Alpha,beta-unsaturated carbonyl compounds

Fischer, H., Klippe, M., Lerche, H., Severin, T., and Wanninger, G. (1990). Electrophilic beta-bromination and nucleophilic alpha-methoxylation of alpha,beta-unsaturated carbonyl compounds. Chem. Ber. 123, 399-404. 

Chung FL, Hecht SS, Palladino G. 1986. Formation of cyclic nucleic acid adducts from some simple alpha, beta-unsaturated carbonyl compounds and cyclic nitrosamines. IARC Sci Publ 70 207-225. 

Chung FL, Harriott SM, Hecht SS. 1986. Generality of formation of cyclic deoxyguanosine adducts by alpha, beta-unsaturated carbonyl compounds [Abstract], Proc Ann Meet Am Assoc Cancer Res 27 85. 

Boy land, E. and Chasseaud, L.F., Enzymes catalysing conjugations of glutathione with alpha-beta-unsaturated carbonyl compounds, B/ocIiera. J., 109,651,1968. 

The two compounds on the right side of Model 2 are examples of alpha,beta-unsaturated carbonyl compounds (a,P-unsaturated carbonyl compoimds). Explain this name. 

Banerjee AK, Carrasco MC, Pena-Matheud CA. Observations on the dehydrogenation of alpha,beta-unsaturated carbonyl compounds with thallium(lll) acetate. Reel. Trav. Chim. Pays-Bas. 1989 108 94-96. 

Kondo K, Tunemoto D. Sulfonyl carbanions in synthesis. 1. Novel route to alpha, beta-unsaturated carbonyl-compounds. Tetrahedron Lett. 1975 (12) 1007-1010. 

One development involves the use of vitamin B 2 to cataly2e chemical, in addition to biochemical processes. Vitamin B 2 derivatives and B 2 model compounds (41,42) cataly2e the electrochemical reduction of alkyl haUdes and formation of C—C bonds (43,44), as well as the 2inc—acetic acid-promoted reduction of nitriles (45), alpha, beta-unsaturated nitriles (46), alpha, beta-unsaturated carbonyl derivatives and esters (47,48), and olefins (49). It is assumed that these reactions proceed through intermediates containing a Co—C bond which is then reductively cleaved. 

Aqueous solutions of unsaturated carbonyls are hydrolyzed under alkaline conditions to produce additional carbonyl-containing compounds. Alkaline conditions traditionally used to accelerate this reaction cascade can be replaced with elevated temperatures and pressures without greatly affecting the overall hydrolysis of these unsaturated carbonyls. Water-mediated retro-aldol degradation of alpha/beta unsaturated carbonyls appears to be significant as a means to thermally-generate flavor-active carbonyls, as well as lead to deterioration of character-impact compounds possessing these features. 

Based on the above discussion it was thought that the trifluoro-methyl ketones would be more polarized and thus create a great electrophilicity on the carbonyl carbon which facilitates -OH attack by the serine residue. Yet there is no carbon-oxygen bond to be cleaved In the ketone moiety, and therefore the enzyme-trifluoromethyl ketone transition state complex does not undergo catalytic conversion. The above rationale seems reasonable as trifluoromethyl ketones were found to be extraordinary selective and potent inhibitors of cholinesterases (56) of JHE from T. ni (57) and of meperidine carboxylesterases from mouse and human livers (58). Since JH homologs are alpha-beta unsaturated esters, a sulfide bond was placed beta to the carbonyl in hopes that it would mimic the 2,3-olefln of JHs and yield more powerful inhibitors (54). This empirical approach was extremely successful since it resulted in compounds that were extremely potent inhibitors of JHEs from different species (51,54,59). 

Dehydration of an aldol product is no more than a functional group interconversion, so the retrosynthesis of a a,P-unsaturated ketone or aldehyde involves making the same disconnection as used for a P-hydroxy ketone or aldehyde between the alpha and beta carbons. It may help to start the retrosynthesis by adding water back in (undoing the dehydration step) to give the more recognizable P-hydroxy carbonyl compound before making the disconnection. 

Like the aldol and the Claisen, the Michael reaction also involves an enolate, so the mechanism begins with the deprotonation of an alpha carbon. In the Michael reaction, however, the electrophile is not an ordinary carbonyl, but an a,P-unsaturated carbonyl. Attack of the stable enolate nucleophile occurs at the beta carbon of the a,P-unsaturated carbonyl (called a 1,4-addition or conjugate addition or even Michael addition) to give an enolate intermediate. Protonation at the alpha carbon of the enolate gives the final product, a 1,5-dicarbonyl compound. 

A typical retrosynthesis of a 1,5-dicarbonyl compound involves making a disconnection from one of the alpha carbons between the two carbonyls. The alpha carbon will be introduced as a nucleophilic enolate the other carbon needs to be electrophilic. Since the electrophilic carbon is beta to a carbonyl, the starting material is derived by installing a double bond between the alpha and beta carbons to make an a,P-unsaturated carbonyl. 

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