Synthesis of phosphonates as conjugated alkene precursors and heterocyclicnucleoside analogs

Abstract

First, several preparative methods were developed toward various phosphonate compounds such as allylphosphonates, β -carbonylphophonates, and 2-phosphonyl-2-cycloalkenones, which could serve as useful precursors for conjugated alkene compounds. Stereoselective synthesis of conjugated allylphosphonates was achieved from the corresponding aldehydes via successive reactions with vinyl magnesium bromide and diethyl chlorophosphite, followed by tandem rearrangement. The resulting compounds are useful intermediates to be applied in the synthesis of various dienes and polyenes. Various β -carbonyl phosphonates including keto, formyl, ester, thioester, amide phosphoante, were successfully synthesized in good yields through ozonolysis of substituted allylic phosphonates with subsequent reductive or oxidative workup. This route enlarges the availability of β -carbonyl phosphonates in terms of short reaction steps, mild conditions, and structural diversity. One pot ozonolysis and aldol condensationf of β -keto- ω -alkenyl phosphonates afforded novel 2-phosphonyl-2-cycloalkenones. Then, their reactivities were investigated to show that they could serve as a new kind of activated enones to induce stereoselective and uncatalyzed conjugate addition, and to facilitate the preparation of synthetically versatile 3-substituted-2-phosphonyl cyclic ketones. Moreover, the scope of their utility could be enlarged by the unique ability of phosphonyl group as a temporary activating group via addition-removal, or as a latent double bond via addition-olefination in one vessel. These interesting aspects may prove to be highly useful in the construction of functionalized and regioselectively substituted cyclic ketones for the further synthetic utilizations. Second, several heterocyclic nucleoside analogs of phosphontates were synthesized via epoxide opening and coupling with purine/pyrimidine base, for the search of novel antiviral compounds. γ, δ -Epoxyphosphonates were treated with ba...