Carbonyl compounds alkylation, regiochemistry

Until recently, a-substitution of carbonyl compounds was largely restricted to those cases where alkyl groups, such as Me, allyl, and benzyl, were introduced via classical enolate alkylation. a-Aiylation of ketones with aryl halides can be effected using K in NH3 [120-123]. However, this reaction does not appear to be satisfactory for selective -alkenylation and a-alkynylation. -Arylation of ketones has also been catalyzed by Ni [124] and Pd [125,126]. The Pd-catalyzed version employed enolstannanes. This reaction has also been applied to a-alkenylation [127]. However, these reactions appear to be of very limited scope. Thus, the Pd-catalyzed procedures appear to be satisfactory mainly for a-substitution of methyl ketones. Furthermore, none of them addresses the critical question of how to control the regiochemistry of c-substitution, i.e., a vs. a. Critically needed from the viewpoint of selective synthesis were... 

J.l Regiochemistry and Stereochemistry of Alkylations of Nitrogen Derivatives of Carbonyl Compounds... 

Ketones and aldehydes can undergo photochemical [2-1-2] cycloaddition reactions with alkenes to give oxetanes. This is called the Paterno-Buchi reaction. For alkyl carbonyl compounds both singlet and triplet excited states seem to be involved, but for aromatic compounds the reaction occurs through the triplet state.The regiochemistry can usually be accounted for on the basis of formation of the most stable 2-oxa-1,4-diradical. For example, styrene and benzaldehyde give 2,3- not 2,4-diphenyloxetane. ... 

The base-catalyzed reaction of j8-ketoesters with a-halogenoketones (Feist-Benary reaction) <02CB 1545,11CB493 > yields 3-alkoxycarbonylfurans (23) (Scheme 16). Usually the reaction starts with an aldol condensation if in the first step an alkylation of the ) -carbonyl compound takes place, the reversed regiochemistry is observed <68JH05>. 

Lewis acid catalyzed ene reactions have been shown to have a broad scope which complements thermal ene reactions. In many cases complex products can be produced with excellent control of stereo- and regiochemistry. During our exploration of these reactions we have found related Lewis acid catalyzed additions of o,p-unsaturated ketones and aldehydes and aldehydes with alkenes which give rise to open zwitterions which imdergo controlled reactions to give cyclobutanes, Y-chloroalcohols, and new carbonyl compounds. From the above results it is clear that or-ganoaluminum compounds, due to their ability to act as proton scavengers and alkyl donors, have an important role to play in the development of Lewis acid catalyzed reactions. 

The regiochemistry of alkylation of simple, non-symmetric ketones may be problematic to control, and polyalkylation can be a competing reaction. The most useful strategy is to ensure complete deprotonation of the carbonyl compound using the strong, non-nucleophilic base LDA, followed by inverse addition of the enolate to an excess of the alkylating agent. 

The enzyme 2-C-methyl-D-erythritol-4-phosphate synthetase appears to catalyse a Bilik reaction (Figure 6.10) the substrate l-deoxyxylulose-5-phosphate is converted to the title compound via an intermediate aldehyde, whose carbonyl derives from C3 of the substrate. The first step is thus a Bilik reaction and the aldehyde is subsequently reduced by the enzyme using NADPH as reductant, The X-ray crystal structure of the Escherichia coli enzyme in complex with the promising antimalarial Fosmidomycin (a hydroxamic acid) reveals a bound Mn " coordinated to oxygens equivalent to the substrate carbonyl and 03. The stereochemistry and regiochemistry follow the normal Bilik course, although the crystallographers favour an alkyl shift rather than a reverse aldol-aldol mechanism. The intermediate aldehyde has been shown to be a catalytically competent intermediate. 

---