Stereoselective Synthesis of ?-(Acyloxy)carboxylic Acids and ?-Lactones Featuring the Switch of Stereopreference of Candida antarctica Lipase B in Sodium ?-Hydroxycarboxylate Homologues

Scalable protocols of straightforward synthesis of enantiomeric gamma-(acyloxy)carboxylic acids and gamma-lactones are presented. The key step is lipase-catalyzed stereoselective acylation of gamma-hydroxycarboxylic acid sodium salt in organic solvent followed by acidification of the product, extraction and acidic relactonization of the unreacted enantiomer. The mixture of gamma-(acyloxy)carboxylic acid and gamma-lactone is separated either by extraction with solution of sodium bicarbonate or by distillation. A switch of enantioinduction of Candida antarctica lipase B along homologous nucleophiles from R configuration of gamma-hydroxyhexanoic acid salt to S configuration of the C7 and longer-chain homologues has been disclosed. Both enantiomers of gamma-(acyloxy)pentanoic acids; gamma-(acetyloxy)octanoic and -nonanoic acids with S configuration; [(1S,5R)-5-(chloroacetyloxy)cyclopent-2-en-1-yl]acetic acid and enantiomeric gamma-lactones derived from them were prepared with e. r. > 98.5/1.5. The rates of acylation of C5 to C9 homologous salts differ by three orders of magnitude but remain applicable for preparative synthesis by variation of the enzyme loading and reaction time.

Automated summary

Scalable protocols for the synthesis of enantiomeric gamma-(acyloxy)carboxylic acids and gamma-lactones are presented. The key step involves lipase-catalyzed acylation of gamma-hydroxycarboxylic acid sodium salt, followed by acidification, extraction, and relactonization. The enantioinduction of Candida antarctica lipase B switches from R to S configuration for longer-chain homologues. Both enantiomers of gamma-(acyloxy)pentanoic acids and S-configured gamma-lactones were prepared with high selectivity. The rates of acylation differ for different chain lengths but can be controlled by adjusting the enzyme loading and reaction time.