Asymmetric phase-transfer Michael addition

Catalytic Asymmetric Phase-Transfer Michael Addition to a,f -Unsaturated Esters 119... 

Scheme 6.3 Catalytic asymmetric phase-transfer Michael addition and counter anion effects.

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. 

The use ofTaddol as an asymmetric phase-transfer catalyst has been adopted by other research groups. For example, Jaszay has used Taddol for Michael additions to a-aminophosphonate derivative 20, as shown Scheme 8.10 [22]. A range ofTaddol derivatives was investigated, but the best results were again obtained with the same catalyst employed by Belokon and Kagan. Thus, phosphoglutamic acid derivative 21 was obtained in 95% yield and with 72% ee when tert-butyl acrylate was employed as the Michael acceptor. 

The paramount importance of Michael additions as versatile C-C bond forming transformations was discussed in some detail earlier in this volume. Thus, it is not surprising that, besides the use of chiral PTCs in asymmetric a-alkylation reactions, their use for stereoselective Michael additions is one of the most carefully investigated reactions in asymmetric phase-transfer catalysis (328, 329). Accordingly, the additional use of this methodology in asymmetric total synthesis has been reported on several occasions. 

Michael-addition of diethyl(acetylamido) malonate to chalcone using asymmetric phase transfer catalyst (ephedrinium salts) in presence of KOH in the solid state has been carried outJ The yield is 56% with ee of 60% (Scheme 10). 

The catalytic enantioselective synthesis of ( )-paroxetine (69, Paxil GlaxoSmithKline, London, U.K.), which is a selective serotonin reuptake inhibitor being used for the treatment of depression, anxiety, and panic disorders, was executed as an application of the catalytic asymmetric mono -a-alkylation of 1,3-amide esters (Scheme 4.16). The characteristic feature of this protocol is the introduction of the C3-stereocenter first by the asymmetric phase-transfer alkylation before installing the C4-center by a diastereoselective Michael addition. Af,A -Di-p-methoxyphenyl malonamide... 

The introduction of a new catalyst system by Maruoka and coworkers using C2-symmetric binaphthyl-based chiral spiro ammonium salts 6 in 1999, paved the way for a new era in asymmetric phase-transfer catalysis. This PTC system was found to be highly effective for a variety of asymmetric transformations (e.g., Michael additions, a-amino acid syntheses, epoxidations. 

With respect to the application of tartaric acid-derived PTCs [22,23] for natural product synthesis, the work of Shibasaki s group should be highlighted herein. Using his powerful bidentate TaDiAS PTCs, asymmetric phase-transfer-catalyzed alkylations, Michael addition reactions, and Mannich-type reactions have been systematically carried out. 

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... 

Acrylonitrile, polymerization, 120 Activity of phase-transfer catalysts Sjj2 reactions, 170-175 weak-nucleophile Sj.Ar reactions, 175-182 Acyltetracarbonyl cobalt compound, cleavage in the carboxyalkylation of alkyl halides, 150 Addition reactions, Michael, catalytic asymmetric, 69,70f... 

A chiral phase transfer catalyst was dissolved in ionic liquid media for the enantioselective Michael reaction of dimethyl malonate with l,3-diphenylprop-2-en-l-one with K2CO3 203). The phase-transfer catalyst was a chiral quininium bromide (Scheme 20). The reaction proceeded rapidly with good yield and good enantioselectivity at room temperature in all three ionic liquids investigated, [BMIM]PF6, [BMIM]BF4 and [BPy]BF4. In the asymmetric Michael addition, the enantioselectivity or the reaction in [BPy]Bp4 was the same as in conventional organic solvents. 

Enantioselective Michael addition of glycine derivatives by means of chiral phase-transfer catalysis has been developed to synthesize various functionalized a-alkyl-a-amino acids. Corey utilized 4d as catalyst for asymmetric Michael addition of glycinate Schiff base 1 to a,(3-unsaturated carbonyl substrates with high enantioselectivity (Scheme 2.15) [35,36]. With methyl acrylate as an acceptor, the a-tert-butyl-y-methyl ester of (S)-glutamic acid can be produced, a functionalized glutamic acid... 

Arai et al. also reported another BINOL-derived two-center phase-transfer catalyst 31 for an asymmetric Michael reaction (Scheme 6.11) [8b]. Based on the fact that BINOL and its derivatives are versatile chiral catalysts, and that bis-ammonium salts are expected to accelerate the reaction due to the two reaction sites - thus preventing an undesired reaction pathway - catalyst 31 was designed and synthesized from the di-MOM ether of (S)-BINOL in six steps. After optimization of the reaction conditions, the use of 1 mol% of catalyst 31a promoted the asymmetric Michael reaction of glycine Schiff base 8 to various Michael acceptors, with up to 75% ee. When catalyst 31b or 31c was used as a catalyst, a lower chemical yield and selectivity were obtained, indicating the importance of the interaction between tt-electrons of the aromatic rings in the catalyst and substrate. In addition, the amine moiety in catalyst 31 had an important role in enantioselectivity (34d and 34e lower yield and selectivity), while catalyst 31a gave the best results. 

Recently, chiral phase-transfer-catalyzed asymmetric Michael addition has received much attention, and excellent enantioselectivity (up to 99% ee) has been reported using cinchona alkaloid-derived chiral phase-transfer catalysts [40]. Among noncinchona alkaloid-derived chiral phase-transfer catalysts Shibasaki s tartrate derived C2-symmetrical two-center catalyst provided a Michael adduct with up to 82% ee [41]. 

Whilst simple alkylations of enolates and Michael additions have been successfully catalyzed by phase-transfer catalysts, aldol-type processes have proved more problematic. This difficulty is due largely o the reversible nature of the aldol reaction, resulting in the formation of a thermodynamically more stable aldol product rather than the kinetically favored product. However, by trapping the initial aldol product as soon as it is formed, asymmetric aldol-type reactions can be carried out under phase-transfer catalysis. This is the basis of the Darzens condensation (Scheme 8.2), in which the phase-transfer catalyst first induces the deprotonation of an a-halo... 

---