合成路线1

The reaction of L-tyrosine (I) with methyl chloroformate (II) by means of NaOH in water gives the carbamate (III), which is methylated at the remaining phenol and carboxylic groups with dimethyl sulfate and K2CO3 in refluxing acetone to yield the 4-O-methyl tyrosine derivative (IV). The hydrolysis of the methyl ester of (IV) with NaOH in dioxane/water, followed by reaction with O-methylhydroxylamine by means of DCC and HOBT, affords the methyl hydroxamate (V). The cyclization of (V) by means of bis(trifluoroacetoxy)iodobenzene in dichloromethane/methanol provides the spirodienone (VI), which is hydrogenated with H2 over Pd/C in ethyl acetate to give the saturated ketone (VII). The protection of the ketonic group of (VII) with ethyleneglycol and PPTS yields the cyclic ketal (VIII), which is reduced with LiAlH4 in THF to afford the methoxyamine (IX). The protection of the N-methylamine of (IX) with benzyl chloroformate and TEA provides the carbamate (X), which is treated with Zn in acetic acid in order to cleave the N-methoxyamine group and yield the spiropyrrolidine (XI). The alkylation of the pyrrolidine NH with benzyl chloroformate (XII) and K2CO3 in warm acetonitrile affords the adduct (XIII), which is treated with H2 over Pd/C in methanol in order to remove the benzyl and benzyloxycarbonyl protecting groups, providing the amino acid (XIV). The cyclization of (XIV) by means of DPPA and NaHCO3 in DMF/dichloromethane gives the tetracyclic compound (XV), which is condensed with 4-(prenyloxy)benzaldehyde (XVI) by means of LDA in THF yielding the aldol condensation product (XVII).