Crown asymmetric Michael addition

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. 

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. 

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. 

Scheme 8.3 Crown ether-induced asymmetric Michael addition of 2-nitropropane to chalcones.

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). 

Carbohydrate crown ethers were obtained with ethylene spacers from a crown ether point of view, the carbohydrate vicinal diols are replacing one ethylene glycol unit [181,182], Cyclic compounds synthesized include bis-gluco-15-crown-5 82, bis-gluco-21-crown-7, and tetra-gluco-24-crown-8 (O Scheme 14). These chiral macrocycles could serve as catalysts in the asymmetric Michael addition of methyl a-phenylacetate to methyl acrylate. With the goal to study molecular interactions, P,P, and Q, Q -bis-maltosides with aliphatic two-, three-, or four-earbon spacers were synthesized [183]. Spaced cyclodextrins were prepared to study their supramolecular properties [184,185]. 

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. 

Scheme 5,41. (a, b) Cram s C2-symmetric chiral crowns for asymmetric Michael addition [204]. 

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

The structural motifs of some excellent chiral crown ethers have been derived from easily accessible natural products. For example, a (+)-camphor-based chiral aza-crown ether 7 was developed and successfully apphed in asymmetric conjugate addition by Brunet [11]. The use of D-glucose-based crown ethers 8 and 9 as chiral phase-transfer catalysts has been intensively studied by Bako and colleagues in the asymmetric Michael addition [12], Darzens condensation [13], and epoxidation [14]. Another carbohydrate-derived chiral crown ether 10 was prepared from chiro-inositol by Aldyama and coworkers, which successfully enabled the enantioselective conjugate addition of N-(diphenylmethylene) glycine tert-butyl ester to several electrophiles [15]. 

Enolase type activity is displayed in the efficient supramolecular catalysis of H/D exchange in malonate and pyruvate bound to macrocyclic polyamines [5.32]. Other processes that have been studied comprise for instance the catalysis of nucleophilic aromatic substitution by macrotricyclic quaternary ammonium receptors of type 21 [5.33], the asymmetric catalysis of Michael additions [5.34], the selective functionalization of doubly bound dicarboxylic acids [5.35] or the activation of reactions on substituted crown ethers by complexed metal ions [5.36]. 

Deracemization. Results from Michael additions described earlier (Scheme 10.8) led Toke and co-workers to an interesting deracemization study. When racemic Michael adduct 106 was reacted with a catalytic amount of base in the presence of the chiral crown 12 for 8 min, the resulting product was optically active (40% ee). The authors propose that a deprotonation followed by reprotonation of the resulting chiral ion-pair accounts for the asymmetric induction [39]. 

A chiral diol was obtained from the asymmetric Diels-Alder reaction of anthracene with dimen-thyl fumarate (see Section 3.5.1. for the dienophile) in 99% ee (for details on this reaction, see ref 17). Conversion of the diol to the crown ether 13 was achieved with pentaethyleneglycol ditosylate and potassium hydroxide18. As for the other crown ethers discussed here, the compound has been used as a catalyst in enantioselective Michael additions (Section D. 1.5.2.1.). 

The asymmetric Michael reaction can be catalysed by enantiomerically pure crown ethers in the presence of base. For instance the addition of cyclic donor (11.16) with acceptor (11.22) occurs with up to 99% ee using an enantiomerically pure crown ether in the presence of potassium tert-butoxide. In fact, enantiomerically pure crown ethers have been used to catalyse other Michael reactions, including the use of crown ether (11.45) in the conjugate addition reaction between the ester (11.46) and Michael acceptor (11.47). The reaction is remarkably rapid (one minute at —78°C). 

The recent results reported by Cram are extremely important because his catalysts are chiral crown ethers, and represent one of the first attempts to develop novel structures without the inherent disadvantages of the ammonium salts described above. Such crowns yield products from Michael additions of 3-ketoesters to methyl vinyl ketone with optical purities up to 99%. A series of novel chiral onium salts derived from methionine have also been reported by Colonna and his coworkers. Although so far these have displayed no asymmetric induction in their reactions, they are important as an imaginative new series of catalysts. 

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. 

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