Metabolism of Deuterated Isomeric 6,7‐Dihydroxydodecanoic Acids in Saccharomyces cerevisiae – Diastereo‐ and Enantioselective Formation and Characterization of 5‐Hydroxydecano‐4‐lactone (=4,5‐Dihydro‐5‐(1‐hydroxyhexyl)furan‐2(3H)‐one) Isomers

Abstract

AbstractThe chemical synthesis of deuterated isomeric 6,7‐dihydroxydodecanoic acid methyl esters 1 and the subsequent metabolism of esters 1 and the corresponding acids 1a in liquid cultures of the yeast Saccharomyces cerevisiae was investigated. Incubation experiments with (6R,7R)‐ or (6S,7S)‐6,7‐dihydroxy(6,7‐2H2)dodecanoic acid methyl ester ((6R,7R)‐ or (6S,7S)‐(6,7‐2H2)‐1, resp.) and (±)‐threo‐ or (±)‐erythro‐6,7‐dihydroxy(6,7‐2H2)dodecanoic acid ((±)‐threo‐ or (±)‐erythro‐(6,7‐2H2)‐1a, resp.) elucidated their metabolic pathway in yeast (Tables 1–3). The main products were isomeric 2H‐labeled 5‐hydroxydecano‐4‐lactones 2. The absolute configuration of the four isomeric lactones 2 was assigned by chemical synthesis via Sharpless asymmetric dihydroxylation and chiral gas chromatography (Lipodex ® E). The enantiomers of threo‐2 were separated without derivatization on Lipodex ® E; in contrast, the enantiomers of erythro‐2 could be separated only after transformation to their 5‐O‐(trifluoroacetyl) derivatives. Biotransformation of the methyl ester (6R,7R)‐(6,7‐2H2)‐1 led to (4R,5R)‐ and (4S,5R)‐(2,5‐2H2)‐2 (ratio ca. 4 : 1; Table 2). Estimation of the label content and position of (4S,5R)‐(2,5‐2H2)‐2 showed 95% label at C(5), 68% label at C(2), and no 2H at C(4) (Table 2). Therefore, oxidation and subsequent reduction with inversion at C(4) of 4,5‐dihydroxydecanoic acid and transfer of 2H from C(4) to C(2) is postulated. The 5‐hydroxydecano‐4‐lactones 2 are of biochemical importance: during the fermentation of Streptomyces griseus, (4S,5R)‐2, known as L‐factor, occurs temporarily before the antibiotic production, and (−)‐muricatacin (=(4R,5R)‐5‐hydroxy‐heptadecano‐4‐lactone), a homologue of (4R,5R)‐2, is an anticancer agent.