Michael addition, acidic enantioselectivity

Silylketene acetals and enolsilanes can also undergo conjugate addition to a,/ -unsaturated carbonyl derivatives. This reaction is referred to as the Mukaiyama-Michael addition and can also be used as a mild and versatile method for C-C bond formation. As shown in Scheme 8-34, in the presence of C2-symmetric Cu(II) Lewis acid 94, asymmetric conjugate addition proceeds readily, giving product with high yield and enantioselectivity.75... 

The utilization of copper complexes (47) based on bisisoxazolines allows various silyl enol ethers to be added to aldehydes and ketones which possess an adjacent heteroatom e.g. pyruvate esters. An example is shown is Scheme 43[126]. C2-Symmetric Cu(II) complexes have also been used as chiral Lewis acids for the catalysis of enantioselective Michael additions of silylketene acetals to alkylidene malonates[127]. 

Chiral, Lewis acidic bisoxazoline complexes of Mg(II) have been employed as catalysts in asymmetric Michael addition of O-benzyUiydroxylamine to unsaturated amides, (115) -> (116). The enantioselectivity (67-90% ee) was rationalized by transition state (117). This approach constimtes a promising methodology for the synthesis of jS-amino acids. °... 

Dicarbonyl compounds are widely used in organic synthesis as activated nucleophiles. Because of the relatively high acidity of the methylenic C—H of 1,3-dicarbonyl compounds, most reactions involving 1,3-dicarbonyl compounds are considered to be nucleophilic additions or substitutions of enolates. However, some experimental evidence showed that 1,3-dicarbonyl compounds could react via C—H activations. Although this concept is still controversial, it opens a novel idea to consider the reactions of activated C H bonds. The chiral bifunctional Ru catalysts were used in enantioselective C C bonds formation by Michael addition of 1,3-dicarbonyl compounds with high yields and enantiomeric excesses. ... 

MacMillan reported a short and effective synthesis of spiculisporic acid which elegantly exemplified his Mukaiyama-Michael addition of silyloxyfurans to a,P-unsatu-rated aldehydes [88], Robichaud and Tremblay augmented this in a formal synthesis of compactin [224], Within this report it was shown that low enantioselectivities were obtained in the conjugate addition to aCTolein. Use of p-silyl acrolein 177 circumvented this and gave butenohde 178 in 95% yield and 82% ee. Conversion of adduct 178 to the decaUn (179) in eight steps resulted in a formal synthesis (Scheme 71). 

The same group utilized thiourea 12 (10mol% loading) for the catalysis of the enantioselective Michael addition of thioacetic acid to various chalcones [214]. At room temperature and otherwise unchanged conditions, in comparison to the... 

Williams group observed low enantioselectivities for the Michael addition of a prochiral nucleophile, ethyl 2-cyanopropionate 623, to methyl vinyl ketone 624 catalyzed by chiral platinum complexes (Scheme 8.196)." The NMR analysis indicated that these cationic Pt complexes act as Lewis acids toward nitriles. The X-ray crystal structure as well NMR analysis showed that the solvent ligand that is readily displaced by an organic substrate is situated cis to the nitrogen donor in the Pt complex and, therefore, is in a chiral pocket created by the oxazoline ring. 

The c 5-23-dimethylchionian-4-one 53 is obtained with fair enantioselectivity through an asymmetric Michael addition in the presence of (-)-quinine (Scheme 32) <99TL3777>. Directed metallation of protected phenols and subsequent reaction of the li derivative with enantiopure Weinreb amides of glycidic acids feature in a route to stereoisomers of 2-alkyl-3-hydroxychroman-4-ones (Scheme 33) <99JOC3489>. 

During our investigations on asymmetric C—C bond formation reactions via conjugate addition of SAMP hydrazones to various a,(3-unsaturated Michael acceptors, it occurred to us to use the chiral hydrazine auxiliary S AM P as a nitrogen nucleophile and a chiral equivalent of ammonia in aza-Michael additions. Thus, we developed diastereo- and enantioselective 1,4-additions for the synthesis of P-amino acids and P-aminosulfonates [14, 15]. 

It is interesting to note that the oxa-analogous Michael addition was reported for the first time in 1878 by Loydl et al. [19] in their work on the synthesis of artificial malic acid, which was five years ahead of the discovery of the actual Michael reaction described first by Komnenos [20], Claisen [21], and later Michael in 1887 [22] as one of the most important methods for C—C bond formation. In continuation of the early work on the oxa-Michael addition [23], the inter- and intramolecular additions of alkoxides to enantiopure Michael acceptors has been investigated, leading to the diastereo- and enantioselective synthesis of the corresponding Michael adducts [24]. The intramolecular reaction has often been used as a key step in natural product synthesis, for example as by Nicolaou et al. in the synthesis of Brevetoxin B in 1989 [25]. The addition of oxygen nucleophiles to nitro-alkenes was described by Barrett et al. [26], Kamimura et al. [27], and Brade and Vasella [28]. 

Chiral organomagnesium amides form an efficient method to realize enantioselective conjugate addition. Sibi and Asano have reported the Michael addition of cr-bound magnesium reagents derived from bisoxazolines to enamidomalonates (equation 41). The enantioselectivity of the addition is discussed in Section El. This method allows the preparation of chiral -amino acid derivatives. ... 

The heterobimetallic multifunctional complexes LnSB developed by Shibasaki and Sasai described above are excellent catalysts for the Michael addition of thiols [40]. Thus, phenyl-methanethiol reacted with cycloalkenones in the presence of (R)-LSB (LaNa3tris(binaphthox-ide)) (10 mol %) in toluene-THF (60 1) at -40°C, to give the adduct with up to 90% ee. A proposed catalytic cycle for this reaction is shown in Figure 8D.9. Because the multifunctional catalyst still has the internal naphthol proton after deprotonation of the thiol (bold-H in I and II), this acidic proton in the chiral environment can serve as the source of asymmetric protonation of the intermediary enolate, which is coordinated to the catalyst II. In fact, the Michael addition of 4-/en-butylbenzcnethiol to ethyl thiomethacrylate afforded the product with up to 93% ee using (R)-SmSB as catalyst. The catalyst loading could be reduced to 2 mol % without affecting enantioselectivity of the reaction. 

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... 

Jew and Park achieved a highly enantioselective synthesis of (2S)-a-(hydroxy-methyljglutamic acid, a potent metabotropic receptor ligand, through the Michael addition of 2-naphthalen-l-yl-2-oxazoline-4-carboxylic acid tert-butyl ester 72 to ethyl acrylate under phase-transfer conditions [38]. As shown in Scheme 5.36, the use of BEMP as a base at —60 °C with the catalysis of N-spiro chiral quaternary ammonium bromide le appeared to be essential for attaining an excellent selectivity. 

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. 

Taddol has been widely used as a chiral auxiliary or chiral ligand in asymmetric catalysis [17], and in 1997 Belokon first showed that it could also function as an effective solid-liquid phase-transfer catalyst [18]. The initial reaction studied by Belokon was the asymmetric Michael addition of nickel complex 11a to methyl methacrylate to give y-methyl glutamate precursors 12 and 13 (Scheme 8.7). It was found that only the disodium salt of Taddol 14 acted as a catalyst, and both the enantio- and diastereos-electivity were modest [20% ee and 65% diastereomeric excess (de) in favor of 12 when 10 mol % of Taddol was used]. The enantioselectivity could be increased (to 28%) by using a stoichiometric amount of Taddol, but the diastereoselectivity decreased (to 40%) under these conditions due to deprotonation of the remaining acidic proton in products 12 and 13. Nevertheless, diastereomers 12 and 13 could be separated and the ee-value of complex 12 increased to >85% by recrystallization, thus providing enantiomerically enriched (2S, 4i )-y-methyl glutamic add 15. 

Direct catalytic Michael addition of aldehydes to nitrostyrenes proceeds in good yield, syn diastereoselectivity, and enantioselectivity (up to 82/90/99%, respectively) using a recyclable dendritic catalyst bearing chiral pyrrolidine moieties.200 High-yielding enantio- and diastereo-selective direct Michael addition of ketones to nitroalkenes to give aldol products employ modular acyclic primary amino acid derivatives as catalysts.201... 

Cinchona alkaloids and their derivatives have been reported to catalyse the Michael addition of (V-heterocycles, such as benztriazole, to nitroalkenes in moderate to high enantioselectivities (<94% ee) 15 The thiourea derivative (149) catalysed Michael addition of thioacetic acid to a range of frafts-/f-nitrostyrenes to afford RCH(SAc)- CH2NO2 (<70% ee) 16 The thiourea derivative (149) and its congeners have been identified as efficient organocatalysts for the Michael addition of a-substituted cyano-acetates RCH(CN)C02Et to vinyl sulfones CH2=C(R)S02Ph (72-96% ee) 17 ... 

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