General Solid-Phase Synthesis of Crown Ethers

Abstract

In a preferred embodiment, there is provided a method for preparing a crown ether, the method comprising: loading a resin having a resin functional group with a linking compound having a functional group selected for coupling to the resin functional group and at least two carbon atoms each having a substituent; coupling the linking compound to a polyethylene glycol having two terminal carbon atoms each bonded to an optionally protected terminal hydroxyl group to obtain a cyclized intermediate, whereby one said at least two carbon atoms or the substituent and an associated one of the two terminal carbon atoms or the hydroxyl groups undergo a coupling or substitution reaction; and removing the linking compound and the cyclized intermediate from the resin.

Claims

1. A method for preparing a crown ether, the method comprising: loading a resin having an amino functional group with a linking compound having a carbonyl selected for forming an imine bond with the amino functional group, the linking compound further comprising at least two carbon atoms each having an optionally protected hydroxyl group; coupling the linking compound to a polyether polyol having two terminal carbon atoms each bonded to an optionally protected hydroxyl group to obtain a cyclized intermediate, whereby each said at least two carbon atoms forms an ether bond with an associated one of the two terminal carbon atoms; and removing the cyclized intermediate from the resin to obtain the crown ether.

2. The method of claim 1, wherein the linking compound comprises a benzene compound, the at least two carbon atoms forming two carbon ring atoms of the benzene compound.

3. The method of claim 2, wherein the carbonyl forms part of a formyl bonded to the benzene compound, the formyl being located para to the optionally protected hydroxyl group of one said two carbon ring atoms.

4. The method of claim 2, wherein the at least two carbon atoms form two adjacent carbon ring atoms of the benzene compound, the polyether polyol comprising polyethylene glycol.

5. The method of claim 4, wherein the polyethylene glycol has the chemical formula H(OCH.sub.2CH.sub.2).sub.nOH, wherein n is an integer between 2 and 18, and terminal hydroxyl groups of the polyethylene glycol are optionally protected.

6. The method of claim 5, wherein n is an integer between 5 and 9.

7. The method of claim 1, wherein the hydroxyl groups of the at least two carbon atoms are unprotected, and the hydroxyl groups of the two terminal carbon atoms are protected, optionally wherein the hydroxyl groups of the two terminal carbon atoms are protected with methanesulfonyl or toluenesulfonyl.

8. The method of claim 1, wherein the linking compound is 3,4-dihydroxybenzaldehyde.

9. The method of claim 1, wherein the resin comprises an aminomethylpolystyrene resin, optionally wherein the aminomethylpolystyrene resin is crushed.

10. The method of claim 1, wherein said coupling the linking compound to the polyether polyol is performed with a base, optionally wherein the base is K.sub.2CO.sub.3.

11. A method for preparing a crown ether, the method comprising: loading a resin having a resin functional group with a linking compound having a functional group selected for coupling to the resin functional group and at least two carbon atoms each having an optionally protected hydroxyl group; coupling the linking compound to a polyether polyol having two terminal carbon atoms each bonded to an optionally protected hydroxyl group to obtain a cyclized intermediate, whereby each said at least two carbon atoms forms an ether bond with an associated one of the two terminal carbon atoms; and removing the cyclized intermediate from the resin to obtain the crown ether.

12. The method of claim 11, wherein the resin functional group is an amino functional group, an aminomethyl functional group, a hydrazinyl functional group, a carbonylmethyl functional group, a hydroxymethyl functional group, a methanethiol functional group, an ethane-1,2-diol functional group, a maleimide functional group or a furanyl functional group.

13. The method of claim 11, wherein the functional group comprises a carbonyl, carboxyl, thiol, ketone, aldehyde, amine, hydrazine, boronic acid or maleimide.

14. The method of claim 11, wherein the linking compound comprises a substituted aryl or heteroaryl compound.

15. The method of claim 14, wherein the at least two carbon atoms form two carbon ring atoms of the substituted aryl or heteroaryl compound.

16. The method of claim 15, wherein the substituted aryl or heteroaryl compound comprises a benzene compound, the functional group being located para to the optionally protected hydroxyl group of one said two carbon ring atoms.

17. The method of claim 14, wherein the at least two carbon atoms form two adjacent carbon ring atoms of the substituted aryl or heteroaryl compound, the polyether polyol comprising polyethylene glycol.

18. The method of claim 17, wherein the polyethylene glycol has the chemical formula HOCH.sub.2CH.sub.2).sub.nOH, wherein n is an integer between 5 and 9, and terminal hydroxyl groups of the polyethylene glycol are optionally protected.

19. The method of claim 11, wherein the hydroxyl groups of the at least two carbon atoms are unprotected, and the hydroxyl groups of the two terminal carbon atoms are protected, optionally wherein the hydroxyl groups of the two terminal carbon atoms are protected with methanesulfonyl or toluenesulfonyl.

20. The method of claim 11, wherein the hydroxyl groups of the at least two carbon atoms are protected, and the hydroxyl groups of the two terminal carbon atoms are unprotected, optionally wherein the hydroxyl groups of the at least two carbon atoms are protected with methanesulfonyl or toluenesulfonyl.

21. The method of claim 11, wherein the resin comprises an aminomethylpolystyrene resin, optionally wherein the aminomethylpolystyrene resin is crushed.

22. The method of claim 11, wherein said coupling the linking compound to the polyether polyol is performed with a base, optionally wherein the base is K.sub.2CO.sub.3.

23. A method for preparing a crown ether, the method comprising: loading a resin having a resin functional group with a linking compound having a functional group selected for coupling to the resin functional group and at least two carbon atoms each substituted with a first substituent; coupling the linking compound to a reactant compound of the formula XCH.sub.2CH.sub.2 (OCH.sub.2CH.sub.2).sub.nX, wherein n is an integer between 1 and 17, and X is a second substituent, one of the first and second substituents being a leaving group and a remaining one of the first and second substituents being a nucleophilic substituent, whereby the linking compound and the reactant compound undergo a substitution reaction with the nucleophilic substituent replacing the leaving group to thereby obtain a cyclized intermediate; and removing the cyclized intermediate from the resin to obtain the crown ether.

24. The method of claim 23, wherein the first substituent is the nucleophilic substituent, and the second substituent is the leaving group.

25. The method of claim 23, wherein the first substituent is the leaving group, and the second substituent is the nucleophilic substituent.

26. The method of claim 23, wherein the leaving group is selected from the group consisting of tosylate, mesylate, bromide, iodide, triflate and chloride.

27. The method of claim 23, wherein the nucleophilic substituent is hydroxyl.

28. The method of claim 23, wherein the resin functional group is an amino functional group, an aminomethyl functional group, a hydrazinyl functional group, a carbonylmethyl functional group, a hydroxymethyl functional group, a methanethiol functional group, an ethane-1,2-diol functional group, a maleimide functional group or a furanyl functional group.

29. The method of claim 23, wherein the functional group comprises a carbonyl, carboxyl, thiol, ketone, aldehyde, amine, hydrazine, boronic acid or maleimide.

30. The method of claim 23, wherein the linking compound comprises a substituted aryl or heteroaryl compound, the at least two carbon atoms forming two adjacent carbon ring atoms of the substituted aryl or heteroaryl compound.

31. The method of claim 30, wherein the substituted aryl or heteroaryl compound comprises a benzene compound, the functional group being located para to the first substituent of one said two adjacent carbon ring atoms.

32. The method of claim 23, wherein n is an integer between 4 and 8.

33. The method of claim 23, wherein the resin comprises an aminomethylpolystyrene resin, optionally wherein the aminomethylpolystyrene resin is crushed.

34. The method of claim 23, wherein said coupling the linking compound to the reactant compound is performed with a base, optionally wherein the base is K.sub.2CO.sub.3.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Reference may now be had to the following detailed description taken together with the accompanying drawings in which:

[0038] FIG. 1 shows photographs of test vials in a ninhydrin test performed after the first trial of removals, where vial C is commercial control; vial 1 used HCl exclusively; vial 2 NH.sub.4OH exclusively; and vial 3 used HCl then NH4OH, and where the photograph on the right shows the vials after 5 minutes, in which vials C and 3 turned purple while vials 1 and 2 remained yellow;

[0039] FIG. 2 shows an outline of reversible imine and related linkages to immobilize the linking compound to the resin, where R, R1 and R2 represent scaffolds attached to diols;

[0040] FIG. 3 shows condensation-related alternatives for the immobilization of linkers to the resin, where R, R1, and R2 represent scaffolds attached to diols;

[0041] FIG. 4 shows furan-maleimide Diels-Alder reaction for reversible conjugation of a linking compound or crown ether substrate to the resin;

[0042] FIG. 5 shows a .sup.1H NMR spectrum of (ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl)bis(4-methylbenzenesulfonate) (1c);

[0043] FIG. 6 shows a .sup.1H NMR spectrum of ((oxybis(ethane-2,1-diyl))bis(oxy))bis(ethane-2,1-diyl)bis(4-methylbenzenesulfonate) (1d);

[0044] FIG. 7 shows a .sup.1H NMR spectrum of 3,6,9,12-tetraoxatetradecane-1,14-diyl bis(4-methylbenzenesulfonate) (1e);

[0045] FIG. 8 shows a .sup.1H NMR spectrum of 3,6,9,12,15-pentaoxaheptadecane-1,17-diyl bis(4-methylbenzenesulfonate) (1f);

[0046] FIG. 9 shows a .sup.13C NMR spectrum of 3,6,9,12,15-pentaoxaheptadecane-1,17-diyl bis(4-methylbenzenesulfonate) (1f);

[0047] FIG. 10 shows a .sup.1H NMR spectrum of 3,6,9,12-tetraoxatetradecane-1,14-diyl dimethanesulfonate (2e);

[0048] FIG. 11 shows a .sup.1H NMR spectrum of on-resin synthesized 4-Formylbenzo[18C6] following purification;

[0049] FIG. 12 shows an IR spectrum of on-resin synthesized 4-Formylbenzo[18C6] following purification;

[0050] FIG. 13 shows a .sup.1H NMR spectrum of on-resin synthesized 4-Formylbenzo[21C7] following purification;

[0051] FIG. 14 shows IR spectra of commercial amine-functionalized polystyrene resin;

[0052] FIG. 15 shows IR spectra of 4-(PS-iminomethyl)benzene-1,2-diol;

[0053] FIG. 16 shows IR spectra of (3,4-dimethoxybenzylidene)methanamine-PS;

[0054] FIG. 17 shows comparative IR spectra, where commercial resin was fresh, unused aminomethyl-PS, loaded SM was 4-(PS-iminomethyl)benzene-1,2-diol, and loaded crown ether was 4-(PS-iminomethyl) 4-formylbenzo 18C6 crown ether, loaded from solution-prepared 4-Formylbenzo[18C6] on to resin using same loaded method as SM; This figure is meant to provide fingerprinting for the user for comparing synthetic batches with prior to cleavage from the resin.

[0055] FIG. 18 shows a .sup.1H NMR spectrum of on-resin synthesized 4-Formylbenzo[18C6] directly removed from resin crude with no workup or isolation other than partial removal of solvent;

[0056] FIG. 19 shows .sup.1H NMR spectrum of dimethoxybenzyl model;

[0057] FIG. 20 shows a .sup.1H NMR spectrum of 2,2-(1,2-phenylenebis(oxy))bis(ethan-1-ol) (A);

[0058] FIG. 21 shows a .sup.13C NMR spectrum of 2,2-(1,2-phenylenebis(oxy))bis(ethan-1-ol) (A);

[0059] FIG. 22 shows .sup.1H NMR spectra of 4-formylbenzo[24C8];

[0060] FIG. 23 shows a .sup.1H NMR spectrum of 4-formylbenzo[27C9]; and

[0061] FIG. 24 shows a .sup.1H NMR spectra of 4-formylbenzo[30C10].

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0062] In a preferred non-limiting embodiment, the method was performed in accordance with the following reaction pathway:

##STR00004##

[0063] Specifically, the reaction pathway as shown above includes initial loading of an aldehyde substituted aromatic base onto a resin having an amino or primary amino functional group, such as an aminomethylpolystyrene resin, through an imine formation. The reaction pathway further includes introducing cyclization conditions, such as those previously established by solution chemistry or solution-phase synthesis, to produce a cyclized intermediate on the resin support and then releasing the cyclized intermediate to obtain a benzocrown ether under acidic conditions. The resin, which would contain a terminal ammonium would be then replenished back into amine by pH adjustment to restore reactivity, so as to permit reuse in future reactions.

[0064] The applicant has appreciated that the method may permit more ready and convenient preparation of a crown ether on a solid support, allowing for separation of resin beads from a reaction mixture and removing or washing away of excess reagents, while maintaining the intended product until cleavage from the resin, while reducing polymerization of reactants, intermediates and/or products at least in part by immobilization of the intermediates to promote intramolecular ring closure and not the polymerization.

[0065] Although the above reaction pathway shows resin loading by imine formation, it is to be appreciated that the loading may be performed with other functional groups and/or reactions. FIG. 2 shows other reactions which may occur during the loading step, with, for example, an aminomethyl resin (top), a hydrazine resin (middle) and a carbonylmethyl resin (bottom). The loading step may be performed with other resins, functional groups and reactions, permitting for coupling between the resin functional group and the functional group of the linking compound. By way of non-limiting examples, and as seen in FIG. 3, such other functional groups and reactions may include esterification, boronate esters, acetals, or disulfides, which may use condensation and related reactions to generate stable intermediates that can be reversed with water and acid or, in the case of disulfides, with reducing conditions. As further seen in FIG. 4, the ligand may be loaded or conjugated to the resin using a reversible Diels-Alder reaction between a furan and maleimide.

Reagents and Instruments

[0066] Commercially available regents used were sourced from Sigma Aldrich, otherwise stated, which includes methylamine polystyrene resin (70-90 mesh and 200-400 mesh 1-1.5 g/mol loading), 3,4-dihydroxybenzyaldehyde, 3,4-dimethoxybenzaldehyde, and Tosylated chloride. Peg chains were sourced from Oakwood Chemicals ACS grade acetonitrile, ethyl acetate, tetrahydrofuran and other chemicals were purchased from Sigma-Aldrich, AK Scientific, Oakwood Chemicals, Alfa Aesar or Acros Chemicals. Reagents were used without prior purification. All heated reactions were conducted using oil baths or metal bead baths on IKA RET Basic stir plates equipped with a P1000 temperature probe. All reactions under elevated temperatures used all glass joints in contact with the solvent. Septa were generally used at the top of condensers. Vacuum and gases were introduced from a Schlenk line using needles through septa during reactions, and generally directly using glass adapters during drying of samples in round bottom flasks. Thin layer chromatography was performed using EMD aluminum-backed silica 60 F254-coated plates and were visualized using either UV-light (254 nm), KMnO.sub.4, vanillin, Hanessian's stain, PMA, or DNP stain. Standard work-up procedure for all reactions undergoing an aqueous wash, unless otherwise stated, involved back extraction of every aqueous phase, a drying of the combined organic phases with anhydrous magnesium sulphate, filtration either using vacuum and a sintered-glass frit or through a glass-wool plug using gravity, and concentration under reduced pressure on a rotary evaporator (Bchi or Synthware). Depending on the compound, various methods were used to purify titled compounds. The exact conditions used would be mentioned in synthetic procedure. .sup.1H NMR spectra were obtained at 300 MHz or 500 MHz, and proton-decoupled, and .sup.13C NMR spectra were obtained at 75 or 125 MHz on Bruker instruments. NMR chemical shifts () are reported in ppm and are calibrated against residual solvent signals of CHCl.sub.3 (7.26), DMSO-d.sub.6 ( 2.54), acetone-d.sub.5 ( 2.05), or methanol-d.sub.3 ( 3.31). Proton NMR was acquired for all crude mixtures prior to purification even when not otherwise stated. LRMS ESI (positive and negative) was run by Advion ESI LR Mass and processed data by Advion MassExpress and Advion DataExpress. HRMS were conducted on Thermo Scientific Orbitrap Velos Pro (Easy-nLC/HESI Hybrid Ion Trap-Orbitrap Mass Spectrometer) by Queens University (Canada). IR was run on Bruker IR using solid loading and measured between 4000 to 400 cm.sup.1. Pictures were taken directly from the software or processed through Microsoft Excel.

Polyethylene Glycol

[0067] While the reaction pathway as identified above is shown with a cyclization reaction involving tosylated polyethylene glycol, it is to be appreciated that the cyclization reaction may be conducted with unprotected polyethylene glycol or polyethylene glycol protected with other protecting groups, such as mesylate. In an alternative embodiment, terminal hydroxyl groups of polyethylene glycol may be replaced with other leaving groups, such as a halogen.

[0068] Provided below is a reaction scheme showing three different methods A to C for converting a polyethylene glycol to include different leaving groups:

##STR00005##

General Method A. Tosylation of PEG components: The method may follow procedure based on previous literature or Y. Chen and G. L. Baker, The Journal of Organic Chemistry, 1999, 64, 6870-6873. PEG (42 mmol) and 4-toluenesulfonyl chloride (24.1 g, 126 mmol) were dissolved in THF (110 ml) and cooled down to 0 C. To the mixture, pestle-and-mortar crushed KOH (14 g, 252 mmol) was dissolved in H.sub.2O (16 ml) and the solution was slowly poured added and stirred for overnight at room temperature. Upon completion, THF was evaporated, and H.sub.2O was added followed by an extraction with diethyl ether (2). After separating the layers, the organic layer was washed with brine then dried with MgSO.sub.4. The solvent was evaporated to obtain a crude.

[0069] By way of selected example of general method A, the following compounds were prepared:

(ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl)bis(4-methylbenzenesulfonate) 1c

Following Method A, the Sample was a White Solid. Yield %: 79% Over 1 Reaction.

[0070] .sup.1H NMR (301 MHZ, CDCl.sub.3) 7.79 (d, J=8.3 Hz, 4H), 7.34 (d, J=8.0 Hz, 4H), 4.19-4.07 (m, 4H), 3.65 (dd, J=5.6, 4.0 Hz, 4H), 3.52 (s, 4H), 2.44 (s, 6H), 1.61 (s, 3H). See FIG. 5.

HRMS (ESI) [M+H].sup.+ calc'd C.sub.20H.sub.27O.sub.8S.sub.2+: 459.11419 (predicted) found: 459.11383.

((oxybis(ethane-2,1-diyl))bis(oxy))bis(ethane-2,1-diyl)bis(4-methylbenzenesulfonate) 1d

Following Method A, the Sample was a Clear Oil. Yield: 96%. Rf: 0.33 in 2 Hexane: 1 DCM: 1 Acetone

[0071] .sup.1H NMR (300 MHz, CDCl.sub.3) 7.85-7.68 (m, 4H), 7.50-7.30 (m, 4H), 4.15 (td, J=5.0, 1.3 Hz, 4H), 3.73-3.64 (m, 4H), 3.56 (dd, J=3.7, 1.4 Hz, 8H), 2.45 (d, J=6.2 Hz, 6H).

See FIG. 6. Similar to reported literature of title compound.

3,6,9,12-tetraoxatetradecane-1,14-diyl bis(4-methylbenzenesulfonate) 1e

Following Method A, the Sample is a White Solid. Yield %: 77%-90% Yield Over 3 Reactions. Rf: 0.52 in 2 Hexane: 1 DCM: 1 Acetone m.p.: 43-45 C.

[0072] .sup.1H NMR (300 MHz, CDCl3) 7.82-7.73 (d, 4H), 7.32 (d, J=8.1 Hz, 4H), 4.18-4.09 (m, 4H), 3.71-3.62 (m, 4H), 3.57 (d, J=6.6 Hz, 12H), 2.43 (s, 6H). See FIG. 7.

3,6,9,12,15-pentaoxaheptadecane-1,17-diyl bis(4-methylbenzenesulfonate) 1f

Following Method A, the Sample is a Thick Slightly Opaque Off-White Oil. Yield %: 95% Yield Over 1 Reaction. Rf: 0.36 in 2 Hexane: 1 DCM: 1 Acetone

[0073] .sup.1H NMR (300 MHz, CDCl.sub.3) 7.78 (d, J=8.4 Hz, 4H), 7.44-7.27 (m, 4H), 4.25-4.07 (m, 4H), 3.77-3.64 (m, 4H), 3.64-3.48 (m, 16H), 2.44 (d, J=3.6 Hz, 6H). .sup.13C NMR (76 MHz, CDCl.sub.3) 144.92, 133.08, 129.94, 128.08, 70.84, 70.71, 70.65, 70.60, 69.37, 68.77, 21.75. See FIGS. 8 and 9.

General Method B. Mesylation of PEG components: In a flamed dried flask, PEG (4.3 mmol) and triethylamine (1.8 ml, 12.9 mmol) were dissolved into DCM (21 ml) at 0 C. Mesyl chloride (1 ml, 8.6 mmol) was added dropwise and left stirring at 0 C. for two hours. The solution was washed with 1M HCl (110 ml), sat. NaHCO.sub.3 (110 ml), and brine (110 ml). The organic layer was dried by Mg.sub.2SO.sub.4 and evaporated by vacuo to afford a crude without further purification and was stored in 20 C. freezer to preserve it.

[0074] By way of selected example of general method B, the following compounds were prepared:

3,6,9,12-tetraoxatetradecane-1,14-diyl dimethanesulfonate 2e

Following Method B, the Sample was a Clear Oil that Slowly Crashed into Colorless Crystals. R.sub.f: 0.30 in 2 Hexane: 1 DCM: 1 Acetone.

[0075] .sup.1H NMR (301 MHz, CDCl3) 4.41-4.31 (m, 4H), 3.79-3.70 (m, 4H), 3.70-3.55 (m, 12H), 3.07 (d, J=1.5 Hz, 6H). ESI HR [M+H].sup.+ calc'd C.sub.12H.sub.27O.sub.10S.sub.2.sup.+ for 395.10401 predicted, 395.10306 g/mol found. See FIG. 10.

[0076] General procedure for dimesylation of polyethylene glycol as a diol may include the following: The diol (5.0 g, 1.0 eq) was dissolved in CH.sub.2Cl.sub.2 (100 mL) and cooled to 0 C. under a nitrogen atmosphere. Triethylamine (2.6 eq) was diluted with CH.sub.2Cl.sub.2 (25 mL) and added to the solution of the diol. To the stirred solution, a solution of methanesulfonyl chloride (2.2 eq) in CH.sub.2Cl.sub.2 (25 mL) was added to the reaction mixture at 0 C., dropwise via an addition funnel. After completion of the addition, the reaction mixture was allowed to warm to room temperature over 2 h. A 5% aq HCl solution was added, and the mixture was stirred for 15 min. The biphasic mixture was decanted into a separatory funnel and the organic layer was separated. The organic solution was washed with saturated aq. NaHCO.sub.3 (50 mL), distilled H.sub.2O (50 mL) and brine (50 mL). The solution was dried over MgSO.sub.4 and the solvent was removed in vacuo. Solid products were recrystallized from MeOH, and the products, which were oils at room temperature, were used without purification after their characterization by .sup.1H NMR and IR spectroscopy.

[0077] Furthermore, as an example of dimesylation of polyethylene glycol, 3,6,9,12-tetraoxatetradecane-1,14-diyl dimethanesulfonate was prepared as follows: In a flamed dried flask, pentaethylene glycol (1 g, 4.3 mmol) and triethylamine (1.8 ml, 12.9 mmol) were dissolved into DCM (21 ml) at 0 C. Mesyl chloride (1 ml, 8.6 mmol) was added dropwise and left stirring at 0 C. for two hours. The solution was washed with 1M HCl (110 ml), sat. NaHCO.sub.3 (110 ml), and brine (110 ml). The organic layer was dried by Mg.sub.2SO.sub.4 and evaporated by vacuo to afford titled compound as a clear oil that slowly crashed into colorless crystals. The crude oil was used without further purification and was stored in 20 C. freezer to preserve it. Rf: 0.30 in 2 hexane: 1 DCM: 1 acetone. .sup.1H NMR (301 MHz, CDCl.sub.3) 4.38-4.35 (m, 4H), 3.87-3.56 (m, 18H 16H?), 3.07 (s? d, J=0.8 Hz, 6H). ESI HR [M+H].sup.+=295.10306 g/mol (395.104 predicted).

[0078] To test synthesis of tosylated polyethylene glycol, ethane-1,2-diyl bis(4-methylbenzenesulfonate) was prepared as follows: A 100 mL round bottom flask equipped with a stir bar was charged with ethylene glycol (0.62 g, 10 mmol), triethylamine (NEt.sub.3, 3.34 mL, 24 mmol), ptosylchloride (TsCl, 4.58 g, 24 mmol), 4-dimethylaminopyridine (DMAP, 0.12 g, 1 mmol) and 20 mL anhydrous DCM. The reaction mixture was stirred overnight at RT. After reaction, 20 mL H.sub.2O was added and the solution was extracted with DCM for three times. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, concentrated under vacuum. The obtained light yellow solid was rinsed with methanol to give target compound 1,2-bis(p-tolylsulfonyloxy) ethane as a white solid (3.62 g, 98%). .sup.1H NMR (400 MHZ, CDCl.sub.3) : 7.75 (d, J=8.4 Hz, 4H), 7.36 (d, J=8.4 Hz, 4H), 4.20 (s, 4H), 2.48 (s, 6H). ppm. .sup.13C NMR (100 MHZ, CDCl.sub.3) : 145.4, 132.3, 130.0, 127.9, 66.7, 21.7 ppm.

[0079] Furthermore, 3,6,9,12-tetraoxatetradecane-1,14-diyl bis(4-methylbenzenesulfonate) was prepared as follows: Pentaethylene glycol (10 g, 42 mmol) and 4-toluenesulfonyl chloride (24.1 g, 126 mmol) were dissolved in THF (110 ml) and cooled down to 0 C. To the mixture, pestle-and-mortar crushed KOH (14 g, 252 mmol) was dissolved in H.sub.2O (16 ml) and the solution was slowly poured added and stirred for overnight at room temperature. Upon completion, H.sub.2O was added then extracted with ether (2). After separating the layers, the organic layer was washed with brine then dried with MgSO.sub.4. The solvent was evaporated to obtain a yellow oil crude that slowly crashed out as pure white solid. There were no further purification. Yield %: 77%-90% yield over 3 reactions. Rf: 0.52 in 2 Hexane: 1 DCM: 1 Acetone m.p.: 43-45 C. .sup.1H NMR (300 MHz, CDCl.sub.3) 7.82-7.73 (d, 4H), 7.32 (d, J=8.1 Hz, 4H), 4.18-4.09 (m, 4H), 3.71-3.62 (m, 4H), 3.57 (d, J=6.6 Hz, 12H), 2.43 (s, 6H).

[0080] In addition, 3,6,9,12,15-pentaoxaheptadecane-1,17-diyl bis(4-methylbenzenesulfonate) was prepared as follows: Hexaethylene glycol (10 g, 35.4 mmol) and 4-toluenesulfonyl chloride (20.3 g, 106 mmol) were dissolved in THF (110 ml) and cooled down to 0 C. To the mixture, pestle-and-mortar crushed KOH (11.9 g, 56 mmol) was dissolved in H.sub.2O (13 ml) and the solution was slowly poured added and stirred for overnight at room temperature. Upon completion, H.sub.2O was added then extracted with ether (2). After separating the layers, the organic layer was washed with brine then dried with MgSO.sub.4. The solvent was evaporated to obtain a thick slightly opaque clear oil crude. There were no further purification. Yield %: 95% yield Rf: 0.36 in 2 Hexane: 1 DCM: 1 Acetone .sup.1H NMR (300 MHz, CDCl.sub.3) 7.78 (d, J=8.4 Hz, 4H), 7.44-7.27 (m, 4H), 4.25-4.07 (m, 4H), 3.77-3.64 (m, 4H), 3.64-3.48 (m, 16H), 2.44 (d, J=3.6 Hz, 6H).

[0081] Pertaining to an embodiment in which terminal hydroxyl groups of a polyethylene glycol is replaced by other leaving groups, 1,14-dichloro-3,6,9,12-tetraoxatetradecane was prepared as follows: 20.0 g (71 mmol) of hexaethylene glycol, 13 mL (179 mmol) of thionyl chloride, 0.1 mL of DMF and 40 mL of dry heptane was heated to reflux for 2 h in a 250 mL round bottom flask fitted with a stirrer and a condenser. Heptane and excess thionyl chloride were removed by distillation, to yield a viscous, yellowish oil. The product was vacuum distilled to render a pure colorless liquid. Yield: 90%. .sup.1H NMR (DMSO): d=3.51 (broad s, 16H); 3.54 (s, 4H); 3.68 (s, 4H). .sup.13C NMR (DMSO): d=43.26; 69.61; 70.40.

Resin method: An example of the method of the invention was conducted in accordance with the following reaction scheme:

##STR00006##

A reaction scheme similar to a solution method was performed on a solid support.

##STR00007##

Either crushed (by pestle and mortar) for 5 minutes, or used directly from the bottle, aminomethyl PS resin (1.0-1.5 mol, 1 g) was mixed with 3,4-dihydroxybenzladehyde (2 mmol, 0.27 g) in ethanol under reflux conditions and nitrogen atmosphere for 3 h The red-brown solid was collected by filtration, washed with ethanol and DCM and dried under vacuum. A test for free amine was tested by taking a sample in a vial and putting two drops of ninhydrin and letting it stand for 15 minutes alongside of a vial of amidomethyl as a control. Any purple color development would indicate some free amine is still present and needs to be re-subjected to reaction conditions. No further purification was performed and continued to next reactions. General mass increase indicated mol loading was within the range stated of the product and exact mol/g of the batch was noted to calculate for further reactions. Resin-bound material was characterized by IR to confirm loading and conjugation (FIG. 15) compared to the base resin (FIG. 14).
It is to be appreciated that other solvents, such as THF, 2-THF, Toluene, DCM, DMF and others alike may be used in the loading step.

##STR00008##

Aminomethyl PS resin (1.0-1.5 mol, 1 g) was mixed with 3,4-dimethoxybenzladehyde (2 mmol) in ethanol under reflux conditions and nitrogen atmosphere for 3 h. The yellow resin was collected by filtration, washed with ethanol and DCM and dried under vacuum. No further purification was performed and continued to next reactions. General mass increase indicated mol loading was within the range stated of the product and exact mol/g of the batch was noted to calculate for further reactions. Resin bound material was characterized by IR (FIG. 16)

##STR00009##

To a round bottom flask was charged-(PS-iminomethyl)benzene-1,2-diol (0.2 mmol loaded material), PEG (0.22 mmol), base (0.6 mmol) in organic solvent (10 ml). The reaction was refluxed for two days under Argon gas. Afterwards, the reaction was halted and the liquid was decanted carefully while keeping the resin in the flask. Washing of the resin began with sonification with DI water (5 ml2) to remove salt then fresh THF (5 ml3), decanting in between and then finally filtered to dry, IR of crude resin suggested conversion (i.e. FIG. 17). The crown ether was cleaved according to the above described procedure, and concentrated to dryness. The mass of the solid was weighed along with an NMR to identify conversion (i.e. FIG. 18). Table 1 features some conditions:

TABLE-US-00001 TABLE 1 Base Resin .sup.a Solvent Conversion .sup.b K.sub.2CO.sub.3 noncrushed MeCN 88% K.sub.2CO.sub.3 crushed MeCN 96% K.sub.2CO.sub.3 noncrushed THF 89% .sup.a Noncrushed refers to using loaded resin that used resin directly from the bottle. Crushed refers to loaded resin that used resin that were crushed for 5 minutes in a pestle and mortar prior to loading step. .sup.b Conversion was determined by NMR through integration ratio of products and unreacted 3,4-dihydroxybenzaldehyde in acetone-d.sub.6.

##STR00010##

The resin was placed into a 4:1 THF: 1M HCl solution and agitated by a sonicator for 45 minutes. The resulting yellow solution was decanted, and the resin was sonicated briefly with fresh THE two more times or until solution ran clear. The THF in the solution was evaporated by vaccou and the remaining liquid is extracted by ethyl acetate (3). The organic layer was combined and washed with brine (1), then dried with magnesium sulfate, filtered, and concentrated. Further purification may be included, depending on the product crown ether.

##STR00011##

Used resins were treated with 4:1 THF: NH.sub.4OH and agitated by a sonicator for 45 minutes. The resulting solution was decanted, and the resins were washed and sonicated in fresh THE two times and filtered to dryness. A sample of the batch was subjected to the ninhydrin test against unused resins to confirm presence of terminal amine. (FIG. 19)

Attaching and Removal Model

[0082] In order to confirm reuse of the resin with the method of the invention, cleavage conditions were investigated using a model to load on and off the same batches of resins. Conditions were explored using a dimethoxybenzaldehyde model attached on the resin bead. To detach from the polystyrene matrix, an imine hydrolysis must occur to retrieve back the aldehyde and free amine. Usual conditions to achieve hydrolysis use acidic aqueous conditions, however, due to the hydrophobic nature of the polymer, a series of test was performed diluted in THF. A model scheme of the investigation is shown below:

##STR00012##

[0083] Three separate batches starting at 100 mg of resins loaded with dimethoxybenzyl were introduced in three separate conditions: 1) 1 M HCl/THF (1:4, 5 ml), 2) NH.sub.4OH/THF (1:4, 5 ml), and 3) 1 M HCl/THF (1:4, 5 ml) then replaced by NH.sub.4OH/THF (1:4, 5 ml). Samples were mechanically agitated for 2 hours total. Once finished, the resins were filtered and dried and the filtrate were extracted. The same recovered resins were re-subjected to reloading of model and detachment for another two times to check on mass recovery and loading capacity over repeated use.

[0084] The filtrate was extracted and confirmed with NMR to show acidic conditions return quantitative mass crude with minimal contamination while NH.sub.4OH featured only trace amounts with significant peaks in grease region. Continuous runs of resin show with NMR (FIG. 19) more lessened grease peaks over time with HCl, but continues to be present in NH.sub.4OH washes, with the exclusive basic wash consistently having less grease than the combined washes, suggesting a possible need for alternative basic wash to facilitate integrity of the resin for longer periods of time. However, the loading sizes remained relatively consistent over all three samples.

[0085] Material recovery was also studied. Conditions 2 and 3 during the run trial were weighed before and after each loading and separation steps (Table 3). The acidic component of condition 3 was able to release the majority of the initially loaded model. Mass loss in the resin over runs is due to removal of resin for sampling.

TABLE-US-00002 TABLE 3 Mass recovery per trial run of dimethoxybenzyl model resin test. Run #1 Run #2 Run #3 .sup.A Resin .sup.A Resin .sup.A Resin mass mass mass .sup.B Recovered (mass) (mass) .sup.B Recovered P (mass) mass Method: (mg) (mg) (mg) .sup.C % (mg) (mg) .sup.C % 2 Only 103 (14.2) 63.3 (8.7) 1.9 .sup.E <22% 39 (12.3) 5.9 .sup.E <50% NH.sub.4OH 3 HCl 106 (14.5) 34.2 (4.7) 4.7 .sup.D >95% 12.3 (2.3) 2.2 .sup.D 95% NH.sub.4OH .sup.A initial total resin mass with Dimethoxybenzyl attached (mass of just Dimethoxybenzyl attached) .sup.B crude mass retrieved by extraction .sup.C Total crude mass percent recovery compared to attached Dimethoxybenzyl model .sup.D Significant amount of P found in crude observed in NMR of HCl Extraction component .sup.E majority of grease found in crude observed in NMR.

[0086] As seen in FIG. 1, the resin component was tested by ninhydrin test along with commercial sample to observe the presence of free amine. Resins subjected to first acid then basic conditions suggested both may be preferred to detach the loaded reagent and then neutralize the amine to become active again. IR was also used to compare with fresh commercial control and found identical results with the combined treatment.

Synthesis of Model Precursors for Optimal Electrophilic/Nucleophilic Placement

[0087] In experimental studies, ring closure with a nucleophile being loaded on the resin and electrophilic tosylated-PEG in solution have been performed. A reverse of that reaction may be performed to assess whether cyclization may occur with a free floating nucleophile. A reaction scheme of the reverse reaction for model precursors is provided below:

##STR00013##

[0088] An overview of studies which may be conducted with the model precursors is provided below:

TABLE-US-00003 [00014] Possible combinations to compare from this set: B-C, B-F A-D, E-D [00015]
Under argon, catechol (5.5 g, 50 mmol) was dissolved in 95% ethanol (50 ml) and placed in an ice bath. A solution of NaOH (5 g in 3:1 ethanol:water, 50 ml) was added in slowly, following dropwise addition of 2-chloroethanol (10 ml). The mixture was refluxed for 48 hr, then evaporated the ethanol via vaccou. The brown crude was washed with water (20 ml) and extracted by DCM (320 ml). The organic solution was collected, dried with MgSO.sub.4, filtered and concentrated. The titled compound was purified by recrystallization of ethanol to produce white solid that could be filtered and dried. Characterization matched reported literature. Yield: 34% Melting point: 72-74 C. .sup.1H NMR (301 MHZ, CDCl3) 6.97 (s, 4H), 4.12 (ddd, J=5.4, 3.0, 1.3 Hz, 4H), 4.01-3.85 (m, 4H), 3.49 (t, J=6.1 Hz, 2H). .sup.13C NMR (76 MHz, CDCl3) 149.28, 122.71, 116.22, 72.17, 61.39.
HRMS (ESI) [M+H].sup.+ (C.sub.10H.sub.15O.sub.4.sup.+)=calc'd 199.09649, found 199.09474. See FIGS. 20 and 21.

##STR00016##

Follows the same procedure to compound A. After recrystallization from ethanol, the titled compound was obtained as a white solid.

[0089] The following crown ethers were prepared using the method of the invention:

4-Formylbenzo[18C6]

Compound is a fluffy white solid. Rf: 0.38-0.44 in 2 Hexane: 1 DCM: 1 Acetone. .sup.1H NMR (300 MHz, CDCl.sub.3) 9.83 (s, 1H), 7.51-7.36 (m, 2H), 6.95 (d, J=8.2 Hz, 1H), 4.23 (q, J=5.3 Hz, 4H), 3.95 (dt, J=9.2, 4.5 Hz, 4H), 3.83-3.75 (m, 4H), 3.75-3.66 (m, 8H). See FIGS. 11 and 12.

4-Formylbenzo[21C7]

Compound can be a fluffy white solid if complexed with metal or yellow oil uncomplexed. Rf: 0.38-0.44 in 2 Hexane: 1 DCM: 1 Acetone. .sup.1H NMR (300 MHZ, CDCl.sub.3) 9.83 (s, 1H), 7.47-7.39 (m, 2H), 6.96 (d, J=8.2 Hz, 1H), 4.37-4.17 (m, 4H), 3.95 (ddd, J=7.0, 5.2, 3.9 Hz, 4H), 3.84-3.59 (m, 17H). See FIG. 13.

4-Formylbenzo[24C8]

[0090] .sup.1H NMR (301 MHz, CDCl.sub.3) 9.81 (s, 1H), 7.47-7.33 (m, 2H), 6.91 (dd, J=9.8, 5.7 Hz, 1H), 4.20 (q, J=4.7 Hz, 4H), 4.01-3.57 (m, 20H). .sup.1H NMR (300 MHz, d.sup.6-Acetone) 9.87 (s, 1H), 7.55 (dd, J=8.2, 1.9 Hz, 1H), 7.44 (d, J=1.9 Hz, 1H), 7.18 (d, J=8.2 Hz, 1H), 4.28 (ddd, J=11.0, 5.5, 2.2 Hz, 4H), 3.93 (td, J=4.4, 1.9 Hz, 4H), 3.78-3.56 (m, 14H). HRMS (ESI) C.sub.21H.sub.33O.sub.9.sup.+ [M+H].sup.+=Observed: m/z 429.2121, Theoretical: m/z 429.2119. C.sub.21H.sub.32O.sub.9Na.sup.+ [M+Na].sup.+=Observed: m/z 451.1939, Theoretical: m/z 451.1939. LC-LRMS: 429.9 (M+H.sup.+), 446.9 (M+NH.sub.4.sup.+). See FIG. 22.

4-Formylbenzo[27C9]

[0091] .sup.1H NMR (301 MHz, CDCl.sub.3) 9.82 (s, 1H), 7.41-7.37 (m, 2H), 7.02 (d, J=0.8 Hz, 1H), 4.22 (t, J=4.5 Hz, 4H), 3.91-3.78 (m, 4H), 3.73-3.53 (m, 20H). HRMS (ESI) C.sub.23H.sub.36O.sub.10[M+H].sup.+=Observed: m/z 473.2378, Theoretical: m/z 473.2381 C.sub.23H.sub.36O.sub.10Na.sup.+ [M+Na].sup.+=Observed: m/z 495.2199, Theoretical: m/z 495.2201. C.sub.23H.sub.36O.sub.10K.sup.+ [M+K].sup.+=Observed: m/z 511.1936, Theoretical: m/z 511.1940. LC-LRMS: 490.1 (M+NH.sub.4.sup.+), 495.2 (M+Na.sup.+), 511 (M+K.sup.+). See FIG. 23.

4-Formylbenzo[30C10]

Solution Method. Conversion: 91.6%
Resin Method. Yield: 62.6%
The compound was not purified. 1H NMR (301 MHz, CDCl3) 9.77 (s, 1H), 7.43-7.33 (m, 2H), 6.96-6.89 (m, 1H), 4.22-4.13 (m, 4H), 3.88 (td, J=6.1, 4.4 Hz, 4H), 3.80-3.54 (m, 29H). 1H NMR (300 MHz, d6-Acetone) 9.85 (s, 1H), 7.59-7.39 (m, 3H), 4.24 (dt, J=11.8, 4.3 Hz, 4H), 3.89 (ddd, J=5.7, 4.5, 3.2 Hz, 5H), 3.77-3.53 (m, 28H). HRMS (ESI) C25H40011[M+H]+=Observed: m/z 517.2641, Theoretical: m/z 517.2643 C25H40011Na+ [M+Na]+=Observed: m/z 539.2457, Theoretical: m/z 539.246. LC-LRMS: 297.4 (M+2K+). See FIG. 24.

[0092] In a separate study, a number of different conditions were used for generating the aryl aldehyde 18C6 derivatives using compound 1e employing 1 or 1.05 equivalents of the di-electrophile. Provided below is a table summarizing the results of the study:

TABLE-US-00004 Resin brand CE abundance with loaded Other Time .sup.b in crude Entry SM .sup.a Base, eq Solvent, ml additions (h) (%) .sup.c 1 Sigma 70-90 NaOH, 1.25 1:1 PhMe:H.sub.2O TBAI 48 16% 1-1.5 mmol/g 4 ml 2 Sigma 70-90 K.sub.2CO.sub.3, 3 1:1 MeCN:THF 48 76% 1-1.5 mmol/g 10 ml 3 Sigma 70-90 NaH, 3 1:1 MeCN:THF 48 43% 1-1.5 mmol/g 10 ml 4 Sigma 70-90 KHCO.sub.3, 2.5 DMF 5 ml 48 9% 1-1.5 mmol/g 5 Sigma 70-90 K.sub.2CO.sub.3, 3 1:5 MeCN:THF 48 62% 1-1.5 mmol/g 10 ml 6 Sigma 70-90 K.sub.2CO.sub.3, 3 1:1 MeCN:THF NaI 48 16% 1-1.5 mmol/g 10 ml 7 Sigma 70-90 K.sub.2CO.sub.3, 3 1:1 DMF:THF 168 83% 1-1.5 mmol/g 10 ml 8 Sigma 70-90 K.sub.2CO.sub.3, 3 1:1 DMF:MeCN 72 59% 1-1.5 mmol/g 10 ml 9 Sigma 70-90 K.sub.2CO.sub.3, 3 DMF 10 ml 72 36% 1-1.5 mmol/g 10 Sigma 70-90 K.sub.2CO.sub.3, 3 MeCN 10 ml 72 55% 1-1.5 mmol/g 11 Sigma 70-90 K.sub.2CO.sub.3, 3 THF 10 ml 72 32% 1-1.5 mmol/g 12 Aaptec K.sub.2CO.sub.3, 3 MeCN 10 ml 72 72% 13 ChemImpex K.sub.2CO.sub.3, 3 MeCN 10 ml 72 12% 14 Sigma 100-200 K.sub.2CO.sub.3, 3 THF 10 ml 72 41% 15 ChemImpex K.sub.2CO.sub.3, 3 THF, 10 ml 72 41-44% 16 ChemImpex K.sub.2CO.sub.3, 3 THF, 10 ml 144 63% .sup.a SM refers to 3,4-dihydroxybenaldehyde that is loaded unto the resin. The scale is either 0.21 or 0.24 mmol of SM. .sup.b refluxing time at boiling point of solvents. .sup.c percentage was determined by NMR through integration between all aldehyde signals of products and unreacted 3,4-dihydroxybenzaldehyde in acetone-d.sub.6. N.R = No reaction, starting material is obtained unchanged

[0093] While the invention has been described with reference to preferred embodiments, the invention is not or intended by the applicant to be so limited. A person skilled in the art would readily recognize and incorporate various modifications, additional elements and/or different combinations of the described components consistent with the scope of the invention as described herein.