Synthesis of chiral pyridino-15-crown-5 type ligands containing α-D-hexapyranoside unit and their application in asymmetric synthesis

The synthesis of novel chiral monoaza-15-crown-5 compounds (1-4) with pyridine-ring starting from methyl-4,6-O-benzylidene-α-D-glucopyranoside and methyl-4,6-O-benzylidene-α-Dmannopyranoside by different methods are reported. These crown ethers showed significant asymmetric induction in a Michael addition (up to 80% ee).


Introduction
The application of chiral crown ethers find increasing interest in asymmetric organic synthesis. 1rown ethers with carbohydrate moieties form a special group of optically active crown ethers.The inexpensive, natural, non toxic sugars are attractive starting materials for the synthesis of chiral macrocycles.Therefore, these compounds should serv as useful tools for the separation of enantiomers, chiral recognition in enzymatic reactions and for the control of asymmetric reactions. 2Stoddart et al. were the first group that published the enantiomeric discriminating ability of certain sugar-based crown compounds towards the antipodes of chiral ammonium salts. 3Although many optically active macrocycles incorporating one or more monosaccharide units have been synthesized, only a few have been successfully applied as catalysts in asymmetric reactions. 4The nature of the crown ether, especially with reference to its chirality, its rigidity and the micro-environment of its cavity, can all be expected to play a significant role in its functions as a catalyst.
We have previously reported the synthesis of new hexapyranoside-based monoaza 15crown-5 type lariat ethers with different side-arms containing a heteroatom at the end. 5These chiral macrocycles proved to be effective asymmetric catalysts in some asymmetric Michael additions, 6 Darzens condensations 6 and epoxidations of double-bond. 7We focused on the synthesis of the analogue hexapyranoside-based crown ethers incorporating a pyridine unit that were expected to exhibit a more rigid structure.It is known that a more rigid structure is always better from the point of view of enantiomeric discrimination.Mention that it is the Lewis basicity of the pyridine moiety that allows for this discrimination.Besides some of these crown ethers were utilized in the resolution of racemates. 8We report herein a convenient synthesis of optically active crown ethers 1 -4 containing two different monosaccharide-units. Changing the substituents on the pyridine ring of the macrocycle 1 can make them suitable for various purposes.For example a methoxy group (2) changes the liphophylity of the molecule (that can be phase transfer catalyst) while an allyloxy group (3) makes possible the attachment of the ligand to silica gel 9 (Figure 1.).

Figure 2
Several possible ways were described for the preparation of 2,6-pyridinedimethyl bistosylate 6. 11 In our case 2,6-bis(hydroxymethyl)pyridine 5 12 was treated with p-toluenesulfonyl chloride in a mixture of THF and 40% aqueous NaOH at low temperature 13 to give bistosylate 6 (87% yield).The synthesis of the "half-crown" diol containing a pyridyl unit 8 was accomplished by the reaction of diol 5 with methyl bromoacetate in the presence of sodium hydride in THF under reflux to afford diester 7 (72% yield), which was converted to diol 8 by reduction with NaBH 4 in ethanol at ambient temperature (83%). 14The ditosylate derivative 9 was obtained by the treatment of diol 8 with two equivalents of p-toluenesulfonic chloride in the presence of finely pulverized KOH at low temperature in THF (product 9 was obtained in a 80% yield). 15ompound 9 was observed to be somewhat unstable (Figure 2).
The dimethyl chelidamate 10 was synthesized by a method described in the literature. 11iester 10 was treated with dimethyl sulfate or allyl bromide in DMF, in the presence of K 2 CO 3 , to obtain 4-substituted dimethyl 2,6-pyridinedicarboxylates 11 and 12, respectively (see Scheme 1).Diesters 11 and 12 were reduced with NaBH 4 in ethanol and the crude ethanol free 2,6pyridinedimethanol derivatives 13 and 15 so obtained were treated with p-toluenesulfonyl chloride in a mixture of THF and aqueous NaOH at low temperature to give bistosylate 14 and 16, respectively (Scheme 1).
Our chiral compounds were the "half-crown" diol 19 containing a glucopyranoside-unit and its bistosylate derivative 20, as well as the diol 23 containing a mannopyranoside moiety (Figure 3).The methyl-4,6-O-benzylidene-α-D-glucopyranoside 17 was treated with sodium chloroacetate in DMF in the presence of sodium hydride to give chiral dicarboxylic 18 (78%), which was reduced with a mixture of NaBH 4 and I 2 in THF to result in the sugar-based diol 19 in a 80% yield after chromatography.Compound 19 was synthesized earlier in four steps including ozonolysis as described by Stoddart et al. (in 51% yield from methyl-4,6-O-benzylidene-α-Dglucopyranoside). 16The reaction of diol 19 with p-toluenesulfonyl chloride in THF/aqueous NaOH furnished bistosylate 20 in a yield of 67% after column chromatography.The dicarboxylic with a mannopyranoside-unit 22 and the corresponding diol 23 were obtained from the methyl-4,6-O-benzylidene-α-D-mannopyranoside 21 in a similar way.Compound 23 was prepared earlier from the 2,3-di-O-tert-butylester derivative by reduction with LiAlH 4 (81% yield for the two steps). 17As far as we experienced, this method gave 23 in a low yield (50%).The reducing agent NaBH 4 +I 2 described by Periasamy 18 gave, however, the sugar-based diols 19 and 23 in good yields after column chromatography.Our method possesses some advantages since it avoids the ozonolysis 16 of the diallylderivatives of 17 and reduction 17 with LiAlH 4 respectively.The synthesis of crown ether 1 was attempted using three different ring closure reactions by varying the coupling partners as shown in Scheme 2. (Methods A, B and C, in DMF in the presence of NaH).The reaction of 2,6-bis(hydroxymethyl)pyridine 5 with glucopyranosidebased diol-ditosylate 20 (Method A) provided macrocycle 1 in only 8% yield.In another version, the reaction of 2,6-pyridinedimethyl ditosylate 6 with 19 glucopyranoside-based diol (Method B) afforded crown ether 1 in 40% yield.The ring forming reaction of ditosylate derivative 9 and sugar derivative 17 (Method C) was not really efficient, as the yield of 1 was only 12%.The yield difference of methods A, B and C may be the consequence of the success of the template effect within both reagents in the intramolecular ring closure reaction.The template effect can be characterized by the complexing abilty of the reagents towards Na + cation.The binding power of the reagents was measured in solution (NBA) in the presence of sodium picrate salt by FAB-MS [19][20][21] to achieve a fast and qualitative screening of the complexation ability of compounds 5, 6, 9, 19 and 20.Table 1 summarizes the relative peak intensities (PI) of [ligand + Na] + as compared to uncomplexated [ligand + 1] + that was regarded to be 100%.On the basis of relative peak intensities in the presence of sodium picrate salt in NBA matrix, assuming that all ligands form similar 1:1 complex.
As indicated in Table 1 the strong complexing ability of 20 (PI=900) and the weak complexing ability of 5 (PI=2.8)result in only a low yield in the ring closure reaction.In contrary, the complexing ability of ditosylate 6 is increased (PI=44) and the half-crown diol 19 even owes a bigger value (PI=410).This is in accordance with the relatively good yield of 40% obtained by Method B. Regarding Method C, the excellent complex forming ability of compound 9 (PI=1450) is not enough as the hydroxy groups of sugar derivative 17 are of low reactivity.This situation results in the low yield of 12%.One of our interesting observations is that the incorporation of the tosyl groups results in better coordinating ability for the diols (template effect).For example for 20 created from 19, the PI value is almost doubled (PI 19 = 410 → PI 20 = 900).This effect has a special importance in the case of compound 5 that has only a week coordinating ability (PI 5 =2.8).Tosylation of 5 results in a 15-fold increase of value PI (PI 6 =44).This effect has already been observed earlier in respect to crown ethers. 22It is worth mentioning that beside of the template effect, other circumstance may also play a role in the yield of the ring closure reaction.We have not studied the ability to elimination of tosylates.It is assumed that method B is favored also because compound 6 can undergo only substitution, in contrast to the case of 20 and 9.
The methoxy-and allyloxy-macrocycles with pyridine ring (2 and 3, respectively) were prepared by Method B. The crown ether 2 was prepared by the reaction of pyridine derivative 14 and sugar-based diol component 19 in 29% yield.Similarly, the reaction of 16 and 19 afforded macrocycle 3 in 33% yield.The α-D-mannopyranoside-based macrocycle 4 was prepared in an analogue way.The reaction of methyl-4,6-O-α-D-mannopyranoside (21) with sodium chloroacetate gave bisacid derivative 22, the reduction of which led to 23 bis-glycol.The reaction of "half crown-diol" 23 and ditosyl derivative 6 resulted in the formation of mannopyranoside-based macrocycle 4 in a yield of 21%.It is noted that compound 4 differs only from 1 in the configuration of its C(2) atom in the sugar moiety.In the glucopyranoside-based 1 the position of the C(2)-O and C(3)-O groups is trans, while that is cis in 4. It was observed from the FAB-MS spectroscopy of the crude products that the glucopyranoside-based crown ethers were mainly formed as sodium complexes, while the mannopyranoside-based macrocycle was present in the crude products in an uncomplexed form.On purification by chromatography on alumina, the complexes were decomposed.
Chiral crown ethers 1-4 were tested in the Michael addition of 2-nitropropane to chalcone (Scheme 3).The solid-liquid phase transfer catalytic reaction was carried out at room temperature in dry toluene, in the presence of solid sodium tert-butoxide (35 mol%) and one of the chiral catalysts 1-4 prepared (7 mol%). 6 In all cases, the products were isolated by preparative TLC after the usual work-up procedure.The enantiomeric excess (ee) was determined by 1 H NMR spectroscopy using (+)-Eu(hfc) 3 as a chiral shift reagent.The experimental data are shown in Table 2.It can be seen that glucopyranoside-based macrocycle 1 gave the product 24 in 48% yield and in 72% ee in favour of the S enantiomer.6c It is also seen that the substituents in the pyridine ring influence the enantioselectivity to only a small extent; in the presence of catalyst 2 (R=OCH 3 ) and 3 (R=OCH 2 CH=CH 2 ) the ee was 76 and 67%, respectively.It is interesting, that while the glucopyranoside-based crown ethers (1-3) induce the formation of the (-)-(S)-enantiomer of the Michael adduct, the mannopyranoside-based species 4 brings about excess of the (+)-(R)enantiomer with ee of 80% .Chiral macrocycles 1-4 were used as catalyst in the epoxidation of trans chalcone. 7In our experiments, the epoxidation of chalcone 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 % aqueous NaOH (3.5 equiv) as the base and 7 mol % of crown ethers having pyridine-ring 1-4 (Scheme 4).The trans-epoxyketone 25 was obtained in all experiments.Table 3 summarizes the results.The epoxidation reaction with these catalysts, however, shows lower enantioselectivity than the Michael addition.The best result of 54% ee was obtained with the glucopyranoside-based catalyst 1 containing no substituent at the pyridine.The lower enantiomer excess (25% and 26% ee) was observed using catalyst 2 and 3 containing methoxy-and allyloxy groups, respectively.It is worth noting that the crown ether incorporating an glucopyranoside unit (1-3) promoted the formation of the (-)-(2R,3S) isomer of epoxyketone 25, while the use of mannopyranoside-based ether 4 resulted in the formation of the other, (+)-(2S,3R) enantiomer in 47% ee.The chiral crown compound synthesised could also be tested in other model reactions as phase transfer catalysts.Currently we are investigating the effect of the crown ethers catalysts in other asymmetric reactions.The allylic substituent in compound 3 makes possible to bind the macrocycle to a solid carrier (silica gel) allowing the separation study of the racemic mixture of chiral ammonium salts.

General method for the preparation of compounds 18, 22
A solution of the sugar-derivative 17 or 21 (8.0 g, 28.4 mmol) in dry DMF (50 mL) was added to a well-stirred suspension of NaH (2.88 g 120 mmol) in dry DMF (50 mL).After stirring for 30 min at 60 °C a solution of sodium chloroacetate (13.2 g, 113.6 mmol) in dry DMF (20 mL) was added in small portions.The mixture was heated and stirred at 100 °C for 40 h.After cooling the mixture was treated with water (6 mL).(TLC eluent toluene-MeOH, 2:1.)DMF was removed by distillation in vacuum.The residue was dissolved in CHCl 3 and the precipitate was filtered off (sodium salt of the product).The precipitate was dissolved in water (250 mL) and extracted with CHCl 3 (3×40 mL).The aqueous phase was cooled to 5 °C and acidified with aq.20 % HCl to pH 2. The precipitate formed was filtered, dissolved in CHCl 3 repeated washed with water, dried (Na 2 SO 4 ) and evaporated to dryness in vacuo to obtain about 11 g of raw product, which was crystallized from a mixture of benzene-acetone.

General method for the preparation of compounds 19, 23
A solution of the carboxylic acid 18 or 22 (4.0 g, 10 mmol) in THF (10 mL) was slowly added to a suspension of NaBH 4 (1.13 g, 30 mmol) in THF (10 mL) at room temperature (10 min).The mixture was stirred until evolution of gas ceases.Iodine (3.18 g, 12.5 mmol) in THF (15 mL) was added slowly (10 min) and additional hydrogen evolved.The contents were further stirred for 5 h.(TLC eluent toluene-MeOH, 10:2.)Dilute HCl (13 mL, 3 N) was added carefully and the mixture was extracted with ether.The combined ether extract was washed with 3 N NaOH (3×25 mL), brine and dried (MgSO 4 ).Evaporation of the organic layer gave the alcohol product, which was purified by column chromatography on silica gel using 2% to 5 % MeOH in CHCl 3 as the eluant.General procedure for the Michael addition of 2-nitropropane to chalcones 6 The corresponding azacrown ether catalyst (0.1 mmol) and sodium tert-butoxide (0.05 g, 0.5 mmol) was added to a solution of 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 24 to 30 h, a new portion of toluene (7 mL) and water (10 mL) were added and the mixture was stirred for several minutes.The organic phase was washed with water and dried (Na 2 SO 4 ).The crude product obtained after evaporating the solvent was purified by preparative TLC (silica gel, hexane-ethyl acetate, 10:1 as the eluant) to give pure adducts 24.Yield: 0. General procedure for the epoxidation of chalcones 7 A mixture of 0.3 g chalcone (1.44 mmol), the appropriate catalyst (0.1 mmol) in 3 mL toluene and 1 mL 20 % aq.NaOH was treated with 0.5 mL 5.5 M tert-butyl hydroperoxide in decane ( 2.88 mmol).The mixture was stirred at 4-5 °C for 4-10 hours.New portion of toluene (7 mL) and water (10 mL) were added and the mixture was stirred for several times.The organic phase was washed with 10% aqueous hydrochloric acid (2 ×10 mL) and then with water (10 mL).The organic phase was dried (Na 2 CO 3 ).The crude product obtained after evaporating the solvent was purified by preparative TLC (silica gel, hexane-ethyl acetate, 10:1 as the eluant) to give 25 in a pure form.Yield: 0.

Table 1 .
Sodium binding ability of compounds 5, 6, 9, 19, 20 on the basis of FAB-MS measurements a

Table 2 .
The effect of the crown ether catalysts 1-4 on the enantioselectivity in the addition of 2nitropropane to chalcone at room temperature aBased on isolation by preparative TLC.bIn CH 2 Cl 2 at 20 °C.cDetermined by 1 H NMR spectroscopy in the presence of Eu(hfc) 3 as chiral shift reagent.Absolute configuration were assigned by comparison of specific rotation with literature value.6a