Helicates with Ether‐Substituted Catechol Esters as Ligands

This is a self-archived version of an original article. This version may differ from the original in pagination and typographic details. Author(s): Title: Year: Version: Copyright: Rights: Rights url: Please cite the original version: CC BY 4.0 https://creativecommons.org/licenses/by/4.0/ Helicates with Ether‐Substituted Catechol Esters as Ligands © 2020 the Authors Published version Mevissen, Christian; Kwamen, Carel; Himmel, Leonard; Chen, Xiaofei; Brückner, Matthias; Huda, Saskia; Göb, Christian; Jenniches, Judith; Oppel, Iris; Ward, James; Rissanen, Kari; Albrecht, Markus Mevissen, C., Kwamen, C., Himmel, L., Chen, X., Brückner, M., Huda, S., Göb, C., Jenniches, J., Oppel, I., Ward, J., Rissanen, K., & Albrecht, M. (2020). Helicates with Ether‐Substituted Catechol Esters as Ligands. European Journal of Organic Chemistry, 2020(32), 5161-5172. https://doi.org/10.1002/ejoc.202000843 2020 Full Paper doi.org/10.1002/ejoc.202000843 EurJOC European Journal of Organic Chemistry Supramolecular Switches Helicates with Ether-Substituted Catechol Esters as Ligands Christian Mevissen, [a] A. Carel N. Kwamen, [a] Leonard Himmel, [a] Xiaofei Chen, [a] Matthias Brückner, [a] Saskia Huda, [a] Christian Göb, [b] Judith Jenniches, [b] Iris Oppel, [b] Jas S. Ward, [c] Kari Rissanen, [c] and Markus Albrecht* [a] Dedicated to Professor Dr. Elmar Weinhold on the occasion of his 60th birthday. Abstract: Monoor biscatechol esters with ether-type substituents or spacers form either triple lithium bridged dimeric helicates or triple stranded helicates with the ability to bind three lithium cations in their interior. Hierarchical helicates with ether or thioether substituents show in solution a monomerdimer equilibrium which is independent of the heteroatom in Introduction Self-assembly provides a facile way to synthesise complex supramolecular structures starting from easily available building blocks. Dynamic behavior of the obtained supramolecular aggregates, which ideally can be controlled by some external stimuli, leads into the world of molecular devices like machines or switches. [1] Many chemical devices have been prepared e.g. based on rotaxane and catenane motifs, but other structural moieties have been successfully used as well. [2] In 2005 we introduced hierarchically [3] formed triple lithium bridged helicates [4] based on dinuclear titanium catecholates, [5] which in solution represent a unique class of lithium dependent molecular switches (Figure 1a). NMR spectroscopy allows to observe the equilibrium between the monomeric and dimeric titanium(IV)triscatecholates. [6] The equilibrium mainly depends on the kind of carbonyl substituent (aldehyde, ketone, thioester, [a] C. Mevissen, Dr. A. C. N. Kwamen, L. Himmel, Dr. X. Chen, M. Brückner, S. Huda, Prof. Dr. M. Albrecht RWTH Aachen University, Institut für Organische Chemie Landoltweg 1, 52074 Aachen, Germany E-mail: [email protected] [b] Dr. C. Göb, J. Jenniches, Prof. Dr. I. Oppel RWTH Aachen University, Institut für Anorganische Chemie Landoltweg 1, 52074 Aachen, Germany [c] University of Jyväskylä, Department of Chemistry, P.O. Box 35, Jyväskylä 40014, Finland Supporting information and ORCID(s) from the author(s) for this article are available on the WWW under https://doi.org/10.1002/ejoc.202000843. © 2020 The Authors published by Wiley-VCH GmbH ·This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. Eur. J. Org. Chem. 2020, 5161–5172 © 2020 The Authors published by Wiley-VCH GmbH5161 the ester substituent. However, dimerization constants are significantly lower than for corresponding alkyl derivatives. Dinuclear helicates with oligoether spacers are well obtained in the presence of lithium cations. Upon removal of the cations the helicates expand and successive addition of LiCl results in compression again. Figure 1. Hierarchically assembled ester substituted helicates and the monomer/dimer equilibrium as observed in solution (a) as well as the corresponding alkyl bridged helicate showing lithium dependent expansion and compression behaviour. Full Paper doi.org/10.1002/ejoc.202000843 EurJOC European Journal of Organic Chemistry ester) at the catechol ligand, on the central metal and on the solvent, but the side chains (sterics, solvophobic effects and even dispersion interactions) have an important influence on the equilibrium as well. [7] A hierarchically formed helicate of this kind even was used as a platform for stereoselective Diels-Alder reactions. Hereby the selectivity of the reaction can be switched on or off by simply shifting the equilibrium from the dimer to the monomer (or vice versa). [8] Bridging the two catechol units by alkyl spacers results in a lithium dependent switch [9] showing some spring-type expansion and compression behavior (Figure 1b). [10] Control of the stereochemistry of the complexes by introduction of a phenyl substituent at the ester group leads to a three state supramolecular switch in which it is possible to switch between the compressed and expanded state and in the expanded form between the rightand the left-handed helix. [11] Herein we present ether substituted catechol esters in order to form non-bridged hierarchical helicates as well as bridged helicates (Figure 1). The monomer/dimer equilibrium is observed for three ethers and their thio-analogues. A series of “spring-type” helicates is made, the switching property is studied and the stereochemistry is influenced by introduction of chiral units in the center of the ligand spacer. Results and Discussion Hierarchically assembled helicates with ether side chains. Glycol based esters and their thio-analogues are easily prepared by esterification of 2,3-dihydroxybenzoic acid following a modified Raymond protocol. [12] The ligands 1a–c-H 2 and 2a–c-H 2 are obtained in moderate to good yields. The corresponding titanium(IV) complexes Li[Li 3 (1/2) 6 Ti 2 ] are formed in methanol by reaction of the ligands with TiO(acac) 2 and Li 2 CO 3 (Scheme 1). Scheme 1. Preparation of the hierarchically formed helicates Li[Li 3 (1/2) 6 Ti 2 ]. Complexes Li[Li 3 (3) 6 Ti 2 ] have been described earlier and are only mentioned for comparison. Negative ESI MS (methanol) shows the peaks of the dimeric complexes [Li 3 (1/2) 6 Ti 2 ] – at m/z= 1377.26 (1a), 1461.35 (1b), 1545.44 (1c), 1473.12 (2a), 1557.23 (2b) and 1641.32 (2c) while NMR spectroscopy in [D 6 ]DMSO reveals the characteristic peaks of the monomer as well of the dimer. E. g., by 1 H NMR in [D 6 ]DMSO the signals of the catechol unit of the dimer Eur. J. Org. Chem. 2020, 5161–5172 www.eurjoc.org © 2020 The Authors published by Wiley-VCH GmbH5162 Li[Li 3 (1a) 6 Ti 2 ] are observed at δ= 6.96, 6.50, and 6.42, and for the dominating monomer Li 2 [(1a) 3 Ti] at δ= 6.77, 6.26, and 6.13. In the dimer the methylene group adjacent to the ester splits into two signals of diastereotopic protons at δ= 3.67 and 3.02 ppm (6H each) while in the monomer one signal at δ= 4.18 ppm (12 H) is observed for this group. From the NMR spectra dimerization constants can be easily extracted (Table 1) at ambient temperature. [6,7] It is observed that the dimerization constants steadily increase with the chain length. However, the observed constants of the glycol and thioglycol derivatives are by one magnitude lower as observed for the corresponding alkyl derivatives. It is assumed that the higher polarity of the heteroatom derivatives results in repulsion between the oxygen or sulfur lone pairs with the hetero atoms and πsystems of neighboring catechol units. This effect is strong despite a related high solvophobicity of ethers and alkanes in DMSO which would rather stabilize the dimer. The similarity of the dimerization constants of the oxygen and sulfur derivatives is remarkable, showing the similarity of the two atoms in their solvophobic as well as electronic features in [D 6 ]DMSO. Table 1. Kdim [L/mol] for the dimerization monomer dimer equilibrium of Li[Li 3 (1–3) 6 Ti 2 ]in[D 6 ]DMSO at r.t. determined at a concentration of 10 –2 mol/ L. Li[Li 3 (1–3) 6 Ti 2 ] X=O X=S X=CH 2 Li[Li 3 (1) 6 Ti 2 ] Li[Li 3 (2) 6 Ti 2 ] Li[Li 3 (3) 6 Ti 2 ] R=CH 3 170 ± 18 160 ± 17 1195 [a] R=C 2 H 6 210 ± 22 275 ± 30 1920 [a] R=C 3 H 7 340 ± 38 350 ± 39 1530 [a] [a] Ref. [7] In addition to the solution studies it was possible to obtain crystal structures of Li[Li 3 (1a) 6 Ti 2 ] and Li[Li 3 (2a) 6 Ti 2 ] (Figure 2). The overall features of the complex structures are similar to the ones observed before for corresponding dimeric helicates. [6,7] The structures seem to indicate, that, due to the repulsion of Figure 2. The molecular structures of the anions [Li 3 (1a) 6 Ti 2 ] – (a) and [Li 3 (2a) 6 Ti 2 ] – (b) in the crystal. Full Paper doi.org/10.1002/ejoc.202000843 EurJOC European Journal of Organic Chemistry the electron pairs, the heteroatoms in the side chains adopt positions which are located far away from each other. The Xray structural results can be correlated with NMR, ESI-MS based structural assignments. However, in solution side chains possess some high flexibility at the side chains. Dinuclear helicates with ether type spacers. Connecting two complex units of the hierarchical helicates leads to compounds which act as lithium dependent expandable/compressable switches. A series of oligoglycol bridged ligands 4,5-H 4 have been made by Steglich type esterification [13] of appropriate diols with dibenzyl protected dihydroxybenzoic acid followed by removal of the benzyl protecting groups (Scheme 2). The coordination chemistry of the ligands with titanium(IV) in the presence of alkali metal cations has been tested. Scheme 2. Preparation of oligo ether linked dicatechol esters. The complexes Li[Li 3 (4b) 3 Ti 2 ] and Na 2 [Na 2 (5a) 3 Ti 2 ] were communicated recently and their crystal structures were presented (Figure 3). Both compounds show a compressed structure with the expected geometry for Li[Li 3 (4b) 3 Ti 2 ] while Na 2 [Na 2 (5a) 3 Ti 2 ] represents a topological isomer to the “classical” helicates with two of the spacers attached to one of the catechols from the inside and to the other from the outside. [14] Figure 3. The structures of Li(DMF) 2 [Li 3 (4b) 3 Ti 2 ] and [Na 2 (5a) 3 Ti 2 ] 2– . In here the ligands 4a,c,d are additionally introduced in order to study the influence of different spacer length on the complex formation. Furthermore, the new ligand 5b represents Eur. J. Org. Chem. 2020, 5161–5172 www.eurjoc.org © 2020 The Authors published by Wiley-VCH GmbH5163 a chiral version of the earlier investigated 5a, allowing the study of the stereochemical influence of the remote chiral group. All ligands 4form compressed dinuclear titanium(IV) complexes with internally bound lithium cations as had been structurally characterized for [Li 3 (4b) 3 Ti 2 ] – . The anionic helicate can be easily observed by ESI MS (m/z= 1371.2078 [Li 3 (4a) 3 Ti 2 ] – , 1635.3604 [Li 3 (4c) 3 Ti 2 ] – , 1767.4446 [Li 3 (4d) 3 Ti 2 ] – ) supporting this assignment. However, 1 H NMR spectroscopy reveals some surprises. For Li[Li 3 (4a) 3 Ti 2 ] and Li[Li 3 (4b) 3 Ti 2 ] the expected spectra are observed which show three resonances for the protons of the catechol units in the aromatic region. In case of the complexes with very long spacers Li[Li 3 (4c) 3 Ti 2 ] and Li[Li 3 (4d) 3 Ti 2 ] two sets of signals are observed for the catechol units (Figure 4). Figure 4. 1 H NMR signals of the catechol protons of the compressed helicates Li[Li 3 (4a-d) 3 Ti 2 ] (in [D 6 ]DMSO). The ESI MS results as well as the NMR spectra indicate that in case of Li[Li 3 (4c,d) 3 Ti 2 ] two different isomers with high symmetry are present. We assume that this only can be due to different orientations of the spacers. The structure of Li[Li 3 (4b) 3 Ti 2 ] reveals that in this case the spacer bridges the ester units in front of the lithium cations (Type I). This is the only possible arrangement in case of short chain length. With longer spacers the alternative Type II structure with the spacers bridging “over” the aromatics becomes also possible. This is schematically illustrated in Figure 5 for the Type I and Type II structures of [Li 3 (4d) 3 Ti 2 ] – . It was possible to obtain crystals of Na[Li 3 (4c) 3 Ti 2 ] which were sufficient for crystal structure analysis. In the crystal the complex adopts a Type I structure with the spacers bridging in front of one lithium cation. Hereby crown ether-type loops are found and in one of those the sodium cation is bound (Figure 6). [15] The lithium as well as the sodium complexes M 4 [(5a) 3 Ti 2 ] (M = Li, Na) have already been described. [14] The potassium salt shows two different sets of signals relating to two complexes which structurally could not be assigned. Based on the ESI MS observations (m/z= 1552.1572 [K 3 (5a) 3 Ti 2 ] – , 1629.0768 K 5 [(5a) 3 Ti 2 ] + ) it is assumed that at least one isomer should adopt the triple stranded helicate structure. Full Paper doi.org/10.1002/ejoc.202000843 EurJOC European Journal of Organic Chemistry Figure 5. Cartoon of the type I and type II isomers of [Li 3 (4d) 3 Ti 2 ] – . Figure 6. Structure of Na[Li 3 (4c) 3 Ti 2 ] as observed in the crystal. View down the Ti-Ti axis. Ligand 5b-H 4[16] represents a chiral version of 5a-H 4 . The coordination compounds M 4 [(5b) 3 Ti 2 ] (M = Li, Na, K) can be obtained from this ligand. The potassium salts K 4 [(5a,b) 3 Ti 2 ] show two major isomers which cannot be structurally assigned. In the case of the lithium complex Li[Li 3 (5b) 3 Ti 2 ] similar shifts as found for Li[Li 3 (5a) 3 Ti 2 ] are observed by proton NMR spectroscopy. [14] However, the dominating signals split into two sets. This is tentatively assigned to the inefficient stereocontrol at Li[Li 3 (5b) 3 Ti 2 ] by the remote chiral units of the spacer resulting in two different diastereoisomers (SSΛΛ and SSΔΔ). The spectrum of the sodium complex Na 2 [Na 2 (5b) 3 Ti 2 ] correlates with the one of the achiral complex Na 2 [Na 2 (5a) 3 Ti 2 ] showing that again the “topological” helicate isomer is formed (Figure 7). [14] Eur. J. Org. Chem. 2020, 5161–5172 www.eurjoc.org © 2020 The Authors published by Wiley-VCH GmbH5164 Figure 7. 1 H NMR signals ([D 6 ]DMSO) of the catechol protons of the helicates M 4 [(5a,b) 3 Ti 2 ] (M = Li, Na, K). CD spectra were measured for the chiral complexes M 4 [(5b) 3 Ti 2 ] (M = Li, Na, K). The transitions at the titanium(IV) catecholate moieties provide information on the chirality (Δvs. Λ). [17] The results show that in the lithium salt, the complexes preferably adopt Δconfiguration which is also favored in the sodium complex. However, in the latter case much lower ellipticity is observed. For the potassium salt, the favored stereochemistry at the catecholate complexes is inverted compared to the lithium or sodium salt (Figure 8). A similar stereochemical inversion effect has been already observed earlier with ester catecholate based titanium(IV) complexes and has been discussed in detail at this time. [11,18] Figure 8. CD spectra of M 4 [(5b) 3 Ti 2 ] (M = Li, Na, K) in DMSO. In order to obtain crystals of the coordination compounds of ligand 5b, different salts were added to lead to better crystallization properties. Thus, the crystal structure of [AsPh 4 ] 2 - [Na 2 (5b) 2 Ti 2 O 2 ]·2MeOH has been obtained. A central bis-μ-oxo bis titanium(IV) moiety is formed. The two titanium centers are Full Paper doi.org/10.1002/ejoc.202000843 EurJOC European Journal of Organic Chemistry bridged by two oxygen atoms as well as two ligands 5b.Two sodium cations are included in the complex, binding to the catecholesters and additionally to one molecule of methanol each (Figure 9). The structure of [Na 2 (5b) 2 Ti 2 O 2 ] 2– is related to the ones observed earlier for dinuclear titanium(IV) complexes with amino acid bridged dicatechol ligands. [19] Figure 9. Structure of [Na 2 (5b) 2 Ti 2 O 2 ] 2– ·2MeOH in the crystal. The methanol molecules are shown in light blue. However, due to the absence of resonances of the free ligand 5b in the crude product spectra of Na 4 [(5b) 3 Ti 2 ] formed from three equivalents of ligand with two equivalents of titanium(IV) ions it is expected that [Na 2 (5b) 2 Ti 2 O 2 ] 2– is only formed under the crystallization conditions. Expansion and compression of helicates with ether type spacers. Due to the expanded and compressed structures of the helicates M 4 [(4/5) 3 Ti 2 ], switching in a spring-type fashion is feasible depending on the cations. The corresponding switching of M 4 [(5a) 3 Ti 2 ] has been already reported. [14] In here consecutive expansion and compression experiments have been performed in one NMR test tube starting with the compressed forms Li[Li 3 (4a-d) 3 Ti 2 ] (Figure 10) or Li[Li 3 (5a,b) 3 Ti 2 ] Figure 10. Reversible switching of the compressed complexes Li[Li 3 (4a– d) 3 Ti 2 ]. Expansion occurs upon addition of [2.1.1]cryptand (A) while compression is induced by addition of LiCl (B). Eur. J. Org. Chem. 2020, 5161–5172 www.eurjoc.org © 2020 The Authors published by Wiley-VCH GmbH 5165 (Figure 11). Upon addition of [2.1.1]cryptand (approx. 10 equiv.) (A), lithium cations are removed from the complexes resulting in expansion of the helicates. Successive addition of 10 equiv. of LiCl (B) leads to compression. This can be easily followed by observing the resonances of the aromatic protons. Figure 11. Reversible switching of the compressed complexes Li[Li 3 (5a,b) 3 Ti 2 ]. Expansion occurs upon addition of [2.1.1]cryptand (A) while compression is induced by addition of LiCl (B). Conclusions In here a series of hierarchical and expandable/compressible helicates with ether-type ester substituents is presented. In many respects those complexes behave as observed for the hydrocarbon analogs. However, some differences are found and some new observations are made: – Hierarchical helicates with ether or thioether-type substituents dissociate into the monomers more easily compared to the analogous alkyl derivatives. Hereby, the dimer stability is independent on the heteroatom oxygen vs. sulfur in the side chain. – Helicate based expandable and compressible molecular switches are obtained with ether containing spacers and can easily be switched. However, for the first time two different isomers are observed for the lithium complexes Li[Li 3 (4c,d) 3 Ti 2 ] which are assigned to Type I and Type II isomers with different positions of the connecting units. – In the chiral derivative Li[Li 3 (5b) 3 Ti 2 ] stereoinduction by the remote chiral unit is not complete. However, with sodium cations the “topological” helicate isomer Na 2 [Na 2 (5b) 3 Ti 2 ]isobserved as it also was found for the corresponding achiral Na 2 [Na 2 (5a) 3 Ti 2 ]. [14] – The new structural motif of a double-stranded dinuclear complex [Na 2 (5b) 2 Ti 2 O 2 ] 2– ·2MeOH could be characterized by X-ray diffraction. Thus, the coordination chemistry of the ether substituted catechol and dicatechol ester ligands is well explored and in the future will be used for host–guest chemistry with cations which may be bound in the loops [15] of M 4 [(4a-d) 3 Ti 2 ] in the presence of lithium but not of other cations. Experimental Section General notes. Unless stated otherwise, all commercial reagents were used without further purification. Substances and chemicals used in this research were purchased from ABCR, Acros Organics, Alfa Aesar or Sigma Aldrich. 2,3-Bis(benzyloxy)benzoic acid was prepared according to a literature procedure. [1] Moisture or oxygen Full Paper doi.org/10.1002/ejoc.202000843 EurJOC European Journal of Organic Chemistry sensitive compounds were prepared under nitrogen atmosphere using standard Schlenk techniques. Thin layer and column chromatography. TLC was carried out using Merck silica gel 60, F254 precoated aluminium foil plates (d = 0.25 nm). Visualization was performed with UV light irradiation or basic aqueous potassium permanganate staining solution. Silica gel (Fluka silica gel (SiO2), 40–60 μm) was purchased by Silicycle and used for medium pressure chromatography (“flash”-chromatography), applying the respective solvent system. NMR spectroscopy. All samples were dissolved and measured in deuterated solvents (CDCl 3 ,[D 6 ]DMSO). Measurements were performed at 25 °C. 1 H NMR spectra were recorded applying a Varian Inova 400 MHz or Varian Inova 600 MHz spectrometer operating at 400 MHz or 600 MHz. Residual proton signals from deuterated solvents were used as standards. 13 C NMR spectra were recorded on a Varian Inova 400 MHz or Varian Inova 600 MHz spectrometer operating at 150 MHz using 13 C signals from deuterated solvents as standards. The chemical shift δis given in ppm. Abbreviations used to denote multiplicity are: s for singlet, d for doublet, t for triplet, q for quartet, p for pentet and m for multiplet. Coupling constants Jare reported in Hertz (Hz). The proton numbers were obtained by integration of the corresponding signals. Mass spectrometry. Mass spectra were measured on a Thermo Finnigan LCQ Deca XP Plus applying electrospray ionisation (ESI). All characteristic masses are given with sum formula and electric charge in the mass/charge ratio (m/z). Elemental analysis. Elemental analysis was performed using a Heraeus CHN-O-Rapid elemental analyzer. Ratios of carbon, hydrogen and if relevant nitrogen are given in mass percentages. IR spectroscopy. IR measurements were recorded by diffusion in KBr on a Perkin-Elmer 1760 FT machine in the range 4000–400 cm –1 .All absorption bands are listed with the location of the bands given in cm –1 . Melting points. Melting points were determined with a BÜCHI B-540 melting point instrument and are reported uncorrected. The given melting points in °C indicate the temperature range between the beginning and the end of the melting process. X-ray crystallography. The experimental and refinement details for K[Li 3 (1a) 6 Ti 2 ], Li[Li 3 (2a) 6 Ti 2 ], Na[Li 3 (4c) 3 Ti 2 ], Na 2 [(5b) 2 Ti 2 ] are given below. Single-crystal X-ray data for K[Li 3 (1a) 6 Ti 2 ] was measured using a Rigaku SuperNova dualsource Oxford diffractometer equipped with an Eos detector using mirror-monochromated Mo-K α (λ= 0.71073 Å) radiation. The data collection and reduction were performed using the program CrysAlisPro7 and Gaussian face index absorption correction method was applied. [20] X-ray data for Li[Li 3 (2a) 6 Ti 2 ] was measured using a Bruker-Nonius KappaCCD diffractometer with an APEX-II detector with graphitemonochromatized Mo-K α (λ= 0.71073 Å) radiation. Data collection and reduction were performed using the program COLLECT [21] and HKL DENZO AND SCALEPACK. [22] respectively, and the intensities were corrected for absorption using SADABS. [23] The structures were solved with intrinsic phasing (SHELXT) [24] and refined by full-matrix leastsquares on F 2 using the OLEX2 software, [25] which utilises the SHELXL2015 module. [24] Single crystal X-ray diffraction data for Na[Li 3 (4c) 3 Ti 2 ] and Na 2 [(5b) 2 Ti 2 ] were collected at 100(2) K by using ω-scans on a Stoe Stadivari Eulerian geometry four-circle diffractometer, equipped with a Cu-K α micro-focused source (GeniX 3D HF Cu, λ= 1.54178 Å) and a Pilatus 200 K hybrid pixel detector (Dectris). Data collection, reduction and absorption correction were performed with the software package X-Area. [26] The space groups were determined using XPREP9 and the structures were solved with Eur. J. Org. Chem. 2020, 5161–5172 www.eurjoc.org © 2020 The Authors published by Wiley-VCH GmbH5166 intrinsic phasing (SHELXT). The structures were refined using SHELXL-201813 with a least-squares procedure against F 2 . Na[Li 3 (4c) 3 Ti 2 ] was refined as a two-component twin (x = –0.017(15)). Due to inadequate data-parameter ratio, the disorder of the crown ether-type moieties could not be refined. The sodium ion was modelled as a disorder over two positions (0.58:0.42). The residual electron density of 1.88 (–0.0699, 0.4020, 0.4446) indicates another likely position for the disordered sodium cation. Disordered solvent in Na 2 [(5b) 2 Ti 2 ] was treated by applying a solvent mask in OLEX2. Eight molecules of methanol can be estimated per formula unit. Hydrogen atoms were refined using riding models with Ueq(H) of 1.5 Ueq(C) for terminal methyl groups, and 1.2 Ueq(C) for other groups. General Procedure for the Preparation of ligands 1,2-H 2 .Ligands 1a-c-H 2 and 2a–c-H 2 were synthesized by esterification, starting with the conversion of 2,3-Dihydroxybenzoic acid (1 equiv.) into its corresponding acid chloride via refluxing in thionyl chloride (30 equiv.) for 1 hour. The excess thionyl chloride was removed under reduced pressure and the remaining acid chloride used in the next step without further purification. The acid chloride was then reacted with a mixture of the corresponding alcohol (3 equiv.) and triethylamine (6 equiv.) in chloroform to afford the desired product after purification via column chromatography. 1a-H 2 .The ligand was prepared from 2-methoxyethan-1-ol (296.01 mg, 3.89 mmol) by modification of the general procedure. The product is isolated by column chromatography (pentane/ethyl acetate, 4:1, R f = 0.18) as a white solid (53 %, 146 mg, 0.69 mmol). 1 H-NMR (600 MHz, CDCl 3 ): δ= 10.82 (s, 1H, OH), 7.42 (dd, J= 8.0, 1.4 Hz, 1H, H arom .), 7.11 (dd, J= 8.0, 1.4 Hz, 1H arom. ), 6.81 (t, J= 8.0 Hz, 1H, H arom. ), 5.65 (s, 1H, OH), 4.50 (t, J= 5.3 Hz, 2H, CH 2 ), 3.73 (t, J= 5.3 Hz, 2H, CH 2 ), 3.42 (s, 3H, CH 3 ) ppm. 13 C-NMR (151 MHz, CDCl 3 :δ= 170.19 (CO 2 CH 2 ), 148.83 (C arom. ), 144.98 (C arom. ), 120.78 (C arom. ), 119.87 (C arom. ), 119.20 (C arom. ), 112.35 (C arom. ), 70.21 (CH 2 ), 64.46 (CH 2 ), 59.14 (CH 3 ) ppm. ESI-MS (positive ESI-MS, MeOH, acidified): m/z: Calculated for C 10 H 12 NaO 5+ [M+Na + ]: 235.0582, found 235.0600. IR (KBr): ν ˜= (cm –1 ) = 3346, 3056, 2999, 2948, 2832, 2472, 2325, 2161, 2039, 1935, 1876, 1666, 1612, 1539, 1455, 1375, 1301, 1264, 1236, 1156, 1123, 1084, 1032, 967, 912, 862, 836, 784, 743. Elemental analysis: Calculated for C 10 H 12 O 5 ·1/20DCM: 55.77 %, H: 5.63 %; found C: 55.53 %, H: 5.54 %. 1b-H 2 .The ligand was prepared from 2-ethoxyethan-1-ol (350.57 mg, 3.89 mmol) by modification of the generalprocedure. The product is isolated by column chromatography (pentane/ethyl acetate, 4:1, R f = 0.21) as colorless oil (46 %, 134 mg, 0.59 mmol). 1 H-NMR (600 MHz, CDCl 3 ): δ= 10.83 (s, 1H, OH), 7.42 (dd, J= 8.0, 1.4 Hz, 1H, H arom. ), 7.11 (dd, J= 8.0,1.5 Hz, 1H, Harom.), 6.80 (t, J= 8.0 Hz, 1H, H arom. ), 5.65 (s, 1H, OH), 4.50 (t, J= 6.5 Hz, 2H, CH 2 ), 3.77 (t, J= 6.5 Hz, 2H, CH 2 ), 3.58 (q, J= 7.0 Hz, 2H, CH 2 ), 1.23 (t, J= 7.0 Hz, 3H, CH 3 ) ppm. 13 C-NMR (151 MHz, CDCl 3 :δ= 170.18 (CO 2 CH 2 ), 148.81 (C arom. ), 144.98 (C arom. ), 120.80 (C arom. ), 119.83 (C arom. ), 119.19 (C arom. ), 112.43 (C arom. ), 68.06 (CH 2 ), 66.80 (CH 2 ), 64.69 (CH 2 ), 15.13 (CH 3 ) ppm. ESI-MS (positive ESI-MS, MeOH, acidified): m/z: Calculated for C 11 H 14 NaO 5+ [M+Na + ]: 249.0739, found 249.0761. IR (KBr): ν ˜= (cm –1 ) = 3633, 3449, 3203, 2976, 1873, 2466, 2327, 2182, 2072, 1916, 1732, 1671, 1608, 1532, 1467, 1379, 1301, 1267, 1237, 1153, 1120, 1069, 1032, 968, 880, 843, 751, 715. Elemental analysis: Calculated for C 11 H 14 O 5 ·1/2H 2 O: H: 6.43 %; found C: 56.18 %, H: 6.30 %. 1c-H 2 .The ligand was prepared from 2-propoxyethan-1-ol (405.14 mg, 3.89 mmol) by modification of the general procedure. The product is isolated by column chromatography (pentane/ethyl acetate, 4:1, R f = 0.13) as colorless oil (47 %, 146 mg, 0.61 mmol). Full Paper doi.org/10.1002/ejoc.202000843 EurJOC European Journal of Organic Chemistry 1 H-NMR (600 MHz, CDCl 3 ): δ= 10.83 (s, 1H, OH), 7.42 (dd, J= 8.1, 1.0 Hz, 1H, H arom. ), 7.11 (dd, J= 8.1, 1.1 Hz, 1H, H arom. ), 6.80 (t, J= 8.1 Hz, 1H, H arom. ), 5.66 (s, 1H, OH), 4.49 (t, J= 6.8 Hz, 2H, CH 2 ), 3.77 (t, J= 6.8 Hz, 2H, CH 2 ), 3.51 (t, J= 6.9 Hz, 2H, CH 2 ), 1.63–1.60 (m, 2H, CH 2 ), 0.92 (t, J= 7.0 Hz, 3H, CH 3 ) ppm. 13 C-NMR (151 MHz, CDCl 3 :δ= 170.18 (CO 2 CH 2 ), 148.80 (C arom. ), 144.98 (C arom. ), 120.78 (C arom. ), 119.81 (C arom. ), 119.19 (C arom. ), 112.45 (C arom. ), 73.14 (CH 2 ), 68.22 (CH 2 ), 64.66 (CH 2 ), 22.79 (CH 2 ), 10.47 (CH 3 ) ppm. ESI-MS (negative ESI-MS, MeOH, acidified): m/z: Calculated for C 12 H 15 O 5– [M – H + ]: 239.0928, found 239.0921. IR (KBr): ν ˜= (cm –1 ) = 3632, 3560, 3435, 3135, 2963, 2874, 2328, 2185, 2156, 2039, 2003, 1671, 1612, 1467, 1371, 1301, 1266, 1153, 1123, 1068, 1033, 990, 882, 841, 751, 713. Elemental analysis: Calculated for C 12 H 16 O 5 ·1/2DCM: 53.10 %, H: 6.06 %; found C: 53.53 %, H: 6.20 %. 2a-H 2 .The ligand was prepared from 2-methylthioethan-1-ol (358.49 mg, 3.89 mmol) by modification of thegeneral procedure. The product is isolated by column chromatography (pentane/ethyl acetate, 8:1, R f = 0.12) as colorless oil (46.5 %, 136 mg, 0.60 mmol). 1 H-NMR (600 MHz, CDCl 3 ): δ= 10.91 (s, 1H, OH), 7.36 (dd, J= 8.2, 1.4 Hz, 1H, H arom. ), 7.10 (dd, J= 8.0, 1.6 Hz, 1H, H arom. ), 6.80 (t, J= 8.0 Hz, 1H, H arom. ), 5.64 (s, 1H, OH), 4.53 (t, J= 6.8 Hz, 2H, CH 2 ), 2.87 (t, J= 6.8 Hz, 2H, CH 2 ), 2.22 (s, 3H, CH 3 ) ppm. 13 C-NMR (151 MHz, CDCl 3 :δ= 170.05 (CO 2 CH 2 ), 148.91 (C arom. ), 145.04 (C arom. ), 120.60 (C arom. ), 119.94 (C arom. ), 119.29 (C arom. ), 112.28 (C arom. ), 64.06 (CH 2 ), 32.44 (CH 2 ), 15.94 (CH 3 ) ppm. ESI-MS (negative ESI-MS, MeOH, acidified): m/z: Calculated for C 10 H 11 O 4 S – [M – H + ]: 227.0386, found 227.0360. IR (KBr): ν ˜= (cm –1 ) = 3455, 3138, 2964, 2920, 2835, 2735, 2325, 2086, 1915, 1669, 1465, 1384, 1302, 1265, 1146, 1067, 987, 843, 750, 704. Elemental analysis: for C 10 H 12 O 4 S·1/3H 2 O: 51.40 %, H: 5.44 %; found C: 51.60 %, H: 5.35 %. 2b-H 2 .The ligand was prepared from 2-ethylthioethan-1-ol (413.05 mg, 3.89 mmol) by modification of the general procedure. The product is isolated by column chromatography (pentane/ethyl acetate, 8:1, R f = 0.15) as colorless oil (38 %, 118 mg, 0.49 mmol). 1 H-NMR (600 MHz, CDCl 3 ): δ= 10.83 (s, 1H, OH), 7.37 (dd, J= 7.8, 1.4 Hz, 1H, H arom. ), 7.11 (dd, J= 7.8, 1.5 Hz, 1H, H arom. ), 6.81 (t, J= 8.0 Hz, 1H, H arom. ), 5.65 (s, 1H, OH), 4.50 (t, J= 6.9 Hz, 2H, CH 2 ), 2.90 (t, J= 6.9 Hz, 2H, CH 2 ), 2.65 (q, J= 7.8 Hz, 2H, CH 2 ), 1.29 (t, J= 7.8 Hz, 3H, CH 3 ) ppm. 13 C-NMR 170.05 (CO 2 CH 2 ), 148.91 (C arom. ), 145.03 (C arom. ), 120.60 (C arom. ), 119.93 (C arom. ), 119.28 (C arom. ), 112.28 (C arom. ), 64.52 (CH 2 ), 29.84 (CH 2 ), 26.30 (CH 2 ), 14.20 (CH 3 ) ppm. ESIMS (positive ESI-MS, MeOH, acidified): m/z: Calculated for C 11 H 14 O 4 SNa + [M+Na + ]: 241.0543, found 241.0565. IR (KBr): ν ˜= (cm –1 ) = 3885, 3458, 3136, 2965, 2928, 2666, 2324, 2099, 1997, 1912, 1669, 1465, 1383, 1302, 1146, 1066, 982, 901, 843, 750, 702. Elemental analysis: for C 11 H 14 O 4 S·1/3H 2 O: 54.53 %, H: 5.82 %; found C: 55.19 %, H: 6.03 %. 2c-H 2 .The ligand was prepared from 2-propylthioethan-1-ol (467.62 mg, 3.89 mmol) by modification of the general procedure. The product is isolated by column chromatography (pentane/ethyl acetate, 8:1, R f = 0.18) as colorless oil (45 %, 148 mg, 0.58 mmol). 1 H-NMR (400 MHz, CDCl 3 ): δ= 10.81 (s, 1H, OH), 7.36 (dd, J= 8.0, 1.5 Hz, 1H, H arom. ), 7.08 (dd, J= 8.0, 1.5 Hz, 1H, H arom. ), 6.78 (t, J= 8.0 Hz, 1H, H arom. ), 5.63 (s, 1H, OH), 4.48 (t, J= 7.0 Hz, 2H, CH 2 ), 2.86 (t, J= 7.0 Hz, 2H, CH 2 ), 2.54 (t, J= 6.7 Hz, 2H, CH 2 ), 1.63–1.60 (m, 2H, CH 2 ), 0.99 (t, J= 7.4 Hz, 3H, CH 3 ) ppm. 13 C-NMR (151 MHz, CDCl 3 :δ= 170.02 (CO 2 CH 2 ), 148.88 (C arom. ), 145.03 (C arom. ), 120.58 (C arom. ), 119.90 (C arom. ), 119.24 (C arom. ), 112.29 (C arom. ), 64.55 (CH 2 ), 34.47 (CH 2 ), 30.23 (CH 2 ), 22.97 (CH 2 ), 13.36 (CH 3 ) ppm. ESI-MS (negative ESI-MS, MeOH, acidified): m/z: Calculated for C 12 H 17 O 4 S – [M – H + ]: 255.0699, found 255.0701. IR (KBr): ν ˜= (cm –1 ) = 3459, 3137, 2958, 2663, 2462, 2316, 2085, 2000, 1914, 1670, 1465, 1383, 1301, Eur. J. Org. Chem. 2020, 5161–5172 www.eurjoc.org © 2020 The Authors published by Wiley-VCH GmbH5167 1147, 1065, 985, 898, 843, 750. Elemental analysis: Calculated for C 12 H 16 O 4 S·1/3H 2 O: 55.07 %, H: 6.39 %; found C: 55.26 %, H: 6.73 %. General procedure for diol esterification (using 4aII as an example). Triethylene glycol 4aI (200 mg, 1.12 mmol, 1.0 equiv.) was dissolved in dichloromethane (50 mL). 2,3-Bis(benzyloxy)benzoic acid (1126 mg, 3.37 mmol, 3.0 equiv.), 4-dimethylaminopyridine (137 mg, 1.12 mmol, 1.0 equiv.) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (646 mg, 3.37 mmol, 3.0 equiv.) were added subsequently and the reaction mixture was stirred at 25 °C for 48 h. Upon completion, the solvent was removed under reduced pressure and the crude product was purified by column chromatography (SiO 2 , 3:2 pentane/ethyl acetate) to afford the title compound (544 mg, 0.69 mmol, 63 %) as a white solid. 1 H-NMR (600 MHz, [D 6 ]DMSO): δ= 7.49–7.46 (m, 4H, H arom. ), 7.41–7.34 (m, 12H, 12H arom. ), 7.29–7.23 (m, 6H, 6H arom. ), 7.23–7.18 (m, 2H, 2H arom. ), 7.14 (t, J= 7.9 Hz, 2H, 2H arom. ), 5.18 (s, 4H, 2CH 2 ), 4.98 (s, 4H, 2CH 2 ), 4.33– 4.21 (m, 4H, 2CH 2 ), 3.70–3.57 (m, 4H, 2CH 2 ), 3.47 (s, 4H, 2CH 2 ) ppm. 13 C-NMR (151 MHz, [D 6 ]DMSO): δ= 165.7 (CO 2 CH 2 ), 152.3 (C arom. ), 146.73 (C arom. ), 137.3 (C arom. ), 136.6 (C arom. ), 128.5 (C arom. ), 128.1 (C arom. ), 128.1 (C arom. ), 128.0 (C arom. ), 127.8 (C arom. ), 127.8 (C arom. ), 126.6 (C arom. ), 124.3 (C arom. ), 121.6 (C arom. ), 117.6 (C arom. ), 74.7 (CH 2 ), 70.2 (CH 2 ), 69.7 (CH 2 ), 68.2 (CH 2 ), 64.0 (CH 2 ) ppm. ESI-MS (positive ESI-MS, MeOH, acidified): m/z: Calculated for C 48 H 46 NaO 10+ [M + Na + ]: 805.2983, found 805.2999. Elemental analysis: Calculated for C 48 H 46 O 10 : C: 73.64 %, H: 5.92 %; found C: 73.56 %, H: 5.96 %. General procedure for removal of benzyl protecting groups (using 4aIII as an example). 4aII (560 mg, 0.72 mmol) was dissolved in dichloromethane (50 mL). Palladium on carbon (13 wt.-% Pd on C, 73 mg) was added and the reaction stirred under H 2 atmosphere (1 atm) at 25 °C for 48 h. Upon completion the reaction mixture was filtered and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (SiO 2 , 3:2 pentane/ethyl acetate) to afford the title compound 4a-H 4 (145 mg, 0.35 mmol, 48 %) as a white solid. 1 H-NMR (600 MHz, [D 6 ]DMSO): δ= 7.22 (dd, J= 7.9, 1.6 Hz, 2H, 2H arom. ), 7.02 (dd, J= 7.9, 1.6 Hz, 2H, 2H arom. ), 6.73 (t, J= 7.9 Hz, 2H, 2H arom. ), 4.42–4.36 (m, 4H, 2CH 2 ), 3.77–3.73 (m, 4H, 2CH 2 ), 3.61 (s, 4H,2CH 2 ) ppm. 13 C-NMR (151 MHz, [D 6 ]DMSO): δ= 169.8 (C arom. ), 150.0 (C arom. ), 146.5 (C arom. ), 121.2 (C arom. ), 120.0 (C arom. ), 119.3 (C arom. ), 113.4 (C arom. ), 70.3 (CH 2 ), 68.5 (CH 2 ), 64.9 (CH 2 ) ppm. ESI-MS (positive ESI-MS, MeOH, acidified): m/z: Calculated for C 22 H 26 NaO 11+ [M + Na + ]: 445.1105, found 445.1095 Elemental analysis: Calculated for C 22 H 26 O 11 : C: 56.87 %, H: 5.25 %; found C: 56.97 %, H: 5.54 %. 4bII. The product was prepared applying the general procedure for diol esterification (see 4aII) starting form tetraethylene glycol 4bI (200 mg, 1.03 mmol) to afford the title compound (468 mg, 0.56 mmol, 55 %) as a white solid. 1 H-NMR (600 MHz, [D 6 ]DMSO): δ= 7.49–7.45 (m, 4H, 4H arom. ), 7.41–7.32 (m, 12H, 12H arom. ), 7.28 (dd, J= 5.1, 2.0 Hz, 6H, 6H arom. ), 7.21 (dd, J= 7.9, 1.5 Hz, 2H, 2H arom. ), 7.16 (t, J= 7.9 Hz, 2H, 2H arom. ), 5.18 (s, 4H, 2CH 2 ), 4.99 (s, 4H, 2CH 2 ), 4.33–4.22 (m, 4H, 2CH 2 ), 3.64–3.58 (m, 4H, 2CH 2 ), 3.45 (dt, J= 3.7, 2.3 Hz, 4H, 2CH 2 ), 3.41 (dt, J= 6.1, 3.7, Hz, 4H, 2CH 2 ) ppm. 13 CNMR (151 MHz, [D 6 ]DMSO): δ= 166.1 (CO 2 CH 2 ), 152.7 (C arom. ), 147.2 (C arom. ), 137.8 (C arom. ), 137.1 (C arom. ), 128.9 (C arom. ), 128.6 (C arom. ), 128.5 (C arom. ), 128.5 (C arom. ), 128.3 (C arom. ), 128.2 (C arom. ), 127.0 (C arom. ), 124.7 (C arom. ), 122.0 (C arom. ), 118.0 (C arom. ), 75.17 (CH 2 ), 70.63 (CH 2 ), 70.15 (CH 2 ), 70.10 (CH 2 ), 68.61 (CH 2 ), 64.44 (CH 2 ) ppm. ESI-MS (positive ESI-MS, MeOH, acidified): m/z: Calculated for C 50 H 50 NaO 11+ [M + Na + ]: 849.3245, found 849.3253. Elemental analysis: Calculated for C 50 H 50 O 11 : C: 72.62 %, H: 6.09 %; found C: 72.08 %, H: 6.09 %. 4b-H 4 .The ligand was prepared applying the general procedure for removal of benzyl protecting groups (see 4a-H 4 ) starting form 4bII Full Paper doi.org/10.1002/ejoc.202000843 EurJOC European Journal of Organic Chemistry (443 mg, 0.54 mmol) to afford the title compound (219 mg, 0.46 mmol, 87 %) as a white solid. 1 H-NMR (600 MHz, [D 6 ]DMSO): δ= 7.49–7.45 (m, 4H, 4H arom. ), 7.22 (d, J= 7.9 Hz, 2H, 2Harom.), 7.01 (d, J= 7.9 Hz, 2H, 2Harom.), 6.73 (t, J= 7.9 Hz, 2H, 2H arom. ), 4.41– 4.35 (m, 4H, 2CH 2 ), 3.71 (dd, J= 5.6, 3.5 Hz, 4H, 2CH 2 ), 3.54 (dd, J= 6.2, 3.5 Hz, 4H, 2CH 2 ), 3.51 (dd, J= 5.6, 3.5 Hz, 4H, 2CH 2 ) ppm. 13 CNMR (151 MHz, [D 6 ]DMSO): δ= 169.8 (CO 2 CH 2 ), 145.0 (C arom. ), 146.5 (C arom. ), 121.2 (C arom. ), 120.0 (C arom. ), 119.4 (C arom. ), 113.4 (C arom. ), 70.3 (CH 2 ), 70.2 (CH 2 ), 68.5 (CH 2 ), 64.9 (CH 2 ) ppm. ESI-MS (positive ESI-MS, MeOH, acidified): m/z: Calculated for C 22 H 26 NaO 11+ [M + Na + ]: 489.1367, found 489.1355. Elemental analysis: Calculated for C 22 H 26 O 11 : C: 56.65 %, H: 5.62 %; found C: 56.67 %, H: 4.91 %. 4cII. The product was prepared applying the general procedure for diol esterification (see 4aII) starting form pentaethylene glycol 4cI (1184 mg, 4.96 mmol) to afford the title compound (2105 mg, 2.42 mmol, 49 %) as a white solid. 1 H-NMR (600 MHz, [D 6 ]DMSO): δ= 7.50–7.45 (m, 4H, 4H arom. ), 7.43–7.32 (m, 12H, 12H arom. ), 7.29 (dd, J= 5.0, 2.0 Hz, 6H, 6H arom. ), 7.22 (dd, J= 7.9, 1.6 Hz, 2H, 2H arom. ), 7.17 (t, J= 7.9 Hz, 2H, 2H arom. ), 5.18 (s, 4H, 2CH 2 ), 5.00 (s, 4H, 2CH 2 ), 4.38–4.21 (m, 4H, 2CH 2 ), 3.66–3.59 (m, 4H, 2CH 2 ), 3.47 (dd, J= 5.8, 3.5 Hz, 4H, 2CH 2 ), 3.42 (dd, J= 5.8, 3.5 Hz, 4H, 2CH 2 ), 3.40 (s, 4H, 2CH 2 ) ppm. 13 C-NMR (151 MHz, [D 6 ]DMSO): δ= 165.7 (CO 2 CH 2 ), 152.3 (C arom. ), 146.74 (C arom. ), 137.3 (C arom. ), 136.6 (C arom. ), 128.4 (C arom. ), 128.2 (C arom. ), 128.1 (C arom. ), 128.0 (C arom. ), 127.8 (C arom. ), 127.8 (C arom. ), 126.6 (C arom. ), 124.3 (C arom. ), 121.6 (C arom. ), 117.6 (C arom. ), 74.8 (CH 2 ), 70.2 (CH 2 ), 69.7 (CH 2 ), 69.7 (CH 2 ), 69.7 (CH 2 ), 68.2 (CH 2 ), 64.0 (CH 2 ) ppm. ESI-MS (positive ESI-MS, MeOH, acidified): m/z: Calculated for C 52 H 54 NaO 12+ [M+Na + ]: 893.3513, found 893.3519. Elemental analysis: Calculated for C 52 H 54 O 12 : C: 71.71 %, H: 6.25 %; found C: 71.67 %, H: 6.30 %. 4c-H 4 .The ligand was prepared applying the general procedure for removal of benzyl protecting groups (see 4a-H 4 ) starting form 4cII (500 mg, 0.57 mmol) to afford the title compound (138 mg, 0.27 mmol, 47 %) as a white solid. 1 H-NMR (600 MHz, [D 6 ]DMSO): δ= 7.22 (dd, J= 7.9, 1.6 Hz, 2H, 2H arom. ), 7.01 (dd, J= 7.9, 1.6 Hz, 2H, 2H arom. ), 6.73 (t, J= 7.9 Hz, 2H, 2H arom. ), 4.42–4.37 (m, 4H, 2CH 2 ), 3.73–3.70 (m, 4H, 2CH 2 ), 3.54 (dd, J= 5.9, 3.6 Hz, 4H, 2CH 2 ), 3.50– 3.47 (m, 4H, 2CH 2 ), 3.46 (s, 4H, 2CH 2 ) ppm. 13 C-NMR (151 MHz, [D 6 ]DMSO): δ= 169.8 (CO 2 CH 2 ), 150.0 (C arom. ), 146.6 (C arom. ), 121.2 (C arom. ), 120.0 (C arom. ), 119.4 (C arom. ), 113.5 (C arom. ), 70.6 (CH 2 ), 69.9 (CH 2 ), 68.5 (CH 2 ), 64.9 (CH 2 ) ppm. ESI-MS (positive ESI-MS, MeOH, acidified): m/z: Calculated for C 24 H 30 NaO 12+ [M+Na + ]: 533.1635, found 533.1616. Elemental analysis: Calculated for C 24 H 30 O 12 : C: 56.47 %, H: 5.92 %; found C: 55.70 %, H: 6.0 %. 4dII. The product was prepared applying the general procedure for diol esterification (see 4aII) starting form hexaethylene glycol 4dI (1200 mg, 4.25 mmol) to afford the title compound (2089 mg, 2.28 mmol, 54 %) as a white solid. 1 H-NMR (600 MHz, [D 6 ]DMSO): δ= 7.49–7.43 (m, 4H, 4H arom. ), 7.42–7.30 (m, 12H, 12H arom. ), 7.27 (dtd, J= 6.2, 4.4, 1.9 Hz, 6H, 6H arom. ), 7.20 (dd, J= 7.8, 1.6 Hz, 2H, 2H arom. ), 7.15 (t, J= 8.0 Hz, 2H, 2H arom. ), 5.17 (s, 4H, 2CH 2 ), 4.99 (s, 4H, 2CH 2 ), 4.32–4.27 (m, 4H, 2CH 2 ), 3.66–3.60 (m, 4H, 2CH 2 ), 3.47 (dd, J= 5.9, 3.5 Hz, 4H, 2CH 2 ), 3.42 (dd, J= 5.9, 3.5 Hz, 4H,2CH 2 ), 3.39 (s, 4H, 2CH 2 ) ppm. 13 C-NMR (151 MHz, [D 6 ]DMSO): δ= 166.2 (CO 2 CH 2 ), 152.7, (C arom. ), 147.2 (C arom. ), 137.8 (C arom. ), 137.1 (C arom. ), 128.9 (C arom. ), 128.6 (C arom. ), 128.5 (C arom. ), 128.4 (C arom. ), 128.3 (C arom. ), 127.1 (C arom. ), 124.7 (C arom. ), 122.0 (C arom. ), 118.0 (C arom. ), 75.2 (CH 2 ), 70.6 (CH 2 ), 70.1 (CH 2 ), 68.6 (CH 2 ), 64.5 (CH 2 ) ppm. ESI-MS (positive ESI-MS, MeOH, acidified): m/z: Calculated for C 54 H 58 NaO 13+ [M + Na + ]: 937.3775, found 937.3773. Elemental analysis: Calculated for C 54 H 58 O 13 : C: 70.88 %, H: 6.39 %; found C: 70.84 %, H: 6.31 %. Eur. J. Org. Chem. 2020, 5161–5172 www.eurjoc.org © 2020 The Authors published by Wiley-VCH GmbH5168 4d-H 4 .The ligand was prepared applying the general procedure for removal of benzyl protecting groups (see 4a-H 4 ) starting form 4dII (600 mg, 0.66 mmol) to afford the title compound (138 mg, 0.39 mmol, 59 %) as a white solid. 1 H-NMR (600 MHz, [D 6 ]DMSO): δ= 7.22 (dd, J= 7.9, 1.6 Hz, 2H, 2H arom. ), 7.01 (dd, J= 7.9, 1.6 Hz, 2H, 2H arom. ), 6.73 (t, J= 7.9 Hz, 2H, 2H arom. ), 4.43–4.37 (m, 4H, 2CH 2 ), 3.75–3.70 (m, 4H, 2CH 2 ), 3.55 (dd, J= 5.9, 3.6 Hz, 4H, 2CH 2 ), 3.52– 3.42 (m, 8H, 4CH 2 ) ppm. 13 C-NMR (151 MHz, [D 6 ]DMSO): δ= 169.8 (CO 2 CH 2 ), 150.0 (C arom. ), 146.6 (C arom. ), 121.2 (C arom. ), 120.0 (C arom. ), 119.4 (C arom. ), 113.5 (C arom. ), 70.6 (CH 2 ), 69.9 (CH 2 ), 68.5 (CH 2 ), 64.9 (CH 2 ) ppm. ESI-MS (positive ESI-MS, MeOH, acidified): m/z: Calculated for C 22 H 26 NaO 11+ [M+Na + ]: 593.1636, found 593.1615. Elemental analysis: Calculated for C 22 H 26 O 11 : C: 56.31 %, H: 6.18 %; found C: 55.70 %, H: 6.33 %. General Procedure for the Preparation of THP protected diols (using 5aII as an example). 1,4-Butanediol 5aI (200 mg, 0.20 mL, 2.22 mmol, 1.0 equiv.) was dissolved in DMF (15 mL). NaH (60 wt.- % dispersion in mineral oil, 444 mg, 11.10 mmol, 5.0 equiv.) was added portion wise over 15 min. Afterwards 2-(2-Bromoethoxy)tetrahydro-2H-pyran (1.39 g, 1.01 mL, 6.66 mmol, 3 equiv.) was added drop wise and the resulting reaction mixture stirred at 70C for 4 h. After completion the reaction mixture was diluted with water (25 mL), extracted with EtOAc (2 × 40 mL) and washed with saturated NH 4 Cl solution. The solvent was removed under reduced pressure and the crude product purified by column chromatography (SiO 2 , 6:1 pentane/ethyl acetate to 1:1 pentane/ethyl acetate) to afford the title compound (740 mg, 2.14 mmol, 96 %) as a colorless oil. 1 H-NMR (600 MHz, [D 6 ]DMSO): δ= 4.57 (t, J= 3.6 Hz, 2H, 2CH), 3.77–3.71 (m, 2H, 2CHH), 3.71–3.66 (m, 2H, m, 2H, 2CHH), 3.51–3.44 (m, 6H, 3CH 2 ), 3.44–3.37 (m, 6H, 3CH 2 ), 1.74–1.66 (m, 2H, 2CHH), 1.65–1.56 (m, 2H, 2CHH), 1.56–1.50 (m, 4H, 2CH 2 ), 1.45 (m, 8H, 4CH 2 ). 13 C-NMR (151 MHz, [D 6 ]DMSO): δ= 98.0 (CH), 70.1 (CH 2 ), 69.4 (CH 2 ), 69.4 (CH 2 ), 66.1 (CH 2 ), 61.2 (CH 2 ), 30.2 (CH 2 ), 26.0 (CH 2 ), 25.0 (CH 2 ), 25.0 (CH 2 ), 19.1 (CH 2 ) ppm. ESI-MS (positive ESI-MS, MeOH, acidified): m/z: Calculated for C 18 H 34 NaO 6+ [M + Na + ]: 369,2248, found 369.2261. Elemental analysis: Calculated for C 18 H 34 O 6 : C: 62.40 %, H: 9.89 %; found C: 62.53 %, H: 9.54 %. General procedure for the removal of THP protecting groups (using 5aIII as an example). 5aII (700 mg, 2.02 mmol, 1.0 equiv.) was dissolved in MeOH (20 mL). Pyridinium p-toluenesulfonate (1523 mg, 6.06 mmol, 3.0 equiv.) was added and the reaction mixture was stirred at 25 °C for 16 h. The solvent was removed under reduced pressure and the crude product purified by column chromatography (SiO 2 , 20:1 pentane/ethyl acetate to, 10:1 ethyl acetate/ methanol) to afford the title compound (193 mg, 1.08 mmol, 54 %) as a colorless oil. 1 H-NMR (600 MHz, [D 6 ]DMSO): δ= 4.56 (t, J= 5.6 Hz, 2H, CH 2 ), 3.47 (q, J= 5.4 Hz, 4H, 2CH 2 ), 3.40–3.35 (m, 8H, 4CH 2 ), 1.52 (h, J= 2.9 Hz, 4H, 2CH 2 ). 13 C-NMR (151 MHz, [D 6 ]DMSO): δ= 72.0 (2CH 2 ), 70.1 (2CH 2 ), 60.3 (2CH 2 ), 26.0 (2CH 2 ) ppm. ESI-MS (positive ESI-MS, MeOH, acidified): m/z: Calculated for C 8 H 18 NaO 4+ [M + Na + ]: 201,1097, found 201,1099. Elemental analysis: Calculated for C 8 H 18 O 4 ·0.5MeOH: C: 52.56 %, H: 10.38 %; found C: 53.12 %, H: 11.09 %. 5aIV. The product was prepared applying the general procedure for diol esterification (see 4aII) using 5aIII (150 mg, 0.84 mmol) as starting material to afford the title compound (471 mg, 0.58 mmol, 69 %) as a white solid. 1 H-NMR (600 MHz, [D 6 ]DMSO): δ= 7.50–7.46 (m, 4H, 4Harom.), 7.41–7.32 (m, 12H, 12H arom. ), 7.28 (dd, J= 5.0, 2.0 Hz, 6H, 6H arom. ), 7.21 (dd, J= 7.9, 1.6 Hz, 2H, 2H arom. ), 7.16 (t, J= 7.9 Hz, 2H, 2H arom. ), 5.18 (s, 4H, 2CH 2 ), 4.99 (s, 4H 2CH 2 ), 4.35– 4.18 (m, 4H 2CH 2 ), 3.62–3.50 (m, 4H 2CH 2 ), 3.31 (q, J= 5.8, 4.5 Hz, H2CH 2 ), 1.44–1.39 (m, 4H, 2CH 2 ) ppm. 13 C-NMR (151 MHz,