The α-alkylation of carbonyl compounds by their conversion into nucleophilic enolates or enolate equivalents and subsequent reaction with electrophilic alkylating agents provides one of the main avenues for regio- and stereo-selective formation of carbon–carbon σ-bonds.1–6 Classical approaches to α-alkylation typically involve the deprotonation of compounds containing doubly activated methylene or methine groups and having pKa values of 13 or below by sodium or potassium alkoxides in protic solvents. Since these conditions lead to monoenolates derived from deprotonation only at the α-site of the substrate, the question of the regioselectivity of C-alkylation does not arise (however, there is competition between C- and O-alkylation in certain cases). In more recent years, dienolates of β-dicarbonyl compounds have been utilized in γ-alkylations with excellent success.

Alkylations of Enols and Enolates

Publisher Summary This chapter discusses the synthesis and structure-activity relationships of peroxidic antimalarials based on artemisinin. Synthetic methodology has been developed for introducing substituents at C-9, O- 11 (as N-R), and C-3 via a total synthetic intermediate; for substitution of carbon for oxygen at O-13 by a separate route; and for a variety of simplified, tricyclic versions of artemisinin. Analogues accrued from these studies have been bioassayed and their structure-activity relationship is discussed in the chapter. However, in terms of rational design, these relationships are complex and the bioassay data more easily utilized by computer aided pharmacophore modeling. Accordingly, with a dataset of over 200 artemisinin analogues, various comparative molecular field analysis (CoMFA) pharmacophore models have been developed based on: (a) the conformational hypotheses that the active conformation of the analogues is the globally minimized structure (b) the conformational hypotheses that the active conformation of the analogues is based on their interaction with the proposed molecular target in the parasite, hemin; (c) the assumption that enantiomers have identical activity; and (d) the assumption that enantiomers have differing activities.

Synthesis and structure-activity relationships of peroxidic antimalarials based on artemisinin

Treatment of α,β-epoxy sulfoxides, prepared from 1-chloroalkyl phenyl sulfoxides with ketones or aldehydes, with sodium benzeneselenolate gives dialkyl ketones or aldehydes in good yields under mild conditions. The mechanism of this reaction and an application of this process to a formal total synthesis of dihydrojasmone are described.

α, β-epoxy sulfoxides as useful intermediates in organic synthesis. I: A novel synthesis of dialkyl ketones and a synthesis of aldehydes from ketones by one carbon elongation

Symmetrical diketones were prepared by the reaction of the lithium salts of alkyl methyl ketone dimethylhydrazones with dibromoalkanes.

A Convenient Synthesis of Diketones via Alkylation of Alkyl Methyl Ketone Dimethylhydrazones

Nickel, palladium and platinum, survey covering the years 1984 and 1985☆

Unsymmetrical ketones were prepared by successive alkylation of acetone dimethylhydrazone. Application of this reaction to the synthesis of dihydrojasmone is described.

The facile synthesis of unsymmetrical ketones using acetone dimethylhydrazone

The alkylation of 3-methyl-2-cyclopenten-1-one N, N-dimethylhydrazone was investigated and was found to Occour at the α-position of the α, β-unsaturated moity of the hydrazone exclusively.By this method, dihydrojasmone and cis-jasmone were prepared in good yield.Isophorone dimethylhydrazone was also alkylated at the a-position, but for ionone dimethylhydrazone, the reaction occured at the α'-position (methyl carbon), not the α-position of the hydrazone.

Minako Tanabe

Papers

The facile synthesis of unsymmetrical ketones using acetone dimethylhydrazone

α-Alkylation of α, β-Unsaturated Ketones via N, N-Dimethylhydrazones

The facile synthesis of unsymmetrical ketones using acetone dimethylhydrazone