Improved Synthesis of Fluorinated Analogues of Anticancer Active Ether Lipids

Abstract

Racemic 2-fluoro-2-(hexadecyloxymethyl)-3-methoxy­propan-1-ol (15a) and its octadecyl homologue 15b were synthesized from ethyl 2-(hexadecyloxymethyl)acrylate (8a) and its homologue 8b, respectively, in five steps (20% or 19% overall yields) using a bromofluorination as the key step. The new compound 15b was transformed into 2′-(trimethylammonium)ethyl-2-methoxymethyl-3-(octadecyloxy)-1-ylphosphate (7b), a fluorinated analogue of anticancer active ether lipids. Enzyme-catalyzed deracemization of the fluorohydrins 15a and 15b using several lipases gave the corresponding enantiomers with low enantiomeric excess in all cases.

Key words

halofluorination - acylations - lipids - enzymes - kinetic resolution

References

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17

Neither the enantiomerically enriched fluorohydrins 15a and 15b nor the corresponding fluoro acetates 14a and 14b obtained by lipase-catalyzed hydrolysis of the acetates or by lipase-catalyzed acetylation of the fluorohydrins, respectively, showed optical rotation in CHCl₃ at
λ = 589 nm, significantly larger than the measuring error. The absolute configuration of the products was not determined.