Synthesis and Characterization of Aza Analogue Inhibitors of Squalene and Geranylgeranyl Diphosphate Synthases

Article abstract of DOI:10.1021/jo00038a038

One-carbon homologation of geranyl and farnesyl chlorides to secondary N-methylamines (12 and 17) via α-lithioformamidine alkylations followed by N-alkylation with bromoacetate esters afforded α-(homogeranylamino)- and α-(homofarnesylamino)acetates 13 and 18.After α-farnesylation of 13, hydride reductions gave branched and straight-chain tertiary β-amino alcohols 15 and 19.The diphosphate derivatives (7 and 8) of 15 and 19 prepared by S_N2 displacements may be regarded as "aza analogs" of plausible carbocation intermediates (5 and 6) in the biosynthesis of squalene and geranylgeranyl diphosphate since, in preliminary collaborative evaluations, they inhibit the respective synthase enzymes at micromolar concentrations.