The synthesis of racemic 2'-(trimethylammonium)ethyl-3-hexadecyloxy-2-fluoro-2-(methoxymethyl)prop-1-yl-phosphate (6), a fluorinated analogue of an anticancer active ether lipid 5 was realized with 3% overall yield in a nine-step synthesis starting from 2-methylene-1,3-propanediol (7) using a bromofluorination as the key step. Both enantiomers of the precursor 8 of the ether lipid 6 were synthesized by lipase-catalyzed desymmetrization of the diacetate 17, either by hydrolysis (83% ee) or by lipase-catalyzed acetylation of the diol 22 (82% ee). The antitumor activity of 6 has been found in an in vivo model of the methylcholanthrene-induced fibrosarcoma of mice.

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Keywords: Allylic ether / Antitumor agents / Bromofluorination / Fluorine / Lipase-catalyzed deracemization / LipidsThe synthesis of racemic 2-fluoro-3-hexadecyloxy-2-methylprop-1-yl 2Ј-(trimethylammonio)ethyl phosphate (10), a fluorinated analogue of the anticancer active and blood platelet activating ether lipids 8 and 9, has been achieved in a sixstep sequence from methallyl alcohol (11). Etherification of 11 with hexadecyl bromide gave allylic ether 12, bromofluorination of which afforded the bromo-substituted fluoride 13, which was subsequently transformed into the acetate 14. Hydrolysis of 14 gave the key intermediate 2-fluoro-2-(hexadecyloxymethyl)propanol (15), which was attached to the phos-

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.Ether lipids continue to attract considerable interest because of their important biological properties. Particularly the platelet activating factor [mixture of (R)-1-O-hexadecyl-2-acetyl-sn-glycero-3-phosphocholine and its octadecyl homologue] 1 and analogues such as Edelfosine (1-Ooctadecyl-2-O-methyl-rac-glycero-3-phosphocholine, 2) were shown to exhibit significant cytotoxic effects against numerous human and murine tumor cell strains both in vitro and in vivo. 1 Fluorinated analogues such as 3 also showed antitumor activity. 2 Variation of substituents at the stereogenic center led to highly potent compounds such as Ilmofosine (4), its oxygen analogue 5, and the octadecyl homologues of both compounds (Figure). 3 The activity of the enantiomers of compounds 4 and 5 was different. 1,3 Figure The structures of ether lipids 1-7.Recently, we reported the syntheses of fluorinated analogues 6 and 7a of such ether lipids. Both compounds showed significant antitumor activity in an in vivo model of the methylcholanthrene induced fibrosarcoma of mice. This activity, however, was lower than that of Cisplatin or Ilmofosine (4) under identical conditions. 4This paper describes an improved access to the Ilmofosine analogue 7a and the synthesis of the octadecyl homologue 7b (Scheme 1). Applying principally known procedures, 3a,5 the unsaturated long chain hydroxy ethers 9a and 9b were synthesized from the corresponding ethyl acrylates 8a and 8b by reduction with DIBAL. The free hydroxy function of 9a and 9b was methylated with methyl iodide and KOH in DMSO 6 to give 10a and 10b. Subsequently, the bromofluorination 7 of 10a with NBS/ Et 3 N×3HF in dichloromethane at 25°C after 16 hours, besides 6% (GC) of starting material, gave 1-bromo-2-fluoro-3-hexadecyloxy-2-(methoxymethyl)propane (11a) (80%, GC), its regioisomer 12a (5%, GC) and 9% (GC) of the dibromide 13a. From this mixture, the desired compound 11a was isolated in 55% yield by column chromatography. The dibromide 13a was also isolated in 5% yield. The regioselectivity of bromofluorination increased from 94:6 in the case of NBS/Et 3 N×3HF to 97:3 using the slightly more acidic Me 3 N×3HF as the fluoride source under identical conditions. The higher selectivity of the latter reagent has already been observed earlier. 4a,8 Lowering the temperature to -10°C did not change the regioselectivity, but increased the part of the dibromide 13a to 21% (GC). The...