Alkylation of Lactic Acid

Alkylation of lactates is not possible directly, since any enolate formation would destroy the chirality at the asymmetric center. This can be circumvented without use of a chiral auxiliary by employing the self-reproduction of chirality approach of Seebach, which incorporates lactic acid into a dioxolane ring and takes advantage of the bulky R group at the newly formed stereo center at C-2 to direct alkylation to the C-5 carbon. 

3-dioxolanone is formed by treating 1 with pivaldehyde under acidic catalysis. This produces a 4 1 mixture of 56 and 57 re 56 (96% ds) is obtained by two recrystallizations of the mixture from ether/pentane at — 78 °C [20,21]. 

Deprotonation of 56 is accomplished with LDA, and alkylation with a primary alkyl, allyl, or benzyl bromide or iodide introduces a second substituent at C-5 (58) with diastereo- 

The enolate of 56 is highly nucleophilic and shows little basicity. Aldehydes as well as acetone, cyclopentanone, and acetophenone react readily to generate adducts in high yield. 

Both enantiomers of frontalin, an aggregation pheromone of the Western pine beetle, have been synthesized using chiral dioxolanones derived from (S)- or (i )-lactic acid [23]. Alkylation of 56 with the dimethyl acetal of 5-iodo-2-pentanone affords trisubstituted dioxolanone 67 in high yield. Reductive cleavage of the hetero ring followed by acid-catalyzed trans-acetalization leads to (R)-( + )-frontalin (69) in 73% overall yield from (S)-( + )-lactic acid 

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