Asymmetric Synthesis of 2-Alkylalkanoic Acids via Alkylation of Chiral Amide Anions.

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Abstract
Acylation of (S)-proline methyl ester (2) gave amide ester 3 (R1 = alkyl), which on reaction with methylmagnesium iodide furnished the tertiary alcohol 4. Alkylation of the dianion from this yielded mainly 1 diastereomer of the amide 5, which on acid hydrolysis gave the chiral 2-alkylalkanoic acid 6 in 75-90% e.e. [enantiomeric excess] and 55-82% chemical yield from the hydroxyamide 4. The latter compound could be recovered from the hydrolyzate with preserved optical purity via acylation without isolation of the tertiary prolinol 7. The diastereomeric mixture of amides 5'' and 5" could be separated by column chromatography leading to the acid 6 in very high optical purity. [This investigation was initiated because of interest in the synthesis of insect pheromones using chiral 2-alkylalkanoic acids as building chiral 2-alkylalkanoic acids as building blocks].