Stereospecific formation Michael addition

In the course of mechanistic studies it was established that aniline does not react with the cyclopropenones (153 and 154) even under reflux conditions. It was therefore assumed that the formation of (158) involves initial nucleophilic attack by the aminopyridine ring nitrogen on the electrophilic cyclopropenone ring. In this way 155 is formed, which is then transformed via the reactive intermediates (156, 157, and/or 161) to the prodticts. Kascheres et al. noted that the formation of 157 is formally a stereospecific trans addition of the 2-aminopyridines to the double bond of the cyclopropenone (153). Such sterospecificity has been observed in kinetically controlled Michael additions. 

A more recent study of this issue by Golding et al. [53] found that, in the absence of added nucleophiles, (Z,Z)-inuconaldehyde isomerized to the(Z, )-iso-mer in under 16 h at SS °C, while further isomerization to the ( , )-isomer did not occur under these conditions. They postulated a thermally allowed electrocycliza-tion to form a minute concentration of 2 -pyran-2-carboxaldehyde (19) to explain this interesting stereospecificity (see Scheme 2) [55]. Rotations of C=C bonds are expected to have barriers too high for this isomerization mode to occur [34]. If such rotation were to occur, then it would be expected to allow Z, to , isomerization. The reversible formation of 19 would explain why Z, to , thermal isomerization is too slow to observe. Golding et al. [55] also found that triethylamine catalyzes isomerization of (Z, )-muconaldehyde to the ( , )-isomer, presumably by reversible Michael addition and they corroborated the earlier-cited results for 6-keto-2,4-hexadienal. 

Stereospecific Michael addition reactions also may be catalyzed by hydrolytic enzymes (Scheme 2.205). When ot-trifluoromethyl propenoic acid was subjected to the action of various proteases, lipases and esterases in the presence of a nucleophile (NuH), such as water, amines, and thiols, chiral propanoic acids were obtained in moderate optical purity [1513]. The reaction mechanism probably involves the formation of an acyl enzyme intermediate (Sect. 2.1.1, Scheme 2.1). Being an activated derivative, the latter is more electrophilic than the free carboxylate and undergoes an asymmetric Michael addition by the nucleophile, directed by the chiral environment of the enzyme. In contrast to these observations made with crude hydrolase preparations, the rational design of a Michaelase from a lipase-scaffold gave disappointingly low stereoselectivities [1514-1517]. 

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