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Chiroptical Inversion of Europium(III) Complexes by Changing a Remote Stereogenic Center of a C2-Symmetric Bispyrrolidinoindoline Manifold Tomoaki Taniguchi, Akira Tsubouchi, Yuki Imai, Junpei Yuasa, and Hiroki Oguri J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02550 • Publication Date (Web): 29 Nov 2018 Downloaded from http://pubs.acs.org on November 29, 2018

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The Journal of Organic Chemistry

Chiroptical Inversion of Europium(III) Complexes by Changing a Remote Stereogenic Center of a C2-Symmetric Bispyrrolidinoindoline Manifold Tomoaki Taniguchi,1 Akira Tsubouchi,1 Yuki Imai,2 Junpei Yuasa,2* and Hiroki Oguri1*

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Division of Applied Chemistry, Graduate School of Engineering, Tokyo University of Agriculture and Technology, 2-24-16 Nakacho, Koganei, Tokyo 184-8588, Japan 2

Department of Applied Chemistry, Tokyo University of Science, 1-3 Kagurazaka, Shinjuku, Tokyo 162-8601, Japan

E-mail: [email protected], [email protected]

Table of Contents

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ABSTRACT As an effort to integrate natural products chemistry and coordination chemistry, a diastereomeric pair of chiral alkaloidal manifolds composed of a bispyrrolidinoindoline (BPI) framework was designed and synthesized to generate luminescent EuIII complexes with switchable chiroptical properties. The C2-symmetric alkaloidal manifolds were linked with bis(benzimidazolyl)pyridine (BBIPy) as an achiral metal-binding component through substituents installed at the stereogenic 2/2’ positions of the BPI manifolds. The resulting diastereomeric pair of ligands, syn-L1 and anti-L2, allow pseudo-mirror symmetrical presentation of the metal-binding BBIPy units due to the stereogenic centers on the alkaloidal manifold. The ligand syn-L1 induces intramolecular coordination to form the 1:1 complex EuIII(syn-L1) composed of a single stranded metal helicate which exhibits a negative split Cotton effect. In contrast, the ligand anti-L2 led to a supramolecular assembly comprising the 2:2 complex EuIII2(anti-L2)2 consisting a bimetallic double-stranded helicate which shows a positive split Cotton effect. Thus, the sp3 stereogenic centers in the BPI manifolds play pivotal roles in controlling both metal-ligand equilibria and chirality-switching of luminescent EuIII complexes. This approach, which exploits diastereomeric natural product-based manifolds, provides a relatively unexplored means for diversifying metal coordination modes and for controlling the chiroptical properties of the resultant luminescent lanthanoid complexes.

INTRODUCTION Chiral lanthanoid complexes are of increasing importance in basic and applied research in photonics, materials chemistry, organic chemistry, and the biological sciences.1 There have been extensive efforts to control the chirality of metal complexes by judicious choice of the asymmetric ligand. Most of asymmetric ligands utilized to date possess either central or axis chirality in the vicinity of the metal binding sites in order to effectively induce asymmetric environments around the metal-ligand complexes.

To date, the research groups of Bünzli and Piguet,2 Gunnlaugsson,3

Hasegawa,1h,4 and Kawai5 have developed a variety of chiral lanthanoid complexes exhibiting valuable chiroptical properties (Figure 1).6 The pioneering research of Piguet and Bünzli on the supramolecular assembly of helical lanthanoid complexes exploited bis(benzimidazole)pyridine (BBIPy) as an achiral tridentate metal binding component.7 A series of dimeric,8 trimeric,9 and oligomeric10 ligands were generated by connecting molecules of the versatile monomeric component BBIPy with either simple methylene or aromatic linkages. Whilst several ligands with a central chirality proximal to the metal coordination site of the BBIPy unit have been reported,2b,11 natural product-based manifolds bearing C2-symmetry remain largely unexplored for the assembly of chiral lanthanoid complexes.


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In our attempts to interface functional lanthanoid (e.g., europium) metal complexes and designer natural product variants,12 we employed bispyrrolidinoindoline (BPI) 1 as a chiral alkaloidal manifold13 amenable to C2-symmetric presentation of BBIPy 2 as the achiral metal binding component. Our intensions is to control both the stoichiometries and the chiroptical properties of the resultant EuIII-ligand complexes. To this end, we herein report the design and synthesis of a diastereomeric pair of ligands, syn-L1 and anti-L2. The stereochemical differences at the 2/2’ positions induced dramatic changes in stoichiometry and chirality upon supramolecular assembly of the chiral EuIII complexes EuIII(syn-L1) and EuIII2(anti-L2)2. This approach exploiting the diastereomeric natural-product-based ligands syn-L1 and anti-L2 allowed control of both the metalligand equilibria and the chirality-switching of the resultant EuIII complexes by choosing readily accessible alkaloidal manifolds with distinct stereochemical configuration at the 2/2’ positions.


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Figure 1. (a) Representative chiral Eu complexes. (b) Diastereomeric chiral ligands (syn-L1 and anti-L2) composed of the BPI manifold bearing a pair of BBIPy units. Assemblies of the C2symmetric ligands syn-L1 and anti-L2 with Eu(NO3)3 ・6H2O, leading to the 1:1 complex EuIII(synL1) and the 2:2 complex EuIII2(anti-L2)2, together with plausible structures.


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RESULTS AND DISCUSSION Design of C2-symmetric ligands A family of biologically intriguing natural products, exemplified by (–)-ditryptophenaline (3) and (+)-WIN64821 (4),14 contain the C2-symmetric bispyrrolidinoindoline (BPI) scaffold 7 as a common structural motif (Figure 2a). As illustrated in Scheme 1, the C2-symmetric chiral BPI motif 7 can adopt conformers A and B through rotation of the central C-C bond connecting the vicinal quaternary carbon centers at the 3a/3a’ positions. Inspired by natural products 3 and 4, which possess distinct stereochemical relationships between the 2/2’ positions and the 3a/3a’ positions, we designed a diastereomeric pair of BPI manifolds (syn-5 and anti-6) by installing an ester group with syn and anti stereo-chemical relationships to the central C-C bond, respectively (Figure 2b).15 As shown in the schematic illustration of syn-8 and anti-9 in Scheme 1, installation of the ester substituent in the vicinity of the central C-C bond could impose conformational constraints on the rotational bond connecting the 3a and 3a’ positions. Stereochemical differences at the 2/2’ positions could thereby induce changes in the spatial orientations of the two BBIPy units comprising the metal binding component for EuIII ion. We sought to exploit these C2-symmetric chiral alkaloidal manifolds (syn-5 and anti-6) to control metal-ligand equilibria through supramolecular assembly. To this end, we took advantage of their biological compatibility for future applications, synthetic accessibility, and convenient manipulation of the preinstalled functional groups. We used tridentate BBIPy (2) as a binding component for EuIII ion in order to induce helical chirality upon complexation.2a,11 Connecting a pair of achiral BBIPy units to the chiral BPI manifolds syn-5 and anti-6 via amide bonds at the 2/2’ positions provided the two diastereomeric ligands syn-L1 and anti-L2. In this study, we verified the effects of the stereochemistries of syn-L1 and anti-L2 on supramolecular assemblies of these diastereomeric ligands binding with EuIII ion. Although the asymmetric carbon centers at the 2/2’ positions in the alkaloidal BPI manifolds are located relatively far from the metal binding components, we anticipated that asymmetric coordination of a pair of BBIPy units with the EuIII metal center would induce chirality in a different way, thereby allowing control of both the stoichiometry and the chiroptical properties of the resulting europium complexes.


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Figure 2. (a) Naturally occurring bispyrrolidinoindolines 3 and 4. (b) Design of a diastereomeric pair of BPI manifolds (syn-5 and anti-6). Scheme 1. Conformational changes of BPI scaffolds 7-9 through rotation of the central C–C bond connecting the vicinal quaternary carbon centers at the 3a/3a’ positions.


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Synthesis of the bis(benzimdazole)pyridine unit (20) We designed bis(benzimidazole)pyridine (BBIPy) 21 bearing a primary amino group at one end as an achiral metal-binding component to allow condensation with the chiral BPI manifolds (Scheme 2). The BBIPy unit was made soluble by installing n-butyl substituents at the N1 positions of two benzimidazole rings. The targeted BBIPy 21 was synthesized by modifying a previously reported protocol8b to connect the central segment, pyridine-2,6-dicarboxylic acid derivative 15, with the left and right segments of the o-nitro aniline derivatives, 11 and 14, respectively. The synthesis began with nucleophilic aromatic substitution of commercially available 4-chloro3-nitrotoluene 10 with n-butylamine giving 11 as the left segment (Scheme 2). The right segment 14 with phthalimide as a precursor of the primary amino group was synthesized in a similar manner, employing 12 with a primary alcohol in place of 10. Installation of the n-butylamine unit followed by Mitsunobu condensation reaction with phthalimide furnished 14. Mono-saponification of dimethyl pyridine-2,6-dicarboxylate 15 followed by treatment of the resultant 16 with thionyl chloride and subsequent condensation with the left segment 11 afforded 17. Basic hydrolysis of 17 and subsequent condensation reaction via an acyl chloride with the right segment 14 furnished 19 in 86% yield based on 18. Reduction of the nitro groups in 19 with sodium dithionite effected intramolecular condensation between the resulting aromatic amino and carbonyl groups of the amides to forge benzimidazole rings on both wings to give 20. The primary amino group was then liberated by treatment with hydrazine to provide BBIPy 21 in 73% yield.


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Scheme 2. Synthesis of bis(benzimidazolyl)pyridine (BPIPy) unit 21.

DIAD = diisopropyl azodicarboxylate.


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Scheme 3. Synthesis of the diastereomeric pair of ligands syn-L1 and anti-L2.

Boc = tert-butoxycarbonyl; DMAP = N,N’-dimethylaminopyridine; PPTS = pyridinium ptoluenesulfonate; NBS = N-bromosuccinimide; DPPE = 1,2-bis(diphenylphosphino)ethane; DMA = N,N-dimethylacetamide; LiHMDS = lithium hexamethyldisilazide; HATU = hexafluorophosphate azabenzotriazole tetramethyl uronium; DMF = N,N-dimethylformamide.

Synthesis of the C2-symmetric ligands syn-L1 and anti-L2 The diastereomeric ligands syn-L1 and anti-L2 were synthesized by condensations of BBIPy 21 with the chiral C2-symmetric BPI manifolds syn-5 and anti-6, as shown in Scheme 3. Employing a previously reported nickel-catalyzed reductive dimerization of pyrrolidinoindoline (23 → syn-24),16 we synthesized the BPI manifolds starting from L-tryptophan derivative 22. Stepwise protection of the two amino groups in 22 with Boc groups and subsequent cyclization by treatment with Nbromosuccinimide (NBS) in the presence of pyridinium p-toluenesulfonate (PPTS) as a Brønsted acid activator17 furnished the pyrrolidinoindoline skeleton 23 with incorporation of bromide at the benzylic position. Reductive dimerization of 23 in the presence of NiI2•6H2O (15 mol%), Mn (1.2 equiv.) in dimethylacetamide afforded the key precursor syn-24 in gram quantities (up to 70% ACS Paragon Plus Environment

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yields). Epimerization of syn-24 into anti-25 proceeded in good yield through generation of the lithium enolate by treatment with LiN(SiMe3)2 and subsequent protonation at the 2/2’ positions.17 Epimerization resulted in substantial changes in the chemical shifts of the methyl ester (3.68 ppm → 3.09 ppm), indicating the distinct orientations of the ester substituents installed at the 2/2’ positions. Hydrolysis of the methyl esters of syn-24 and anti-25 followed by condensation with BBIPy unit 21 with a primary amine afforded the corresponding amides syn-26 and anti-27. The tetra-N-Boc groups of syn-26 and anti-27 were then efficiently removed by treatment with trimethylsilyl iodide in acetonitrile to provide syn-L1 and anti-L2, respectively.

Complex formation between EuIII and syn-L1 X-ray structure analysis of syn-L1 and anti-L2 complexed with EuIII would aid characterization of these complexes; however, the conformational flexibility of syn-L1 and anti-L2 (Scheme 1), attributed primarily to rotamer isomerization, makes crystallization difficult. Hence, the ability of syn-L1 and anti-L2 to form complexes with EuIII was investigated by absorption and luminescence titration experiments (vide infra, Figure 3–5). We used europium(III) nitrate hexahydrate (Eu(NO3)3·5H2O) as a metal source to satisfy the coordination number (typically, n = 8–12) of EuIII in the resulting complexes (this study, n = 8), where one NO3– anion coordinates each EuIII core (vide infra, Figure 6). Addition of 0–4 equivalents of Eu(NO3)3 to an acetonitrile solution of syn-L1 (1.0 × 10-5 M) induced spectral changes in the absorption band of the BBIPy moiety (Figure 3a), indicating binding of EuIII to the BBIPy coordination site. Titration (Figure 3b) was followed at 355 nm as a function of the molar ratio ([EuIII]/[syn-L1]) and allowed estimation of the coordination stoichiometry between EuIII and the syn-L1 ligand. There are at least two breaks in the resulting titration curve (Figure 3b) at around [EuIII]/[syn-L1] = 1.0 and 2.0, and the isosbestic point shifts from 340 to 343 nm (Figure 3a, inset and Figure S1 in Supporting Information), suggesting multistep complex formation between EuIII and syn-L1 (Scheme 4a). Next, a luminescence titration experiment was conducted under the same conditions as used for the absorption titration experiment ([syn-L1] = 1.0 × 10-5 M). Titration of the syn-L1 ligand with EuIII results in 5D0 → 7F1–4 transition bands of EuIII (Figure 4a and 4b), clearly suggesting efficient photosensitization by the syn-L1 ligand for EuIII luminescence.18 Indeed, significant fluorescence quenching was observed during luminescence titration (Figure 4a, inset), where binding of EuIII to syn-L1 results in rapid intersystem-crossing of syn-L1.19 Titration curves were constructed by plotting the emission intensity at 618 nm due to the 5D0 → 7F2 transition of EuIII and that at 380 nm due to ligand fluorescence (red circles and blue triangles in Figure 4c, respectively). The ligand fluorescence intensity approaches zero at around [EuIII]/[syn-L1] = 1.0, and the EuIII emission intensity becomes essentially maximum. As the equivalents of EuIII ion increase in the range [EuIII]/[syn-L1] > 1.0, the ACS Paragon Plus Environment

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EuIII emission intensity begins to decrease and approaches a minimum value at around [EuIII]/[synL1] = 2.0. This observation indicates that the syn-L1 ligand predominantly forms a M1L1-type complex with EuIII at a molar ratio of [EuIII]/[syn-L1] = 1.0 (Scheme 4a), after which the M1L1-type complex coverts into M2L1-type complexes. Among these species, the M1L1-type complex is likely to be stable, because both of the trivalent BBIPy sites in syn-L1 coordinate EuIII affording stable eight coordination around the EuIII center with an additional divalent NO3– anion. The corresponding cationic species [EuIII(syn-L1)(NO3)2]+ and [EuIII(syn-L1)(NO3)]2+ were detected based on an ESI mass study of an equimolar mixture of syn-L1 and EuIII in acetonitrile. These observed major peaks (m/z = 1579.6193 and 758.8140) were unambiguously assigned by comparison with their calculated isotopic distributions (Figure S11, Supporting Information). Similarly, the formation of M2L1-type complex was confirmed by the detection of the corresponding dicationic species (m/z = 1918.5007 for [EuIII2(syn-L1)(NO3)4]2+, see Figure S12, Supporting Information). As previously described, these observations indicated that a pair of tridentate BBIPy units in syn-L1 coordinated to EuIII ion to generate an intramolecular chelate complex with a 1:1 molar ratio in acetonitrile solution.20 The energy minimized molecular model for the 1:1 complex shown in Figure 6 is consistent with both the ESI-mass analysis and the series of titration studies. It is difficult to exclude the possible involvement of other EuIII complexes with distinct compositions on the basis of the titration analyses (Figure 3), since the corresponding absorption spectral change is attributed mainly to electronic reorganization of the  system accompanied by conformational changes (trans, trans →

cis, cis) of each tridentate BBIPy ligand upon

complexation.21 Hence, further discussion of the primary species is currently not possible.


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Figure 3. (a) Variation in the absorption spectra observed during titration of syn-L1 (1.0 × 10-5 M) with Eu(NO3)3·5H2O in MeCN over the range [EuIII)/[syn-L1] = 0 – 4; inset: expansion around the isosbestic points at 340 nm for the range [EuIII]/[syn-L1] = 0 – 4. (b) Plot of absorption at 355 nm vs. [EuIII]/[syn-L1].


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Figure 4. (a) Emission spectra of syn-L1 around 618 nm (1.0 × 10-5 M in acetonitrile) (excited at  = 340 nm) during titration with Eu(NO3)3·5H2O in MeCN in the range [EuIII]/[syn-L1] = 0 – 1.0, and inset: emission spectra around 400 nm (excited at  = 309 nm). (b) Emission spectra of syn-L1 around 618 nm during titration with Eu(NO3)3·5H2O in MeCN in the range [EuIII]/[syn-L1] = 1.0 – 2.0, (c) Plots of emission intensities at 380 nm ( ▲ ) and 618 nm ( ● ) of syn-L1 as a function of [EuIII]/[syn-L1].


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Scheme 4. A plausible mechanism for the observed metal-ligand equilibria in acetonitrile solution.

(a) Ligand syn-L1 can form the 1:1 complex with induction of helical chirality resulting from the intramolecular binding of two BPPI units to an EuIII ion in the range [EuIII]/[syn-L1] < 1. (b) Interaction of ligand anti-L2 with EuIII is likely to generate the stable 2:2 complex almost exclusively in the presence of more than two equivalents of EuIII, in which intermolecular binding of the two BBPI units to an EuIII ion showed chiroptical properties oppositional to the intramolecular 1:1 complex formed by syn-L1.

Complex formation between Eu(III) and anti-L2 Using the same approach as for syn-L1, we studied the ability of anti-L2 to form complexes with EuIII based on titration experiments (absorption and luminescence spectra, Figure 5). Absorption titration of anti-L2 with Eu(NO3)3·5H2O gave spectral changes (Figure 5a) similar to those observed with syn-L1 (vide supra, Figure 3). The resulting titration curve shows a break at around a molar ratio of [EuIII]/[anti-L2] = 2.0 (inset of Figure 5a). Similarly, ligand fluorescence quenching (at 380 nm) was observed in the titration of anti-L2 with Eu(NO3)3·5H2O, with a concomitant increase in EuIII emission at the 5D0 → 7F1–4 transition bands (Figure 5b), indicating the photosensitization capability of the anti-L2 ligand for EuIII luminescence. Ligand fluorescence quenching was plotted against the molar ratio of [EuIII]/[anti-L2] in comparison with the ligand-sensitized EuIII emission at the 5D0 → 7F2 transition (at 618 nm) band (inset of Figure 5b, blue triangles and red circles, respectively).

Similar to EuIII/syn-L1 titration results, the ligand fluorescence of anti-L2 was

completely quenched at a molar ratio of [EuIII]/[anti-L2] = 1.0 (inset of Figure 5b, blue triangles). Furthermore, the intensity of the ligand-sensitized EuIII emission is essentially constant above a molar ratio of [EuIII]/[anti-L2] = 1.0, indicating that EuIII-anti-L2 complexes were the primary ACS Paragon Plus Environment

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species formed at higher molar ratios. Unfortunately, the corresponding UV/vis spectral changes do not allow determination of the exact stoichiometry of the resulting EuIII complexes, and thus the EuIII-anti-L2 complexes were further investigated by ESI mass spectrometry. Since ESI ionization is known to give very few fragmentation, observed major peaks likely correlate with the major EuIIIanti-L2 species bearing substantial stabilities in the solution.22 Major peaks at m/z = 1579.6168 corresponding to [EuIII2(anti-L2)2(NO3)4]2+ (a M2L2-type complex) can be detected in the ESI mass spectrum of an acetonitrile solution of anti-L2 and Eu(NO3)3·5H2O at a ratio of [Eu(III)]:[anti-L2] = 1:1 (Figure S13, Supporting Information). It should be noted that no appreciable ESI mass peak due to the 1:1 complex was detected in the ESI mass spectrum of EuIII-anti-L2. The 2:2 complex would be the more probable species in the [Eu(III)]/anti-L2 system, since neither rotamer A nor B (Scheme 1) arranges the two BBIPy ligands in close proximity suitable for formation of the M1L1-type complex. Conversely, association of the 2:2 complex allows favorable eight-coordination geometry for each Eu(III) center with additional coordination of NO3– anions (n = 6 + 2 = 8), as judged from the energy-minimized structure of EuIII2(anti-L2)2 (Figure 6). These results strongly suggested the formation of an intermolecular double helical complex as illustrated in Scheme 4b. Thus, the stereochemistries at the 2/2’ positions of the BPI skeleton played pivotal roles in determining the stoichiometries and the modes of coordination of the metal-ligand complexes.


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Figure 5. (a) Spectrophotometric titration of anti-L2 (1.0 × 10-5 M) with Eu(NO3)3·5H2O in MeCN over the range [EuIII]/[anti-L2] = 0 – 4; inset: plot of absorption at 355 nm vs. [EuIII]/[anti-L2]. (b) Emission spectra of anti-L2 around 618 nm (1.0 × 10-5 M in acetonitrile) (excited at  = 340 nm) during titration with Eu(NO3)3·5H2O in MeCN over the range [EuIII]/[anti-L2] = 0 – 2.2, inset (left): emission spectra around 400 nm (excited at  = 309 nm), inset (right) plots of emission intensity at 380 nm (▲) and 618 nm (●) of anti-L1 as a function of [EuIII]/[anti-L2].


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1:1 complex EuIII(syn-L1)

2:2 complex EuIII2(anti-L2)2 (b)

Figure 6. (a) Plausible structures for the EuIII complexes of the C2-symmetric ligands syn-L1 and anti-L2. with Eu(NO3)3·5H2O: upper for EuIII(syn-L1) and lower for EuIII2(anti-L2)2. Molecular models were constructed using Materials Studio with energy minimization. (b) Drawings for the modes of coordination around EuIII ion for EuIII(syn-L1) (left) and EuIII2(anti-L2)2 (right and middle). Hydrogen (white), carbon (gray), nitrogen (blue), oxygen (red), europium (light blue).


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Circular dichroism and circularly polarized luminescence spectroscopy studies Having elucidated the stoichiometries of the self-assembled complexes of syn-L1 and anti-L1 with EuIII ion in acetonitrile, we next verified the effects of the stereochemical differences at the 2/2’ positions on the chiroptical properties of the resultant EuIII complexes using CD (circular dichroism) and circularly polarized luminescence (CPL) spectroscopy. The measured samples were prepared by mixing europium(III) nitrate and either syn-L1 or anti-L2 (1.0 × 10-5 M) in a 1:1 ratio, affording the 1:1 complex EuIII(syn-L1) and the 2:2 complex EuIII2(anti-L2)2, respectively, in acetonitrile (vide supra). The acetonitrile solution of the 1:1 complex EuIII(syn-L1) showed strong CD absorptions (Figure 7a, red line) between 300 and 400 nm corresponding to the –* transition of BBIPy unit (Figure 7b) with an apparent negative split Cotton effect attributed to exciton coupling between the pair of tridentate BBIPy units in the 1:1 complex. In sharp contrast, the corresponding CD spectrum for the 2:2 complex EuIII2(anti-L2)2 exhibited a positive split Cotton effect (blue line). It should be noted that unbound (free) syn-L1 and anti-L2 exhibited only weak CD signals below 350 nm (Figure S14, Supporting Information). Hence, the observed biphasic CD signals indicate that the pair of BBIPy units are proximally positioned in asymmetric arrangements through complex formation with EuIII. More importantly, the 1:1 and 2:2 complexes showed pseudo mirror-symmetrical absorptions with a negative split Cotton effect (red line) for the 1:1 complex EuIII(syn-L1) and a positive split Cotton effect (blue line) for the 2:2 complex EuIII2(anti-L2)2, suggesting that the tridentate BBIPy units coordinate to EuIII metal with opposite helicities. Whilst X-ray analysis of the two EuIII complexes to elucidate their structures including their absolute configurations has been unsuccessful to date, the sp3 stereogenic centers at the 2/2’ positions were demonstrated to induce drastic changes to the stoichiometries of the metal-ligand complexes with distinct coordination modes.23 These changes could induce helicity inversion of the BBIPy units upon complexation with EuIII to form either single-stranded or double-stranded helicates.


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Figure 7. CD spectra (a) and absorption spectra (b) of EuIII complexes of syn-L1 (red) and anti-L2 (blue) with an equimolar amount of Eu(NO3)3 in acetonitrile ([L] = 1.0 × 10-5 M).

Conversely, the helicity of the BBIPy units should effectively induce a chiral environment around the metal center of the 1:1 complex EuIII(syn-L1) and the 2:2 complex EuIII2(anti-L2)2. Hence, dissymmetry factors (glum)24 of the EuIII complexes were measured at the 5D0 → 7F1 (magnetic dipole) transition band, which often gives particularly large circular polarization25 due to satisfying the magnetic-dipole selection rule, ΔJ = 0, ± 1 (except 0 ↔ 0). The complexes EuIII(syn-L1) and EuIII2(anti-L2)2 exhibited relatively large glum values with opposite signs: +0.44 (em = 593 nm) and 0.24 (em = 591 nm), respectively. These results demonstrate that the changes in stereochemistry at the 2/2’ positions (2R for syn-L1, and 2S for anti-L2) can invert the sign of the chiral optical properties of the resulting EuIII complexes. The chiral complex [EuIII(syn-L1)] showed a larger dissymmetry factor (+0.44) than that of [EuIII2(anti-L2)2(NO3)6] (-0.24). The observed substantial difference in luminescence dissymmetry factor supports distinct coordination modes between the two EuIII-ligand complexes. A pioneering achievement by Piguet and Bünzli8a showed that ditopic hexa-coordinate ligands consisting of two BBIPy components connected through a flexible methylene group can assemble into triple-stranded bimetallic helicates with EuIII ion. In contrast, employment of rigid phenylene linkers instead of a flexible methylene group resulted in the formation of single-stranded dimetallic ACS Paragon Plus Environment

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complexes, similar to the 2:1 complex [EuIII2(syn-L1)] formed in the range [EuIII]/[syn-L1] > 1.0.11,8d,8e In comparison to the previously reported ditopic hexa-coordinate ligands bearing two BBIPy components, the present approach employing the ligands syn-L1 and anti-L2 displaying a pair of BBIPy units on C2-symmetric BPI manifolds has notable features. First, the ligand syn-L1 allowed formation of the 1:1 complex EuIII(syn-L1) through intramolecular coordination of the two BBIPy units to a single EuIII ion in the range [EuIII]/[syn-L1] < 1.0. Second, the ligand anti-L2 enabled generation of the 2:2 complex EuIII2(anti-L2)2 forming a double-stranded bimetallic helicate. As described above, most of previously reported approaches sought to generate bimetallic europium triple-stranded helicates, whereas our approach allowed formation of chiral EuIII complexes with unique stoichiometries and binding geometries. Furthermore, the resulting two complexes, the intramolecular monometallic EuIII(syn-L1) helicate and the double-stranded EuIII2(anti-L2)2 helicate, showed pseudo enantiomeric chiral optical properties. Notably, the stereochemistries at the 2/2’ positions modulated the rotational behaviors of the central C-C bonds in syn-L1 and anti-L2 as anticipated (Scheme 1), thereby inducing drastic changes in the stoichiometries as well as inversion of the signs of the helical chiralities in the resulting EuIII complexes. To our knowledge, the current study provides an unprecedented example of controlling the chirality of luminescent EuIII complexes composed of BBIPy units. Thus, this approach employing a diastereomeric pair of C2-symmetric alkaloidal manifolds could offer a relatively unexplored but effective means to diversify the coordination modes between the EuIII ion and tridentate ligands allowing the switching of their chiroptical properties.

CONCLUSION In summary, we designed and synthesized a diastereomeric pair of C2-symmetric chiral ligands (syn-L1 and anti-L2) bearing distinct stereochemistries at the 2/2’ positions of alkaloidal BPI manifolds (syn-5 and anti-6b) for different spatial arrangements of the two BBIPy units. Whilst intramolecular coordinations of the two BBIPy components with EuIII ion generated the luminescent 1:1 complex EuIII(syn-L1), supramolecular assembly of anti-L2 led to the formation of the luminescent 2:2 complex EuIII2(anti-L2)2 composed of a double-stranded bimetallic helicate. Depending on the stereochemistry at the 2/2’ positions of the ligands, the resulting EuIII complexes exhibited opposite signs, both in the split Cotton effects in the CD spectra and in the glum values obtained by CPL. In the absence of europium metal, the ligands mainly adopt an extended conformation, in which the pair of metal coordinating BBIPy units are distant from each other. In contrast, upon complex formation, the six nitrogen atoms effectively bring the two BBIPy units into ACS Paragon Plus Environment

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close proximity, accompanied by dynamic conformational changes of the chiral alkaloidal BPI manifolds. More importantly, we have demonstrated that the chiralities of the resulting luminescent EuIII complexes generated through the asymmetric coordination of two BBIPy units are clearly dependent on the central chiralities despite the relatively distant location of the 2/2’ positions from the metal coordination sites. Finally, the natural product-based manifolds have remained largely unexploited in the field of chiral lanthanoid complexes. Given the untapped potentials of natural product-based manifolds bearing precise and modifiable molecular recognition capabilities,26 integration of coordination chemistry and natural products chemistry could offer new opportunities for the development of functional lanthanoid complexes.

EXPERIMENTAL SECTION General Information. All reactions were performed under a nitrogen atmosphere unless otherwise specified. NMR spectra were recorded on JEOL AL300 (1H/300 MHz, 13C/75 MHz), JEOL ECA400 (1H/400 MHz,

13C/100

MHz), and JEOL ECA500 (1H/500 MHz,

13C/125

MHz) spectrometers.

Chemical shifts are reported in δ (ppm) using chloroform as an internal standard of 7.26 for 1H and 77.16 for

13C

NMR. Acetonitrile (δ 1.94 for 1H and 118.26 for

2.50 for 1H and 39.52 for

13C

13C

NMR), dimethyl sulfoxide (δ

NMR), and methanol (δ 4.78 for 1H and 36.07 for

13C

NMR) were

used as internal standards in certain cases. Data for 1H NMR are reported as follows: chemical shift (number of hydrogens, multiplicity, coupling constant). Multiplicity is abbreviated as follows: s (singlet), d (doublet), t (triplet), q (quartet), q (quintet), m (multiplet), br (broad). UV-VIS spectra were measured on a JASCO V-600 spectrometer. Fluorescence spectra were recorded on JASCO FP-6500. CD and CPL spectra were recorded by JASCO J-725 and a homemade CPL spectroscopy system, respectively.5d,5f ESI-Mass spectra were recorded on Bruker Daltonics micrOTOF-QII. GPC was performed for purification by JAI LC-9110II (GPC), if necessary. Reaction were monitored by thin layer chromatography using Merck Millipore TLC Silica gel F254 plates (0.25 mm) which were visualized using UV light, p-anisaldehyde stain, PMA (phosphomolybdic acid) stain, ninhydrin stain. Flash column chromatography was performed using Kanto Silica Gel 60N. Spectrometric Measurements In practice, aliquots of stock solutions of Eu(NO3)3 (2.0 × 10–3 M) in acetonitrile were added to a cuvettes containing an acetonitrile solution of syn-L1 or anti-L2 (1.0 × 10–5 M) and the absorption and emission spectra of the mixed solutions were recorded. CD spectra of syn-L1 and anti-L2 were measured in a similar manner as described above.


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Synthesis of Bis(benzimidazolyl)pyridine Moiety 21 N-Butyl-4-methyl-2-nitroaniline (11): A mixture of 4-chloro-3-nitrotoluene (10) (1.71 g, 10.0 mmol) and butylamine (10.0 mL, 102 mmol) was heated at 92 °C for 4 days. The resulting mixture was concentrated in vacuo to give crude 11 (2.19 g, 10.5 mmol, quant.) as an orange oil, which was used for the next reaction without further purification. 11: 1H-NMR (500 MHz, CDCl3): δ 7.91 (2H, s), 7.22 (1H, d, J = 8.6 Hz), 6.73 (1H, d, J = 8.6 Hz), 3.27–3.23 (2H, m), 2.22 (3H, s), 1.70–1.64 (2H, m), 1.49–1.41 (2H, m), 0.96 (3H, t, J = 7.5 Hz);

13C{1H}-NMR

(125 MHz, CDCl3): δ 144.0,

137.8, 131.3, 126.0, 124.5, 113.8, 42.8, 31.1, 20.3, 20.1, 19.9, 13.8. HRMS (ESI, m/z): calcd. for C11H17N2O2+, [M+H]+ 209.1285; found, 209.1295. 2-(4-(butylamino)-3-nitrobenzyl)isoindoline-1,3-dione

(14):

A

mixture

of

(4-chloro-3-

nitrophenyl)methanol (12) (2.50 g, 13.3 mmol) and butylamine (14.0 mL, 144 mmol) was heated under reflux for 36 h. Excess butylamine was removed in vacuo. After treatment with aqueous solution of ammonium chloride, the mixture was extracted with CH2Cl2. The separated organic layer was washed with brine, dried over Na2SO4. Filtration and concentration in vacuo afforded crude [3nitro-4-(propylamino)phenyl]methanol (13) (3.04 g). The resulting 13 was used without further purifications. To a solution of 13, phthalamide (2.75 g, 18.7 mmol) and triphenylphosphine (4.92 g, 18.8 mmol) in THF (157 mL) was added diisopropyl azodicarboxylate (DIAD) (36.8 mL, 18.7 mmol) at room temperature. After being stirred for 12 h at room temperature, the resulting mixture was then treated with water and extracted with CH2Cl2. The separated organic layer was washed with H2O, dried over Na2SO4. After filtration and concentration, the residue was purified by silica gel chromatography (hexane/EtOAc) to afford 14 (1.28 g, 3.62 mmol, 27% in 2 steps) as an orange solid, mp 109–110 ºC. 14: 1H-NMR (400 MHz, CDCl3): δ 8.23 (1H, d, J = 2.3 Hz), 8.02 (1H, br t, J = 5.2 Hz), 7.85–7.81 (2H, m), 7.72–7.68 (2H, m), 7.52 (1H, dd, J = 8.7, 2.3 Hz), 6.79 (1H, d, J = 8.7 Hz), 4.73 (2H, s), 3.26 (2H, dt, J = 5.2, 7.0 Hz), 1.71–1.63 (2H, m), 1.48–1.39 (2H, m), 0.95 (3H, t, J = 7.3 Hz); 13C{1H}-NMR (100 MHz, CDCl3): δ 168.1, 145.3, 137.0, 134.2, 132.1, 131.3, 127.1, 123.5, 123.3, 114.4, 42.9, 40.6, 31.0, 20.3, 13.8. HRMS (ESI, m/z): calcd. for C19H20N3O4+, [M+H]+ 354.1448; found, 354.1434. 6-(Methoxycarbonyl)picolinic acid (16):27 To a solution of dimethyl pyridine-2,6-dicarboxylate (15) (6.00 g, 30.7 mmol) in MeOH (30 mL) was added an almost saturated solution of KOH (1.72 g, 30.7 mmol) dissolved in a minimal amount of H2O at room temperature. The mixture was stirred for 14 h and then concentrated under reduced pressure. The resulting mixture was diluted with H2O and washed with CH2Cl2. The aqueous layer was acidified with 1 M HCl and the extracted with EtOAc. The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo to give monoester 16 (3.57 g, 19.7 mmol, 64%) as a white solid, which was used without further


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purification. 16: 1H-NMR (300 MHz, CDCl3): δ 8.43 (1H, dd, J = 7.8, 1.2 Hz), 8.37 (1H, dd, J = 7.8, 1.2 Hz), 8.13 (1H, t, J = 7.8 Hz), 4.04 (3H, s). Methyl 6-(butyl(4-methyl-2-nitrophenyl)carbamoyl)picolinate (17): The monoester 16 (1.12 g, 6.18 mmol) was placed in a flask and then thionyl chloride (9.00 mL, 124 mmol) and DMF (2 drops) were added at room temperature. The mixture was heated under reflux for 30 min and then concentrated in vacuo. The resulting residue containing the acid chloride was dissolved in CH2Cl2 (17 mL) and then treated with a solution of the crude 11 (1.45 g, 6.96 mmol) and triethylamine (2.16 mL, 15.5 mol) in CH2Cl2 (14 mL). After being refluxed for 12 h, the mixture was concentrated in vacuo. The residue was treated with aqueous solution of ammonium chloride and extracted with CH2Cl2. The combined organic extracts were washed with H2O, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (CH2Cl2/MeOH) to give 17 (2.27 g, 6.11 mmol, 99%) as a yellow oil. 17 (ratio of rotamer = 87:13): 1H-NMR

(400 MHz, CDCl3; major rotamer): δ 8.01 (1H, dd, J = 7.8, 1.4 Hz), 7.92 (1H, dd, J = 8.2,

0.9 Hz), 7.80 (1H, dd, J = 8.2, 7.8 Hz), 7.77 (1H, d, J = 1.4 Hz), 7.34 (1H, dd, J = 8.2, 1.4 Hz), 7.26 (1H, d, J = 8.2 Hz), 4.15 (1H, ddd, J = 13.5, 10.2, 5.9 Hz), 3.81 (3H, s), 3.56 (1H, ddd, J = 13.5, 10.1, 5.9 Hz), 2.40 (3H, s), 1.70–1.53 (2H, m), 1.42–1.29 (2H, m), 0.91 (3H, t, J = 7.3 Hz); 13C{1H}NMR (100 MHz, CDCl3; major isomer): δ 166.2, 165.1, 153.0, 145.7, 145.6, 138.8, 137.9, 135.1, 134.5, 132.0, 127.8, 125.9, 125.7, 52.5, 51.3, 29.5, 21.0, 20.4, 14.0. HRMS (ESI, m/z): calcd. for C19H22N3O5+, [M+H]+ 372.1554; found, 372.1551. 6-[N-Butyl-N-(4-methyl-2-nitrophenyl)carbamoyl]picolinic acid (18): To a solution of 17 (2.27 g, 6.11 mmol) in THF (20 mL) was added a solution of LiOH·H2O (1.28 g, 30.6 mmol) in a mixture of MeOH (52 mL) and H2O (13 mL) dropwise at 0 °C. After being stirred at 0 °C for 4 h. The mixture was then acidified (pH 2) by treatment with 1 M HCl. The volatiles were removed under reduced pressure. The resulting aqueous phase was extracted with CH2Cl2. The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo to afford crude 18 (2.03 g, 5.58 mmol, 93%) as an orange oil. 18:1H-NMR (400 MHz, CDCl3): δ 8.17 (1H, dd, J = 7.8, 1.2 Hz), 8.10 (1H, dd, J = 7.8, 1.2 Hz), 7.98 (1H, dd, J = 7.8, 7.8 Hz), 7.66 (1H, d, J = 1.4 Hz), 7.41 (1H, dd, J = 8.2, 1.4 Hz), 7.27 (1H, d, J = 8.2 Hz), 4.10 (1H, dt, J = 14.2, 7.9 Hz), 3.65 (1H, dt, J = 14.2, 7.9 Hz), 2.42 (3H, s), 1.67–1.60 (2H, m), 1.42–1.33 (2H, m), 0.94 (3H, t, J = 7.6 Hz);

13C{1H}-NMR

(100

MHz, CDCl3): δ 165.2, 163.3, 151.8, 146.6, 143.9, 140.3, 139.6, 134.6, 134.2, 130.8, 129.3, 125.8, 125.0, 51.7, 29.5, 21.1, 20.4, 13.9. HRMS (ESI, m/z): calcd. for C18H20N3O5+, [M+H]+ 358.1397; found, 358.1393. N2,N6-Dibutyl-N2-[4-(1,3-dioxoisoindolin-2-yl)methyl-2-nitrophenyl]-N6-(4-methyl-2nitrophenyl)pyridine-2,6-dicarboxamide (19): To a solution of 18 (997 mg, 2.79 mmol) in CH2Cl2 (7 mL) was added thionyl chloride (2.02 mL, 27.8 mmol) and DMF (two drops) at room ACS Paragon Plus Environment

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temperature. The mixture was heated under reflux for 1.5 h and then concentrated in vacuo. The residue was dissolved in CH2Cl2 (4 mL) and then treated dropwise with a mixture of 14 (1.10 g, 3.11 mmol) and triethylamine (0.58 mL, 4.2 mmol) in CH2Cl2 (4 mL) at room temperature. After being heated under refluxed for 3 h, the mixture was then cooled to room temperature, stirred for 12 h and the concentrated in vacuo. The residue was treated with aqueous solution of NH4Cl and extracted with CH2Cl2. The combined organic extracts were dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography (CH2Cl2/MeOH = 100/4) to give 19 (1.61 g, 2.32 mmol, 83%) as a yellow solid, mp 111–114 ºC. 19: 1H-NMR (400 MHz, DMSO-d6): δ 8.06–6.48 (13H, m), 4.94–4.78 (2H, m), 4.17–3.04 (4H, m), 2.47–2.26 (3H, m), 1.65–1.05 (8H, m), 0.98–0.52 (6H, m). The NMR spectra showed broad and complex signals even at elevated temperature (up to 90 °C in DMSO-d6 , see supporting information) due to a mixture of rotamers. HRMS (ESI, m/z): calcd. for C37H37N6O8+, [M+H]+ 693.2667; found, 693.2656. 2-{{1-Butyl-2-[6-(1-butyl-5-methyl-1H-benzo[d]imidazol-2-yl)pyridin-2-yl]-1Hbenzo[d]imidazol-5-yl}methyl}isoindoline-1,3-dione (20):7c To a suspension of Na2S2O4 (2.83 g, 16.3 mmol) in EtOH (7 mL) were added 19 (1.36 g, 1.96 mmol) and DMF (7 mL) successively at room temperature. The mixture was heated at 85 °C for 5 min, then warmed up to at 100 °C, and stirred for 24 h at the same temperature. After being cooled to room temperature, the mixture was concentrated in vacuo. The residue was treated with aqueous solution of NH4Cl and extracted with Et2O and CH2Cl2. Combined organic extracts were dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography (hexane/EtOAc = 1/2) to give 20 (0.444 g, 0.744 mmol, 38%) as a colorless oil. 20: 1H-NMR (400 MHz, CDCl3): δ 8.308.25 (2H, m), 8.02 (1H, dd, J = 8.0, 8.0 Hz), 7.91 (1H, s), 7.87–7.82 (2H, m), 7.72–7.67 (2H, m), 7.63 (1H, s), 7.46 (1H, dd, J = 8.3, 1.6 Hz), 7.38 (1H, d, J = 8.3 Hz), 7.33 (1H, d, J = 8.3 Hz), 7.17 (1H, dd, J = 8.3, 1.4 Hz), 5.02 (2H, s), 4.69 (2H, t, J = 7.3 Hz), 4.67 (2H, t, J = 7.3 Hz), 2.51 (3H, s), 1.73–1.62 (4H, m), 1.12–1.02 (4H, m), 0.68 (3H, t, J = 7.3 Hz), 0.67 (3H, t, J = 7.3 Hz); 13C{1H}-NMR (100MHz, CDCl3): δ 168.2, 150.9, 150.2, 150.0, 143.2, 143.0, 138.2, 136.0, 134.5, 134.1, 132.5, 132.3, 131.3, 125.6, 125.5, 125.2, 124.4, 123.4, 120.3, 120.1, 110.6, 110.0, 44.8, 44.7, 41.9, 32.2, 21.7, 19.9, 13.60, 13.57. HRMS (ESI, m/z): calcd. for C37H37N6O2+, [M+H]+ 597.2973; found, 597.2977. {1-Butyl-2-[6-(1-butyl-5-methyl-1H-benzo[d]imidazol-2-yl)pyridin-2-yl]-1H-benzo[d]imidazol5-yl}methylamine (21): A mixture of 20 (4.34 g, 7.27 mmol) and hydrazine hydrate (3.00 ml, 72.7 mmol) in EtOH (80 mL) was heated at 65 °C for 24 h. The resultant white solid was filtered off through a Celite pad and washed with toluene. The filtrate was concentrated in vacuo to give 21 (2.48 g, 5.31 mmol, 73%) as a pale yellow solid, mp 76–78 ºC, which was used without further purification. 21: 1H-NMR (500 MHz, CDCl3): δ 8.28–8.24 (2H, m), 8.01 (1H, dd, J = 8.0, 8.0 Hz), 7.78 (1H, s), 7.64 (1H, s), 7.39 (1H, d, J = 8.0 Hz), 7.34 (1H, d, J = 8.5 Hz), 7.35–7.33 (1H, m), 7.18 (1H, dd, J = 8.5, 1.5 Hz), 4.69 (2H, t, J = 7.5 Hz), 4.68 (2H, t, J = 7.5 Hz), 4.05 (2H, s), 3.52 (2H, br ACS Paragon Plus Environment

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s), 2.52 (3H, s), 1.72–1.64 (4H, m), 1.12–1.04 (4H, m), 0.683 (3H, t, J = 7.5 Hz), 0.681 (3H, t, J = 7.5 Hz); 13C{1H}-NMR (125 MHz, CDCl3): δ 150.7, 150.2, 149.9, 143.2, 143.0, 138.3, 135.6, 134.5, 132.6, 125.6, 125.5, 125.2, 123.6, 120.1, 118.9, 110.6, 110.1, 46.5, 44.8, 44.7, 32.2, 21.8, 20.0, 13.63, 13.62. HRMS (ESI, m/z): calcd. for C29H35N6+, [M+H]+ 467.2918; found, 467.2917.

Preparation of Ligands syn-L1 and anti-L2 1,8-Di-tert-butyl 2-methyl (2S,3aR,8aR)-3a-bromo-2,3,3a,8a-tetrahydropyrrolo[2,3-b]indole1,2,8-tricarboxylate (23):16 To a mixture of L-tryptophane methyl ester hydrochloride (22) (10.0 g, 39.4 mmol), THF (160 mL), and H2O (80 mL) was added Na2CO3 (36.7 g, 346 mmol) portionwise at room temperature. After being stirred for 15 min, di-tert-butyl dicarbonate (18.9 g, 86.7 mmol) was added dropwise, and the resulting mixture was stirred for 1 h at room temperature. The reaction was diluted with H2O and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue containing mono N-Boc tryptophane methyl ester was dissolved in THF (120 mL) and then treated with DMAP (N,Ndimethylaminopyridine) (962 mg, 7.87 mmol) at 0 °C . After being stirred for 15 min at 0 °C, the mixture was treated with H2O and extracted with EtOAc. Combined organic extracts were washed with H2O, 1M HCl, saturated aqueous solution of Na2CO3, and brine, and then dried over Na2SO4. Filtration and concentration in vacuo gave the crude Boc-Try(Boc)-OMe14 (16.9 g), which was used without further purification. 1H-NMR (300 MHz, CDCl3): δ 8.11 (1H, br d, J = 6.8 Hz), 7.48 (1H, d, J = 7.7 Hz), 7.39 (1H, br s), 7.33–7.28 (1H, m), 7.25–7.20 (1H, m), 5.12 (1H, br d, J = 7.9 Hz), 4.68–4.62 (1H, m), 3.69 (3H, s), 3.26 (1H, dd, J = 14.8, 5.6 Hz), 3.17 (1H, dd, J = 14.8, 5.6 Hz), 1.66 (9H, s), 1.43 (9H, s). To a solution of the crude Boc-Try(Boc)-OMe (16.9 g) in CH2Cl2 (380 mL) were successively added PPTS (10.2 g, 40.5 mmol) and NBS (7.21 g, 40.5 mmol) at room temperature. After being stirred for 1 h at room temperature, the resulting mixture was treated with brine. The organic layer was separated, washed with aqueous solutions of NaHCO3, Na2SO3, and brine, and dried over Na2SO4.

After filtration and concentration in vacuo, the residue was purified by silica gel

chromatography (Hexane/EtOAc = 4/1) to afford 23 (16.3 g, 32.8 mmol, 83 % in 3 steps) as a white solid. 1H-NMR (300 MHz, CDCl3): δ 7.55 (1H, br s), 7.37–7.29 (2H, m), 7.12 (1H, dd, J = 8.1, 7.4 Hz), 6.40 (1H, s), 3.89 (1H, dd, J = 10.4, 6.3 Hz), 3.75 (3H, s), 3.21 (1H, dd, J = 12.6, 6.3 Hz), 2.82 (1H, dd, J = 12.6, 10.4 Hz), 1.59 (9H, s), 1.40 (9H, br s). Preparation of syn-24:16 A mixture of tertiary benzylic bromide 24 (6.00 g, 12.1 mmol), DPPE (721 mg, 1.81 mmol), NiI2 •6H2O (761 mg, 1.81 mmol, 15 mol%) in DMA (9.8 mL) was degassed by four cycles of gentle pumping and argon replacement. After addition of manganese (762 mg, ACS Paragon Plus Environment

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13.9 mmol), the mixture was then degassed by the four cycles in an almost identical manner. The mixture was then allowed to be stirred for 14 h at room temperature under argon. The mixture was diluted with EtOAc, treated with 1 M HCl and then extracted with EtOAc. The organic extracts was washed with 1 M HCl, H2O, saturated aqueous solution of Na2SO3, and brine and then dried over Na2SO4, filtered and concentrated in vacuo. During the concentration, white solid was precipitated and filtered off.

The filtrate was concentrated and purified by silica gel chromatography

(Hexane/EtOAc) to give syn-24 (3.51 g, 42.2 mmol, 70%) as a white solid, mp 199–200 ºC.

1H-

NMR (400 MHz, DMSO-d6, 95 °C): δ 7.37 (2H, d, J = 8.0 Hz), 7.21–7.11 (4H, m), 6.91 (2H, m), 6.09 (2H, s), 3.70 (2H, m), 3.68 (6H, s), 2.64 (2H, dd, J = 12.7, 7.0 Hz), 2.25 (2H, dd, J = 12.7, 9.5 Hz), 1.57 (18H, s), 1.33 (18H, s). Preparation of anti-25: To a stirred solution of syn-24 (3.21 g, 3.84 mmol) in THF (76 mL) was added lithium bis(trimethylsilyl)amide (1.0 M in THF, 23.0 mL, 23.0 mmol) dropwise at 0 ºC. The mixture was stirred for 1 h at the same temperature, and then cooled to -78 ºC. The resulting lithium enolate was then protonated by dropwise treatment with MeOH (35 mL). The resulting mixture was allowed to warmed up to room temperature and treated with a saturated aqueous solution of NH4Cl. The mixture was concentrated to one fourth of the initial volume under reduced pressure and then extracted with CHCl3. The combined organic extracts were dried over Na2SO4, filtered, concentrated in vacuo, and purified by silica gel chromatography (hexane/EtOAc) to afford anti-25 (2.94 g, 3.54 mmol, 92%) as a white amorphous, mp 136–141 ºC. anti-25: 1H-NMR (500 MHz, DMSO-d6, 90 ºC): δ 7.32 (2H, d, J = 8.0 Hz), 7.10–7.07 (4H, m), 6.79 (2H, t, J = 7.4 Hz), 6.14 (2H, s), 4.57 (2H, d, J = 9.2 Hz), 3.09 (3H, s), 2.84 (2H, dd, J = 12.9, 9.5 Hz), 2.53–2.49 (2H, m), 1.56 (18H, s), 1.41 (18H, s);13C{1H}-NMR (75 MHz, DMSO-d6, 90 ºC): δ 170.0, 152.0, 150.8, 142.5, 130.3, 128.5, 123.0, 121.7, 115.5, 80.6, 79.6, 78.5, 58.6, 58.3, 50.8, 35.7, 27.5. HRMS (ESI, m/z): calcd. for C44H58N4NaO12+, [M+Na]+ 857.3949; found, 857.3961. Preparation of syn-L1: (1) Saponification of syn-24. A mixture of syn-24 (800 mg, 0.962 mmol), H2O (9.8 mL), and MeOH (6.5 mL) in THF (13 mL), was added lithium hydroxide monohydrate (808 mg, 19.2 mmol) at 0 ºC. The resulting mixture was stirred for 15 min at 0 ºC and then warmed up to at room temperature, After being stirred for 20 h, the mixture was acidified (pH < 3) with 1 M HCl and extracted with CHCl3. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give crude carboxylic acid syn-5 (817 mg) as a white solid, which was used for the next reaction without further purification: 1H-NMR (500 MHz, CD3OD, 50 ºC): δ 7.38 (2H, br s), 7.16–7.13 (4H, m), 6.94–6.91 (2H, m), 6.31 (2H, s), 3.73–3.68 (2H, m), 2.61 (2H, br s), 2.47–2.43 (2H, m), 1.62 (18H, s), 1.38 (18H, s); 13C{1H}-NMR (125 MHz, CD3OD, 50 ˚C): δ 175.5, 153.4, 143.2, 132.4, 130.4, 125.2, 124.2, 118.1, 83.4, 82.5, 80.7, 68.8, 60.4, 59.7, 36.5, 28.7, 28.4. ACS Paragon Plus Environment

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(2) Condensation with bis(benzimidazolyl)pyridine component 21: To a mixture of the crude carboxylic acid syn-5 (549 mg), the BBIPy component 21 (952 mg, 0.680 mmol), and HATU (1.03 g, 2.72 mmol) in DMF (4 mL), was added iPr2NEt (0.47 mL, 2.72 mmol). After being stirred for 20 h at room temperature, the resulting mixture was treated with H2O and extracted with CH2Cl2. Combined organic extracts were washed with saturated aqueous solution of NaHCO3 and H2O, dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography (EtOAc/MeOH) to give syn-26 (888 mg, 0.521 mmol, 81% in 2 steps) as an off-white solid, mp 206–207 ºC. syn-26: 1H-NMR

(500 MHz, DMSO-d6, 90 ºC): δ 8.27–8.22 (6H, m), 8.15 (2H, dd, J = 7.7, 7.7 Hz), 7.69

(2H, s), 7.60 (2H, d, J = 8.0 Hz), 7.53 (2H, s), 7.52 (2H, d, J = 8.0 Hz), 7.33 (2H, d, J = 8.0 Hz), 7.29 (2H, d, J = 8.0 Hz), 7.16 (4H, d, J = 8.0 Hz), 7.07 (2H, dd, J = 8.0, 8.0 Hz), 6.83 (2H, dd, J = 8.0, 8.0 Hz), 6.25 (2H, s), 4.70 (4H, t, J = 7.5 Hz), 4.69 (4H, t, J = 7.5 Hz), 4.48 (2H, dd, J = 14.5, 5.7 Hz), 4.42 (2H, dd, J = 14.5, 5.7 Hz), 3.80 (2H, dd, J = 9.2, 6.9 Hz), 2.61 (2H, dd, J = 12.6, 6.9 Hz), 2.52 (2H, dd, J = 12.5, 9.2 Hz), 2.46 (6H, s), 1.68–1.61 (8H, m), 1.59 (18H, s), 1.26 (18H, s), 1.131.03 (8H, m), 0.64 (6H, t, J = 7.2 Hz), 0.63 (6H, t, J = 7.2 Hz);

13C{1H}-NMR

(125 MHz,

DMSO-d6, 90 ºC): δ 170.8, 151.7, 150.6, 149.6, 149.4, 149.3, 149.2, 142.4, 142.1, 141.3, 137.8, 134.9, 134.0, 132.9, 131.4, 131.0, 128.2, 124.6, 124.3, 123.2, 123.0, 121.7, 118.9, 118.5, 115.5, 110.2, 110.0, 80.4, 79.2, 79.0, 59.1, 57.5, 43.7, 42.7, 35.6, 31.2, 31.1, 27.6, 27.4, 20.6, 18.62, 18.59, 12.6. HRMS (ESI, m/z): calcd. for C100H119N16O10+, [M+H]+ 1704.9323; found, 1704.9143. [α]D20 – 40 (c 1.00, CHCl3). (3) Removal of N-Boc groups: To a solution of syn-26 (700 mg, 0.410 mmol) in acetonitrile (8 ml) was added iodotrimethylsilane (583 μL, 4.11 mmol) dropwise at 0 ºC. After being stirred for 1 h at 0 ºC, the reaction was quenched by addition of saturated aqueous solution of Na2SO3. The product was extracted with CHCl3 and combined extracts were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by GPC (CHCl3) to afford syn-L1 (336 mg, 0.258 mmol, 63%) as an off-white solid, dec >190 ºC. syn-L1: 1H-NMR (500 MHz, DMSO-d6, 90 ºC): δ 8.23 (2H, s), 8.26 (2H, J = 8.0 Hz), 8.27 (2H, d, J = 7.5 Hz), 8.15–8.18 (2H, m), 8.11 (2H, br t, J = 5.6 Hz), 7.61 (2H, s), 7.58 (2H, d, J = 8.6 Hz), 7.53 (2H, s), 7.53–7.52 (2H, m), 7.23 (2H, d, J = 8.6 Hz), 7.18–7.15 (4H, m), 6.89 (2H, dd, J = 7.5, 7.5 Hz), 6.50 (2H, dd, J = 7.5, 7.5 Hz), 6.43 (2H, d, J = 7.5 Hz), 5.71 (2H, s), 4.98 (2H, s), 4.73–4.69 (8H, m), 4.44 (2H, dd, J = 14.8, 5.7 Hz), 4.38 (2H, dd, J = 14.8, 5.7 Hz), 3.39 (2H, dd, J = 10.6, 5.3 Hz), 2.47 (6H, s), 2.33 (2H, dd, J = 12.0, 10.6 Hz), 2.22 (2H, dd, J = 12.0, 5.3 Hz), 2.22 (2H, dd, J = 12.0, 5.3 Hz), 1.68–1.63 (8H, m), 1.13–1.05 (8H, m), 0.65 (6H, t, J = 7.5 Hz), 0.64 (6H, t, J = 7.2 Hz);

13C{1H}-NMR

(125 MHz, DMSO-d6, 90 ºC): δ

172.8, 149.6, 149.4, 149.33, 149.27, 142.4, 142.1, 137.9, 134.8, 134.0, 133.1, 131.0, 130.9, 127.4, 124.7, 124.6, 124.3, 122.7, 118.9, 117.9, 116.4, 110.2, 110.0, 107.8, 81.3, 78.7, 62.4, 60.5, 43.6, 42.0, 39.5, 31.2, 20.6, 18.6, 12.6. HRMS (ESI, m/z): calcd. for C80H87N16O2+, [M+H]+ 1303.7193; found, 1303.7128. [α]D20 –38 (c 1.00, CHCl3). ACS Paragon Plus Environment

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Preparation of anti-L2: (1) Saponification of anti-25. To a solution of anti-25 (251 mg, 0.30 mmol) and MeOH (2 ml) in THF (4 mL) was slowly added aqueous solution of LiOH (2 M, 1.50 ml, 3.00 mmol) at 0 ºC and stirred for 30 min at 0 ºC. The mixture was then warmed up to room temperature and stirred for 14 h. After being cooling to 0 ºC, the mixture was acidified (pH < 3) with 1N HCl. The resulting mixture was extracted with CHCl3 three times, and combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give crude dicarboxylic acid anti-6 (264 mg) as a white solid, which was used for the next reaction without further purification: 1HNMR (500 MHz, CD3OD, 50 ºC): δ 7.29 (2H, d, J = 8.0 Hz), 7.13 (2H, d, J = 7.5 Hz), 7.04 (2H, dd, J = 8.0, 7.8 Hz), 6.78 (2H, dd, J = 7.8, 7.5 Hz), 6.40 (2H, s), 4.57 (2H, d, J = 9.7 Hz), 2.81 (2H, dd, J = 12.9, 9.7 Hz), 2.70 (2H, d, J = 12.9 Hz), 1.62 (18H, s), 1.47 (18H, s); 13C{1H}-NMR (125 MHz, CD3OD, 50 ºC): δ 173.9, 154.9, 153.7, 144.5, 132.3, 130.2, 125.2, 123.9, 118.1, 83.0, 82.2, 80.7, 60.8, 60.4, 37.2, 28.8, 28.7. HRMS (ESI, m/z): calcd. for C42H54N4NaO12+, [M+Na]+ 829.3636; found, 829.3650. (2) Condensation with bis(benzimidazolyl)pyridine unit 21: To a solution of the crude dicarboxylic acid anti-6 (184 mg) and BBIPy unit 21 (329 mg, 0.705 mmol) in DMF (1.3 mL) were successively added HATU (377 mg, 0.992 mmol) and iPr2NEt (171 μL, 0.992 mmol) at 0 ºC. After being stirred for 4 h at room temperature, the mixture was treated with H2O at 0 ºC and then extracted with CHCl3. The combined organic extracts were dried over Na2SO4, filtered, concentrated, and purified by silica gel column chromatography to afford anti-27 (238 mg, 0.140 mmol, 67% in 2 steps) as an amorphous solid. anti-27:1H-NMR (500 MHz, DMSO-d6, 90 ºC): δ 8.59 (2H, dd, J = 8.0, 1.2 Hz), 8.26 (2H, dd, J = 8.0, 1.2 Hz), 8.19 (2H, dd, J = 8.0, 8.0 Hz), 7.54–7.50 (6H, m), 7.41 (2H, s), 7.27 (2H, d, J = 8.3 Hz), 7.17 (2H, d, J = 8.3 Hz), 7.10 (2H, d, J = 8.0 Hz), 7.04–7.00 (2H, m), 6.99 (2H, dd, J = 8.3, 1.4 Hz), 6.92 (2H, br s), 6.78–6.75 (2H, m), 6.31 (2H, s), 4.73–4.70 (8H, m), 4.51 (2H, d, J = 9.5 Hz), 4.09 (2H, dd, J = 14.5, 5.9 Hz), 3.73 (2H, dd, J = 14.5, 5.9 Hz), 2.77 (2H, dd, J = 12.6, 9.5 Hz), 2.63 (2H, d, J = 12.6 Hz), 2.47 (6H, s), 1.69–1.62 (8H, m), 1.52 (18H, s), 1.41 (18H, s), 1.14–1.05 (8H, m), 0.65 (12H, t, J = 7.5 Hz);

13C{1H}-NMR

(125 MHz, DMSO-d6, 90 ºC): δ

169.0, 152.8, 150.9, 149.7, 149.4, 149.3, 149.2, 142.4, 142.1, 141.8, 137.9, 134.9, 134.0, 132.6, 131.01, 130.96, 128.2, 124.6, 124.5, 124.3, 123.0, 122.6, 122.0, 118.9, 118.0, 115.4, 110.1, 110.0, 80.6, 80.0, 79.4, 78.7, 60.5, 59.0, 43.6, 42.3, 36.0, 31.2, 27.5, 20.6, 18.62, 18.58, 12.6. HRMS (ESI, m/z): calcd. for C100H119N16O10+, [M+H]+ 1704.9323; found, 1704.9130. [α]D20 –55 (c 1.00, CHCl3). (3) Removal of N-Boc groups: Employing an essentially identical protocol for the preparation of syn-L1, anti-L2 (137 mg, 0.105 mmol, 62%) was obtained as a off-white solid, mp 217–218 ºC, from anti-27 (290 mg, 0.170 mmol) by the treatment with TMSI (340 mg, 1.70 mmol) in MeCN (3.4 ml) at 0 ºC for 50 min. anti-L2: 1H-NMR (500 MHz, DMSO-d6, 90 ºC): δ 8.29–8.17 (8H, m), 7.88 (2H, br t, J = 5.6 Hz), 7.54–7.51 (4H, m), 7.46 (2H, s), 7.18 (2H, d, J = 8.6 Hz), 7.13 (2H, d, J = 6.7 ACS Paragon Plus Environment

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Hz), 7.03 (2H, d, J = 8.6 Hz), 6.91–6.90 (2H, m), 6.55–6.52 (2H, m), 6.44 (2H, d, J = 8.0 Hz), 5.84 (2H, s), 4.79 (2H, s), 4.71 (8H, t, J = 7.2 Hz), 4.19 (2H, dd, J = 14.8, 5.6 Hz), 3.76 (2H, dd, J = 14.8, 5.6 Hz), 3.67 (2H, d, J = 9.7 Hz), 2.69 (2H, dd, J = 11.5, 9.7 Hz), 2.47 (6H, s), 2.35 (2H, d, J = 11.5 Hz), 1.70–1.64 (8H, m), 1.14–1.07 (8H, m), 0.66 (12H, t, J = 7.5 Hz);

13C{1H}-NMR

(125 MHz,

DMSO-d6, 90 ºC): δ 172.8, 149.6, 149.4, 149.33, 149.27, 142.4, 142.1, 137.9, 134.8, 134.0, 133.1, 131.0, 130.9, 127.4, 124.7, 124.6, 124.3, 122.7, 118.9, 117.9, 116.4, 110.2, 110.0, 107.8, 81.3, 78.7, 62.4, 60.5, 43.6, 42.0, 39.5, 31.2, 20.6, 18.6, 12.6. HRMS (ESI, m/z): calcd. for C80H87N16O2+, [M+H]+ 1303.7192; found, 1303.7221. [α]D20 –41 (c 1.00, CHCl3). Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: XXX. Spectrophotometric titration (UV-vis and Emission), ESI-MS, CD, and excitation spectra of EuIII complexes, and NMR spectra (PDF).

Acknowledgments We thank Professor Keiji Mori (Tokyo University of Agriculture and Technology) for his supports in experiments using the gel-permeation chromatography. We are grateful for financial support from the Japan Science and Technology Agency (JST) "Precursory Research for Embryonic Science and Technology (PRESTO)" for the project "Molecular technology and creation of new functions" awarded to (JU) and (HO). This work was supported by JSPS and MEXT Grants-in-Aid for Scientific Research, Grant Numbers: JP17H05386 (JU), and JP18H04388 (HO) as well as by the Asahi Glass Foundation (JU) and Takahashi Foundation (JU). This work was inspired by the international and interdisciplinary environments of the JSPS Asian CORE Program, “Asian Chemical Biology Initiative” and the JSPS A3 Foresight Program.

References and Notes (1)

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