The condensation of 4-O-benzyl-L-tyrosine methyl ester (I) with 4-methoxybenzaldehyde (II) in methanol gives the imine (III), which is oxidized with MCPBA yielding the oxaziridine (IV). The reaction of (IV) with NH2OH affords the 4-O-benzyl-N-hydroxy-L-tyrosine methyl ester (V), which is condensed with cyclohexane-1,4-dione monobutyleneketal (VI) in ethanol giving the imine oxide (VII). The cyclization of (VII) with ethyl acrylate (VIII) in refluxing toluene yields the spiranic isoxazolidine (IX). The hydrogenolysis of the O-N bond of (IX) with H2 over Pd/C, followed by lactam formation by means of AcOH affords the spiranic hydroxypyrrolidinone (X), which is alkylated at the phenolic OH with 3-methyl-2-butenyl bromide (XI) and Cs2CO3 in hot acetone providing the phenolic ether (XII). The reaction of (XII) with tosyl chloride, TEA and DMAP gives the tosylate (XIII), which is treated with sodium azide in DMF to affords the azide (XIV). The reduction of (XIV) with LiAlH4 followed by reductive methylation of the resulting amine with formic acetic anhydride and LiAlH4 provides the methyl-amino derivative (XV).

Intermediate (XV) is submitted to cyclization by means of trifluoroacetic anhydride (TFAA) and TEA in DMSO furnishing the spiranic 1,4-diazabicyclo[3.2.1]heptane derivative (XVI). The oxidation of (XVI) with DDQ in dichloromethane provides eniminium salt (XVII), which is reduced with NaCNBH3 to affords the butyleneketal of the target compound that is deprotected with HCl in aqueous acetone.

The condensation of 4-O-benzyl-L-tyrosine methyl ester (I) with 4-methoxybenzaldehyde (II) in methanol gives the imine (III), which is oxidized with MCPBA yielding the oxaziridine (IV). The reaction of (IV) with NH2OH affords the 4-O-benzyl-N-hydroxy-L-tyrosine methyl ester (V), which is condensed with cyclohexane-1,4-dione monobutyleneketal (VI) in ethanol giving the imine oxide (VII). The cyclization of (VII) with ethyl acrylate (VIII) in refluxing toluene yields the spiranic isoxazolidine (IX). The hydrogenolysis of the O-N bond of (IX) with H2 over Pd/C, followed by lactam formation by means of AcOH affords the spiranic hydroxypyrrolidinone (X), which is alkylated at the phenolic OH with 3-methyl-2-butenyl bromide (XI) and Cs2CO3 in hot acetone providing the phenolic ether (XII). The reaction of (XII) with tosyl chloride, TEA and DMAP gives the tosylate (XIII), which is treated with sodium azide in DMF to affords the azide (XIV). The reduction of (XIV) with LiAlH4 followed by reductive methylation of the resulting amine with formic acetic anhydride and LiAlH4 provides the methylamino derivative.

Intermediate (XV) is submitted to cyclization by means of trifluoroacetic anhydride (TFAA) and TEA in DMSO furnishing the spiranic 1,4-diazabicyclo[3.2.1]heptane derivative (XVI). The oxidation of (XVI) with DDQ in dichloromethane provides eniminium salt (XVII), which is reduced with NaCNBH3 to afford the butyleneketal intermediate that is deprotected with HCl in aqueous acetone yielding the TAN-1251a (XVIII). Finally, this compound is treated with LDA in THF giving a mixture of enolates that is quenched with TMSCl. This mixture of silyl enolates is oxidized with OsO4 in aqueous tert-butanol yielding a mixture of hydroxylated compounds that is resolved by a cumbersome chromatographic separation on a reverse phase HPLC column, followed by a chiral Chiralpak AD column.