Stereocontrolled regeneration of olefins from epoxides

Abstract

Through treatment with NaI and trifluoroacetic anhydride, which presumably forms trifluoroacetyl iodide in situ, epoxides can be converted to olefins. This reaction now has been shown to tolerate remote olefins without loss of their individual stereochemistry. A reaction sequence involving regiospecific epoxidation of an isoprenoid alcohol, conversion of the alcohol to an azide, and cycloaddition with an acetylene, followed by conversion of the epoxide back to the original olefin, has allowed stereocontrolled preparation of triazole bisphosphonates with a farnesyl or a geranylgeranyl substituent. This strategy may be applicable selective protection of an alkene in other polyolefins, including substrates for metathesis reactions.

Recent Advances in the Development of Mammalian Geranylgeranyl Diphosphate Synthase Inhibitors

“…The observed activity of the bishomogeranyl/neryl series further confirmed the importance of olefin stereochemistry as the bishomoneryl triazole was noted to be more potent than the corresponding bishomogeranyl [ 38 ]. Finally, longer-chained derivatives, including farnesyl, homofarnesyl, geranylgeranyl, and homogeranylgeranyl, have weak or no activity as GGDPS inhibitors ( Table 1 ) [ 36 , 41 ]. A V-shaped dialkylated triazole bisphosphonate ( 9 ) containing homoprenyl and geranyl substituents did display inhibitory activity (IC 50 0.38 μM) ( Figure 2 ), but was less active than the mono-alkylated homogeranyl triazole [ 37 ].…”

Synthesis of carboxyphosphonates and bisphosphonates as potential GGTase II and GGDPS inhibitors

“…39 Therefore, to avoid unnecessary cellular effects, it would be advantageous to develop an enzyme inhibitor that targets downstream of FDPS to ultimately inhibit protein geranylgeranylation. The Wiemer group has prepared a number of non-nitrogenous bisphosphonates, 40,41 nitrogenous bisphosphonates, 42 and carboxyphosphonates 43 as shown in Figure 6. This is an indirect approach and might result in disruption of other cellular processes in the IBP upstream of GGTase II, such as the production of cholesterol.…”