Chiral 18-crown-6 derivatives

A base-promoted (2 -t- 2) cyclization between l,2 5,6-di-0-isopropylidene-D-mannitol (Figure Ab) and diethylene glycol ditosylate had previously been applied (88, 106, 107) successfully to the preparation of the chiral 18-crown-6 derivative dd-27 (p. 228), whence dd-28 to dd-30 can be obtained. However,... 

Chiral 18-crown-6 derivatives incorporating both one and two L-glyceralde-hyde dithioethylacetal residues have also been reported (128) recently. Also, a benzo-18-crown-6 ring has been appended (129) to the C-5 and C-6 positions of 1,2-0-isopropylidene-3-(9-methyl-a-D-glucofuranose. 

The way of designing aixi synthesizing a chiral 20-crown-6 derivative ddd-98 incorporating two 1,2-U-isopropylidene-D-mannitol residues and one 1,3 4,6-di-O-methylene-D-mannitol residue starting from appropriately constracted mono- and di-extended diacetone mannitol units is outlined (136) in Scheme 6. It relies on the local C2 symmetry of all the carbr ydrate residues and the C2 symmetry present in the final product. By developing a strategy not dissimilar to that described in Scheme 3, dithiol-bearing chiral 18-crown-6 derivatives... 

The chiral 18-crown-6 derivative 1 (Scheme 4.1), and similar structures derived from it, are capable of exhibiting enantiomeric differentiation in the complexation of racemic primary ammonium salts. Compound ll-1 has been... 

The structural effect and substrate recognition of the chiral 18-crown-6 derivatives (98) was reported. The binding strength is dominated by electrostatic interactions. The tetra-carboxylate derivative (99 X = ) forms by far the most stable... 

We recently reported a novel enzyme model for the synthesis of peptides by using the multi-functionalized chiral 18-crown-6 derivatives [3]. The new hosts have achieved the assembly of plural guests by covalent bonds formed through non-covalent complexes between the host and the guest, and then enhanced the bond formation between the bound guests. This enzyme model has mimicked the general concept of enzyme catalysis, in which the reactive enzyme-substrate covalent intermediate (E/v aSi) is formed from the noncovalent complex (E Si), and then reacts with the second substrate (S2) to give the product (Sj—S2) as shown in Equation (1) [4]. 

The threefold S5nnmetry of qnatemarized amines makes them ideal guests for 18-crown-6 and its derivatives. Consequently, reverse-phase chromatographic colnmn materials modified with chiral 18-crown-6 derivatives have been used to successfully separate racemic mixtures of the common amino acids. The separation coefficients were enhanced at lower temperatnres and at higher loading levels of the crown ether. ... 

An interesting feature of the synthesis is the use of allyl as a two-carbon extension unit. This has been used in the stereospecific synthesis of dicyclohexano-18-crown-6 (see Eq. 3.13) and by Cram for formation of an aldehyde unit (see Eq. 3.55). In the present case, mannitol bis-acetonide was converted into its allyl ether which was ozonized (reductive workup) to afford the bis-ethyleneoxy derivative. The latter two groups were tosylated and the derivative was allowed to react with its precursor to afford the chiral crown. The entire process is shown below in Eq. (3.59). 

Early examples of enantioselective extractions are the resolution of a-aminoalco-hol salts, such as norephedrine, with lipophilic anions (hexafluorophosphate ion) [184-186] by partition between aqueous and lipophilic phases containing esters of tartaric acid [184-188]. Alkyl derivatives of proline and hydroxyproline with cupric ions showed chiral discrimination abilities for the resolution of neutral amino acid enantiomers in n-butanol/water systems [121, 178, 189-192]. On the other hand, chiral crown ethers are classical selectors utilized for enantioseparations, due to their interesting recognition abilities [171, 178]. However, the large number of steps often required for their synthesis [182] and, consequently, their cost as well as their limited loadability makes them not very suitable for preparative purposes. Examples of ligand-exchange [193] or anion-exchange selectors [183] able to discriminate amino acid derivatives have also been described. 

The highest enantioselectivities in the base-catalyzed Michael additions have so far been obtained using achiral bases complexed to chiral crown ethers. The addition of methyl 2,3-dihydro-l-oxo-1//-indene-2-carboxylate (1) to 3-buten-2-one using 4 mol% of a [l,T-binaphthalcnc]-2,2 -diol derived optically active crown ether 3 in combination with potassium AY/-butoxide as the base illustrates this successful method 259 260 It is assumed that the actual Michael donor is the potassium enolate complex of 1 and crown ether 3. 

A remarkably high enantioselectivity of 81 % is achieved using the simple C2-symmetric chiral crown ether 6 derived from (2,S ,3b )-butanediol263. 

E. Brunet, A. M. Poveda, D. Rabasco, E. Oreja, L. M. Font, M. S. Batra, J. C. Rodrigues-Ubis, New Chiral Crown Ethers derived from Camphor and Their Application to Asymmetric Michael Addition. First Attempts to Rationalize Enantioselection by AMI and AMBER Calculations , Tetrahedron Asymmetry 1994, 5, 935-948. 

P. Bako, E. Czinege, T. Bako, M. Czugler, L. Toke, Asymmetric C-C Bond Forming Reactions with Chiral Crown Catalysts derived from D-Glucose and D-Galactose , Tetrahedron Asymmetry 1999, 10, 4539-4551 and references cited therein. 

An extremely important aspect in pharmaceutical research is the determination of drug optical purity. The most frequently applied technique for chiral separations in CZE remains the so-called dynamic mode where resolution of enantiomers is carried out by adding a chiral selector directly into the BGE for in situ formation of diastereomeric derivatives. Various additives, such as cyclodextrins (CD), chiral crown ethers, proteins, antibiotics, bile salts, chiral micelles, and ergot alkaloids, are reported as chiral selectors in the literature, but CDs are by far the selectors most widely used in chiral CE. 

Among the 1,4-di-O-substituted-L-threitol derivatives (Figure 14a) the one that has found most use in chiral crown ether synthesis is the 1,4-dibenzyl ether. Not only has it provided (88, 106, 107) a ready entry into the chiral tetrasub-stituted 18-crown-6 derivatives ll-31 to ll-34, but it has also proved to be a usehil chiral precursor for the preparation of chiral disubstituted 9-crown-3 (107), 12-crown-4 (108), 15-crown-5 (108), and 18-crown-6 (109) derivatives l-57, l-58, l-59, and l-60, respectively. In the preparation of l-S8 the base-promoted cyclization with triethylene glycol ditosylate is best carried out (108) with a... 

The incoiporation of two asymmetric precursors into chiral crown ethers with C2 symmetiy must be carried out with total constitutional and stereochemical control during the reaction sequence. This has been accomplished elegantly during the synthesis of the three chiral benzo-15-crown-5 derivatives (SS)-79, and (5S)- 0 from (S)-lactic acid (122, 123). 

Closely related to the synthetic work reported in the previous section is the incorporation (131) of a 2,5-anhydro-3,4Hdi-0-methyl-D-mannitol residue (Figure 15) into the 18-crown-6 derivative d-91. Other derivatives of D-mannitol that have been built into crown ether receptors include l,4 3,6-dianhydro-D-maiuiitol (132), l,3 4,6-di-0-methylene-D-marmitol (13 134), and 1,3 4,6-di-O-benzylidene-D-mannitol (134). Examples of chiral crown compounds containing these residues include dd-92, dd-93, d-94, and d-95. Although not derived from carbohydrates—but rather (135) from the terpene, (-t-)-pulegone—... 

The incorporation of two nonidentical chiral residues, each supporting C2 symmetry, into a mactocyclic poly ether affords a chiral crown compound with C2 symmetry provided its structure is constitutionally symmetrical. Thus, base-promoted reaction of the half-crown diol prepared from (5)-birraphthol with the half-crown ditosylate d-72 synthesized tom diacetone-manrritol affords (144) the 20-crown-6 derivative (S)-d-113 with C2 symmetry. When d-72 is condensed in like fashion with (/ 5)-binaphthol, then the diastereoisomeric 20-crown-6 derivative (/ )-d-114 can be separated chromatogiaphically tom (S)-d-113. In this matmer, (/ 5)-binaphthol is resolved by the carbohydrate unit during the synthesis. 

Very recently, chiral crown ethers incorporating 9,9 -biphenanthryl (158) and 4,4 -biphenanthryl (159) moieties have been prepared from the corresponding optically active 10,10 -dihydroxy and 3,3 -dihydroxy derivatives, respectively. Both 20-crown-6 macrocycies, for example, (S)-130, containing one chiral unit and 22-crown-6 macrocycies, for example, (/U )-131, containing two chiral units are known. 

Prelog and co-workers (160, 161) chose 9,9 -spirobifluorene as a starting material for synthesizing chiral crown ethers since (i) it has a more rigid carbon skeleton than the 1,1 -binaphthyl unit, and (ii) it can be substituted easily in the 2 and 2 positions by electrophilic reagents. Thus, the 2,2 -diacetyl derivative (Figure 19) obtained after a Friedel-Crafts on 9,9 -spirobifluoiene can be con-... 

A number of chiral crown compounds containing more than one macrocyclic polyether ring have been described in the literature. They have been derived... 

Chiral crown ether phosphine-palladium complexes have been used to catalyse the alkylation of carbanions derived from a-nitro ketones and a-nitro esters,63 and proline rubidium salts have been used to catalyse asymmetric Michael addition of nitroalkanes to prochiral acceptors 64 80% enantioselectivity can be achieved in each case. 

Scheme 71 Axial chiral crown-like binaphthyl derivatives 128-131...

Currently, the chiral phase-transfer catalyst category remains dominated by cinchona alkaloid-derived quaternary ammonium salts that provide impressive enantioselec-tivity for a range of asymmetric reactions (see Chapter 1 to 4). In addition, Maruoka s binaphthyl-derived spiro ammonium salt provides the best results for a variety of asymmetric reactions (see Chapters 5 and 6). Recently, some other quaternary ammonium salts, including Shibasaki s two-center catalyst, have demonstrated promising results in asymmetric syntheses (see Chapter 6), while chiral crown ethers and other organocatalysts, including TADDOL or NOBIN, have also found important places within the chiral phase-transfer catalyst list (see Chapter 8). 

The use of chiral crown ethers as asymmetric phase-transfer catalysts is largely due to the studies of Bako and Toke [6], as discussed below. Interestingly, chiral crown ethers have not been widely used for the synthesis of amino acid derivatives, but have been shown to be effective catalysts for asymmetric Michael additions of nitro-alkane enolates, for Darzens condensations, and for asymmetric epoxidations of a,P-unsaturated carbonyl compounds. 

Akiyama s group employed naturally occurring L-quebrachitol 6 to prepare the C2-symmetrical 18-membered chiral crown ether 7 [14]. Compound 7 was found to be an active catalyst for the enantioselective Michael additions of glycine enolates. Thus, deprotonation of ester 8 using potassium tert-butoxide in dichloromethane (DCM) in the presence of crown ether 7 (20 mol %), followed by addition of a Michael acceptor, gave amino-acid derivatives 9 with up to 96% ee, as shown in Scheme 8.4. 

In the addition of 2-nitropropane to chalcone Toke et al. achieved 90% ee by using the D-glucose-derived chiral crown ether 38 as phase-transfer catalyst (Scheme 4.12) [19]. The related crown ether 39, with a pendant phosphonate group, afforded the chalcone adduct with 83% ee, albeit with only 39% chemical yield (Scheme 4.12) [20]. N-Alkylated or N-arylated derivatives of the crown ether 38 afforded lower ee (max. 60%) in the addition of 2-nitropropane to chalcone [21],... 

In the last two decades, chiral receptors containing amidic functions were designed almost exclusively for binding protected amino acids [49-57], oligopeptides [54,58], and lactic [59], tartaric [60,61] or camphoric acid derivatives [62]. Usually, chiral building blocks such as spirobifluorene [49, 60], binaphthalene [51,57],or amino acid chains containing macrocycles [52-56,58] were employed. An interesting receptor was synthesized via connection of the calix[4]arene moiety with an aza-crown derivative [61]. 

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