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.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...

Selective Synthesis of Monofluorinated Compounds Applying Amine/HF Reagents

“…[65] An intermediate for the synthesis of fluorinated analogues of anticancer active ether lipids of the Ilmofosin-type, a fluorohydrin with a tertiary fluorine, was prepared by treatment of a gem-disubstituted epoxide with Olah's reagent at À 10 °C, while no ring opening occurred by heating of the epoxide with neat Me 3 N • 3HF at 100 °C for 3 h. Due to partial oligomerization and the challenging isolation of the fluorohydrin, the crude product was acetylated resulting in 30 % overall yield of the acetate (Scheme 30). [66] For alternative approaches to such acetates and the complete synthesis of phosphocholine ether lipids see Scheme 62.…”

Regio- and stereoselective synthesis of vicinal fluorohydrins

“…We selectively synthesized several more regioisomeric terminal fluorohydrins either by ring opening with Olah's reagent or KHF 2 in the presence of a crown ether [96][97][98][99][100].…”

“…Racemate cleavage of several derivatives of these 2-fluoro-1-hydroxy ether lipids by lipase-catalyzed acylation was also shown to be weakly selective (Scheme 74) [167].…”