Synthesis of the farnesyl ether 2,3,5-trifluoro-6-hydroxy-4-[(E,E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yloxy]nitrobenzene, and related compounds containing a substituted hydroxytrifluorophenyl residue: novel inhibitors of protein farnesyltransferase, geranylgeranyltransferase I and squalene synthase

Abstract

Pentafluoronitrobenzene was converted via two successive phase-transfer catalysed S_NAr reactions with (E,E)-farnesol or geraniol followed by hydroxide ion into the 2,3,6-trifluoro-5-hydroxy-4-nitrophenyl farnesyl ether 3a and the geranyl ether 3b. Analogues containing a cyano (3c) or carbamoyl (3d) group in place of nitro or an epoxygeranyl (3e) group as the prenyl (3-methylbut-2-enyl) containing residue were similarly prepared. Those containing a sulfonic acid (35a, 35b) or a methyl sulfone (41) group were made by modifications of this approach involving the use of protecting groups. The synthesis of carboxy analogues (27a, 27b) involved the alkylation of a protected fluorinated ortho-hydroxybenzoic acid derivative (25) with (E,E)-farnesyl or geranyl bromide. The non-fluorinated compound 18 was analogously prepared via compound 17a. Mitsunobu reactions were used in the synthesis of 15, a dihydroxylated analogue of 3b, and of 8, the non-fluorinated analogue of 3a. The nitro compounds 3a and 3b were moderate inhibitors of both farnesyl transferase and geranylgeranyl transferase I, the geranyl carboxy derivative 27b of the latter enzyme and the farnesyl sulfonic acid derivative 35a of squalene synthase.