Asymmetric chiral crown ethers

Asymmetric Lewis-Acid Catalyzed. Another important advance in aqueous Mukaiyama aldol reaction is the recent success of asymmetric catalysis.283 In aqueous ethanol, Kobayashi and co-workers achieved asymmetric inductions by using Cu(OTf)2/chiral >A(oxazoline) ligand,284 Pb(OTf)2/chiral crown ether,285 and Ln(OTf)3/chiral Mv-pyridino-18-crown-6 (Eq. 8.105).286... 

The Darzens reaction can also proceed in the presence of a chiral catalyst. When chloroacetophenone and benzaldehyde are subjected to asymmetric Darzens reaction, product 89 with 64% ee is obtained if chiral crown ether 88 is used as a phase transfer catalyst (Scheme 8-30).69... 

The first successful results of the asymmetric Michael addition under phase transfer catalyzed conditions were achieved by use of ingeniously designed chiral crown ethers 13 and 52.1441 The 3-keto ester 49 reacted with methyl vinyl ketone by use of 13 to give the Michael product 50 with excellent enantioselectivity but in moderate yield, as shown in Scheme 18. The Michael addition of methyl 2-phenylpropionate 51 to methyl acrylate afforded the diester 53 by use of another crown ether 52 in good yield with good enantioselectivity.1441 Various chiral crown ethers were studied to... 

S. Aoki, S. Sasaki, K. Koga, Simple Chiral Crown Ethers Complexed with Potassium tert>Butoxide as Efficient Catalysts for Asymmetric Michael Additions , Tetrahedron Lett. 1989, 30, 7229-7230. 

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. 

L. Toke, P. Bako, G. M. Keserii, M. Albert, L. Fenichel, Asymmetric Michael Addition and Deracemization of Enolate by Chiral Crown Ether , Tetrahedron 1998, 54, 213-222. 

Therefore, the chiral cyanohydrins are valuable and versatile synthons as their single hydroxyl asymmetric centre is accompanied by at least one other chemical functionality. Thus with careful functional group protection, differential and selective chemical transformations can be performed. Such synthetic techniques lead to production of interesting bioactive compounds and natural products. These products include intermediates of j3-blockers 15 1117], j3-hydroxy-a-amino acids 16 [118],chiral crown ethers 17 [lll],coriolic acid 18 [120], sphingosines 19 [121], and bronchodilators such as salbutamol 20 [122] (Fig. 3). 

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). 

Chiral metal alkoxides and naphthoxides have been used as catalysts for asymmetric Michael reaction. An early successful example was reported by Cram et al., who used 4 mol % of KO Bu-chiral crown ether 8 complex as the catalyst to afford the Michael adduct with up to 99% ee (Scheme 8D.7) [16], In this case KO Bu complexed with chiral crown ether 8 plays two... 

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. 

Chiral crown ethers. Cram and Sogah4 have observed that potassium bases [KOC(CH3)3 or KNHj] complexed by the chiral crown ethers 1 or 2 catalyze asymmetric Michael additions to methyl vinyl ketone and to methyl acrylate to give adducts in 60 99% optical purity. 

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). 

In the following sections, progress made in asymmetric phase-transfer catalysis using chiral crown ethers, taddolates, Nobin and metal(salen) complexes is surveyed. Each section is further subdivided according to the reaction being catalyzed. 

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. 

In recent years, many chiral catalysts for the enantioselective synthesis of optical active 1,5-dicarbonyl compounds have been developed, such as chiral crown ethers with potassium salt bases and chiral palladium complexes, including bimetallic systems. Nakajima and coworkers reported on enantioselective Michael reactions of S-keto esters to a,/3-unsaturated carbonyl compounds in the presence of a chiral biquinoline N,N dioxide-scandium complex, which catalyzed the additions in high yields and with enan-tioselectivities up to 84% ee . Kobayashi and coworkers found that the combination of Sc(OTf)3 with the chiral bipyridine ligand 149 (equation 41) was also effective as a chiral catalyst for asymmetric Michael additions of 1,3-dicarbonyl compounds 147 to a,/3-unsaturated ketones 148. The corresponding Michael adducts 150 were obtained in good to high yields with excellent enantiomeric excesses in most cases (Table 10). 

Finally, it is notable that the title reagent has been used to prepare even larger ring systems such as chiral crown ethers, and the use of l,l -binaphthalene-2,2 -dithiol as ligand for rhodium(I) in the asymmetric hydroformylation of styrene has been described. ... 

When borohydride reductions are carried out in the presence of either a chiral phase transfer catalyst or a chiral crown ether, asymmetric reduction of ketones occurs but optical yields are low. In the reduction of acetophenone with NaBH4 aided with a phase transfer catalyst (57), 10% ee was obtained. Similarly, reduction of acetophenone with NaBH4 in the presence of the chiral crown ether (58) was ineffective (6% ee)J Sodium borohydride reduction of aryl alkyl ketones in the presence of a protein, bovine semm albumin, in 0.01 M borax buffer at pH 9.2 affords (R)-carbinols in maximum 78% cc. ... 

Seebach and Oei [446,447] reported the asymmetric hydrodimerization of acetophenone (a maximum asymmetric yield of 6.4%) in a chiral cosolvent. The use of small amounts of chiral crown ethers was attempted however, no significant asymmetric induction was observed [443]. It is interesting that in the presence of /5-cyclodextrin, head-to-tail coupling of acetophenone leads to optically active dimeric monoalcohol (ca. 24% ee), whereas the head to head coupling gives optically inactive pinacols [448,449]. 

With regard to the catalytic asymmetric reaction , only a few successful examples, except those reactions using chiral transition metal complexes, have been reported. For example, the cinchona-alkaloid-catalyzed asymmetric 1,4-addition of thiols or 6-keto esters to Michael acceptors quinidine catalyzed the asymmetric addition of ketene to chloral and the highly enantioselective 1,4-addition of ) -keto esters in the presence of chiral crown ethers to Michael acceptors have been most earnestly studied. 

Lewis acid-catalyzed asymmetric aldol reactions of silyl enol ethers with aldehydes are among the most powerful carbon-carbon bond-forming methods aprotic anhydrous solvents and low reaction temperatures are, however, usually needed for successful reaction. To perform the catalytic asymmetric aldol reaction in aqueous media a chiral crown ether-Pb(OTf)2 complex was employed as a chiral catalyst stable in water-ethanol [9]. Good to high yields and high levels of diastereo-and enantioselectivity were obtained at 0°C in aqueous media (Scheme 13.64). 

The asymmetric Michael addition of active methylene or methyne compounds to electron deficient olefins, particularly a,P-unsaturated carbonyl compounds, represents a fundamental and useful approach to construct functionalized carbon frameworks [51]. The first successful, phase-transfer-catalyzed process was based on the use of well-designed chiral crown ethers 69 and 70 as catalyst. In the presence of 69, P-keto ester 65 was added to methyl vinyl ketone (MVK) in moderate yield but with virtually complete stereochemical control. In much the same way, crown 70 was shown to be effective for the reaction of methyl 2-phenylpropionate 67 with methyl acrylate, affording the Michael adduct 68 in 80% yield and 83% ee (Scheme 11.15) [52]. 

Cram found that chiral crown ethers in the presence of alkali metal bases catalyzed the asymmetric Michael addition [46]. Ketoester 6 underwent addition to 7 in more than 99% ee in the presence of (S,S)-49 and KOf-Bu (4 mol %). Another crown ether, R)-50, and KNH2 promoted the addition of 41 to 42 giving (S)-43 in 60% ee. Since then, this reaction was examined using various optically active crown ethers [47,48,49,50,51,52,53,54,55,56], which are summarized in Scheme 10 showing the configuration and enantiomeric excess of 43. Slight changes in the structure of the crown ethers drastically affected the stereochemistry of the reaction. A brief structure-activity relationships may be presented. 

Asymmetric Michael additions of the prochiral acceptors using crown ethers are rare. The reaction of 60 and 46 using chiral crown ethers 62,63,64, etc., was reported by Yamamoto and other researchers (Scheme 11) [57, 58]. The phe-nylthio group could be removed under radical conditions giving 61. 

Asymmetric Michael reactions can be catalyzed by KOferf-Bu in the presence of chiral crown ethers [253, 559, 766], Crown ether 3.5 derived from binaphihol has given the best results. 

Lanthanide triflates are stable Lewis acids in water and are successfully used in several carbon-carbon bond-forming reactions in aqueous solutions. The reactions proceed smoothly in the presence of a catalytic amount of the triflate under mild conditions. Moreover, the catalysts can be recovered after the reactions are completed and can be re-used. Lewis acid catalysis in micellar systems will lead to clean and environmentally friendly processes, and it will become a more important topic in the future. Finally, catalytic asymmetric aldol reactions in aqueous media have been attained using Ln(OTf)3-chiral crown ether complex as a catalyst. 

Furthermore, lead(II) and lanthanide(III) complexes were synthesized, which work well as chiral Lewis acids in aqueous media. Until then chiral crown ether-based Lewis acids had not been successfully used in catalytic asymmetric reactions. The asymmetric aldol reactions, however, proceed smoothly at — 10 to 0°C in water-alcohol solutions, while high levels of diastereo- and enantioselectivity are retained. In most previously established catalytic asymmetric aldol reactions the use of aprotic anhydrous solvents and reaction temperatures of — 78 °C were... 

Recently reported uses of optically pure stilbene diol in asymmetric synthesis include. (1) the dimethyl ether as a ligand for effecting enantioselective conjugate addition 6 (2) the preparation of a,p-unsaturated ketals for achieving diastereoselective Simmons-Smith cyclopropanation 10 (3) the preparation of enantiomercially pure p-halohydrlns 11 and (4) the preparation of chiral crown ethers.12... 

Enantioselective Reductions. NaBH4 has been employed with less success than LiAULt or BH3 in enantioselective ketone reductions. Low to moderate ee values have been obtained in the asymmetric reduction of ketones with chiral phase-transfer catalysts, chiral crown ethers, -cyclodextrin, and bovine serum albumin. On the other hand, good results have been realized in the reduction of propiophenone with NaBH4 in the presence of isobutyric acid and of diisopropylidene-D-glucofuranose (ee = 85%), " or in the reduction of cr-keto esters and -keto esters with NaBHa-L-tartaric acid (ee >86%). ... 

The presence of asymmetric carbons in selenomethionine, other a-selenoamino acids, and related compounds produces different chiral enantiomers with different physiological activities. HPLC separation of enantiomers is possible with a range of chiral stationary phases, d- and 1-Selenomethionine enantiomers have been resolved with an a-cyclodextrin stationary phase and other species with a teicoplanin-based chiral phase. Hybrid chiral methodologies based on GC, HPLC, and capillary electrophoresis, coupled with ICP-MS are feasible. Enantiomers of d,l-selenocystine, d,l-selenomethio-nine, and d,l-selenoethionine were examined in a range of commercial dietary supplements using a chiral crown ether stationary phase and ICP-MS detection. Selenium-em-iched onion, garlic, and yeast were analyzed and some of the selenoamino acid enantiomers were identified. l-Fluoro-2, 4-dinitro-phenyl-5-l-alanine amide was used to derivatize enantiomers of selenoamides for enhanced resolution. 

Scheme 2.89 Asymmetric Michael addition catalyzed by chiral crown ether 149...

Thio-bearing chiral crown ethers show enantioselective thiolysis of cramino-acid 4-nitrophenyl ester salts, HX—OAr (X = L-Ala, D-Ala, Phe, D-Phc, Val, D-Val). The asymmetric reduction of ketones with sodium borohydride may be accomplished with chiral crown ethers. ... 

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