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Dynamically Chiral Helical Polymers: A New Frontier in Asymmetric Catalysis? Scott E. Denmark
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Roger Adams Laboratory, University of Illinois at Urbana−Champaign, Urbana, Illinois 61801, United States
formulated, this connection between the molecular and macroscopic worlds forms the foundation for the sui generis character of chemistry. Just as Pasteur recognized that macroscopic chirality, i.e., optical rotation or hemihedral crystal faces, can arise from both dissymmetric (e.g., tartrates) and symmetric (e.g. silica) molecular building blocks, so too can mesoscopic objects be constructed from both kinds of molecular entities. Nowhere is this phenomenon more dramatically manifest than in the field of materials-chirality.2 The vast majority of polymers adopt chiral architectures ranging from isotactic polypropylene to DNA. However, whereas the chirality of these polymers arises from the stereogenic centers in the main chain or the chirality of the subunits (nucleotides), other polymers can adopt chiral architectures from the induced conformation of the backbone constructed from achiral subunits. The most common chiral architecture is helicity, and the sense of helicity can be controlled in a number of ways. Most commonly, attachment of stereogenic, chirotopic groups to the monomers is very effective at controlling the helicity of a polymer. However, as first shown by Green in 1993, chiral media, such as solvents, can also induce a specific sense of helicity.3 The use of chiral solvents to control the stereochemical course of reactions has been studied for decades.4 However, these solvents are designed to effect specific interactions with substrate molecules making them rather unique, engineered, and expensive. Moreover, for inexpensive, readily available chiral solvents to be of general utility, they cannot contain many reactive functional groups. Accordingly, the interactions that such compounds can engender are likely to be rather weak and nonspecific. This problem is elegantly addressed by the cumulative effect of small energetic contributions that leads to the folding of polymers.5 Most importantly, if the polymer helicity is dynamic, then the enantiomeric composition of the polymer will be dependent on the degree of polymerization (DP)
Chiral solvents can control the screw sense of helically chiral polymers which can then function as enantioselective catalysts when fitted with chemically active residues.
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he impact of asymmetric catalysis for the synthesis of enantiomerically enriched compounds cannot be overstated. In view of the importance of chiral compounds in myriad applications including agrochemicals, pharmaceuticals, flavors and fragrances, sensors, and functional materials, the synthesis of these compounds in single enantiomer form represents a continuing challenge. In the never-ending search for new methods and concepts to effect asymmetric synthesis, Suginome et al. have introduced a novel approach that leverages the cumulative effect of small perturbations provided by chiral solvents to induce a helical conformation in a polymer that subsequently acts as an enantioselective catalyst for a number of useful transformations.1
In the never-ending search for new methods and concepts to effect asymmetric synthesis, Suginome et al. have introduced a novel approach that leverages the cumulative effect of small perturbations provided by chiral solvents to induce a helical conformation in a polymer that subsequently acts as an enantioselective catalyst for a number of useful transformations. In 1848, a 26-year old Louis Pasteur made the first attempt to find a causal connection between a macroscopic phenomenon (optical rotation) and molecular structure (dissymmetry). Although a full rationalization would have to wait until 1874 when the theory of tetrahedral carbon was © XXXX American Chemical Society
A
DOI: 10.1021/acscentsci.9b00644 ACS Cent. Sci. XXXX, XXX, XXX−XXX
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the n-propoxymethyl side chain (M3) and (R)-limonene as the superior combination reaching a maximum of 72% se for the right-handed helix (P)-PQX1. To create a helically homogeneous polymer, the authors evaluated the screw excess of (P)-PQX1 as a function of the degree of polymerization which reached >99% se at DP ≥ 120 (Scheme 1B). Next, following their previous protocols, random copolymers of M3 and phosphine M2 were prepared with DP = 1000, and this polymer, PQXphosL1 (990/10), was employed as a ligand for various palladiumcatalyzed reactions (Scheme 1C). To evaluate the efficiency of PQXphosL1 (990/10) in the Suzuki−Miyaura cross-coupling reaction, the ligand was combined with a palladium catalyst precursor and tested in the reaction between bromide 1 and boronic acid 2 (Scheme 1D). By carrying out the cross-coupling in a 95:5 mixture of (R)-limonene and THF, the 1,1-binaphthyl product 3 was generated in 66% yield and with 98% ee of (S) absolute configuration. A number of careful control experiments in the same solvent mixture using polystyrenebased phosphines as well as monomeric phosphines failed to
which allows the small contributions to accumulate to a significant energetic bias for single handedness. In previous studies, Suginome and co-workers have used stereogenic side chains to bias the helicity of poly(quinoxaline-2,3-diyl) polymers (Scheme 1).6 Through copolymerization of the chiral monomer (R,R)-M1 with a phosphine-bearing monomer M2, a helically chiral polymer (R,R)-PQXphos (950/50) is generated that is highly effective in various enantioselective reactions using palladium catalysts (including the Suzuki−Miyaura crosscoupling). Furthermore, the authors made the striking observation that the screw sense of the polymer was solvent dependent. This observation, together with the known influence of chiral solvents on polymer helicity,7 inspired the work described in this publication.1 To create a chiral polymer with high helical homogeneity [specified as screw excess (% se)] using achiral monomers, the authors first evaluated the polymerization of 1,2diisocyanobenzene monomers bearing five different side chains in five different, commercially available chiral solvents. These experiments led to the identification of B
DOI: 10.1021/acscentsci.9b00644 ACS Cent. Sci. XXXX, XXX, XXX−XXX
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produce 3 or produced it as a racemic mixture thus confirming the critical role of the helical polymer in controlling the stereochemical course of the reaction. With the exponential increase in the development of ligands and other chiral compounds for application in asymmetric catalysis, a parallel effort in the practical application of these methods has also increased. In particular, the adoption of asymmetric catalytic reactions in industrial processes has lagged behind owing to many factors, including cost which could be ameliorated by recoverability and reusability of precious catalysts. This motivation has provided the impetus for extensive research into immobilization of small molecule catalysts on surfaces, in polymers (both soluble and insoluble) and on inorganic supports.8 It is in this context that the contribution from Suginome et al. should be evaluated. Although it would appear at first glance to be a nonstarter for fine chemical synthesis, limonene is used industrially as a degreasing agent and paint stripper. The demand for limonene is growing in view of the trend toward renewable, biobased solvents. Nevertheless, cost will still be a major deterrent for the near term. In recognition of this potential problem, Suginome and co-workers did isolate PQXphosL1 (990/10) by precipitation from (R)-limonene with methanol and used this material in the Suzuki−Miyaura cross-coupling in an achiral solvent (THF). The product, 3, was formed in comparable yield but only 45% ee whereas, in 1-propanol (in which the ligand is much less soluble), 3 was formed in 88% ee. Thus, the dynamic character of the helical chirality which allows for the formation of highly screw enriched polymers is also a major liability when used in normal solvents.
provides fundamental insights into the fascinating world of materials-chirality. One final word about nomenclature is in order. The authors have, for the most part, eschewed the commonly used and technically incorrect neologism of “chirality transfer” and “memory of chirality”. As has been eloquently pointed out by Cozzi and Siegel, chirality cannot be transferred or forgotten and remembered.9 All of the processes discussed in this paper are rooted in structure and bonding (stereogenicity) not symmetry (chirality). It is hoped that the readers of this paper will show similar restraint. Author Information
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Scott 0000-0002-1099-9765 ScottE.E.Denmark: Denmark : 0000-0002-1099-9765
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REFERENCES REFERENCES (1) Nagata, Y.; Takeda, R.; Suginome, M. Asymmetric Catalysis in Chiral Solvents: Chirality Transfer with Amplification of Homochirality through Helical Macromolecular Scaffold. ACS Cent. Sci. 2019, in press. DOI: 10.1021/acscentsci.9b00330. (2) Green, M. M., Nolte, R. J. M., Meijer, E. W., Eds. Materials Chirality. In Topics in Stereochemistry; Wiley-Interscience: Hoboken, 2003; Vol. 24. (3) Green, M. M.; Khatri, C.; Peterson, N. C. A Macromolecular Conformational Change Driven by a Minute Chiral Solvation Energy. J. Am. Chem. Soc. 1993, 115, 4941−4942. (4) Reichardt, C.; Welton, T., Eds. Solvents and Solvent Effects in Organic Chemistry, 4th ed.; Wiley-VCH: Weinheim, 2011. (5) Zhao, Y.; Moore, J. S. Foldamers Based on Solvophobic Effects. In Foldamers; Wiley-VCH: Weinheim, 2007; Chapter 3. (6) Suginome, M.; Yamamoto, T.; Nagata, Y. Poly(quinoxaline-2,3diyl)s: A Fascinating Helical Macromolecular Scaffold for New Chiral Functions. Yuki Gosei Kagaku Kyokaishi 2015, 73, 1141−1155. (7) Yashima, E.; Ousaka, N.; Taura, D.; Shimomura, K.; Ikai, T.; Maeda, K. Supramolecular Helical Systems: Helical Assemblies of Small Molecules, Foldamers, and Polymers with Chiral Amplification and Their Functions. Chem. Rev. 2016, 116, 13752−13990. (8) Ding, K., Uozumi, Y., Eds. Handbook of Asymmetric Heterogeneous Catalysis; Wiley-VCH: Weinheim, 2008. (9) Cozzi, F.; Siegel, J. S. Chirony of stereochemical metaphors. Org. Biomol. Chem. 2005, 3, 4296−4298.
the adoption of asymmetric catalytic reactions in industrial processes has lagged behind owing to many factors, including cost which could be ameliorated by recoverability and reusability of precious catalysts When compared to the performance of the helically chiral ligands such as (R,R)-PQXphos (950/50) in reactions carried out in achiral solvents, the ligand derived from achiral monomers performs at approximately the same level in both yield and enantioselectivity. Thus, from a purely practical perspective, the use of the dynamically chiral ligands does not offer obvious advantages. However, from a conceptual perspective, this work constitutes an exceptionally novel application of dynamic polymer structure and also C
DOI: 10.1021/acscentsci.9b00644 ACS Cent. Sci. XXXX, XXX, XXX−XXX
