Combining (3-aminopropyl)carbamic acid benzyl ester (CBZ-protected propylene diamine) (I) with 2-oxoethylphosphonic acid diethyl ester under reductive amination conditions in the presence of sodium cyanoborohydride gives the CBZ-protected phosphonoethyl-substituted propylene diamine (II). The condensation of (II) with 3,4-diethoxy-3-cyclobutene-1,2-dione at room temperature in ethanol leads to the squaric acid analog (III). Removal of the CBZ protecting group under catalytic transfer hydrogenation conditions followed by spontaneous cyclization provides the penultimate diethylphosphonate ester (IV), which is hydrolyzed in the presence of bromotrimethylsilane in refluxing 1,2-dichloroethane to yield the final product in 15% overall yield.
The monoprotection of propane-1,3-diamine (I) with Boc2O in dichloromethane gives the N-(3-aminopropyl)carbamic acid tert-butyl ester (II), which is condensed with vinylphosphonic acid diethyl ester (III) to yield the aminoethylphosphonic ester derivative (IV). The condensation of (IV) with 3,4-diethoxycyclobutene-1,2-dione (V) in ethanol affords the disubstituted 2-aminoethylphosphonic ester derivative (VI), which is cyclized by means of trifluoroacetic acid in dichloromethane to provide the bicyclic phosphonic ester (VII). Finally, the phosphonic ester group of (VII) is hydrolyzed by means of trimethylsilyl bromide in dichloromethane to furnish the target phosphonic acid.