N-Boc-ethylenediamine (I) was treated with S-methylisothiourea (II) yielding guanidine (III). The Boc group of (III) was then cleaved by treatment with HCl.

Coupling of alpha-bromoacrylic acid (V) with 1-methyl-4-aminopyrrole-2-carboxylic acid (VI) using DCC gave amide (VII). Subsequent treatment with thionyl chloride furnished acid chloride (VIII).

The known tripyrrole carboxylic acid derivative (IX) was coupled with aminoethylguanidine (IV) by means of DCC and HOBt to afford amide (X). The nitro group of (X) was reduced by catalytic hydrogenation over Pd/C, and the resulting amine (XI) was finally coupled with acid chloride (VIII) under Schotten-Baumann conditions yielding the title amide.

In a related procedure, aminoethylguanidine (IV) was treated with 1-methyl-4-nitropyrrole-2-carbonyl chloride (XII) producing amide (XIII). Catalytic hydrogenation of the nitro group of (XIII) gave amine (XIV), which was again coupled with acid chloride (XII). The resulting adduct (XV) was then subjected to a new hydrogenation-coupling cycle providing the tripyrrole derivative (X).

The reaction of Distamycin A (I) with succinic anhydride and Na2CO3 in hot DMF gives the nitrile (II), which is treated with Boc2O and DMAP in dichloromethane to yield the monocarbamate (III). The reaction of (III) with Boc2O and DMAP in DMF affords the bis carbamate (IV), which is hydrolyzed with LiOH in THF/water to provide the carboxylic acid (V). The condensation of (V) with N-(2-aminoethyl)guanidine (VI) by means of by means of TBTU in DMF gives the guanidinoethyl amide (VII), which is deprotected by means of TFA in dichloromethane to yield the aminopyrrole derivative (VIII). Finally, this compound is condensed with the acid chloride (IX) by means of NaHCO3 in dioxane/water to provide the target brostallicin.

The hydrolysis of Distamycin A (I) with NaOH in refluxing methanol gives the aminoacid (II), which is treated with Boc2O and TEA in DMF to yield the carbamate (III). The Curtius rearrangement of (III) by means of DPPA and TEA in hot DMF affords the imidazolidinone (IV), which is hydrolyzed with NaOH in DMF to provide the 2-aminoethyl amide (V). The reaction of (V) with the protected guanidine (VI) by means of TEA in hot DMF gives the protected 2-guanidinoethyl amide (VII), which is treated with 6N HCl in methanol to eliminate the carbamoyl and trityl protecting group and yield the precursor (VIII). Finally, this compound is condensed with the acyl chloride (IX) by means of NaHCO3 in dioxane/water to afford the target brostallicin.

The reaction of ethylenediamine (I) with Boc2O in dioxane gives the monocarbamate (II), which is condensed with O-methylisourea (III) to yield the aminoguanidine carbamate (IV). The cleavage of the carbamate group of (IV) by means of HCl in methanol affords the aminoguanidine (V), which is condensed with 1-methyl-4-nitropyrrole-2-carbonyl chloride (VI) by means of NaHCO3 in dioxane/water to provide the amide (VII). The reduction of the nitro group of (VII) by means of H2 over Pd/C in 1N HCl affords the 4-aminopyrrole-2-carboxamide (VIII), which is condensed with the acid chloride (VI) as before to give the diamide (IX). Reduction of the nitro group of (IX) under the same conditions described above yields the amino diamide (X), which is condensed with the 14-labeled acid chloride (XI) as described above to afford the triamide (XII). Further reduction of the nitro group of (XII) gives the amino triamide (XIII), which is finally condensed with 4-(2-bromopropenamido)-1-methylpyrrole-2-carbonyl chloride (XIV) by means of NaHCO3 in dioxane/water to yield the target 14C labeled pentaamide compound.

The reaction of deuterium labeled ethylenediamine (I) with Boc2O in dioxane gives the monocarbamate (II), which is condensed with O-methylisourea (III) to yield the labeled aminoguanidine carbamate (IV). The cleavage of the carbamate group of (IV) by means of HCl in methanol affords the aminoguanidine (V), which is condensed with 1-methyl-4-nitropyrrole-2-carbonyl chloride (VI) by means of NaHCO3 in dioxane/water to provide the amide (VII). The reduction of the nitro group of (VII) by means of H2 over Pd/C in 1N HCl affords the 4-aminopyrrole-2-carboxamide (VIII), which is condensed with the acid chloride (VI) as before to give the diamide (IX). Reduction of the nitro group of (IX) under the same conditions described above yields the amino diamide (X), which is condensed with acid chloride (VI) as described above to afford the triamide (XI). Further reduction of the nitro group of (XI) gives the amino triamide (XII), which is finally condensed with 4-(2-bromopropenamido)-1-methylpyrrole-2-carbonyl chloride (XIII) by means of NaHCO3 in dioxane/water to yield the target deuterium labeled pentaamide compound.