Wynberg lactone

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... 

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... 

While the original Wynberg and Staring approach was limited to parent ketene and either electron-deficient aldehydes or ketones, Tennyson and Romo have expanded the scope and practicality of this process by the use of in situ generated monosubstituted ketenes [29]. The use of less reactive dichlorinated aldehydes 44 was also demonstrated, with the utility of the (3-lactone products 45 showcased via a range of derivatization strategies, including conversion to the (3-hydroxy ester 46 (Scheme 3.8). 

Further utility of the parent Wynberg and Staring lactone 40 was demonstrated by Tennyson and Romo. In this report, the use of trichloromethyl-(3-lactone 40 as an amino acid synthon is outlined [30]. This strategy proceeds via ring... 

The first application of the Wynberg process to employ nonactivated aldehydes was reported in 2001 by Romo and coworkers and introduced the nucleophile-catalyzed aldol-lactonization (NCAL) methodology (Scheme 3.17) [40]. In this manifold an in situ generated ammonium enolate, formed via an activated acid, undergoes intramolecular formal [2+2] cycloaddition with an aldehyde moiety to generate the... 

Tertiary Amines It is significant to note that in both Pracejus asymmetric ketene alcoholysis and Wynberg s ketene-chloral cycloaddition, the catalysts of choice were both members of the cinchona alkaloid family that promoted the desired asymmetric process in remarkably high levels of stereocontrol. In 1996, Calter reported a catalytic, asymmetric dimerization of methylketene 89 using cinchona alkaloid catalysts to afford enantiomerically enriched (3-lactones 90 that were reduced in situ using lithium aluminum hydride (LiAlH4) to afford l-hydroxy-3-ketones 91 (Scheme 3.20) [54]. 

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