Acetaldehyde, Michael addition, enamine

Surprisingly, such selectivity was observed only recently in an aldehyde series. Indeed the group of Barbas developed a catalyst able to perform anti-selective Michael addition of aldehydes [26]. To facilitate such a transformation, several parameters were adjusted to promote the formation of (Z)-enamine, which is necessary to obtain an anti-selectivity (i) the classical secondary amine catalyst was changed for primary amine 17, which is less sterically hindered, favoring the (Z)-enamine, and (ii) the substrate was chosen to be able to form a stabilizing intramolecular H-bonding in favor of the (Z)-enamine. For these reasons (tert-butyldimethylsilyloxy)acetaldehyde (18) was selected as pro-nucleophile. Excellent level of enantio- and diastereoselectivity were obtained on combining these both parameters (Scheme 34.1). In the postulated transition state, covalent interaction... 

As for iminium catalysis, the enamine Michael addition was shown to have a great potential for the fast construction of simple drugs. The group led Benjamin List reported on the highly challenging addition of acetaldehyde to nitroolefins for the synthesis of three different small bioactive natural products (Scheme 11.21). " The Michael adducts 83 obtained using commercial catalyst in 88% to 94% ee and containing both aldehyde and nitro functionality could be transformed by a classic one- to three-step transformation... 

Bridging the gap between organocatalysis and biocatalysis has been attained with the promiscuous enzyme 4-oxalocrotonate tautomerase (4-OT) that has been shown to catalyse the Michael-type addition of acetaldehyde to nitrostyrene. The reaction proceeds in water, affords the (5)-configured product in 89% ee, and is believed to proceed via enamine formation that employs the amino-terminal proline of the enzyme. 2 0... 

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