Synthesis and extraction properties of some lariat ethers derived from the spontaneously resolved guaifenesin, 3-(2-methoxyphenoxy)propane-1,2-diol

Capable of spontaneous resolution rac -3-(2-methoxyphenoxy)propane-1,2-diol, guaifenesin 1 has been proposed as a cheap and readily available enantiopure precursor for the synthesis of nonracemic crown ethers having ligating OAr and OMe arms (lariat ethers). The crowns studied failed to form stable host/guest complexes with amine hydrochloride salts; the effective complexation was achieved using hexafluorophosphate salts. Moderate enantiomeric recognition of R*NH 2 ·HPF 6 was achieved with the lariat ethers 11c . As a whole, the enantioselectivity of the extraction is inversely related to the extractive power of the lariat ether.


Introduction
Cyclic polyethers (crowns) are one of the most popular classes of the synthetic receptors capable of selective binding and transport of organic and inorganic ions and molecules. 1Some nonracemic chiral (usually simply named as "chiral") crowns show a capacity for chiral recognition and predominantly bind one of the pair of enantiomers. 2The first chiral crown ethers were prepared by Cram et al. 3 These enantiopure macrocycles showed from moderate to significant enantiomeric recognition toward biologically interesting ammonium guests. 4By now a large number of different crown ethers have been synthesized and studied for molecular recognition toward free and protonated chiral amino acid esters and/or other amines. 5,6n effective chiral recognition requires that a chiral receptor would be capable of forming sufficiently stable complexes with substrate enantiomers and that a chiral barrier would be present, which reduces the stability of one of the diastereomeric complexes thus formed.It is agreed that the binding abilities of chiral crown ethers could be enhanced particularly by the presence of a flexible side arm with an electron donor site (the case of so called lariat ethers). 7he lariat ethers chiral recognition ability towards amino acid derivatives was recently investigated. 8The common feature of the studied crowns was the presence in their structure of the chiral OCH2C*H(CH2OC6H4OMe-p)O unit, the fragment of 3-(4-methoxyphenoxy)propane-1,2-diol.The last compound has been prepared through p-methoxyphenol addition to (S)glycidol.
In the early work of Gokel et al. 9 it was found that within the pair of 15-crown-5 lariat ethers having (CH2OC6H4OMe) side arms, the ortho-methoxy derivative was much more effective host for sodium cation than the para-methoxy one.The obvious reason for this lies in the fact that two oxygen atoms of the substituent could be involved in the cation binding in the case of ortho, whereas the oxygen atom of the p-methoxyl could not be involved in this complexation by steric reasons.Having these facts in mind we decided that 3-(2-methoxyphenoxy)propane-1,2-diol 1, chiral drug guaifenesin, would be the more suitable starting material for the synthesis of the lariat ethers capable of chiral recognition.
Some years ago we have disclosed the conglomerate-forming nature of guaifenesin and developed cheap and very effective resolution procedure based on this property. 10In the present investigation we have used both enantiomers of guaifenesin prepared through entrainment procedure for construction of the series of nonracemic lariat crown ethers.In addition to that, the binding and chiral recognition ability of the so obtained hosts with respect to αphenylethylammonium salts and two α-amino acid methyl ester salts is discussed here.

Synthesis
For the synthesis of chiral lariat ethers 9-11 the documented general approaches were used.8a,11-13 Scheme 1 is representative of the major synthetic sequences.
Both enantiomers of the key starting diol guaifenesin 1 were obtained through spontaneous resolution of the racemic material according to our published procedure. 10Both enantiomeric building block diols 3 were prepared by the reaction of diol 1 and tosylate 4, which in turn was obtained via dihydropyranyl monoprotection of ethylene glycol.8a Macrocycles 9 and 10 have been synthesized in 15-31% yield by the ring closure of chiral subunit diol 1 with tri-or tetraethylene glycol di(p-toluenesulfonate) in the presence of NaH in THF under high dilution conditions.The 18-membered cyclic ethers 11a,b and the 20-membered cyclic ethers 11c have been synthesized by the reaction of enantiomerically pure diols 1 or 3 with the appropriate ditosylates 6 or 8 in the presence of base.The ditosylates 6a-c were synthesized by the reactions of dihydroxyaromatic compounds, such as catechol 2a, 2,3dihydroxynaphthalene 2b and 1,1′-bi-2-naphthol (S)-2c with ethylene oxide or chloroethanol followed by the interaction of the obtained diols 5 with p-toluenesulfonylchloride. The crown ether (R)-11a was prepared by ring closure of diol (R)-3 with ditosylate 6a in 15% yield.The crown ethers (S)-11b and (aS,S)-11c were prepared by ring closure of diol (S)-3 with ditosylate 6b or (aS)-6c in 21% and 17% yield, respectively.The yield of the crowns increased approximately two times if the cyclization of diol and ditosylate 8 was explored.Thus, the crown ethers (R)-11b and (aR,R)-11c were prepared by ring closure of diol (R)-1 with ditosylate 8b or (aR)-8c in 44% and 41% yield, respectively.
Lariat ethers 10, 11b, and 11c were prepared as both enantiomers.Only (R)-enantiomers were obtained in the case of 9 and 11a.Crowns 11c contain two different chirality elements in their structures, the centre and the axis.The last element is the attribute of nonracemic (aR)-or (aS)-BINOL 2c.We have tested only enantiomeric (aR,R)-and (aS,S)-diastereomers.
For the purpose of comparison the extraction effectiveness of the lariat ethers with OMe group in ortho-and para-position in the benzene ring we have prepared also (S)-[(4-methoxyphenoxy)methyl]-15-crown-5, (S)-10a; the compound was synthesized through the above outlined approach starting with (S)-3 The structures of the all obtained lariat ethers were consistent with the 1 H NMR, 13 C NMR and mass spectra.

Molecular recognition. 1 H NMR experiments
We have employed NMR spectroscopy to detect and quantify molecular recognition of lariat ethers 9-11 as host molecules.The set of chiral guests investigated in our paper consists of alanine and phenylglycine methyl esters 12 and 13, and α-phenylethylamine 14.Scheme 2. Guest molecules studied.
In attempt to find the evidences of the supramolecular binding between the lariat ethers and amine guests we have investigated CDCl3 solutions of (R)-10 and hydrochlorides of 12 and 14.It was found that 1 H chemical shifts perturbations ( 1 H CSPs) in (R)-10 + 12 .HCl and (R)-10 + 14 .HCl systems (for both enantiomers of the amine components) relative to individual host or guest solutions were less than 0.02 ppm, and hence they cannot be used as indicators of complex formation.Furthermore, increasing of concentration (from 1 to 10 mM) of the individual hydrochloride salts in CDCl3 solutions leads to notable (ca 0.2 ppm) CSPs of CH-and Me protons for 12 .HCl and to negligible CSPs for 14 .HCl.Thus, self-association of 12 .HCl molecules couldn't be excluded.
As a whole it is evident that 1 H CSs are not very useful instrument in the case of the hydrochloride salts, which is in complete agreement with early Cram et al. observations. 4herefore to get insight of the phenomenon under question, an additional NMR method, namely DOSY, that provides diffusivity information, which is expressed in terms of self-diffusion coefficient D, was invoked. 14The simple physical meaning of the self-diffusion coefficient (the bigger the D the smaller the molecular system mass and vice versa) make for its wide use in compexation studies. 15efore to study binary systems, the self-associative properties of the individual components were analyzed (Table 1).Because of almost no change of the D((R)-10) with concentration it is conceivable that no self-association of the host (R)-10 in solution was occurred.On the contrary, decreasing of D with increasing of concentration proves that 14 .HCl and, in particular, 12 .HCl self-associates.Therefore self-diffusion coefficients of the guests (12 .HCl and 14 .HCl) in the binary systems (10 + 12 .HCl) and (10 + 14 .HCl) can hardly be used to monitor complexation between the components because the salts molecules are in fast exchange between free, selfaggregated and complexed states and its self-diffusion coefficients are weighted average.On the other hand almost no changes of D (10) in the studied systems (Table 1) indicates the absence of the more or less stable complexes formation between the host and these guests.This observation correlates well with the early Cram conclusion.  4 established that a precondition for observing diastereomeric complexes of crown ethers with amine salts was that X  of RNH3 + X  be unable to hydrogen bond strongly with NH3 + .They found that the PF6  , AsF6  , and SbF6  ions fulfilled this condition, whereas F  , Cl  , Br  , SCN  , and CCl3CO2  did not.Choosing the RNH3 + PF6  salts for our subsequent experiments we were guided by these recommendations.However salts with PF6  anion are found to be non-soluble in CDCl3.Thus D of individual solutions of guests couldn't be determined.For this reason we have used 1 H NMR monitored liquid-liquid extraction for the binding properties evaluation in our concluding experiments.
Hexafluorophosphate salts of the amines 12-14 are not accessible as solids, so they were produced in D2O solution by ion exchange with excess of LiPF6 and the corresponding amine hydrochloride.The host 9-11 solution in CDCl3 (0.01 M, 1 equiv) was used to extract ~ 3 equiv of aqueous RNH3 + PF6  salts.The LiPF6 not only served as the source of the extractible PF6  anion, but Li + , Cl  , and excess PF6  ions "salted out" the organic guest complex from D2O layer to CDCl3 one.After extraction the organic phase was dried and analyzed.Typically, the relative concentrations of the enantiomeric guests in CDCl3 layer were determined from the 1 H NMR spectra of their diastereomeric complexes.Analysis of intensities of guest's and host's signals in the 1 H NMR spectra of studied systems allows estimating the relative quantities of the corresponding substances (Table 2).The 1 H NMR chemical shifts of the CH3, NC*H protons (chiral carbon is marked by asterisk) of the guests are represented in Table 2. 1 H NMR integral ratios of CH3 or NC*H protons to those of Ar (Ph) multiplets are listed in Table 2 as guest/host ratio.In the control experiments no traces of amines were detected in the CDCl3 phase free of the crown hosts.
Before proceeding to analyze the Table 2 data it must be noted that any enantiomer of methyl alaninate hexafluorophosphate 12 .HPF6 could not be traceable after extraction in the any of the studied host containing organic phase.In accordance with the Cram data, this phenomenon was associated with the great hydrophilicity of the alanine moiety.Thus, only enantiomeric αphenylethylammonium hexafluorophosphate 14 .HPF6 and methyl phenylglicinate hexafluorophosphate 13 .HPF6 were used for quantitative experiments.
As it follows from Table 2, runs 1-3, amine extraction is negligible in the case of 12membered crown 9.The small cavity dimension is the obvious reason for the effect.
As the cavity dimension increases, as in the case of crowns 10 and 11a-b, so does the quantity of amine extracted into the chloroform phase increases too.This is evidenced by increase of the G/H values in Table 2. Some important tendencies could be traced from the runs 5-18.Firstly, the enantioselectivity of extraction is approximately inversely related to the quantity of extracted material.Thus maximum extraction potential demonstrates naphthyl containing crown 11b (runs 15-18).At the same time the enantioselectivity of these extractions is close to zero.Secondly, the effectiveness of the lariat ethers 10, having ortho-OMe substituent in the benzene ring, is approximately ten times larger in the amine guest transfer from water to organic phase than the same ability for lariat ethers 10a, with OMe group in para-position.An introduction of the BINOL chiral moiety instead of catechol fragment in the structure of crown 11a not only enlarges the macrocycle cavity in the case of 11c, but disturbs it in the asymmetric way.As a result, the general complexation ability for the crowns 11c decreases, yet the enantioselectivity of this complexation increases.Thus, during amine salt extraction by crown host (aS,S)-11c about 22% of the (S)-14 .HPF6 finds its way into chloroform phase, whereas (R)-14 .HPF6 does not (runs 19-20).
As one could see, for the 11c+13 .HPF6 system (runs 21-22) there is a noticeable difference in extraction for different enantiomers, too.That's why this system was used for quantitative extraction of rac-13 .HPF6 D2O solutions with CDCl3 solutions of optically pure host (aS,S)-11c.
During this experiment the layers were equilibrated, the neutral guest was isolated from the complex transferring into organic layer, and the optical rotations of the individual 13 were taken.The isolated by this means phenylglycine methyl ester has had an optical purity of 22%, enriched in the (R)-enantiomer.

Conclusions
Summering up, we could say that the conglomerate nature and the developed on this basis the effective procedure of direct resolution of guaifenesin 1 enable an easy access to the family of enantiomeric lariat crown ethers 9-11.These crowns show no evidence of host/guest association with hydrochloride salts of chiral amines.In the same time these crowns show a capacity for host/guest binding of some ammonium hexafluorophosphate salts which is embodied in the extraction of the guest molecules from aqueous to organic phase.The effectiveness of the lariat ethers 10, having ortho-OMe substituent in the benzene ring, is larger than the same ability for ethers 10a, with OMe group in para-position.Moderate enantiomeric recognition of organic ammonium hexafluorophosphates was achieved with lariat ethers 11c.By and large, the enantioselectivity of extraction is approximately inversely related to the quantity of extracted material.

Experimental Section
General.The NMR spectra were recorded on a Bruker Avance-600 spectrometer (600.13MHz for 1 H; 150.864MHz for 13 C) in CDCl3 with TMS or the signals of the solvent as the internal standard.Optical rotations were measured on a Perkin-Elmer model 341 polarimeter (concentration c is given as g/100 mL).Melting points were determined using a Boëtius apparatus and are uncorrected.The UV-Vis spectra were measured by a Perkin Elmer Lambda 35UV spectrometer.HPLC analyses were performed on a Shimadzu LC-20AD system controller, and UV monitor 275 nm was used as a detector.As a rule, the column used, from Daicel, Inc., was Chiralcel OD (0.46 x 25 cm); column temperature 40 о С; flow rate: 0.4 ml/min.Mass spectra EI were recorded on a mass-spectrometer MAT-212, mass spectra MALDI-TOF were recorded on a mass-spectrometer ULTRAFLEX III.

NMR experiments
Self-diffusion coefficients determination.The 2D DOSY experiments were performed by STE-BPLED sequence. 26Data was acquired with a 20-50 ms diffusion delay in all experiments, bipolar gradient pulses duration from 2.3 to 3.5 ms (depending on a system under investigation), 1 ms spoil gradient pulse (30%) and a 5 ms eddy current delay.The bipolar pulse gradient strength was varied incrementally from 0.01 to 0.32 T/m.The experimentally observed diffusion coefficients were then determined from 2D DOSY plots obtained by Bruker XWinNmr software package.Several measures of D were obtained at more than one place in the spectrum and all experiments were carried out in duplicate or triplicate mode.The reported results are the mean value of multiple data points and the standard deviations are less than 0.05•10 -9 m 2 /s in all cases.The temperature was set and controlled at 298 K with a 535 l/h airflow rate in order to avoid any temperature fluctuations owing to sample heating during the magnetic field pulse gradients.2. Run 5.The 0.6 ml of D2O solution contained 4.4 mg (0.029 mmol) of LiPF6 and 4.6 mg (0.029 mmol) of (S)phenylethylammonium hydrochloride (S)-14 .HCl was shaken for 1 min at r.t. with 0.8 ml of (S)-10 (2.8 mg, 0.0078 mmol) in CDCl3 (0.01 M).The organic layer was dried (MgSO4) and the spectrum taken.The runs 1-4 and 6-22 were carried by analogy with the corresponding host and guest.Extraction, isolation, and rotation experiment of methyl phenylglicinate hexafluorophosphate Host (aS,S)-11c (80 mg, 0.128 mmol) was dissolved in 0.7 ml of CDCl3 to give a 0.18 M solution.This solution was used to extract 3 eq. of racemic methyl phenylglicinate hydrochloride rac-13•HCl (77.2 mg, 0.383 mmol) dissolved in 0.4 ml of an aqueous D2O solution (0.92 M in guest) contained 0.0582 g (0.383 mmol) of LiPF6.After equilibration at r.t.(about 30 min), the phases were carefully separated, and the meniscus was discarded.The organic phase was diluted with 1 ml of CH2Cl2 and extracted with three 0.8 ml portions of 0.1N HCl.The combined aqueous extracts were added to 2.6 ml of CH2Cl2 and aqueous ammonium hydroxide was added to adjust the pH to 10.The organic phase was withdrawn, the aqueous phase was reextracted with another 1.5 ml of CH2Cl2, and the combined organic extracts were dried with MgSO4.The solvent was evaporated to give 10 mg of the amino ester 13 as an oil (0.06 mmol);
5.05 a CRF -chiral recognition factor, [G]R/[G]S, where [G]R and [G]S is the relative amounts of R-or S-guest extracted into CDCl3 phase.b d, J = 7 Hz.c traces.