Sugar-based Crown Ethers in Enantioselective Syntheses

A number of chiral macrocyclic compounds have been prepared that contain a monosaccharide-derived sub-unit. These sugar-based crown ethers were used as chiral phase transfer catalysts in a few asymmetric reactions. A few of them proved to be effective catalysts in Michael additions, a Darzens condensation and an epoxidation of α,β-enones. It was found that the type of the monosaccharide, the substituents on the sugar unit and on the nitrogen atom of the macroring have a significant influence on both the yield and the enantioselectivity.


Introduction
The synthesis and investigation of sugar-based crown ethers was an interesting and up to date topic in the last decades at our department.The basis of our research is the finding that the chiral crown ethers incorporating monosaccharide moiety in their ring, are able to generate asymmetric induction as chiral phase transfer (PT) catalysts in certain reactions.Phase transfer catalysis has been recognized as a versatile methodology for organic synthesis, based on its simple experimental operations, mild reaction conditions using inexpensive and environmentally benign reagents and solvents (very often water).A few of chiral PT catalysts have been successfully used in asymmetric reactions.Chiral phase transfer catalysis has become an attractive area in the "green" chemical discipline, and many types of chiral catalysts have been developed and applied over the past few decades [1][2][3].
Crown ethers with carbohydrate moieties form a special group of the chiral PT catalysts.Sugars are suitable source of chirality and their basic chemistry is well explored.They are available in enantiomerically pure form with known chiroptical properties.Carbohydrates are unusually well-endowed with functionality which can be used to build in secondary binding sites, as well as catalytic sites.A part of the starting monosaccharides is easily available commercial product.Crown ethers containing a sugar unit incorporated in the macrocyclic ring may be built from various monosaccharides; thus macrocycles of different chirality are available [4][5].

Results and discussion
We have synthesized a variety of chiral crown ethers containing one sugar unit in annelation with the macrocyclic ring from various monosaccharides such as d-glucose, d-mannose, d-galactose, d-altrose, 2-deoxy-d-ribo-hexopyranoside, l-arabinose and from sugar alcohols as l-treitol, d-mannitol.These macrocycles differed significantly from each other by the chirality of the sugar units, the size of macrocyclic ring and the number and sort of the heteroatoms in the crown ring.The most important types of the sugar-based crown ethers developed by us can be seen in Fig. 1.
Monoaza-15-crown-5 type macrocycles annelated to protected monosaccharides with different side arms (with heteroatoms at the end) on the nitrogen atom of the crown ring, were synthesized in many steps (1)(2)(3)(4)10).This type of macrocycles named lariat (lasso) ethers or armed crown ethers having heteroatom containing podand arms are suitable to be involved in encapsulated complexation and display high lipophilic character and unique guest specificity due to the macroring -side arm cooperativity [6][7].
In all cases, first a protected monosaccharide derivative with two free vicinal hydroxyl groups was prepared, then the crown ring was built up on the hydroxyl groups of the compound.The preparation of lariat ethers is shown via the example of the 2-deoxy-ribo-hexopyranoside-based macrocycles (4) (Fig. 2) [10].
The synthesis of one of the key compounds (16) involves the opening of the benzylidene acetal ring of 2,3-anhydro derivative 13 that was performed with N-bromosuccinimide (NBS).The benzoyl group of the intermediate was removed by reaction with sodium methylate in methanol to provide bromo sugar 14.The bromo function of intermediate 14 was removed by hydrogenolysis in the presence of Pd/C to give species 15.The regioselective reductive ring opening was accomplished by LiAlH 4 in THF to afford methyl 2,6-dideoxy-α-d-ribo-hexopyranoside (16).

Enantioselective reactions
The sugar-based crown ethers were used as chiral phase transfer catalysts in a few asymmetric reactions.A few of them proved to be efficient catalyst in two Michael additions, in a Darzens condensation and in the epoxidation of α,β-enones.It was found that the type of the monosaccharide, the substituents on the sugar unit and on the nitrogen atom of the macroring have had a significant influence on both the yield and the enantioselectivity [5].
Choosing chalcone (24a, Ar 1 =Ar 2 =Ph) as the starting material, the relationship between the structure of the catalyst and its  effect was studied.The l-arabinose-based lariat ethers (4) generated 61-64 % enatiomeric excess (ee) in this reaction [9].The d-glucopyranoside-( 6) and d-mannopyranoside-( 7) based macrocycles incorporating a pyridine-ring induced ee values of 72 % and 67 %, respectively [11].Using crown ethers comprising an α-d-glucopyranoside unit (1), formation of the (+)-R enantiomer was preferred, while applying α-d-mannose-based catalysts (2), the (-)-S enantiomer was in excess.The monoaza-15-crown-5 type lariat ethers annelated to the methyl 4,6-O-benzylidene-αd-glucopyranoside unit (1) proved to be the most efficient catalysts.The effect of different N-substituents (R) could be observed from the results of the reaction carried out in the presence of lariat ether 1.A few experiments selected are shown in Table 1.The enantioselectivities were better with the catalysts having hydroxyl/methoxy group (entries 3-5) or a P-function (entries 6-9) at the end of the side arm, as compared to the cases with alkyl and arylalkyl groups at the end (entries 1-2).The best result (95 % ee) was obtained with the catalyst containing a Ph 2 P(O) (CH 2 ) 4 substituent (1i).The chain length of substituents is of crucial importance.There is an optimum length for the hydrocarbon spacer connecting the MeO or Ph 2 P(O) moiety to the nitrogen atom of the azacrown ring.Among the catalysts tested, lariat ether 1e with a three carbon atom spacer [(CH 2 ) 3 -OCH 3 ] and macrocycle 1i with a four carbon atom chain [(CH 2 ) 4 -P(O)Ph 2 ] proved to be the best (90 % ee and 95 % ee, respectively) [5].
Another Michael reaction, the conjugate addition of substituted diethylmalonates 28 to β-nitrostyrenes 27 was carried out in a (1:4) mixture of THF-ether as the solvent in the presence of dry Na 2 CO 3 (used in two-fold excess) employing 15 mol% of the crown ether (Fig. 4).The (-)-(S) enantiomer of compound 29 was formed in the presence of catalyst 1d [14][15].
It was found that the α-substituents of diethylmalonate influenced the extent of asymmetric induction.The results on the addition of a few α-substituted diethyl malonate to β-nitrostyrene were summarized in Table 2 (Entries 1-5).
As compared to the unsubstituted product 29a, the substituted derivatives were formed in higher ee values.The methyl-, butyl-, OAc and NHAc derivatives (29b, 29c, 29d and 29e) were obtained in ee values of 42 %, 22 %, 29 % and 99 %, respectively.The ee value of 99 % detected in the reaction of acetamidomalonate is indeed considerable and refers to the role of the NH group in the asymmetric induction.It was found that the substituents of nitrostyrene also influenced the enantioselectivity.The results of the reaction of a few chloro-nitrostyrenes and nitro-substituted derivatives are shown in Table 2 (entries 6-9).It can be seen that the 4-chloro and the 4-nitro substituted products (29h and 29i) were obtained in the highest (97-99 %) ee, in a yield of 65 % and 78 %, respectively [15].
The maximum selectivity (96 % ee) was detected in the reaction of 4-phenyl-α-chloroacetophenone with benzaldehyde (Table 3, entry 2).The substituents of benzaldehyde used as the reactants had a significant impact on the yield and enantioselectivity (Table 3, entries 3-4 and 6-9) [17].The α,β-epoxyketones with a furan (Table 3, entries 6-7) or a thiophene (Table 3, entries 8-10) moiety were obtained in good enantioselectivities (up to 86 % ee) as well as excellent diastereoselectivities (up to 98:2), but the epoxyketone with a pyrrole ring was formed in a low yield and enantioselectivity (Table 3, entry 11).The mannose-based crown ethers 2 generated lower enantioselectivities and promoted the formation of the enantiomer with a positive optical rotation [16].
The absolute configuration of a few epoxyketones was determined by single crystal X-ray analysis.As an example, we show the ORTEP representation of the epoxyketone obtained in the reaction of 4-phenyl-α-chloroacetophenone with 2-chlorobenzaldehyde.According to this, the absolute configuration is 2R,3S (Fig. 6).It is reasonable to assume that the other epoxyketone derivatives with negative optical rotation also possess the same 2R,3S absolute configuration [17].
The reaction of cyclic α-chloroketones with aromatic aldehydes was studied under the conditions described above in the presence of catalysts 1 and 2. The reactions of 2-chloro-1-indanone (33) and 2-chloro-1-tetralone (34) with various aromatic aldehydes (31) were completed after a stirring of 20-40 minutes at 0°C in the presence of catalyst 1 (Fig. 7).The trans-epoxyketones (35 and 36) were obtained in good yields with high diastereoselectivites (de of >98 %) and with moderate to good enantioselectivities [14,17].The reaction of 2-chloro-1-indanone (33) and benzaldehyde gave epoxyketone 35a (Ar = Ph) in a yield of 59 % and in an ee value of 65 %.Among the substituted benzaldehydes, the best results were obtained in the reaction with 2-chlorobenzaldehyde; in this case, product 35b (Ar = 2-Cl-C 6 H 4 ) was formed in an ee of 85 %.It was found that the change in the ring size (replacing the 5-membered ring by a 6-membered ring, i.e. going from 33 to 34, respectively) had a dramatic impact on the isolated yields and optical purities.In the reaction of 2-chloro-1-tetralone (34) with benzaldehyde, epoxyketone 36a (Ar = Ph) was formed in a yield of 84 % and in an enantioselectivity of 74 %.The effect of the substituents of the benzaldehyde was evaluated.The substituted derivatives were formed in lower (32-70 %) ee values.In the case of both cyclic α-chloroketones, the configurations of the stereogenic centers were found to be 2R,3'S on the basis of single crystal X-ray analysis.The mannose-based crown ethers 2 generated lower ee values and the chiral epoxyketones were formed with a 2S,3'R configuration.As an example, in the presence of catalyst 2 (R=(CH 2 ) 3 OH) products 35b and 36a were formed in ee values of 64 % and 61 %, respectively [14,17].
The relationship between the structure of the catalyst and its effect was studied in the epoxidation of chalcone (Ar 1 =Ph, Ar 2 =Ph).It was found that the yield and enantioselectivity are significantly affected by the type of the monosaccharide moiety and the N-substituents of the crown ring.Comparing the enantioselectivity obtained in the presence of the catalysts with different monosaccharide units 1-10, the d-glucose-based lariat ethers (1) gave the best results.The effect of the different side arms have been studied in the case of this catalyst (1) (Table 4).Using glucose-based crown ethers 1, formation of the (-)-(2R,3S) enantiomer was preferred, while applying mannose-based 2 as the catalysts, the (+)-(2S,3R) antipode was in excess [5].
The best results (94 % and 81 % ee) were obtained applying crown ethers with γ-hydroxypropyl and β-hydroxyethyl substituents (as in 1d and 1c), respectively.Using the δ-hydroxybutyl derivative (1f), the ee was 41 %.It can be concluded that the length of the chain connecting the hydroxyl group to the nitrogen atom plays an important role in the asymmetric induction; a chain of three carbon atoms is the optimum.It is also interesting that the methylation of the hydroxyl group in 1d resulted in a dramatic decrease in the enantioselectivity as was demonstrated by the ee 23 % obtained with 1e.It is clear that the hydrophilic hydroxyl substituents [(CH 2 ) n OH]) promote the transport of the catalyst between the two phases (toluene and water), while the lipophilic (CH 2 ) n OMe substituents have an opposite effect [5].
It was found that the position of the substituents in the aromatic ring of the chalcone had a great impact on the yield and enantioselectivity.The lowest enantioselectivities (62-83 % ee) were found in the case of the ortho-substituted model compounds, while the highest ee values (ee of 95-99 %) were obtained in the case of para-substituted models (good results of a few experiments in Table 5, entries 1-4).The epoxidation of the chalcone analogues are summarized in Table 5 (entries 5-10).The best enantiomeric excess values were obtained for the epoxyketone with R 1 =But and R 2 =Ph, (90 % ee) or R 1 =But and R 2 =2-naphthyl (92 % ee) [19].Finally, two glucopyranoside-based crown ethers, with acridine fluorescent signalling units were synthesized, the 15-membered ligand 12a and the 21-membered ligand 12b.Their complexation properties toward alkali and alkali earth metal ions, and their enantioselectivity towards chiral ammonium salts were studied by absorption and fluorescence spectroscopic experiments.Macrocycle 12a formed 1:1 complexes with all the metal ions selected and the stability constants were low (lg K < 2.3).The cavity-size of 12b only afforded the complexation of organic ammonium ions.It showed chiral discrimination in case of all the four ammonium salts used as model guest compounds.The highest enantioselectivity (K(R)/K(S) ~ 3) was observed in case of the enantiomers of phenylethyl-ammonium (PEA) perchlorate.Ligand 12b forms much more stable complexes with metal ions, the highest stability constant was obtained for the Ca 2+ complex (lg K = 6.15).The coordination of metal ions by species 12b was accompanied by a marked fluorescence enhancement, whereas the binding of ammonium ions by the same ligand resulted in significant fluorescence quenching [12].

Summary
We have synthesized a variety of chiral crown ethers containing one sugar unit in annelation with the macrocyclic ring from various monosaccharides such as d-glucose, d-mannose, d-galactose, d-altrose, 2-deoxy-d-ribo-hexopyranoside, l-arabinose and from sugar alcohols as l-treitol, d-mannitol.A few representatives of the monosaccharide-based crown ethers induced a considerable asymmetric induction in certain reactions.On the basis of our experiences, it can be concluded that in the case of monoaza-15-crown-5 lariat ethers incorporation of a d-glucose moiety results in the most efficient catalysts.The glucose-based catalysts with (CH 2 ) 3 OH substituent on the nitrogen atom (1d) showed the best results regarding the enantioselectivity.In the reaction of 2-nitropropane with chalcone and chalcone analogue α,β-enones 48-95 % ee values were measured.Addition of diethylmalonates to β-nitrostyrenes gave the Michael adducts in an enantioselectivity of 20-97 %.The epoxyketones were obtained in 51-96 % ee values in Darzens condensations and in 67-99 % ee values in epoxidation of α,β-enones in the presence of catalyst 1d.The development of novel catalysts is of practical importance, as the lariat ethers can be utilized in a variety of phase transfer catalytic reactions, a part of which is to be explored.

Table 1
Effect of the side arms of the catalyst in the reaction of 2-nitropropane and chalcone

Table 2
Addition of diethylmalonates 28 to β-nitrostyrenes 27 in the presence of catalyst 1d

Table 3
Asymmetric Darzens condensations in the presence of catalyst 1d a Based on isolation by preparative TLC; products 32 had a negative specific rotation; b Determined by1H NMR spectroscopy

Table 4
Effect of the N-side arms of the catalyst 1 in the epoxidation of chalcone (24, A 1 =A 2 =Ph) Based on isolation by preparative TLC; b Enantioselectivities were determined by 1 H NMR spectroscopy; the (-)-(2R,3S)-antipode of the epoxyketone 32 was formed a

Table 5
Asymmetric epoxidation of chalcone, substituted chalcones and chalcone analogues in the presence of the catalyst 1d Based on isolation by preparative TLC; b Enantioselectivities were determined by 1 H NMR spectroscopy; the (-)-(2R,3S)-antipode of the epoxyketone 32 was formed a