Synthesis of a Fluorinated Analogue of Anticancer Active Ether Lipids

Abstract

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.

Synthesis of optically active 2-fluoroalk-1-en-3-yl esters and chirality transfer in their Claisen-type rearrangements

“…As a model compound for the resolution experiments we chose 3-acetoxy-2-fluorodec-1-ene (2a). Based on our earlier investigations on kinetic resolution of fluorohydrins [22][23][24][25][26], we tested three different lipases, namely those from Pseudomonas cepacia (Amano PS), Candida rugosa and Candida antarctica (Novozym435 1 ), to find optimal conditions for maximal enantioselectivity (Scheme 3).…”

Olefin Metathesis Route to Antiviral Nucleosides

“…In order to achieve diversification within the acyclic nucleoside family, we have explored and optimized the cross-metathesis reaction of two terminal olefins, 2,2-dimethyl-4-vinyl- [1,3]dioxolane [64] (99) and 5-methylene-2-phenyl- [1,3]dioxane (100), with allyluracils (101a-d), [65]. Under optimized conditions moderate to good yields of the desired products were obtained (Scheme 15).…”

Regio- and stereoselective synthesis of vicinal fluorohydrins

“…With fluorinated analogues of anticancer active ether lipids, the lipases tested PPL, CRL and CAL did not show satisfying enantioselectivity. Additionally, quite long reaction times were necessary [165]. Only PCL was more selective showing good conversion of the acetate and good enantiomeric excess in the (À)-enantiomer of the fluorohydrin (Scheme 73) [165,166].…”

“…Better chemical yield (71%), but slightly lower enantioselectivity was observed by acylation of the corresponding diol to form the (þ)-enantiomer of the fluorohydrin [165].…”