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Synthesis of a Fluorinated Ether Lipid Analogous to a Platelet Activating Factor
Author(s) -
Haufe Günter,
Burchardt Annegret
Publication year - 2001
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/1099-0690(200112)2001:23<4501::aid-ejoc4501>3.0.co;2-j
Subject(s) - chemistry , ether , enantioselective synthesis , bromide , kinetic resolution , lipase , hydrolysis , stereochemistry , candida antarctica , organic chemistry , enzyme , catalysis
The synthesis of racemic 2‐fluoro‐3‐hexadecyloxy‐2‐methylprop‐1‐yl 2′‐(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 six‐step 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 phosphocholine residue in the final step. Enzyme‐catalyzed deracemization of the fluorohydrin 15 by acetylation with several lipases gave optically active compounds 14 and 15 , with a maximum ee of 61% for 15 with Candida antarctica lipase catalysis after 74% conversion. An enantioselective synthesis of 10 , based on a planned eight‐step synthesis starting from α‐methylstyrene, failed. The anticancer activity of racemic 10 has been observed in an in vivo model of methylcholanthrene‐induced mouse fibrosarcoma.