news & views ASYMMETRIC SYNTHESIS
Cascades of catalytic selectivity
A combination of catalytic asymmetric diboration of terminal alkenes and Suzuki–Miyaura cross-coupling has been exploited in the synthesis of a variety of important medicinal agents. The process overcomes a number of problems in the application of these important catalytic processes.
Rian D. Dewhurst and Todd B. Marder
O
rganic synthesis is, at its heart, a study of carbon–carbon bond-forming processes. Homogeneous catalysis of organic reactions is dominated by processes that create C–C bonds, the primary goals being high chemo-, regio- or stereoselectivity, along with attempts to reduce waste, cost and environmental impact. The prominence of catalysis as a tool in modern organic synthesis is reflected in its repeated recognition by the Nobel committee, recently for asymmetric catalysis (2001), catalytic olefin metathesis (2005) and palladium-catalysed cross-coupling (2010)1. Metal-catalysed cross-couplings, particularly those using palladium, have developed into extraordinarily useful tools for C–C bond formation, built on a relatively simple concept: the coupling of a pseudocarbocationic ‘electrophile’, for example an aryl halide, with a pseudocarbanionic ‘nucleophile’, such as an organo-tin (Stille coupling), zinc (Negishi coupling), copper (Sonogashira coupling), magnesium (Kumada–Tamao coupling) or boron (Suzuki–Miyaura coupling) reagent 2. The Suzuki–Miyaura reaction3, using boronic acids or esters4 as the ‘nucleophilic’ partner, is one of the most versatile of the cross-coupling protocols, and is widely used in the pharmaceutical and agrochemical industries. Boronic esters and acids are much less toxic than tin reagents and, unlike more reactive organometallic magnesium or zinc species, are typically air- and moisture-stable. They also tend to be more compatible with other functional groups, eliminating the need for costly protection and deprotection steps. In addition, the empty p orbital on an sp2-hybridized boron makes it well-suited to mediate the transfer of the organic group to the palladium in the important transmetallation step of the catalytic cross-coupling process. With the utility of organoboron reagents assured, much attention has been directed to the development of advanced procedures5–7 for the installation of boronic ester groups into organic compounds. Writing in Nature, James Morken and co-workers tackle the functionalization of an important class
Problem 1
Problem 2 B
B H
H
B
B
H
B
Problem 3 B
?
M B
(desired)
M H
H
or B
B
B
B
?
or B
B B
M +
M
One-pot procedure Pd-catalysed cross-coupling Functionalization of primary boronic ester site (Problem 3)
Pt-catalysed asymmetric diboration Suppression of β–H elimination (Problem 1) B(pin) High stereoselectivity (Problem 2) B(pin)
B(pin) R
R = aryl or alkenyl
Figure 1 | Problems and solutions in the asymmetric functionalization of terminal olefins. Top: Common problems involved in the catalytic asymmetric diboration of terminal olefins and their subsequent crosscoupling procedures. Problem 1: Catalytic diboration of olefins is complicated by β-elimination pathways and many by-products. Problem 2: Asymmetric functionalization of aliphatic terminal olefins often leads to low enantio- or diastereoselectivity. Problem 3: Diboration creates two borylated sites and thus selectivity issues in the cross-coupling metalation step. Bottom: The one-pot procedure developed by Morken and co-workers8 combines Pt-catalysed asymmetric diboration with site-selective Pd-catalysed cross-coupling at the primary boronic ester site. B(pin) = 4,4,5,5-tetramethyl-1,3,2-dioxaborolyl.
of substrates — terminal alkenes — and develop8 a one-pot procedure for diboration followed by selective catalytic cross-coupling. The catalytic diboration5 of carbon– carbon double or triple bonds makes use of B–B-bonded diboron reagents, which are now produced commercially on scales of hundreds of kilograms. The diboration of alkynes is straightforward and clean; highly active monophosphine-based platinum catalysts for this reaction have been developed. In contrast, the diboration of alkenes5 is more complex in that, following insertion of the C=C bond into a metal boryl M–B bond, β-hydride elimination can compete successfully with reductive elimination of the B–C bond (Problem 1, Fig. 1). The latter process leads to the desired diborated product, whereas the former leads to both metal hydride and vinylboronate species. This mixture can go on to generate a wide range of side-products, including compounds with 0, 1, 2 or even 3 boronate
NATURE CHEMISTRY | VOL 6 | APRIL 2014 | www.nature.com/naturechemistry
© 2014 Macmillan Publishers Limited. All rights reserved
groups. Thus, for effective diboration, this β-hydride elimination step must be avoided. If this can be accomplished, the focus can then move to the development of asymmetric versions of the reaction. Distinguishing between the two enantiotopic faces of the double bond in terminal olefins (Problem 2, Fig. 1) is especially difficult, but highly desirable for the preparation of homochiral compounds that are the active ingredients of pharmaceuticals and agrochemicals. A number of successful alkene diboration catalysts, based on gold, rhodium, or phosphine-free platinum species5, were developed in the 1990s, but the most notable subsequent achievements in the area are the development, by Morken and co-workers, of chiral rhodium catalysts7 and, more recently, platinum catalysts bearing monodentate chiral phosphorus ligands9. These provide high yields of the desired diboronated products with excellent control of stereochemistry, and require 279
news & views only a very small (catalytic) amount of a metal and chiral ligand, both of which are relatively expensive. The final problem that must be overcome in order to make new C–C bonds following successful asymmetric alkene diboration is how to carry out selective cross-coupling reactions of the alkyl bis(boronate) ester at the primary rather than at the secondary site (Problem 3, Fig. 1). Until relatively recently, crosscoupling of alkyl groups required the use of the more reactive — but less stable — alkylboranes. But using RuPhos (one of a series of dicyclohexylbiphenylphosphine ligands developed by the Buchwald group), Dreher, Molander and co-workers have shown that primary alkyl trifluoroborates can be coupled10, and this has recently been extended to coupling of primary alkyl boronate esters by Steel, Marder, Liu and co-workers11. The challenge of selectively coupling a primary boronate in the presence of a secondary boronate had not, however, been addressed, and is complicated because it has previously been shown that secondary alkyl monoboronates are more reactive12. The methodology reported by Morken and co-workers solves all of these problems
280
in a single flask. Their platinum catalyst system9, incorporating a very bulky, chiral, monodentate phosphonite ligand, gives both high yields and excellent enantioselectivities in the alkene diboration process. The steric bulk and electronic properties of the phosphonite ligand combine to suppress β-hydride elimination (Problem 1) and provide the high stereoselectivities observed (Problem 2). Using the RuPhos–Pd catalyst system for the subsequent cross-coupling step gave especially interesting results. Thus, the coupling takes place exclusively at the primary boronate site (Problem 3), with retention of configuration at this carbon centre (as shown by a deuterium labelling study). This leaves the chiral secondary boronate site intact for downstream reactions, leading overall to extremely useful homoallylic alcohols and amines. Indeed, it is elegantly shown that the presence of this secondary boronate moiety greatly enhances the rate of cross-coupling at the primary site. Overall, the tandem reaction sequence is a stunning example of control and efficiency in catalytic chemistry. The protocol was demonstrated with a broad range of examples including a number of pharmaceutically relevant products. The sequence gives
excellent chemo- and stereoselectivities, is a one-pot, single-solvent process using low catalyst loadings and commercially available metal sources and ligands. There is much potential for this chemistry in both target-oriented and diversity-based organic synthesis, using starting materials as simple and abundant as propene. ❐ Rian Dewhurst and Todd Marder are at the Institut für Anorganische Chemie, Julius-MaximiliansUniversität Würzburg, Am Hubland, 97074 Würzburg, Germany. e-mail: [email protected] References 1. http://www.nobelprize.org/nobel_prizes/chemistry/laureates/ 2. Molnar, Á. (ed.) Palladium-Catalyzed Cross-Coupling Reactions (Wiley, 2013). 3. Miyaura, N. & Suzuki, A. Chem. Rev. 95, 2457–2483 (1995). 4. Hall, D. G. (ed.) Boronic Acids: Preparation and Applications in Organic Synthesis, Medicine and Materials 2nd edn (Wiley, 2011). 5. Marder, T. B. & Norman, N. C. Top. Catal. 5, 63–73 (1998). 6. Mkhalid, I. A. I., Barnard, J. H., Marder, T. B., Murphy, J. M. & Hartwig, J. F. Chem. Rev. 110, 890–931 (2010). 7. Burks, H. E. & Morken, J. P. Chem. Commun. 4717–4725 (2007). 8. Mlynarsky, S. N., Schuster, C. H. & Morken, J. P. Nature 505, 386–390 (2014). 9. Coombs, J. R., Haefner, F., Kliman, L. T. & Morken, J. P. J. Am. Chem. Soc. 135, 11222–11231 (2013). 10. Dreher, S. D., Lim, S.-E., Sandrock, D. L. & Molander, G. A. J. Org. Chem. 74, 3626–3631 (2009). 11. Yang, C.-T. et al. Angew. Chem. Int. Ed. 51, 528–532 (2012). 12. Imao, D., Glasspoole, B. W., Laberge, V. S. & Crudden, C. M. J. Am. Chem. Soc. 131, 5024–5025 (2009).
NATURE CHEMISTRY | VOL 6 | APRIL 2014 | www.nature.com/naturechemistry
© 2014 Macmillan Publishers Limited. All rights reserved
Cascades of catalytic selectivity
A combination of catalytic asymmetric diboration of terminal alkenes and Suzuki–Miyaura cross-coupling has been exploited in the synthesis of a variety of important medicinal agents. The process overcomes a number of problems in the application of these important catalytic processes.
Rian D. Dewhurst and Todd B. Marder
O
rganic synthesis is, at its heart, a study of carbon–carbon bond-forming processes. Homogeneous catalysis of organic reactions is dominated by processes that create C–C bonds, the primary goals being high chemo-, regio- or stereoselectivity, along with attempts to reduce waste, cost and environmental impact. The prominence of catalysis as a tool in modern organic synthesis is reflected in its repeated recognition by the Nobel committee, recently for asymmetric catalysis (2001), catalytic olefin metathesis (2005) and palladium-catalysed cross-coupling (2010)1. Metal-catalysed cross-couplings, particularly those using palladium, have developed into extraordinarily useful tools for C–C bond formation, built on a relatively simple concept: the coupling of a pseudocarbocationic ‘electrophile’, for example an aryl halide, with a pseudocarbanionic ‘nucleophile’, such as an organo-tin (Stille coupling), zinc (Negishi coupling), copper (Sonogashira coupling), magnesium (Kumada–Tamao coupling) or boron (Suzuki–Miyaura coupling) reagent 2. The Suzuki–Miyaura reaction3, using boronic acids or esters4 as the ‘nucleophilic’ partner, is one of the most versatile of the cross-coupling protocols, and is widely used in the pharmaceutical and agrochemical industries. Boronic esters and acids are much less toxic than tin reagents and, unlike more reactive organometallic magnesium or zinc species, are typically air- and moisture-stable. They also tend to be more compatible with other functional groups, eliminating the need for costly protection and deprotection steps. In addition, the empty p orbital on an sp2-hybridized boron makes it well-suited to mediate the transfer of the organic group to the palladium in the important transmetallation step of the catalytic cross-coupling process. With the utility of organoboron reagents assured, much attention has been directed to the development of advanced procedures5–7 for the installation of boronic ester groups into organic compounds. Writing in Nature, James Morken and co-workers tackle the functionalization of an important class
Problem 1
Problem 2 B
B H
H
B
B
H
B
Problem 3 B
?
M B
(desired)
M H
H
or B
B
B
B
?
or B
B B
M +
M
One-pot procedure Pd-catalysed cross-coupling Functionalization of primary boronic ester site (Problem 3)
Pt-catalysed asymmetric diboration Suppression of β–H elimination (Problem 1) B(pin) High stereoselectivity (Problem 2) B(pin)
B(pin) R
R = aryl or alkenyl
Figure 1 | Problems and solutions in the asymmetric functionalization of terminal olefins. Top: Common problems involved in the catalytic asymmetric diboration of terminal olefins and their subsequent crosscoupling procedures. Problem 1: Catalytic diboration of olefins is complicated by β-elimination pathways and many by-products. Problem 2: Asymmetric functionalization of aliphatic terminal olefins often leads to low enantio- or diastereoselectivity. Problem 3: Diboration creates two borylated sites and thus selectivity issues in the cross-coupling metalation step. Bottom: The one-pot procedure developed by Morken and co-workers8 combines Pt-catalysed asymmetric diboration with site-selective Pd-catalysed cross-coupling at the primary boronic ester site. B(pin) = 4,4,5,5-tetramethyl-1,3,2-dioxaborolyl.
of substrates — terminal alkenes — and develop8 a one-pot procedure for diboration followed by selective catalytic cross-coupling. The catalytic diboration5 of carbon– carbon double or triple bonds makes use of B–B-bonded diboron reagents, which are now produced commercially on scales of hundreds of kilograms. The diboration of alkynes is straightforward and clean; highly active monophosphine-based platinum catalysts for this reaction have been developed. In contrast, the diboration of alkenes5 is more complex in that, following insertion of the C=C bond into a metal boryl M–B bond, β-hydride elimination can compete successfully with reductive elimination of the B–C bond (Problem 1, Fig. 1). The latter process leads to the desired diborated product, whereas the former leads to both metal hydride and vinylboronate species. This mixture can go on to generate a wide range of side-products, including compounds with 0, 1, 2 or even 3 boronate
NATURE CHEMISTRY | VOL 6 | APRIL 2014 | www.nature.com/naturechemistry
© 2014 Macmillan Publishers Limited. All rights reserved
groups. Thus, for effective diboration, this β-hydride elimination step must be avoided. If this can be accomplished, the focus can then move to the development of asymmetric versions of the reaction. Distinguishing between the two enantiotopic faces of the double bond in terminal olefins (Problem 2, Fig. 1) is especially difficult, but highly desirable for the preparation of homochiral compounds that are the active ingredients of pharmaceuticals and agrochemicals. A number of successful alkene diboration catalysts, based on gold, rhodium, or phosphine-free platinum species5, were developed in the 1990s, but the most notable subsequent achievements in the area are the development, by Morken and co-workers, of chiral rhodium catalysts7 and, more recently, platinum catalysts bearing monodentate chiral phosphorus ligands9. These provide high yields of the desired diboronated products with excellent control of stereochemistry, and require 279
news & views only a very small (catalytic) amount of a metal and chiral ligand, both of which are relatively expensive. The final problem that must be overcome in order to make new C–C bonds following successful asymmetric alkene diboration is how to carry out selective cross-coupling reactions of the alkyl bis(boronate) ester at the primary rather than at the secondary site (Problem 3, Fig. 1). Until relatively recently, crosscoupling of alkyl groups required the use of the more reactive — but less stable — alkylboranes. But using RuPhos (one of a series of dicyclohexylbiphenylphosphine ligands developed by the Buchwald group), Dreher, Molander and co-workers have shown that primary alkyl trifluoroborates can be coupled10, and this has recently been extended to coupling of primary alkyl boronate esters by Steel, Marder, Liu and co-workers11. The challenge of selectively coupling a primary boronate in the presence of a secondary boronate had not, however, been addressed, and is complicated because it has previously been shown that secondary alkyl monoboronates are more reactive12. The methodology reported by Morken and co-workers solves all of these problems
280
in a single flask. Their platinum catalyst system9, incorporating a very bulky, chiral, monodentate phosphonite ligand, gives both high yields and excellent enantioselectivities in the alkene diboration process. The steric bulk and electronic properties of the phosphonite ligand combine to suppress β-hydride elimination (Problem 1) and provide the high stereoselectivities observed (Problem 2). Using the RuPhos–Pd catalyst system for the subsequent cross-coupling step gave especially interesting results. Thus, the coupling takes place exclusively at the primary boronate site (Problem 3), with retention of configuration at this carbon centre (as shown by a deuterium labelling study). This leaves the chiral secondary boronate site intact for downstream reactions, leading overall to extremely useful homoallylic alcohols and amines. Indeed, it is elegantly shown that the presence of this secondary boronate moiety greatly enhances the rate of cross-coupling at the primary site. Overall, the tandem reaction sequence is a stunning example of control and efficiency in catalytic chemistry. The protocol was demonstrated with a broad range of examples including a number of pharmaceutically relevant products. The sequence gives
excellent chemo- and stereoselectivities, is a one-pot, single-solvent process using low catalyst loadings and commercially available metal sources and ligands. There is much potential for this chemistry in both target-oriented and diversity-based organic synthesis, using starting materials as simple and abundant as propene. ❐ Rian Dewhurst and Todd Marder are at the Institut für Anorganische Chemie, Julius-MaximiliansUniversität Würzburg, Am Hubland, 97074 Würzburg, Germany. e-mail: [email protected] References 1. http://www.nobelprize.org/nobel_prizes/chemistry/laureates/ 2. Molnar, Á. (ed.) Palladium-Catalyzed Cross-Coupling Reactions (Wiley, 2013). 3. Miyaura, N. & Suzuki, A. Chem. Rev. 95, 2457–2483 (1995). 4. Hall, D. G. (ed.) Boronic Acids: Preparation and Applications in Organic Synthesis, Medicine and Materials 2nd edn (Wiley, 2011). 5. Marder, T. B. & Norman, N. C. Top. Catal. 5, 63–73 (1998). 6. Mkhalid, I. A. I., Barnard, J. H., Marder, T. B., Murphy, J. M. & Hartwig, J. F. Chem. Rev. 110, 890–931 (2010). 7. Burks, H. E. & Morken, J. P. Chem. Commun. 4717–4725 (2007). 8. Mlynarsky, S. N., Schuster, C. H. & Morken, J. P. Nature 505, 386–390 (2014). 9. Coombs, J. R., Haefner, F., Kliman, L. T. & Morken, J. P. J. Am. Chem. Soc. 135, 11222–11231 (2013). 10. Dreher, S. D., Lim, S.-E., Sandrock, D. L. & Molander, G. A. J. Org. Chem. 74, 3626–3631 (2009). 11. Yang, C.-T. et al. Angew. Chem. Int. Ed. 51, 528–532 (2012). 12. Imao, D., Glasspoole, B. W., Laberge, V. S. & Crudden, C. M. J. Am. Chem. Soc. 131, 5024–5025 (2009).
NATURE CHEMISTRY | VOL 6 | APRIL 2014 | www.nature.com/naturechemistry
© 2014 Macmillan Publishers Limited. All rights reserved
