and inexpensive, to afford bulky secondary arylamines that are either very difficult to obtain or inaccessible with existing methods. Aromatic amines (also referred to as arylamines or anilines) appear as substructures in more than one-third of drug candidates (4, 5) that serve as key chemical building blocks for the preparation of biologically active compounds, especially in medicinal chemistry. There are many well-established methods (see the figure, panel A) available in a modern organic chemist’s toolbox for the synthesis of amines and, for the nonspecialist, it might appear that amines of any structural type can be quickly and reliably prepared. However, the preparation of sterically hindered (i.e., bulky) N-aryl-N-alkyl amines (structures I to IV, panel B of the figure) is still a major challenge, as none of the currently used methods allow their rapid and cost-effective synthesis. These bulky amine building blocks are highly sought-after, as the presence of the sterically demanding alkyl groups markedly improves the druglike properties of biologically active compounds, including their lipophilicity (i.e., solubility in fats, oils, and lipids) and metabolic stability toward many enzymes that are present in living organisms (6). Thus, the continued development of novel and powerful methods in synthetic organic chemistry is needed to make complex structures quickly and cost-effectively. The formal hydroamination process is operationally simple, scalable, and avoids the use of protecting groups, which tend to reduce efficiency by adding extra steps to a synthetic sequence. The scope of both cou-
SCIENCE sciencemag.org
pling partners, especially in terms of their steric and electronic properties, is exceptionally wide and renders this transformation a compelling alternative to currently utilized copper- and palladium-catalyzed cross-coupling (7) approaches that proceed with considerably reduced efficiency in the case of sterically demanding arylamine targets. The method developed by Gui et al. is orthogonal (i.e., nonoverlapping) to other arylamine syntheses and provides rapid preparative access to structurally diverse secondary amine products via a simple onepot process that takes place under mild re-
“…there can be little doubt that this new transformation will find wide applicability in both academic and industrial laboratories.” action conditions. The chemoselectivity, the preferential reaction of one functional group over others in the same molecule, is excellent, and sensitive functional groups such as ketones, free alcohols/amines, and even boronic acids are well tolerated. Aromatic C(sp2)-halogen and C(sp2)-O-triflate bonds remain unchanged, which allows product diversification via classical C-C, C-N, and C-O cross-coupling reactions (8). Key to the success of this method is the simultaneous generation of a tertiary alkyl radical (VII, panel C of the figure) from the olefin and the efficient reduction of the nitroarene to the corresponding nitrosoarene (VI). An inexpensive iron salt is used as the catalyst and a silane as the stoichiometric reducing agent, a set of conditions that Baran and co-workers had identified for the radical coupling of alkenes (9). Two equivalents of the alkyl radical (VII) add across the N=O double bond of the nitrosoarene (VI) to afford an N,O-alkylated adduct (VIII); the de-
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Address as of 1 June 2015: Department of Chemistry, Rice University, Houston, TX 77005, USA. E-mail: [email protected] 22 MAY 2015 • VOL 348 ISSUE 6237
Published by AAAS
863
Downloaded from www.sciencemag.org on May 21, 2015
sibility can be obtained by pressing various leaves onto methanol medium containing or lacking La3+ (see the figure). For some but not all leaves, addition of La3+ results in an increased number of pink-pigmented methylotrophs. Are all lanthanides equal in their ability to support XoxF function? In 2014, Pol et al. investigated the ability of lanthanides to support growth of Methylacidiphilum fumariolicum SolV, a bacterium isolated from volcanic mud pots (6). Growth of M. fumariolicum SolV in the laboratory was poor unless volcanic mud pot water was added to the growth medium. Different lanthanides such as La3+, Ce3+, Pr3+, and Nd3+ could substitute for the mud pot water, allowing rapid growth of the strain. Further, the catalytic properties of purified XoxF from M. fumariolicum SolV differed from those previously described for XoxF from Methylobacterium species: Methanol was oxidized to formate instead of formaldehyde, neutral pH was optimal for the reaction, and activation by ammonia was not required (6). XoxF crystal structure analysis and density functional theory calculations together support the hypothesis that, relative to Ca2+, lanthanides are more efficient Lewis acids in the polarization of PQQ (which is necessary for substrate activation) (6, 11). The recent isolation of a hybrid MDH containing two XoxF and two MxaI subunits from Candidatus Methylomirabilis oxyfera highlights the potential diversity of these PQQ-dependent enzymes (12). Our understanding of the biological role of lanthanides is in its early stages. It is unknown how these highly insoluble elements are acquired and transported into cells. Studies on the biological roles of lanthanides may allow researchers to isolate and culture new organisms from the environment, to engineer a wide array of dehydrogenases for use in industry, to develop bioremediation strategies for cleanup of REE mining sites, and to reduce the potential for toxicity in our food and water. ■
INSIGHTS | P E R S P E C T I V E S
Synthetic routes to amines, then and now A
R’
R’-X, base
H
N
H
R
B
H
2° N, N-Dialkyl amine
O
Then add [H] or add R-MX
R
HO
N
O
Me
N
NH
HN
Imine Ar
Arylation by C-N cross-coupling
N
Me Me
Me
NH
Cl
i. Fe(acac)3 (30 mol %) PhSiH3 (2 equivalents) EtOH, 60°C, 1 hour ii. Zn (xs), HCI (aq)
Me
O
sired bulky secondary arylamine product (V) is revealed after a simple reductive workup in which the N-O bond is cleaved. Radicals tend to react in a highly chemoselective fashion, so harsh reaction conditions can be avoided and functional group interconversions can be kept at a minimum (10). Given that an excess olefin coupling partner is needed (i.e., 3 equivalents), structurally complex and valuable olefin building blocks are not practical to use in this transformation. Nonetheless, this previously unexploited C-N bond disconnection invented by Gui et al. allows rapid synthetic access to valuable, and heretofore hard-to-prepare, bulky sec-
Cl
HIV-1 reverse transcriptase inhibitor intermediate (IV)
O
Me
N
+2
Nitrosoarene (VI)
Me
O Me
3° Alkyl radical (VII)
Me Me O Cl
Me
O
Me
N
Me
Me Me O
V (1 step, 41% yield)
Synthetic access to bulky amines. (A) Several well-established methods for the synthesis of amines are shown. (B) Examples of sterically hindered amine building blocks that are difficult to access with currently available synthetic methods. (C) Gui et al. use an inexpensive iron salt and reducing agent for one-pot cross-coupling of nitoarenes with olefins to afford bulky secondary arylamines. Two key intermediates are formed in situ: a nitrosoarene and a tertiary alkyl radical that initially afford a N,O-alkylated adduct that is later reduced to the desired product.
NBoc
N
NO2 Cl
NH Me N
F
Reactive intermediates
O
NH2
Me
Me Me
N N
Glucocorticoid receptor modulator intermediate (III)
R
(3 equivalents)
Michael addition not possible
Me
H
2° N-Aryl-Nalkyl amine
New bulky amine synthesis
CN
Medicinal chemistry building block (II)
NHBz
Me
R
Ar-X, metal catalyst
864
O
N Me H
ORL1 receptor inhibitor intermediate (I)
M = Mg, Li
Cl
BnO
Me
Reductive amination
1° Amine
C
H N
R
Alkylation
R
N
N,O-Alkylated adduct (VIII)
ondary aryl amine building blocks in which molecular complexity is built up in a single step. Since the starting materials and the reagents are inexpensive, the iron catalyst is abundant, and protecting groups are mostly unnecessary, the overall cost and material throughput of a given synthetic sequence that utilizes this new olefin hydroamination process will be vastly improved compared to existing approaches. Thus, there can be little doubt that this new transformation will find wide applicability in both academic and industrial laboratories. It is expected that modified and improved versions of this transformation will be developed that address some of the current shortcomings such as the need for multiple equivalents of olefin coupling partner and for the final reductive cleavage of the N-O bond. Moreover, the atom economy of the process would improve if the phenylsilane reducing agent could be replaced by cheaper and more abundant sources, such as H2. Functional group compatibility would improve if the combination of excess zinc metal and strong acid could be substituted with a nonmetal reduction source under neutral
conditions for the final N-O bond cleavage. The report of Gui et al. raises the intriguing possibility about potentially rendering this olefin hydroamination reaction catalytic and asymmetric, as in several of the products a new and fully substituted carbon stereogenic center is created. ■ REFERENCES
1. A. Ricci, Ed., Amino Group Chemistry: From Synthesis to the Life Sciences (Wiley-VCH, Weinheim, Germany, 2008). 2. Y. Ishihara, A. Montero, P. S. Baran, The Portable Chemist’s Consultant (iBook, Apple Publishing Group, New York, 2013). 3. J. Gui et al., Science 348, 886 (2015). 4. Z. Rappoport, Ed., The Chemistry of Anilines, Part 1 and 2. Patai Series: The Chemistry of Functional Groups (Wiley, Chichester, UK, 2007). 5. S. D. Roughley, A. M. Jordan, J. Med. Chem. 54, 3451 (2011). 6. L. Wanka, K. Iqbal, P. R. Schreiner, Chem. Rev. 113, 3516 (2013). 7. A. K. Yudin, Ed., Catalyzed Carbon-Heteroatom Bond Formation (Wiley-VCH, Weinheim, Germany, 2011). 8. A. de Meijere, S. Braese, M. Oestreich, Eds., MetalCatalyzed Cross-Coupling Reactions and More (Wiley-VCH, Weinheim, Germany, 2014), vol. 1 to 3. 9. J. C. Lo, Y. Yabe, P. S. Baran, J. Am. Chem. Soc. 136, 1304 (2014). 10. S. L. Castle, Nature 516, 332 (2014).
10.1126/science.aab2812
sciencemag.org SCIENCE
22 MAY 2015 • VOL 348 ISSUE 6237
Published by AAAS
Streamlining amine synthesis László Kürti Science 348, 863 (2015); DOI: 10.1126/science.aab2812
This copy is for your personal, non-commercial use only.
If you wish to distribute this article to others, you can order high-quality copies for your colleagues, clients, or customers by clicking here. Permission to republish or repurpose articles or portions of articles can be obtained by following the guidelines here.
Updated information and services, including high-resolution figures, can be found in the online version of this article at: http://www.sciencemag.org/content/348/6237/863.full.html A list of selected additional articles on the Science Web sites related to this article can be found at: http://www.sciencemag.org/content/348/6237/863.full.html#related This article cites 5 articles, 1 of which can be accessed free: http://www.sciencemag.org/content/348/6237/863.full.html#ref-list-1 This article appears in the following subject collections: Chemistry http://www.sciencemag.org/cgi/collection/chemistry
Science (print ISSN 0036-8075; online ISSN 1095-9203) is published weekly, except the last week in December, by the American Association for the Advancement of Science, 1200 New York Avenue NW, Washington, DC 20005. Copyright 2015 by the American Association for the Advancement of Science; all rights reserved. The title Science is a registered trademark of AAAS.
Downloaded from www.sciencemag.org on May 21, 2015
The following resources related to this article are available online at www.sciencemag.org (this information is current as of May 21, 2015 ):
