Issue in Honor of Prof. Karsten Krohn ARKIVOC 2004 (xiii) 79-96
Ac2O, Py 75% Z OAc Br NBS, DME, H2O, 0 °C, 4 h 90% O Z OH Z = OH 17K2CO3, MeOH 63% HClO4, THF/H2O 73% 181955% 1) (NBu4)3HP2O7, MeCN, 2 Z = OAc 2) (NH4 +)-DOWEX 2 2 2OH OH 19NCS, Me2S, CH2Cl2, -30 °C to r.t. 98% 2021O2OH P O P O O O-O- Z = OH Z = Cl OH
O- OH
6
Scheme 5. Synthesis of (E,E)-10,11-dihydroxyfarnesyl diphosphate 6.
The synthesis of (E,E)-10,11-dihydroxyfarnesyl diphosphate started from all-trans farnesol (Scheme 5), protected as acetate 17. For selective epoxidation of the 10,11-double bond we followed a method developed by van Tamelen et al.19 Farnesyl acetate was treated with NBS in aqueous tert-butyl alcohol20 or aqueous 1,2-dimethoxyethane21 to give the desired bromohydrin 18 in 29% and 90% yield, respectively. Base induced the formation of epoxide 19,21 which in turn, was ring-opened with aqueous perchloric acid to give triol 20.22 (E,E)-10,11-Dihydroxyfarnesol 20 was converted into chloride 21, which was finally transformed into (E,E)-10,11-dihydroxyfarnesyl diphosphate according to Davisson et al.23
COOH COOH
PPO
ubiA-transferase
H n
+
H OH OH
n 22 GPP, n = 2 23 GHB, n = 2
Scheme 6. Chemoenzymatic synthesis of geranyl hydroxybenzoate (GHB, 23).
UbiA-Transferase inhibition
The compounds described above were tested for their ability to inhibit ubiA-transferase using a membrane fraction of a cell disruption of the E. coli K12 strain pALMU3.24 Compounds were assayed in competition to 1 mM geranyl diphosphate (GPP) at concentrations ranging up to 1 mM (Scheme 6). These results, expressed as the geranyl hydroxylbenzoate (GHB) formation in the presence of the compound divided by the GHB formation in the absence of the compound (i.e. relative conversions) are shown in Figures 3 and 4.
ISSN 1424-6376 Page 83 ©ARKAT USA, Inc
