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Self-Sorting Assembly of Molecular Trefoil Knots of Single Handedness Jiankang Zhong, Liang Zhang, David August, George F. S. Whitehead, and David A. Leigh J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b06127 • Publication Date (Web): 07 Aug 2019 Downloaded from pubs.acs.org on August 7, 2019
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Journal of the American Chemical Society
Self-Sorting Assembly of Molecular Trefoil Knots of Single Handedness Jiankang Zhong,†,‡ Liang Zhang,†,‡,§ David P. August,‡ George F. S. Whitehead,‡ David A. Leigh‡,§,* §School of Chemistry and Molecular Engineering, East China Normal University, 200062 Shanghai, China. ‡School of Chemistry, University of Manchester, Manchester M13 9PL, UK. ABSTRACT: We report on the stereoselective synthesis of trefoil knots of single topological handedness in up to 90 % yield (over two steps), through the formation of trimeric circular helicates from ligand strands containing either imine or, unexpectedly, amide chelating units and metal ion templates of the appropriate coordination character (zinc(II) for imines; cobalt(III) for amides). The coordination stereochemistry of the octahedral metal complexes is determined by asymmetric carbon centers in the strands, ultimately translating into trefoil knots that are a single enantiomer, both physically and in terms of their fundamental topology. Both the imine-zinc and amide-cobalt systems display self-sorting behavior, with racemic ligands forming knots that individually contain only building blocks of the same chirality. The knots and the corresponding trimeric circular helicate intermediates (Zn(II)3 complex for the imine ligands; Co(III)3 complex for the amide ligands) were characterized by NMR spectroscopy, mass spectrometry and X-ray crystallography. The latter confirms the trefoil knots as 84-membered macrocycles with each of the metal ions sited at a crossing point for three regions of the strand. The stereochemistry of the octahedral coordination centers impart alternating crossings of the same handedness within each circular helicate. The expression of chirality of the knotted molecules was probed by circular dichroism: the topological handedness of the demetallated knots was found to have a greater effect on the CD response than the Euclidean chirality of an individual chiral center.
INTRODUCTION Molecular knots and entanglements occur in some proteins,1 DNA,2 and spontaneously form in any polymers of sufficient length and flexibility.3 Most knots, including the trefoil4 (the simplest prime knot), are topologically chiral (i.e. the structure cannot be deformed—even ignoring the normal limits on bond lengths and angles—to superimpose on its mirror image without bonds breaking or passing through each other).5 Knot chirality has been utilized in asymmetric catalysis6 and could potentially be useful for other applications that depend on or exploit chirality (e.g. chiral recognition, chiral liquid crystal phases, nonlinear optics, etc.).7 However, although a number of synthetic strategies to racemic trefoil knots have been developed or discovered by chance,8 the resolution of their topological enantiomers9 or enantioselective synthesis6,10 remains rare. We recently described the efficient two-step synthesis of a racemic trefoil knot via a trimeric circular helicate based on a ligand strand containing pyrazine-imine units chelating to Zn(II) ions.8o We envisioned that by introducing stereogenic carbon centers close to the metal coordination sites, it might be possible to translate the point-chirality of amine building blocks (e.g. (S)-1 or (R)-1) into homochiral circular helicates in a similar manner to other supramolecular assemblies.11 Furthermore, by changing from imine to amide chelating groups (e.g. (S,S)-4 or (R,R)-4), the same basic ligand architecture might, in principle, be adaptable to a very different type of metal template, such as cobalt(III) ions. Achiral versions of similar amide building blocks have previously been found to form tetrameric, rather than trimeric, cyclic complexes.12 Accordingly, such a strategy could ultimately provide a route for the enantioselective synthesis of
topologically chiral knots and/or links that can bind to different types of metal ions.
RESULTS AND DISCUSSION
Trefoil knots of single handedness from homochiral cyclic complexes of imine ligands with zinc(II) ions Amine (S)-1 and its enantiomer (R)-1 were prepared in three steps from commercially available building blocks (see Supporting Information). A 2:1:1 mixture of (S)-1, pyrazine2,5-dicarbaldehyde and Zn(II) tetrafluoroborate in acetonitrile was heated at 60 °C for 24 hours. Recrystallization of the resulting product from dichloromethane and diethyl ether gave trimeric circular helicate -2 in 90 % yield (Scheme 1, step a). The symmetry of the 1H NMR spectrum of the isolated complex showed all of the six imine groups to be in equivalent environments (Figure 1c), which is only possible for a circular metal-ligand complex of single handedness (later confirmed by X-ray crystallography of the closed-loop trefoil knots to be -2 when starting from (R)-1, see Supporting Information). The size of the circular helicate was shown to be a trimer by electrospray ionization mass spectrometry (ESI-MS), indicating that whilst the sterics of the added point-chirality is sufficient to direct the handedness of helicity formed, methylation at the -position of the amine is not detrimental to the formation of a cyclic imine complex of the desired size.
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Scheme 1. Enantioselective synthesis of left-handed trefoil knot -3a
a Reagents and conditions: (a) Zn(BF ) ·H O, acetonitrile, 60 °C, 4 2 2 24 h, 90 %; (b) Hoveyda-Grubbs second generation catalyst, 1,2-dichloroethane/nitromethane (1:1), 60 °C, 48 h, 98 %.
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Journal of the American Chemical Society Figure 1. 1H NMR Spectra (600 MHz, 298 K, CD3CN) of (a) pyrazine-2,5-dicarbaldehyde; (b) amine (S)-1; (c) trimeric circular helicate -2; (d) trefoil knot -3. The signal assignments correspond to the labeling shown in Scheme 1.
To join the end groups of the cyclic helicate, olefin metathesis was carried out on -2 using the Hoveyda-Grubbs second generation catalyst in a 1:1 mixture of nitromethane and 1,2-dichloroethane at 60 °C (Scheme 1, step b). After 48 hours, the catalyst was quenched with ethyl vinyl ether and the trefoil knot -3 isolated by precipitation with diethyl ether in near-quantitative yield. 1H NMR confirmed the loss of the terminal alkene protons Hj (Figure 1d) and ESI-MS showed multiply-charged ions corresponding to [-3·(BF4)n](6-n)+ (n=24). Substituting (R)-1 for (S)-1 generated the enantiomeric trefoil knot, -3, in analogous fashion in 90 % overall yield for the two-step, nine-ligand-building-blocks-plus-three-metalions assembly process. The CD spectra of the metalcoordinated trefoil knot enantiomers -3 and -3 have exciton couplings of equal and opposite sign at 238, 298 and 312 nm, in line with their different handedness (Figure S24). Slow diffusion of diethyl ether into a 2 mM solution of 3 or -3 in acetonitrile afforded single crystals suitable for X-ray diffraction. The solid state structures confirmed the trefoil knot topology, with an -handed knot resulting from (S)-1 building blocks while (R)-1 generates the -handed knot. Each cyclized knotted ligand contains only E olefins and weaves an 84-atom-long continuous path around three zinc centers. When compared with a racemic trefoil knot with an achiral backbone,8o the addition of the methyl group at the position of the amine building blocks results in slightly longer Npy-Zn (2.10 vs 2.07) and Nimine-Zn (2.09 vs 2.07) bonds and larger Npz-Zn-Npz corner angles (79.4o vs 76.1o). Moreover, the substitution of a hydrogen atom for a methyl group on the CH2-CH2 bridge increases the Cb-Cc-C angles from 107.6° to 113.0°. Narcissistic self-sorting in the assembly of trefoil knots of single handedness from chiral amines, pyrazine-2,5dicarbaldehyde and zinc(II) ions Inspection of models indicates that a mismatch in the stereochemistry of any of the asymmetric carbon centers on the strand could not be tolerated by the metal-knot coordination complex, which leads to self-sorting behavior in the assembly process. A 1:1 mixture of (R)-1 and (S)-1 with pyrazine-2,5-dicarbaldehyde and Zn(II) tetrafluoroborate in acetonitrile at 60 °C for 24 hours gave a single set of 1H NMR signals corresponding to a 1:1 mixture of the zinc(II)3-trimeric circular helicate enantiomers -2 and -2 (Figure 2). The formation of mixed ligand helicates would result in diastereomers (Figure S19).
Figure 2. Narcissistic self-sorting of a 1:1 mixture of (R)-1 and (S)1 in the presence of Zn(II) (Zn(BF4)2·H2O, acetonitrile, 60 °C, 24 h). Only one major set of peaks, corresponding to zinc(II)3trimeric circular helicate 2, is observed by 1H NMR, indicating self-sorting of the enantiomeric building blocks during the assembly process. A small amount (
