Chloral enantioselectivity

The Ti(0 Pr)2Cl2/D-DIPT poison has also been used for the Ti(0 Pr)2Cl2/ BINOL-catalyzed asymmetric carbonyl-ene reaction with chloral (Scheme 8.8). With the Ti(0 Pr)4/D-DIPT poison in a 1 3 ratio, both the regioselectivity and the enantioselectivity of the ene product are improved. 

Aldehydes, ketones, and quinones react with ketenes to give p-lactones, diphenylketene being used most often. The reaction is catalyzed by Lewis acids, and without them most ketenes do not give adducts because the adducts decompose at the high temperatures necessary when no catalyst is used. When ketene was added to chloral Cl3CCHO in the presence of the chiral catalyst (+ )-quinidine, one enantiomer of the p-lactone was produced in 98% enantiomeric excess.777 Other di- and trihalo aldehydes and ketones also give the reaction enantioselectively, with somewhat lower ee values.778 Ketene adds to another molecule of itself ... 

Cinchona alkaloids, naturally ubiquitous /3-hydroxy tertiary-amines, are characterized by a basic quinuclidine nitrogen surrounded by a highly asymmetric environment (12). Wynberg discovered that such alkaloids effect highly enantioselective hetero-[2 -I- 2] addition of ketene and chloral to produce /3-lactones, as shown in Scheme 4 (13). The reaction occurs catalytically in quantitative yield in toluene at — 50°C. Quinidine and quinine afford the antipodal products by leading, after hydrolysis, to (S)- and (/ )-malic acid, respectively. The presence of a /3-hydroxyl group in the catalyst amines is not crucial. The reaction appears to occur... 

Polymer-supported organocatalysts have been used for cycloaddition of ketene, 127, to chloral, 128 [141]. Use of homo-acrylate polymers of cinchona alkaloids led to formation of the desired /Mactone (S)-130 with enantioselectivity up to... 

In 1982, Wynberg and coworkers discovered the cinchona alkaloid catalyzed enantioselective aldol lactonization of ketenes with chloral or trichloroacetone [35], in which the zwitterionic acyl ammonium enolate provides the carbon nucleophile. This work is probably one of the most important early contributions to enantioselective organocatalysis [36], One drawback associated with this process is the severe substrate limitations. The aldehydes should be highly reactive, presumably due to the relatively limited nudeophilicity of ammonium enolates. Nelson and coworkers first addressed the scope and reactivity problems associated with Wynberg s original protocol by combining a cinchona alkaloid derivative (O-trimethylsilylquinine (12) or O-trimethylsilylquinidine (13)) with a metal Lewis acid as a cocatalyst to... 

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. 

Quinidine [3, (9S)-6 -methoxy-9-cinchonanol] is mostly applied for the same purposes as quinine, such as the addition of zinc alkyls to carbonyl compounds (Section D 1.3.1.4.), or addition of thiophenol to acrylic derivatives (Section D.2.I.). An important technical synthesis of malic acid is based on the quinidine catalyzed enantioselective [2 + 2] cycloaddition of ketene to chloral (see Section D. 1.6.1.3.). Esters and ethers of dihydroquinidine (4) (just like the corresponding derivatives of dihydroquinine) have been used as chiral ligands in osmium tetroxide catalyzed dihydroxylations of alkenes (Section D.4.4.). 

L-Malic acid ](S)-13] was the starting material for the synthesis of chiral dienophiles (Section D.l. 6.1.1.1.1.1.). The resolution with 1-phenylethylamine is comparatively difficult18, but asymmetric synthesis by the enantioselective addition of chloral to ketene catalyzed by cinchona alkaloids is an attractive alternative (Section D.l.6.1.3.)19. It is also commercially available. The chiral dienophile 14 is readily obtained in two steps (formation of cyclic imide and acid-catalyzed esterification)20. 

Peters and co-workers developed a tertiary amine-catalyzed enantioselective [4+2] cycloaddition of a,p-unsaturated acid chlorides 76a-e and electron-poor aldehyde chloral (77) to provide 5-lactones 79a-e, Scheme 3.27 [42], Vinylketene, which was formed in situ by dehydrohalogenation of a,p-unsaturated acid chloride... 

Scheme 15.9 Enantioselective addition of ketene to chloral derivatives.

Mimicking the pyruvate aldol reaction has been a long-standing goal for chemists. In 2005, Dondoni and co-workers reported the dimerization of ethyl pyruvate in the presence of a diamine catalyst [53]. This donor also reacts with chloral monohydrate, giving the desired aldol with both moderate enantioselectivity (86% cc) and yield (55%), most likely due to insufficient reactivity [28c]. Pyruvic aldehyde dimethyl acetal is a decent aldol donor for aromatic as well as aliphatic aldehydes (Chart 3.3)... 

Historically, one of the first examples of enantioselective arene (i.e., phenols) decoration was reported by an Italian team (Casiraghi and coworkers) [4] that documented on the efficiency of (-)-menthoxy(ethyl)aluminum chloride 3 as a chiral stoichiometric LA, in promoting the condensation of a range of phenols 1 with chloral 2. Enantiomeric excesses up to 80% were obtained (Scheme 5.1a). Shortly after, the first catalytic variant was realized by Erker and coworkers that described the stereoselective addition (ee up to 84%) of 1-hydroxynaphthalene (5a) to methyl or ethylpyruvate (6a,b) in the presence of chiral zircono-cene 7 (Scheme 5.1b) [5]. 

In 1988, Yamamoto, Maruoka and coworkers reported a highly enantioselective car bony 1-ene reaction using their modified BINOL-based aluminum Lewis acid (46a) as a chiral catalyst [35]. Sterically bulky substituent at the 3 and 3 positions of the catalyst is crucial, since, not only owing to the low yield of the ene-adduct, chiral induction was not observed with the diphenyl derivative (47) in the reaction of chloral and 2-phenylthiopropene, while the catalyst (46a) gave the ene-adduct in 69% yield with 57% ee (Scheme 6.30). 

Interesting results were obtained with proHne-tetrazole 22 in the reaction between ketones and chloral monohydrate or anhydrous chloral and water (100mol%). High yields and stereoselectivities were observed (Scheme 24.4). Addition of a higher amount of water increased the enantioselectivity of the reac-hon and decreased the diastereoselechvity. In contrast, the use of a catalytic amount of water (20 or 50mol%) disabled the catalyhc cycle (ca. 5% conversion). 

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