Hydrazones, chiral anions, alkylation

Electrophilic substitution. A number of chiral nucleophilic species have been described that result in optically active a-alkyl aldehydes, ketones, acids, and acid derivatives upon alkylation and (usually) subsequent hydrolytic cleavage. Enders provides a number of examples (Figure 3) one of which results in the ant alarm pheromone, 4-methyl 3-heptanone (26 2 7). Studies by A. I. Meyers of the chemistry of anions of chiral oxazolines (Figure 4) were the first of the genre, however ( 8 ). Related reactions of chiral anions of metalloenamines and hydrazones (29, 30, 31) have in common with the alkylation of oxazolines metallated azaenolate intermediates that predispose one face of an azaenolate double bond to reaction with the electrophile. 

Hantzsch dihydropyridine synthesis. The original Hantzsch synthesis2 involves condensation of two equivalents of a keto ester with an aldehyde in the presence of ammonia. In an enantioselective version.5 the chirality is introduced by use of a chiral hydrazone (2) of an alkyl acetoacetate prepared from 1. The anion of 2 is then treated with Michael acceptors to form adducts (3), which cyclize to 4-aryl-l,4-dihydropyridines (4), in 64-72% overall yield and in 84-98% ee. 

Enantiosekctive a-alkylation of cyclohexanone. A polymeric form of this chiral amine (1) has been prepared as shown in equation (I). The reaction of 1 with cyclohexanone leads to the polymer-bound chiral alkoxyimine (2). Alkylation of the anion of 2 followed by mild acid cleavage results in an (S)-2-alkylcyclohexanone (4). When methyl iodide is the alkylating reagent, the optical yield is 95% it is somewhat less when isopropyl iodide is used. These results compare favorably with those obtained by Enders and Eichenauer by alkylation of a chiral hydrazone of cyclohexanone (7, 10-11). For a related reaction, see Benzyl(methoxymethyl)methyl-amine, this volume. 

The stereoselective formation and reaction of hydrazone anions has been reported enantioselective alkylations of aldehydes and ketones (both cyclic and acyclic ) via their chiral hydrazones (97) are achieved in good yield and high optical purity (Scheme 71). 

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