Protection of the phenolic group of duocarmycin B2 (I) with tert-butyldimethylsilyl chloride and imidazole afforded silyl ether (II). The methyl ester group of (III) was then converted to either allyl ester (III) or benzyl ester (IV) upon treatment with the respective alcohols and K2CO3 at 0 C. Reduction of (III) or (IV) with NaBH4 in allyl alcohol provided the 3alpha-hydroxy compounds (V) and (VI). Subsequent BF3-catalyzed Wagner-Meerwein type rearrangement in (V) or (VI) produced the indole-3-carboxylates (VII) and (VIII). Carboxylic acid (IX) was then obtained by deprotection of the allyl group of (VII) using Pd(PPh3)4/dimedone or the benzyl group of (VIII) using Pd/C in the presence of ammonium formate.
Decarboxylation of (IX) in refluxing bromobenzene yielded (X), which was converted to the 3-bromoindole (XI) by reaction with N-bromosuccinimide in the presence of silicagel. Desilylation of (XI) with tetrabutylammonium fluoride gave phenol (XII), and further intramolecular cyclization of (XII) with simultaneous amide hydrolysis by treatment with NaOMe produced the cyclopropyl cyclohexadienone (XIII). Finally, the 4-methoxycinnamoyl group was introduced in (XIII) by condensation with the 4-nitrophenyl ester (XIV) in the presence of NaH at -20 C.