- Email: [email protected]
Multisubstituted Unnatural Prolines for Asymmetric Catalytic Domino Reactions
coherence among excitons might be prolonged as a result of synchronized nuclear motion. 2D-STEPS maps provide clear data visualization of how the nuclear motion modulates the electronic state of each exciton and how the excitons show synchronized spectral motion after excitation. The second approach, 2D-TRIPS (twodimensional time-resolved interexciton perturbation spectroscopy), probes how the nuclear motion localized on a specific exciton can affect another one. 2D-TRIPS, although less intuitive, revealed that couplings do exist between the nuclear motion of distinct excitons, similarly to coupling between numerous harmonic oscillators. In particular, 2D-TRIPS maps show that nuclear motions localized on a specific exciton do affect the energy gap of other excitons in a correlated manner, such that energy levels do not fluctuate randomly. Further elucidation of how these collective nuclear motions influence coupled multi-chromophore
systems could help us understand how energy-transfer dynamics can be optimized and perhaps directed.
ACKNOWLEDGMENTS Financial support from the Photosynthetic Antenna Research Center, an Energy Frontier Research Center funded by the Basic Energy Sciences program of the US Department of Energy Office of Science under award DE-SC 0001035, and the H2020 Marie Skłodowska-Curie Actions Project PHOEBUS (no. 655059) is gratefully acknowledged.
coherence in photosynthetic systems. Nature 446, 782–786. 4. Panitchayangkoon, G., Hayes, D., Fransted, K.A., Caram, J.R., Harel, E., Wen, J., Blankenship, R.E., and Engel, G.S. (2010). Long-lived quantum coherence in photosynthetic complexes at physiological temperature. Proc. Natl. Acad. Sci. USA 107, 12766–12770. 5. Rolczynski, B.S., Zheng, H., Singh, V.P., Navotnaya, P., Ginzburg, A.R., Caram, J.R., Ashraf, K., Gardiner, A.T., Yeh, S.-H., Kais, S., et al. (2018). Correlated protein environments drive quantum coherence lifetimes in photosynthetic pigment-protein complexes. Chem 4, this issue, 138–149. 6. Dosta´l, J., Psenc´ık, J., and Zigmantas, D. (2016). In situ mapping of the energy flow through the entire photosynthetic apparatus. Nat. Chem. 8, 705–710.
1. Mirkovic, T., Ostroumov, E.E., Anna, J.M., van Grondelle, R., Govindjee, and Scholes, G.D. (2017). Light absorption and energy transfer in the antenna complexes of photosynthetic organisms. Chem. Rev. 117, 249–293.
7. Tiwari, V., Peters, W.K., and Jonas, D.M. (2013). Electronic resonance with anticorrelated pigment vibrations drives photosynthetic energy transfer outside the adiabatic framework. Proc. Natl. Acad. Sci. USA 110, 1203–1208.
2. Chenu, A., and Scholes, G.D. (2015). Coherence in energy transfer and photosynthesis. Annu. Rev. Phys. Chem. 66, 69–96.
8. Christensson, N., Kauffmann, H.F., Pullerits, T., and Mancal, T. (2012). Origin of long-lived coherences in light-harvesting complexes. J. Phys. Chem. B 116, 7449–7454.
3. Engel, G.S., Calhoun, T.R., Read, E.L., Ahn, T.K., Mancal, T., Cheng, Y.C., Blankenship, R.E., and Fleming, G.R. (2007). Evidence for wavelike energy transfer through quantum
9. Abramavicius, D., and Mukamel, S. (2011). Exciton dynamics in chromophore aggregates with correlated environment fluctuations. J. Chem. Phys. 134, 174504.
Preview
Multisubstituted Unnatural Prolines for Asymmetric Catalytic Domino Reactions Xiang-Yu Chen1 and Dieter Enders1,* Derivatives of multisubstituted unnatural prolines show catalytic reactivities different from those of the natural amino acid and indicate a high potential for new organic reaction sequences. Recent work published in Angewandte Chemie by Cossı´o and co-workers reports a novel asymmetric organocatalytic domino reaction employing a catalytic system based on multisubstituted unnatural prolines. The catalytic asymmetric synthesis of complex chiral molecules is a continuing challenge at the forefront of synthetic chemistry and of particular attraction in
both industrial and academic laboratories. This has resulted in the development of quite a number of novel protocols for their synthesis. Organoca-
talytic domino reactions as defined by Tietze and Beifuss1 turned out to be one of the rapidly growing subfields in this respect. Such highly stereoselective multicomponent one-pot procedures have many advantages over the classical stop-and-go methods, such as the avoidance of costly, time-consuming protection and deprotection of functional groups and the purification of reaction intermediates. Since the turn of the millennium, the research field of organocatalysis has
1Institute
of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany *Correspondence: [email protected] https://doi.org/10.1016/j.chempr.2017.12.007
Chem 4, 16–26, January 11, 2018 ª 2017 Elsevier Inc.
21
A
B
C
Scheme 1. The Novel Asymmetric Organocatalytic Domino Reaction Employing a Catalytic System Based on Multisubstituted Unnatural Prolines (A) The multisubstituted-unnatural-proline derivative 1 catalyzed the domino reactions of ketones, nitroalkenes, and carboxylic acids. (B) Application of the new domino strategy for the asymmetric synthesis of (+)-pancracine. (C) Significant steps of the proposed reaction mechanism.
developed with a breathtaking speed and is now considered the third pillar beside bio-catalysis and metal catalysis. One of the greatest advantages of these organocatalysts is their ability to promote various reactions in one process through different activation modes, which make them ideal for application in domino reactions. In particular, secondary amines are capable of combining iminium-enamine activation modes and have witnessed great success in the field of domino reactions. Bui and Barbas,2 List and co-workers,3 MacMillan and co-workers,4 and Jørgensen and coworkers5 carried out early studies on domino reactions by merging iminiumenamine activation modes. In 2006, our group6 developed an asymmetric organocatalytic triple domino reaction of aliphatic aldehydes, nitroalkenes, and a,b-unsaturated aldehydes with a readily available proline derivative, which was introduced to organocatalysis by Jørgensen and co-workers7 and Hayashi et al.8 Since then, a series of triple and
22
Chem 4, 16–26, January 11, 2018
quadruple domino reactions through secondary amine catalysis have been developed by our and other groups. Despite this progress, usually only consecutive classical transformations are involved in these domino reactions, and the development of new reaction pathways in domino sequences is still highly desirable. Cossı´o and co-workers reported that 1,3-dipolar cycloaddition reactions of nitroalkenes and azomethine ylides turned out to be efficient approaches for the asymmetric synthesis of derivatives of multisubstituted unnatural prolines9 and thus serve as a new class of catalysts for iminium-enamine domino processes. Having obtained these derivatives of multisubstituted unnatural prolines, the authors initially examined their ability as organocatalysts in aldol reactions. Derivative 1 showed efficient reactivity for aldol reactions and resulted in products with a configuration opposing that obtained with
(S)-proline organocatalysis. The difference was due to the sterically hindered 5-phenyl group. Further studies established several characteristics of the optimal catalyst: (1) The C2 substituent should be a single group. (2) The alkoxycarbonyl group should not be bulky. (3) The C3 and C4 substituents must be trans to each other. (4) The C5 substituent should be an aryl group.
The novel ability of 1 was further displayed in the study of conjugate additions of ketones to nitroalkenes. Recently in Angewandte Chemie, Cossı´o and co-workers demonstrated a new domino process10 among ketones 2, nitroalkenes 3, and carboxylic acids 4 to give the interesting bicyclic octahydro-2H-indol-2-one scaffolds 5 instead of the normal Michael adducts (Scheme 1A). This domino reaction was complete after 24 hr in the presence of 20 mol % of 1 as the
catalyst at 45 C, leading to the desired products in very good yields with excellent stereoselectivities, whereas the same reaction in the presence of 10 mol % of catalyst required 60 hr in order to obtain a similar yield of product. The authors’ catalytic system showed a broad substrate scope. Aliphatic, electron-rich, and electronpoor aromatic acids 4 all reacted smoothly with a variety of cyclic ketones 2 and nitroalkenes 3 to give the desired products 5 in 38%–91% yields with uniformly high stereoselectivities. It should be noted that other natural organocatalysts—such as (S)-proline, O-silylprolinol derivatives, and cinchona alkaloid derivatives—are inefficient in the catalysis of this threecomponent domino reaction. The steric and electronic features of catalyst 1 are believed to result in this different behavior. To demonstrate the synthetic utility of this novel organocatalytic domino strategy, Cossı´o and co-workers developed a convenient protocol for the asymmetric synthesis of the alkaloid pancracine. The resulting cycloadduct 5e could be easily transformed to (+)-pancracine (Scheme 1B). This application demonstrates the usefulness of organocatalysis based on multisubstituted unnatural prolines and opens a novel short stereoselective entry to (+)-pancracine. On the basis of the control experiments, 18O-labeling experiments, and
density-functional-theory calculations, Cossı´o and co-workers also discussed the mechanism of this domino reaction (Scheme 1C). The corresponding enamine I generated from cyclohexanone 2a underwent a Michael addition to the nitroalkene 3a to provide the protonated nitronate II, which in turn acted as an electrophile for a nucleophilic addition of benzoic acid (4a). The resulting adduct III underwent dehydration to form adduct IV, which formed zwitterionic intermediate V. The following rearrangement gave adduct VI. Then, the intramolecular nucleophilic addition of VI afforded VII, which released catalyst 1 and formed cation adduct VIII. Finally, the hydration of VIII yielded final product 5a. Cossı´o and co-workers’ catalytic system based on multisubstituted unnatural prolines for new domino reactions shows great potential for the synthesis of valuable complex molecules, although several challenges need to be addressed. In the case of domino reactions catalyzed by unnatural prolines, a wider range of carbonyl compounds—especially enals, aldehydes, and acyclic ketones—should be investigated as substrates, and compared with proline and its simple derivatives, low-loading catalysts are still needed. 1. Tietze, L.F., and Beifuss, U. (1993). Sequential transformations in organic chemistry: a synthetic strategy with a future. Angew. Chem. Int. Ed. 32, 131–163.
2. Bui, T., and Barbas, C.F. (2000). A proline-catalyzed asymmetric Robinson annulation reaction. Tetrahedron Lett. 41, 6951–6954. 3. Yang, J.W., Hechavarria Fonseca, M.T., and List, B. (2005). Catalytic asymmetric reductive Michael cyclization. J. Am. Chem. Soc. 127, 15036–15037. 4. Huang, Y., Walji, A.M., Larsen, C.H., and MacMillan, D.W.C. (2005). Enantioselective organo-cascade catalysis. J. Am. Chem. Soc. 127, 15051–15053. 5. Halland, N., Aburel, P.S., and Jørgensen, K.A. (2004). Highly enantio- and diastereoselective organocatalytic asymmetric domino Michael-aldol reaction of beta-ketoesters and alpha,beta-unsaturated ketones. Angew. Chem. Int. Ed. 43, 1272–1277. 6. Enders, D., Hu¨ttl, M.R.M., Grondal, C., and Raabe, G. (2006). Control of four stereocentres in a triple cascade organocatalytic reaction. Nature 441, 861–863. 7. Marigo, M., Wabnitz, T.C., Fielenbach, D., and Jørgensen, K.A. (2005). Enantioselective organocatalyzed alpha sulfenylation of aldehydes. Angew. Chem. Int. Ed. 44, 794–797. 8. Hayashi, Y., Gotoh, H., Hayashi, T., and Shoji, M. (2005). Diphenylprolinol silyl ethers as efficient organocatalysts for the asymmetric Michael reaction of aldehydes and nitroalkenes. Angew. Chem. Int. Ed. 44, 4212–4215. 9. Conde, E., Bello, D., de Co´zar, A., Sa´nchez, M., Va´zquez, M.A., and Cossı´o, F.P. (2012). Densely substituted unnatural L- and D-prolines as catalysts for highly enantioselective stereodivergent (3 + 2) cycloadditions and aldol reactions. Chem. Sci. 3, 1486–1491. 10. de Gracia Retamosa, M., Ruiz-Olalla, A., Bello, T., de Co´zar, A., and Cossı´o, F.P. (2017). Three-component enantioselective cyclization reaction catalyzed by an unnatural amino acid derivative. Angew. Chem. Int. Ed. Published online November 9, 2017. https://doi.org/10. 1002/anie.201708952.
Chem 4, 16–26, January 11, 2018
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systems could help us understand how energy-transfer dynamics can be optimized and perhaps directed.
ACKNOWLEDGMENTS Financial support from the Photosynthetic Antenna Research Center, an Energy Frontier Research Center funded by the Basic Energy Sciences program of the US Department of Energy Office of Science under award DE-SC 0001035, and the H2020 Marie Skłodowska-Curie Actions Project PHOEBUS (no. 655059) is gratefully acknowledged.
coherence in photosynthetic systems. Nature 446, 782–786. 4. Panitchayangkoon, G., Hayes, D., Fransted, K.A., Caram, J.R., Harel, E., Wen, J., Blankenship, R.E., and Engel, G.S. (2010). Long-lived quantum coherence in photosynthetic complexes at physiological temperature. Proc. Natl. Acad. Sci. USA 107, 12766–12770. 5. Rolczynski, B.S., Zheng, H., Singh, V.P., Navotnaya, P., Ginzburg, A.R., Caram, J.R., Ashraf, K., Gardiner, A.T., Yeh, S.-H., Kais, S., et al. (2018). Correlated protein environments drive quantum coherence lifetimes in photosynthetic pigment-protein complexes. Chem 4, this issue, 138–149. 6. Dosta´l, J., Psenc´ık, J., and Zigmantas, D. (2016). In situ mapping of the energy flow through the entire photosynthetic apparatus. Nat. Chem. 8, 705–710.
1. Mirkovic, T., Ostroumov, E.E., Anna, J.M., van Grondelle, R., Govindjee, and Scholes, G.D. (2017). Light absorption and energy transfer in the antenna complexes of photosynthetic organisms. Chem. Rev. 117, 249–293.
7. Tiwari, V., Peters, W.K., and Jonas, D.M. (2013). Electronic resonance with anticorrelated pigment vibrations drives photosynthetic energy transfer outside the adiabatic framework. Proc. Natl. Acad. Sci. USA 110, 1203–1208.
2. Chenu, A., and Scholes, G.D. (2015). Coherence in energy transfer and photosynthesis. Annu. Rev. Phys. Chem. 66, 69–96.
8. Christensson, N., Kauffmann, H.F., Pullerits, T., and Mancal, T. (2012). Origin of long-lived coherences in light-harvesting complexes. J. Phys. Chem. B 116, 7449–7454.
3. Engel, G.S., Calhoun, T.R., Read, E.L., Ahn, T.K., Mancal, T., Cheng, Y.C., Blankenship, R.E., and Fleming, G.R. (2007). Evidence for wavelike energy transfer through quantum
9. Abramavicius, D., and Mukamel, S. (2011). Exciton dynamics in chromophore aggregates with correlated environment fluctuations. J. Chem. Phys. 134, 174504.
Preview
Multisubstituted Unnatural Prolines for Asymmetric Catalytic Domino Reactions Xiang-Yu Chen1 and Dieter Enders1,* Derivatives of multisubstituted unnatural prolines show catalytic reactivities different from those of the natural amino acid and indicate a high potential for new organic reaction sequences. Recent work published in Angewandte Chemie by Cossı´o and co-workers reports a novel asymmetric organocatalytic domino reaction employing a catalytic system based on multisubstituted unnatural prolines. The catalytic asymmetric synthesis of complex chiral molecules is a continuing challenge at the forefront of synthetic chemistry and of particular attraction in
both industrial and academic laboratories. This has resulted in the development of quite a number of novel protocols for their synthesis. Organoca-
talytic domino reactions as defined by Tietze and Beifuss1 turned out to be one of the rapidly growing subfields in this respect. Such highly stereoselective multicomponent one-pot procedures have many advantages over the classical stop-and-go methods, such as the avoidance of costly, time-consuming protection and deprotection of functional groups and the purification of reaction intermediates. Since the turn of the millennium, the research field of organocatalysis has
1Institute
of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany *Correspondence: [email protected] https://doi.org/10.1016/j.chempr.2017.12.007
Chem 4, 16–26, January 11, 2018 ª 2017 Elsevier Inc.
21
A
B
C
Scheme 1. The Novel Asymmetric Organocatalytic Domino Reaction Employing a Catalytic System Based on Multisubstituted Unnatural Prolines (A) The multisubstituted-unnatural-proline derivative 1 catalyzed the domino reactions of ketones, nitroalkenes, and carboxylic acids. (B) Application of the new domino strategy for the asymmetric synthesis of (+)-pancracine. (C) Significant steps of the proposed reaction mechanism.
developed with a breathtaking speed and is now considered the third pillar beside bio-catalysis and metal catalysis. One of the greatest advantages of these organocatalysts is their ability to promote various reactions in one process through different activation modes, which make them ideal for application in domino reactions. In particular, secondary amines are capable of combining iminium-enamine activation modes and have witnessed great success in the field of domino reactions. Bui and Barbas,2 List and co-workers,3 MacMillan and co-workers,4 and Jørgensen and coworkers5 carried out early studies on domino reactions by merging iminiumenamine activation modes. In 2006, our group6 developed an asymmetric organocatalytic triple domino reaction of aliphatic aldehydes, nitroalkenes, and a,b-unsaturated aldehydes with a readily available proline derivative, which was introduced to organocatalysis by Jørgensen and co-workers7 and Hayashi et al.8 Since then, a series of triple and
22
Chem 4, 16–26, January 11, 2018
quadruple domino reactions through secondary amine catalysis have been developed by our and other groups. Despite this progress, usually only consecutive classical transformations are involved in these domino reactions, and the development of new reaction pathways in domino sequences is still highly desirable. Cossı´o and co-workers reported that 1,3-dipolar cycloaddition reactions of nitroalkenes and azomethine ylides turned out to be efficient approaches for the asymmetric synthesis of derivatives of multisubstituted unnatural prolines9 and thus serve as a new class of catalysts for iminium-enamine domino processes. Having obtained these derivatives of multisubstituted unnatural prolines, the authors initially examined their ability as organocatalysts in aldol reactions. Derivative 1 showed efficient reactivity for aldol reactions and resulted in products with a configuration opposing that obtained with
(S)-proline organocatalysis. The difference was due to the sterically hindered 5-phenyl group. Further studies established several characteristics of the optimal catalyst: (1) The C2 substituent should be a single group. (2) The alkoxycarbonyl group should not be bulky. (3) The C3 and C4 substituents must be trans to each other. (4) The C5 substituent should be an aryl group.
The novel ability of 1 was further displayed in the study of conjugate additions of ketones to nitroalkenes. Recently in Angewandte Chemie, Cossı´o and co-workers demonstrated a new domino process10 among ketones 2, nitroalkenes 3, and carboxylic acids 4 to give the interesting bicyclic octahydro-2H-indol-2-one scaffolds 5 instead of the normal Michael adducts (Scheme 1A). This domino reaction was complete after 24 hr in the presence of 20 mol % of 1 as the
catalyst at 45 C, leading to the desired products in very good yields with excellent stereoselectivities, whereas the same reaction in the presence of 10 mol % of catalyst required 60 hr in order to obtain a similar yield of product. The authors’ catalytic system showed a broad substrate scope. Aliphatic, electron-rich, and electronpoor aromatic acids 4 all reacted smoothly with a variety of cyclic ketones 2 and nitroalkenes 3 to give the desired products 5 in 38%–91% yields with uniformly high stereoselectivities. It should be noted that other natural organocatalysts—such as (S)-proline, O-silylprolinol derivatives, and cinchona alkaloid derivatives—are inefficient in the catalysis of this threecomponent domino reaction. The steric and electronic features of catalyst 1 are believed to result in this different behavior. To demonstrate the synthetic utility of this novel organocatalytic domino strategy, Cossı´o and co-workers developed a convenient protocol for the asymmetric synthesis of the alkaloid pancracine. The resulting cycloadduct 5e could be easily transformed to (+)-pancracine (Scheme 1B). This application demonstrates the usefulness of organocatalysis based on multisubstituted unnatural prolines and opens a novel short stereoselective entry to (+)-pancracine. On the basis of the control experiments, 18O-labeling experiments, and
density-functional-theory calculations, Cossı´o and co-workers also discussed the mechanism of this domino reaction (Scheme 1C). The corresponding enamine I generated from cyclohexanone 2a underwent a Michael addition to the nitroalkene 3a to provide the protonated nitronate II, which in turn acted as an electrophile for a nucleophilic addition of benzoic acid (4a). The resulting adduct III underwent dehydration to form adduct IV, which formed zwitterionic intermediate V. The following rearrangement gave adduct VI. Then, the intramolecular nucleophilic addition of VI afforded VII, which released catalyst 1 and formed cation adduct VIII. Finally, the hydration of VIII yielded final product 5a. Cossı´o and co-workers’ catalytic system based on multisubstituted unnatural prolines for new domino reactions shows great potential for the synthesis of valuable complex molecules, although several challenges need to be addressed. In the case of domino reactions catalyzed by unnatural prolines, a wider range of carbonyl compounds—especially enals, aldehydes, and acyclic ketones—should be investigated as substrates, and compared with proline and its simple derivatives, low-loading catalysts are still needed. 1. Tietze, L.F., and Beifuss, U. (1993). Sequential transformations in organic chemistry: a synthetic strategy with a future. Angew. Chem. Int. Ed. 32, 131–163.
2. Bui, T., and Barbas, C.F. (2000). A proline-catalyzed asymmetric Robinson annulation reaction. Tetrahedron Lett. 41, 6951–6954. 3. Yang, J.W., Hechavarria Fonseca, M.T., and List, B. (2005). Catalytic asymmetric reductive Michael cyclization. J. Am. Chem. Soc. 127, 15036–15037. 4. Huang, Y., Walji, A.M., Larsen, C.H., and MacMillan, D.W.C. (2005). Enantioselective organo-cascade catalysis. J. Am. Chem. Soc. 127, 15051–15053. 5. Halland, N., Aburel, P.S., and Jørgensen, K.A. (2004). Highly enantio- and diastereoselective organocatalytic asymmetric domino Michael-aldol reaction of beta-ketoesters and alpha,beta-unsaturated ketones. Angew. Chem. Int. Ed. 43, 1272–1277. 6. Enders, D., Hu¨ttl, M.R.M., Grondal, C., and Raabe, G. (2006). Control of four stereocentres in a triple cascade organocatalytic reaction. Nature 441, 861–863. 7. Marigo, M., Wabnitz, T.C., Fielenbach, D., and Jørgensen, K.A. (2005). Enantioselective organocatalyzed alpha sulfenylation of aldehydes. Angew. Chem. Int. Ed. 44, 794–797. 8. Hayashi, Y., Gotoh, H., Hayashi, T., and Shoji, M. (2005). Diphenylprolinol silyl ethers as efficient organocatalysts for the asymmetric Michael reaction of aldehydes and nitroalkenes. Angew. Chem. Int. Ed. 44, 4212–4215. 9. Conde, E., Bello, D., de Co´zar, A., Sa´nchez, M., Va´zquez, M.A., and Cossı´o, F.P. (2012). Densely substituted unnatural L- and D-prolines as catalysts for highly enantioselective stereodivergent (3 + 2) cycloadditions and aldol reactions. Chem. Sci. 3, 1486–1491. 10. de Gracia Retamosa, M., Ruiz-Olalla, A., Bello, T., de Co´zar, A., and Cossı´o, F.P. (2017). Three-component enantioselective cyclization reaction catalyzed by an unnatural amino acid derivative. Angew. Chem. Int. Ed. Published online November 9, 2017. https://doi.org/10. 1002/anie.201708952.
Chem 4, 16–26, January 11, 2018
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