Synthesis of L -arabinose-based crown ethers and their application as enantioselective phase transfer catalysts

New chiral monoaza-15-crown-5 type macrocycles anellated to 3,4-O -isopropylidene-β- L - arabinopyranose ( 5a-b ), to β-L -arabinopyranose ( 6 ) and to 3,4-O -benzyliden-β- L - arabinopyranose ( 11 ) have been synthesized. The cation binding ability of the new lariat ethers was evaluated by the picrate extraction method in liquid-liquid system. Some representatives of these crown ethers showed moderate asymmetric induction as chiral phase transfer catalysts, among them 11 with a benzylidene group proved to be the most efficient one inducing 64% ee in the Michael addition of 2-nitropropane to chalcone and 61% ee in the addition of diethyl acetamidomalonate to trans - β -nitrostyrene. An induction of 65% ee was observed in the epoxidation of a chalcone analogue with tert -butyl hydroperoxide in the presence of catalyst 5a .


Introduction
The development of new methodologies for efficient asymmetric synthesis is of tremendous importance due to the increasing demand for optically active compounds. 1One of the techniques of catalytic asymmetric synthesis attracting currently considerable interest is phase transfer catalysis, in which the enantioselectivity is generated by a chiral crown ether. 2 Crown ethers with carbohydrate moieties form a special group of optically active macrocycles.Unexpensive natural sugars are "green" and cheep starting materials in organic syntheses.Over the past three decades, numerous macrocycles incorporating one or more monosaccharide units have been synthesized. 3he hexopyranoside-based lariat ethers described earlier by us possess special complexing ability due to their flexible side arm containing a heteroatom at the end. 4The overall complexing ability is influenced by the steric and electronic properties of the N-substituent.A few of the monosaccharide-based chiral lariat ethers have been found to be efficient phase transfer catalysts in certain types of asymmetric reactions. 5A review has been recently published by us in this topic. 6Valuable information has been accumulated on the structure -enantioselectivity relationship.Regarding the crown, a monoaza-15-crown-5 type structure seems to be advantageus.Beside this, the catalytic effect strongly depends on the carbohydrate moiety anellated to the azacrown ring and on the nature of the side arm of the crown ether.Among the alkyl-, alkoxy-, aralkyl-and other (e.g.P-functionalized) N-substituents, the hydroxypropyl, and in some cases, the methoxypropyl side arm was the most advantageous from the point of view of enantioselectivity. 6n this article, L-arabinose-based monoaza-15-crown-5 type chiral macrocycles with a hydroxypropyl-and methoxypropyl side arms (lariat ethers) are described.
The starting material, 3,4-O-isopropylidene-β-L-arabinopyranose (2) was prepared by the reaction of L-arabinose (1) with 2,2-dimethoxypropane in dry DMF in the presence of ptoluenesulfonic acid (PTSA) as catalyst, at room temperature. 7Beside compound 2, different byproducts (e.g.1,2;3,4-di-O-isopropylidene-β-L-arabinopyranose) were also formed, which were removed by flash chromatography.The pure mono isopropylidene derivative (2) was obtained after cristallization in a yield of 70%.Anellation of the crown ring in positions 1 and 2 of the arabinopyranose acetals (2) was accomplished in three steps, as described earlier. 4The vicinal hydroxyl groups of compound 2 were alkylated with bis(2-chloroethyl)ether in the presence of tetrabutylammonium hydrogen sulfate catalyst and 50% aq.NaOH in a liquid-liquid two-phase system by the Gross method 8 to give intermediate 3 which was purified by chromatography.The exchange of chlorine to iodine in intermediate 3 was accomplished in reaction with NaI in boiling acetone to afford bisiodo derivative 4. Compound 4 was then cyclized with two kinds of primary amines, such as 3-aminopropanol and 3methoxypropylamine, in boiling acetonitrile, in the presence of dry Na2CO3 to afford azacrown ethers 5a and 5b, respectively after purification by column chromatography.The yield of the cyclizations reactions was around 60% (Scheme 1).
The isopropylidene protecting group in compound 5b was removed by a cation exchanger resin (Amberlite IR-120) in methanol to give lariat ethers 6 with free hydroxyl groups in positions 3 and 4.

Scheme 2. Synthesis of a macrocycle anellated to β-L-arabinopyranose.
We wished to incorporate an aromatic moiety in the form of benzylidene acetal, instead of the isopropylidene group.Starting from L-arabinose, we tried out a few reagents (the ZnCl2 complex of benzaldehyde, benzaldehyde-dimethylacetal), but we failed to synthesize the expected benzylidene acetal (7, Scheme 3).

Scheme 3. Experiments for preparation of 3,4-O-benzylidene-β-L-arabinopyranose.
The problem could be solved by starting from bischloro podand 3 instead of L-arabinose (Scheme 4).The isopropylidene protecting group was removed from compound 3 using cation exchanger resin (Amberlite IR-120) and the L-arabinose-based podand 8 so obtained was converted to derivative 9 using benzaldehyde-dimethylacetal.The yield was 75%.Then the chlorine atoms in compound 9 were exchanged to iodine to afford species 10.The ring closure with 3-aminopropanol was performed as described earlier and the related azacrown ether 11 was obtained in a yield of 78%.The yield was better then that obtained for the isopropylidene analogue 5a.Scheme 4. Synthesis of a chiral crown ether anellated to 3,4-O-benzyliden-β-L-arabinopyranose.
Regarding the position of the phenyl ring in the benzylidene-acetal ring of compound 9, the ratio of the isomers endo/exo was 85:15 on the basis of 1 H NMR. Chromatography afforded the pure endo isomer ( = 5.94 ppm for the endo and = 6.27 ppm for the exo isomer) 9 .All intermediates and new products were characterized by 1 H NMR 13 C NMR, mass spectroscopy and elemental analysis.

Extracting properties
The phase transfer properties of the newly synthesized crown ethers were characterized by the extraction of picrate salts (lithium, sodium, potassium, rubidium, cesium and ammonium picrate) from water into dichloromethane (CH2CH2) by the method of Kimura. 10The concentration of the picrates in the aqueous phase was determined by UV spectroscopy.The extracting ability (EA%) is mainly based on the complex forming ability of the macrocycle, although some other factors (e.g.solubility, lipophilicity, etc) may also influence it.Table 1 contains the EA data obtained with compounds 5a-b and 6, 11.The data show the amount of the transferred salt as a percentage of the initial salt concentration (Extractability %).A higher value indicates a better phase transfer capability of the crown.a Room temperature; aqueous phase (5 mL); [picrate] = 5x10 -3 M; organic phase (CH2Cl2 5 mL); [crown ether] = 1x10 -2 M; Defined as % picrate extracted into the organic phase, determined by UV spectroscopy.Error = ±1%.
It is not surprising that from among the metal cations, all crown ethers form the strongest complex with the Na + cation as the size of this cation suits best the cavity of the 15-crown-5.With the cations of bigger size, the binding ability towards the crown ether is much weeker.By comparing the EA values of lariat ethers 5a and 5b, it can be seen that the change of the hydroxyl group at the end of the side arm (as in 5a) to methoxy group (as in 5b), the extracting ability is somewhat increased probably due to the increase in the lipophilicity.The smallest EA value (2-8%) was revealed by compound 6, while the best extracting ability (17-45%) was detected with macrocycle 11.The benzylidene moiety on the arabinose moiety has two effects.On the one hand, it increases the lipophilicity, on the other hand, it may be involved in a π-π interaction with the aromatic moiety of the picrates enhancing the formation of stronger complexes.The transport of NH4 + (2-38%) may not be compared with that of the metal cations, as the complexes with ammonium cation are known to have a structure with three-point hydrogen bridge connection.It can be concluded that the L-arabinose-based lariat ethers posses weak or medium extracting abilities as compared to the glucose analogues with a similar structure.4a

Asymmetric induction
The chiral crown compounds synthesized could also be tested in some model reactions as enantioselective phase transfer catalysts.In all cases, the products were isolated by preparative TLC after the usual work-up procedure.The enantiomer excess (ee) was determined by 1 H NMR spectroscopy or chiral HPLC.
The macrocycles 5a-b, 6 and 11 were tested in the Michael addition of 2-nitropropane to chalcone (Scheme 5).The solid-liquid phase transfer catalytic reaction was carried out at room temperature in dry toluene, in the presence of solid sodium tert-butylate (35 mol%) and one of the chiral catalysts prepared by us (7 mol%).5b

Scheme 5. Asymmetric addition of 2-nitropropane to chalcone
The experimental data are shown in Table 2.It can be seen that the L-arabinose-based macrocycles resulted in variable enantioselectivities (17-64%) in favour of the S antipode with 46-61% yields.The "methylation" of the hydroxypropyl side arm influenced the enantioselectivity to only a small extent; in the presence of catalyst 5a (R=H) and 5b (R=CH3) the ee was 49 and 53%, respectively.The lowest enantiomer excess (17%) was observed with catalyst 6 that is without a protecting group, that can be explained by assuming that in the absence of an acetal ring, the molecule becomes more flexible.It is known that a more rigid structure is always better from the point of view of enantiomeric discrimination.It is also a significant change that the lipophilicity of catalyst 6 also decreased (lower solubility in toluene phase).The best result of 64% was obtained in the presence of 11 having a benzylidene protecting group and a hydroxypropyl side arm.Regarding the results obtained with catalysts 5a and 11 (Table 2. entry 1 and 4), it can be seen that the presence of a benzylidene acetal group is more advantageous from the point of view of enantioselectivity.
Another Michael reaction is the conjugate addition of diethyl acetamidomalonate 15 to βnitrostyrene 14 under phase transfer catalytic conditions in the presence of L-arabinose-based lariat ethers (Scheme 6).Scheme 6. Asymmetric addition of diethyl acetamidomalonate to β-nitrostyrene.
The Michael addition was carried out in a solid-liquid two-phase system by employing 15 mol% of crown ether.The organic phase comprised the starting materials and the catalyst in a solvent mixture of THF-ether (4:1), while Na2CO3 used in two-fold excess formed the solid phase.Products 16 were obtained by preparative TLC, and the optical purity was measured by chiral HPLC. 11The best results were obtained with catalyst 5a having an isopropylidene group and species 11 having a benzylidene protecting group resulting in an ee of 52% and 61%, respectively.The R absolute configuration of Michael adduct 16 is characterized by a positive optical rotation.
In the experiments, the epoxidation of chalcones was carried out with tert-butyl hydroperoxide (TBHP, 2 equiv.)at 5 o C in toluene, in a liquid-liquid two-phase system, employing 20 % aq.NaOH (3.5 equiv) as base and 7 mol % of L-arabinose-based lariat ethers as catalyst.The reactions took place after 4-8 h in good yields (84-90%).The trans-epoxyketones 17a-b were obtained in all experiments, with a configuration of (+)-(2S,3R).Regarding 17a, the best results of 58 and 45% were obtained with catalyst 5a and 11 respectively, that contained hydroxypropyl side arms.In the presence of these catalysts (5a and 11) product 17b was formed with an enantioselectivity of 65 and 61%, respectively.It is interesting that the methylation of the hydrophilic functions in 5a resulted in a dramatic decrease in the enantioselectivity as was demonstrated by the ee of 23 % for epoxyketone 17a obtained in the presence of 5b.
It can be concluded that the L-arabinose-based lariat ethers induced enantioselectivities of medium size in the asymmetric reactions studied.These results are more modest than those obtained with the D-glucose-based crown ethers. 5In the future, we wish to study the enantiomeric discrimination ability of the lariat ethers synthesized toward chiral ammonium salts.

Experimental Section
General.Melting points were taken on using a Büchi 510 apparatus and are uncorrected.Optical rotations were measured with a Perkin-Elmer 241 polarimeter at 20 °C. 1 H NMR spectra were recorded on a Bruker 300 and a Bruker DRX-500 or a Varian Inova 500 instrument in CDC13 with TMS as internal standard.The exact mass measurements were performed using Q-TOF Premier mass spectrometer (Waters Corporation, 34 Maple St, Milford, MA, USA) in positive electrospray ionization mode.Elemental analyses were determined on a Perkin-Elmer 240 automatic analyzer.Analytical and preparative thin layer chromatography was performed on silica gel plates (60 GF-254, Merck), while column chromatography was carried out using 70-230 mesh silica gel (Merck).Chemicals and the shift reagent Eu(hfc)3 were purchased from Aldrich Chem.Co.

General procedure for the Michael addition of 2-nitropropane to chalcones 5a-c
The corresponding azacrown ether catalyst (0.10 mmol) and sodium tert-butoxide (0.05 g, 0.5 mmol) were added to a solution of the chalcone (0.3 g, 1.44 mmol) and 2-nitropropane (0.3 mL, 3.36 mmol) in dry toluene (3 mL).The mixture was stirred at RT under argon.After a reaction time of 8 to 30 h, a new portion of toluene (7 mL) and water (10 mL) was added and the mixture was stirred for several minutes.The organic phase was washed with water and dried (Na2SO4).The crude product obtained after evaporating the solvent was purified by preparative TLC (silica gel, hexane-ethyl acetate, 10:1 as eluent) to give adducts 13 in a pure form.Yield: 0.21 g (59%).General procedure for the addition of diethyl acetamidomalonate to trans-β-nitro-styrene 11 The trans-β-nitrostyrene (0.15 g, 1.0 mmol), diethyl acetamidomalonate (15) (0.32 g, 1.5 mmol) and the crown ether (0.15 mmol) were dissolved in a mixture of anhydrous THF (0.6 mL) and Et 2 O (2.4 mL) and dry Na 2 CO 3 (0.22 g, 2.08 mmol) was added.The reaction mixture was stirred at room temperature.After completition of the reaction (2-7 h), the organic phase was concentrated in vacuo and the residue was dissolved in toluene (10 mL) and washed with cold 10% HCl (3 x 10 mL) and water (20 mL), dried (Na2CO3) and concentrated.The crude product was purified on silica gel by preparative TLC with hexane-EtOAc (3:1) as eluent.Enantioselectivities were determined by chiral HPLC analysis using a Chiralpack AD column, (20 o C, 256 nm, 85/15 hexane/i-PrOH, 0.8 mL/min) in comparison with authentic racemic samples; tR=17.8min (major), tR=27.7 min (minor).

Table 1 .
Extraction of alkali metal and ammonium picrates with L-arabinose-based crown ethers

Table 2 .
The effect of the L-arabinose-based crown catalyts on the enantioselectivity in the addition of 2-nitropropane to chalcone at room temperature 1 Based on isolation by preparative TLC; b In CH2Cl2 at 20 °C; c Determined by1H NMR spectroscopy in the presence of Eu(hfc)3 as chiral shift reagent.The absolute configurations were assigned by comparison of the specific rotation with the corresponding literature value 6a